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Cao ZT, Mao JL, Huang CY, Wang HL, Wang MZ, Wang WL, Zhou YB, Li J. PRL-3: unveiling a new horizon in cancer therapy. Acta Pharmacol Sin 2025:10.1038/s41401-025-01563-1. [PMID: 40341216 DOI: 10.1038/s41401-025-01563-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 04/08/2025] [Indexed: 05/10/2025]
Abstract
PRL-3, a protein tyrosine phosphatase (PTP), has a significant influence on the pathogenesis of various cancers with its overexpression significantly correlating with tumor invasion, metastasis and poor prognosis. It significantly affects tumor cell behavior through its involvement in cell proliferation, migration and metabolic processes. Furthermore, the interaction between PRL-3 and the tumor microenvironment characterized by its adaptability to stress and its role in metabolic reprogramming enhances tumor cell survival and dissemination. Targeted therapies against PRL-3, encompassing small molecule inhibitors and the monoclonal antibody PRL-3-zumab, have shown promise in clinical and preclinical studies, presenting new avenues for cancer treatment. In addition, innovative approaches such as CAAX motif-targeting agents and PRL-3 degradation strategies hold promise for developing more precise and effective interventions. This review explores PRL-3's multifaceted roles across different tumor types and microenvironments, while discussing current and emerging therapeutic strategies aimed at exploiting its oncogenic potential.
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Affiliation(s)
- Zi-Tong Cao
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China
| | - Jia-Luo Mao
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Chang-Ying Huang
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Han-Lin Wang
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Ming-Zhi Wang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wen-Long Wang
- School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China.
| | - Yu-Bo Zhou
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Jia Li
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China.
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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Phi LTH, Cheng Y, Funakoshi Y, Bertucci F, Finetti P, Van Laere SJ, Zou F, Long JP, Ogata S, Krishnamurthy S, Reuben JM, Foulks JM, Warner SL, Rosenbluth JM, Sood AK, Tripathy D, Ueno NT, Wang X. AXL promotes inflammatory breast cancer progression by regulating immunosuppressive macrophage polarization. Breast Cancer Res 2025; 27:70. [PMID: 40329335 PMCID: PMC12057249 DOI: 10.1186/s13058-025-02015-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 04/03/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are key promoters of inflammatory breast cancer (IBC), the most aggressive form of breast cancer. The receptor tyrosine kinase AXL is highly expressed in various cancer types, including IBC, but its role in TAMs remains unexplored. METHODS We examined the effects of AXL inhibitor TP-0903 on tumor growth and tumor microenvironment (TME) component M2 macrophages (CD206+) in IBC and triple-negative breast cancer mouse models using flow cytometry and immunohistochemical staining. Additionally, we knocked out AXL expression in human THP-1 monocytes and evaluated the effect of AXL signaling on immunosuppressive M2 macrophage polarization and IBC cell growth and migration. We then investigated the underlying mechanisms through RNA sequencing analysis. Last, we performed CIBERSORT deconvolution to analyze the association between AXL expression and tumor-infiltrating immune cell types in tumor samples from the Inflammatory Breast Cancer International Consortium. RESULTS We found that inhibiting the AXL pathway significantly reduced IBC tumor growth and decreased CD206+ macrophage populations within tumors. Mechanistically, our in vitro data showed that AXL promoted M2 macrophage polarization and enhanced the secretion of immunosuppressive chemokines, including CCL20, CCL26, and epiregulin, via the transcription factor STAT6 and thereby accelerated IBC cell growth and migration. RNA sequencing analysis further indicated that AXL signaling in immunosuppressive M2 macrophages regulated the expression of molecules and cytokines, contributing to an immunosuppressive TME in IBC. Moreover, high AXL expression was correlated with larger populations of immunosuppressive immune cells but smaller populations of immunoactive immune cells in tissues from patients with IBC. CONCLUSIONS AXL signaling promotes IBC growth by inducing M2 macrophage polarization and driving the secretion of immunosuppressive molecules and cytokines via STAT6 signaling, thereby contributing to an immunosuppressive TME. Collectively, these findings highlight the potential of targeting AXL signaling as a novel therapeutic approach for IBC that warrants further investigation in clinical trials.
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Affiliation(s)
- Lan T H Phi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Yating Cheng
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yohei Funakoshi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Francois Bertucci
- Laboratoire d'Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France
- Département d'Oncologie Médicale, Institut Paoli-Calmettes, Marseille, France
| | - Pascal Finetti
- Laboratoire d'Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France
| | - Steven J Van Laere
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Fang Zou
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - James P Long
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Suguru Ogata
- Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, HI, USA
- University of Hawai'i Inflammatory Breast Cancer Clinic and Research Program, Honolulu, HI, USA
| | - Savitri Krishnamurthy
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - James M Reuben
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | | | - Jennifer M Rosenbluth
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Debu Tripathy
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naoto T Ueno
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, HI, USA.
- University of Hawai'i Inflammatory Breast Cancer Clinic and Research Program, Honolulu, HI, USA.
| | - Xiaoping Wang
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Cancer Biology Program, University of Hawai'i Cancer Center, Honolulu, HI, USA.
- University of Hawai'i Inflammatory Breast Cancer Clinic and Research Program, Honolulu, HI, USA.
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Yan J, Liao Q, Xie Y, Chen S. CCL26 as a prognostic biomarker in hepatocellular carcinoma: integrating bioinformatics analysis, clinical validation, and radiomics score. Discov Oncol 2025; 16:502. [PMID: 40205283 PMCID: PMC11981991 DOI: 10.1007/s12672-025-02280-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/01/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND CCL26 has been identified as a potential prognostic biomarker in hepatocellular carcinoma (HCC). This study aimed to assess the prognostic significance of CCL26 and develop a radiomics score (Rad-score) for predicting outcomes in HCC patients. METHODS Data from 316 HCC patients, including genomic information, computed tomography (CT) images, and clinicopathological data, were analyzed. The prognostic value of CCL26 was evaluated in 295 TCGA patients using Kaplan-Meier and Cox regression analyses, and validated in 21 patients from Jiujiang No. 1 People's Hospital. Gene set variation and immune cell infiltration analyses were conducted to elucidate the biological functions of CCL26. Radiomic models for predicting CCL26 expression were constructed using CT images and genomic data from 34 TCGA patients. Radiomic features were extracted from tumor regions and screened using maximum relevance minimum redundancy (mRMR) and recursive feature elimination (RFE). Two Rad-scores were generated via logistic regression and validated using internal fivefold cross-validation. A prognostic nomogram incorporating the optimal Rad-score, gender, and hepatic inflammation was developed using Cox proportional hazards regression. RESULTS Elevated CCL26 levels correlated with poor prognosis, as confirmed by immunohistochemistry. The optimal Rad-score, combined with gender and hepatic inflammation, accurately predicted overall survival (OS), with areas under the receiver operating characteristic curve (AUCs) of 0.819, 0.902, and 0.982 for 24-, 36-, and 48 month survival, respectively. Calibration curves and decision curve analysis (DCA) demonstrated the accuracy and clinical utility of the model. CONCLUSIONS CCL26 serves as a significant prognostic biomarker in HCC. The developed Rad-score provides an effective, non-invasive tool for predicting patient outcomes and enhancing clinical decision-making. This study not only highlights the prognostic role of CCL26 but also offers a novel approach for evaluating HCC patient prognosis through radiomics.
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Affiliation(s)
- Junjun Yan
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, China
- Department of Gastroenterology, Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, 332000, China
| | - Qiangming Liao
- Department of Gastrointestinal Surgery, Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, 332000, China
| | - Yong Xie
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, China.
| | - Sihai Chen
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, China.
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Nassir S, Yousif M, Li X, Severson KJ, Hughes A, Kechter J, Hwang A, Boudreaux B, Bhullar P, Zhang N, Butterfield RJ, Ma T, Leibovit-Reiben Z, Stockard A, Ogbaudu E, Costello CM, Nelson SA, DiCaudo DJ, Sekulic A, Baum CL, Pittelkow MR, Mangold AR. Multi-omic Sequencing of Intermediate to High-Risk Cutaneous Squamous Cell Carcinoma Identifies Critical Genes and Expression Patterns Associated with Disease and Poor Outcomes. J Invest Dermatol 2025:S0022-202X(25)00082-X. [PMID: 39884456 DOI: 10.1016/j.jid.2025.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 12/24/2024] [Accepted: 01/05/2025] [Indexed: 02/01/2025]
Abstract
Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in humans and kills as many people annually as melanoma. The understanding of the transcriptional changes with respect to high-risk clinical/histopathological features and outcome is poor. Here, we examine stage-matched, outcome-differentiated cSCC using whole exome and transcriptome sequencing. Exome analysis identified key driver mutations including TP53, CDKN2A, NOTCH1, SHC4, MIIP, CNOT1, C17orf66, LPHN2, and TTC16 and pathway enrichment of driver mutations in replicative senescence, cellular response to UV, cell-cell adhesion, and cell cycle. Transcriptomic analysis identified pathway enrichment of immune signaling/inflammation, cell-cycle pathways, extracellular matrix function, and chromatin function. Integrative analysis identified 183 critical genes in carcinogenesis and were used to develop a gene expression panel (GEP) for outcome. Three outcome-related gene clusters included those involved in keratinization, cell division, and metabolism. We found 16 genes whose expression may be associated with metastasis (risk score ≥ 9 Met & risk score < 9 NoMet) with an AUC of 97.1%, sensitivity 95.5%, specificity 85.7%, and overall accuracy of 90%. Eleven genes were chosen to generate the risk score for Overall Survival (OS) with an OS prediction of 80.8% and each risk gene increasing the risk of death by 2.47 (HR: 2.47; p<0.001).
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Affiliation(s)
- Shams Nassir
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | - Miranda Yousif
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | - Xing Li
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | | | - Alysia Hughes
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | - Jake Kechter
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | - Angelina Hwang
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | - Blake Boudreaux
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | - Puneet Bhullar
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | - Nan Zhang
- Mayo Clinic Department of Research and Biostatistics, Scottsdale, AZ
| | | | - Tao Ma
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | | | - Alyssa Stockard
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | - Ewoma Ogbaudu
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | | | - Steven A Nelson
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | - David J DiCaudo
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ
| | | | | | | | - Aaron R Mangold
- Mayo Clinic Arizona, Department of Dermatology, Scottsdale, AZ.
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Liu L, Guan S, Xue Y, He Y, Ding L, Fu Y, Chen S, Wang Z, Wang Y. The immunological landscape of CCL26 High invasive oral squamous cell carcinoma. Front Cell Dev Biol 2025; 13:1502073. [PMID: 39931245 PMCID: PMC11808134 DOI: 10.3389/fcell.2025.1502073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 01/08/2025] [Indexed: 02/13/2025] Open
Abstract
Background Our previous study demonstrated that CCL26 secreted by cancer-associated fibroblasts (CAF) promoted the invasive phenotype of oral squamous cell carcinoma (OSCC), however, more comprehensive clinical expression patterns of CCL26 and its role in immunotherapy remains ambiguous. Methods CCL26 levels in different cancer and normal tissues were analyzed and validated in 67 OSCC patients through immunohistochemical staining (IHC). The clinical spatial distribution pattern of CCL26 in tumor microenvironment was determined, and its clinical outcomes were investigated. We also determined the invasive phenotype of tumor cells with distinct CCL26 level and explored its immune checkpoint and immunocytes relevance by differentially expressed gene (DEG) analysis, GSEA, and GO analysis. We collected peripheral blood from 28 OSCC patients to assess the percentage and absolute number of lymphocytes by flow cytometry. Results CCL26 was upregulated in HNSC and preferentially high-expressed on CAFs and tumor cells in OSCC patients, which exhibits a trend toward decreased overall survival. CCL26high OSCC had a characteristic of tumor invasive phenotype with upregulated CLDN8/20 and reduced keratin KRT36, which was significantly associated with EMT markers (CDH1, CDH2, VIM, SNAI2). In addition, CCL26high OSCC was found to be associated with immunoglobulin mediated immune response, B cell mediated immunity et al. Indeed, immune checkpoint molecules (PD-L1, PD-L2, et al.) also decreased in CCL26high OSCC. However, CCL26 did not affect T/B/NK lymphocytes in peripheral blood of OSCC patients. Conclusion CCL26 could regulate Immune balance and promote invasiveness of OSCC, which gave a new insight into a potential immunotherapy strategy.
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Affiliation(s)
- Lingyun Liu
- Central Laboratory of Stomatology, Affiliated Hospital of Medical School, Nanjing Stomatological Hospital, Nanjing University, Nanjing, China
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Shuo Guan
- Central Laboratory of Stomatology, Affiliated Hospital of Medical School, Nanjing Stomatological Hospital, Nanjing University, Nanjing, China
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Yizhuo Xue
- Central Laboratory of Stomatology, Affiliated Hospital of Medical School, Nanjing Stomatological Hospital, Nanjing University, Nanjing, China
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Yijia He
- Central Laboratory of Stomatology, Affiliated Hospital of Medical School, Nanjing Stomatological Hospital, Nanjing University, Nanjing, China
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China
| | - Liang Ding
- Central Laboratory of Stomatology, Affiliated Hospital of Medical School, Nanjing Stomatological Hospital, Nanjing University, Nanjing, China
| | - Yong Fu
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Medical School, Nanjing Stomatological Hospital, Nanjing University, Nanjing, China
| | - Sheng Chen
- Department of Oral Pathology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Zhiyong Wang
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Medical School, Nanjing Stomatological Hospital, Nanjing University, Nanjing, China
| | - Yi Wang
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Medical School, Nanjing Stomatological Hospital, Nanjing University, Nanjing, China
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Cao X, Lan Q, Xu H, Liu W, Cheng H, Hu X, He J, Yang Q, Lai W, Chu Z. Granulocyte-like myeloid-derived suppressor cells: The culprits of neutrophil extracellular traps formation in the pre-metastatic niche. Int Immunopharmacol 2024; 143:113500. [PMID: 39510029 DOI: 10.1016/j.intimp.2024.113500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 10/05/2024] [Accepted: 10/22/2024] [Indexed: 11/15/2024]
Abstract
Neutrophil extracellular traps (NETs) have been shown to exhibit chemotactic effects on circulating tumor cells at metastatic sites, promoting the progression of colorectal cancer liver metastasis (CRLM). However, the origin and factors contributing to the formation of NETs (NETosis) in the pre-metastatic niche (PMN) of target organs remain unclear. In this study, we investigated the relationship between phosphatase of regenerating liver-3 (PRL-3), myeloid-derived suppressor cells (MDSCs), neutrophils, and NETs through a retrospective clinical cohort study and a mouse model of CRLM. Our clinical findings revealed associations between PRL-3 expression and the infiltration of neutrophils and MDSCs in CRLM patients. Moreover, NETosis emerged as a robust indicator of poor prognosis for overall survival in these patients. In CRLM models, PRL-3 overexpression enhanced both primary tumor growth and liver metastasis. We found that the first week after tumor cell implantation appeared to be a crucial period for PMN formation, with notable infiltration of neutrophils, MDSCs, and NETosis during this time. Notably, co-culturing neutrophils with MDSCs induced NETosis in vitro, particularly with granulocyte-like MDSCs (Gr-MDSCs), the predominant subtype of infiltrating MDSCs. In summary, our findings elucidate the likely origin of NETs in the PMN during CRLM development and underscore the significant influence of PRL-3. These findings may offer potential immunotherapeutic targets for patients at risk of developing CRLM, warranting further investigation in clinical settings.
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Affiliation(s)
- Xintong Cao
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, Guangdong Province, China
| | - Qiusheng Lan
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, Guangdong Province, China
| | - Heyang Xu
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, Guangdong Province, China
| | - Wentao Liu
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China
| | - Huaxi Cheng
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China
| | - Xinwen Hu
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, Guangdong Province, China
| | - Jiehua He
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan 528200, Guangdong Province, China
| | - Qiong Yang
- Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China.
| | - Wei Lai
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China.
| | - Zhonghua Chu
- Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, Guangdong Province, China.
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Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
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Sun W, Xie S, Liu SF, Hu X, Xing D. Evolving Tumor Characteristics and Smart Nanodrugs for Tumor Immunotherapy. Int J Nanomedicine 2024; 19:3919-3942. [PMID: 38708176 PMCID: PMC11070166 DOI: 10.2147/ijn.s453265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 04/11/2024] [Indexed: 05/07/2024] Open
Abstract
Typical physiological characteristics of tumors, such as weak acidity, low oxygen content, and upregulation of certain enzymes in the tumor microenvironment (TME), provide survival advantages when exposed to targeted attacks by drugs and responsive nanomedicines. Consequently, cancer treatment has significantly progressed in recent years. However, the evolution and adaptation of tumor characteristics still pose many challenges for current treatment methods. Therefore, efficient and precise cancer treatments require an understanding of the heterogeneity degree of various factors in cancer cells during tumor evolution to exploit the typical TME characteristics and manage the mutation process. The highly heterogeneous tumor and infiltrating stromal cells, immune cells, and extracellular components collectively form a unique TME, which plays a crucial role in tumor malignancy, including proliferation, invasion, metastasis, and immune escape. Therefore, the development of new treatment methods that can adapt to the evolutionary characteristics of tumors has become an intense focus in current cancer treatment research. This paper explores the latest understanding of cancer evolution, focusing on how tumors use new antigens to shape their "new faces"; how immune system cells, such as cytotoxic T cells, regulatory T cells, macrophages, and natural killer cells, help tumors become "invisible", that is, immune escape; whether the diverse cancer-associated fibroblasts provide support and coordination for tumors; and whether it is possible to attack tumors in reverse. This paper discusses the limitations of targeted therapy driven by tumor evolution factors and explores future strategies and the potential of intelligent nanomedicines, including the systematic coordination of tumor evolution factors and adaptive methods, to meet this therapeutic challenge.
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Affiliation(s)
- Wenshe Sun
- The Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China
- Qingdao Cancer Institute, Qingdao University, Qingdao, 266071, People’s Republic of China
- Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China
| | - Shaowei Xie
- Department of Ultrasound, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People’s Republic of China
| | - Shi Feng Liu
- The Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China
| | - Xiaokun Hu
- The Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China
| | - Dongming Xing
- The Affiliated Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China
- Qingdao Cancer Institute, Qingdao University, Qingdao, 266071, People’s Republic of China
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9
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Gregory KJ, Mason H, Casaubon J, Schneider SS. SFRP1 decreases WNT-Mediated M2 macrophage marker expression in breast tissue. Cancer Immunol Immunother 2024; 73:86. [PMID: 38554160 PMCID: PMC10981600 DOI: 10.1007/s00262-024-03638-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 01/16/2024] [Indexed: 04/01/2024]
Abstract
The Wnt family of secreted proteins are involved in mammary gland development and tumorigenesis. It has recently been shown that Wnt ligands promote M2 macrophage polarization and so we sought to determine the effects of a Wnt signaling antagonist, Secreted Frizzled Related Protein 1 (SFRP1), on M2 marker expression. We measured a murine M2 marker (Arg1) in mice with a targeted deletion of Sfrp1 during different stages of mammary gland development including puberty, pregnancy, and lactation, as well as in response to obesity. Next, to determine whether Wnt signaling/antagonism affects human M2 markers (CD209 and CCL18), we treated a human patient derived explant (PDE) breast tissue sample with exogenous Wnt3a in the presence and absence of rSFRP1. Finally, we expanded our PDE study to 13 patients and performed bulk RNAseq analysis following the treatment described above. We found that in loss of Sfrp1 in the murine mammary gland increased Arg1 expression. Moreover, we showed that Wnt3a increases CD209 and CCL18 mRNA and protein expression in breast PDEs and that their expression is decreased in response to rSFRP1. Our RNAseq analysis unveiled novel genes that were affected by Wnt3a treatment and subsequently reversed when rSFRP1 was added. Validation of these data exhibited that chemokines involved in promoting macrophage polarization and cancer metastasis, including CCL11 and CCL26, were stimulated by Wnt3a signaling and their expression was abrogated by treatment with rSFRP1. Our data suggest that SFRP1 may be an important mediator that tempers Wnt signaling in the tumor microenvironment.
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Affiliation(s)
- Kelly J Gregory
- Pioneer Valley Life Sciences Institute, Baystate Medical Center, Springfield, MA, 01199, USA.
- Biology Department, University of Massachusetts, Amherst, MA, 01003, USA.
| | - Holly Mason
- Department of Surgery, UMass Chan Medical School- Baystate Medical Center, Springfield, MA, 01107, USA
| | - Jesse Casaubon
- Department of Surgery, UMass Chan Medical School- Baystate Medical Center, Springfield, MA, 01107, USA
| | - Sallie S Schneider
- Pioneer Valley Life Sciences Institute, Baystate Medical Center, Springfield, MA, 01199, USA
- Department of Surgery, UMass Chan Medical School- Baystate Medical Center, Springfield, MA, 01107, USA
- Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, 01003, USA
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10
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Yang Y, Zhang Q, Cai H, Feng Y, Wen A, Yang Y, Wen M. RNA-seq analysis of chlorogenic acid intervention in duck embryo fibroblasts infected with duck plague virus. Virol J 2024; 21:60. [PMID: 38454409 PMCID: PMC10921813 DOI: 10.1186/s12985-024-02312-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
INTRODUCTION Chlorogenic acid, the primary active component in Chinese medicines like honeysuckle, exhibits anti-inflammatory and antiviral effects. It has been demonstrated that chlorogenic acid effectively prevents and treats Duck enteritis virus (DEV) infection. This study aims to further elucidate the mechanism by which chlorogenic acid prevents DEV infection. METHODS Duck embryo fibroblast (DEF) cells were pre-treated with chlorogenic acid before being infected with DEV. Cell samples were collected at different time points for transcriptomic sequencing, while qPCR was used to detect the proliferation of DEV. Additionally, 30-day-old ducks were treated with chlorogenic acid, and their lymphoid organs were harvested for histopathological sections to observe pathological damage. The proliferation of DEV in the lymphoid organs was also detected using qPCR Based on the transcriptomic sequencing results, NF-κB1 gene was silenced by RNAi technology to analyze the effect of NF-κB1 gene on DEV proliferation. RESULTS Compared to the viral infection group, DEF cells in the chlorogenic acid intervention group exhibited significantly reduced DEV load (P < 0.05). Transcriptomic sequencing results suggested that chlorogenic acid inhibited DEV proliferation in DEF cells by regulating NF-κB signaling pathway. The results of RNAi silencing suggested that in the three treatment groups, compared with the DEV experimental group, there was no significant difference in the effect of pre-transfection after transfection on DEV proliferation, while both the pre-transfection after transfection and the simultaneous transfection group showed significant inhibition on DEV proliferation Furthermore, compared to the virus infection group, ducks in the chlorogenic acid intervention group showed significantly decreased DEV load in their lymphoid organs (P < 0.05), along with alleviated pathological damage such as nuclear pyretosis and nuclear fragmentation. CONCLUSIONS Chlorogenic acid effectively inhibits DEV proliferation in DEF and duck lymphatic organs, mitigates viral-induced pathological damage, and provides a theoretical basis for screening targeted drugs against DEV.
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Affiliation(s)
- Yunyun Yang
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Qiandong Zhang
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Haiqing Cai
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Yi Feng
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Anlin Wen
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Ying Yang
- School of Animal Science, Guizhou University, Guiyang, China
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China
| | - Ming Wen
- School of Animal Science, Guizhou University, Guiyang, China.
- Guizhou Provincial Animal Biological Products Engineering Technology Research Center, Guiyang, China.
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11
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Yang Z, Yuan H, He H, Qi S, Zhu X, Hu X, Jin M, Zhang XX, Yuan ZG. Unlocking the role of EIF5A: A potential diagnostic marker regulating the cell cycle and showing negative correlation with immune infiltration in lung adenocarcinoma. Int Immunopharmacol 2024; 126:111227. [PMID: 37977067 DOI: 10.1016/j.intimp.2023.111227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Despite EIF5A upregulation related to tumor progression in LUAD (lung adenocarcinoma), the underlying mechanisms remain elusive. In addition, there are few comprehensive analyses of EIF5A in LUAD. METHODS We investigated the EIF5A expression level in LUAD patients using data from the TCGA and GEO databases. We employed qRT-PCR and western blot to verify EIF5A expression in cell lines, while immunohistochemistry was utilized for clinical sample analysis. We analyzed EIF5A expression in tumor-infiltrating immune cells using the TISCH database and assessed its association with immune infiltration in LUAD using the "ESTIMATE" R package. Bioinformatics approaches were developed to discover the EIF5A-related genes and explore EIF5A potential mechanisms in LUAD. Proliferation ability was verified through CCK-8, clone formation, and EdU assays, while flow cytometry assessed apoptosis and cell cycle. Western blot was used to detect the expression of pathway-related proteins. RESULTS EIF5A was significantly upregulated in LUAD. Moreover, we constructed a MAZ-hsa-miR-424-3p-EIF5A transcriptional network. We explored the potential mechanism of EIF5A in LUAD and further investigated the cAMP signaling pathway and the cell cycle. Finally, we proved that EIF5A silencing induced G1/S Cell Cycle arrest, promoted apoptosis, and inhibited proliferation via the cAMP/PKA/CREB signaling pathway. CONCLUSION EIF5A serves as a prognostic biomarker with a negative correlation to immune infiltrates in LUAD. It regulated the cell cycle in LUAD by inhibiting the cAMP/PKA/CREB signaling pathway.
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Affiliation(s)
- Zipeng Yang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China
| | - Hao Yuan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China
| | - Houjing He
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China
| | - Shuting Qi
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China
| | - Xiaojing Zhu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China
| | - Xiaoyu Hu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China
| | - Mengyuan Jin
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China
| | - Xiu-Xiang Zhang
- College of Agriculture, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China.
| | - Zi-Guo Yuan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, Guangdong Province 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong Province 510642, PR China.
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12
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Ren JX, Chen L, Guo W, Feng KY, Cai YD, Huang T. Patterns of Gene Expression Profiles Associated with Colorectal Cancer in Colorectal Mucosa by Using Machine Learning Methods. Comb Chem High Throughput Screen 2024; 27:2921-2934. [PMID: 37957897 DOI: 10.2174/0113862073266300231026103844] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/11/2023] [Accepted: 09/30/2023] [Indexed: 11/15/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) has a very high incidence and lethality rate and is one of the most dangerous cancer types. Timely diagnosis can effectively reduce the incidence of colorectal cancer. Changes in para-cancerous tissues may serve as an early signal for tumorigenesis. Comparison of the differences in gene expression between para-cancerous and normal mucosa can help in the diagnosis of CRC and understanding the mechanisms of development. OBJECTIVES This study aimed to identify specific genes at the level of gene expression, which are expressed in normal mucosa and may be predictive of CRC risk. METHODS A machine learning approach was used to analyze transcriptomic data in 459 samples of normal colonic mucosal tissue from 322 CRC cases and 137 non-CRC, in which each sample contained 28,706 gene expression levels. The genes were ranked using four ranking methods based on importance estimation (LASSO, LightGBM, MCFS, and mRMR) and four classification algorithms (decision tree [DT], K-nearest neighbor [KNN], random forest [RF], and support vector machine [SVM]) were combined with incremental feature selection [IFS] methods to construct a prediction model with excellent performance. RESULT The top-ranked genes, namely, HOXD12, CDH1, and S100A12, were associated with tumorigenesis based on previous studies. CONCLUSION This study summarized four sets of quantitative classification rules based on the DT algorithm, providing clues for understanding the microenvironmental changes caused by CRC. According to the rules, the effect of CRC on normal mucosa can be determined.
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Affiliation(s)
- Jing Xin Ren
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Lei Chen
- College of Information Engineering, Shanghai Maritime University, Shanghai, 201306, China
| | - Wei Guo
- Key Laboratory of Stem Cell Biology, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, 200030, China
| | - Kai Yan Feng
- Department of Computer Science, Guangdong AIB Polytechnic College, Guangzhou, 510507, China
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Tao Huang
- Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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13
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Goto A, Komura S, Kato K, Maki R, Hirakawa A, Tomita H, Hirata A, Yamada Y, Akiyama H. C-X-C domain ligand 14-mediated stromal cell-macrophage interaction as a therapeutic target for hand dermal fibrosis. Commun Biol 2023; 6:1173. [PMID: 37980373 PMCID: PMC10657354 DOI: 10.1038/s42003-023-05558-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 11/08/2023] [Indexed: 11/20/2023] Open
Abstract
Dupuytren's contracture, a superficial dermal fibrosis, causes flexion contracture of the affected finger, impairing hand function. Specific single-nucleotide polymorphisms within genes in the Wnt signalling pathway are associated with the disease. However, the precise role of Wnt signalling dysregulation in the onset and progression of Dupuytren's contracture remains unclear. Here, using a fibrosis mouse model and clinical samples of human Dupuytren's contractures, we demonstrate that the activation of Wnt/β-catenin signalling in Tppp3-positive cells in the dermis of the paw is associated with the development of fibrosis. Fibrosis development and progression via Wnt/β-catenin signalling are closely related to stromal cell-macrophage interactions, and Wnt/β-catenin signalling activation in Tppp3-positive stromal cells causes M2 macrophage infiltration via chemokine Cxcl14, resulting in the formation of a TGF-β-expressing fibrotic niche. Inhibition of Cxcl14 mitigates fibrosis by decreasing macrophage infiltration. These findings suggest that Cxcl14-mediated stromal cell-macrophage interaction is a promising therapeutic target for Wnt/β-catenin-induced fibrosis.
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Affiliation(s)
- Atsushi Goto
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Shingo Komura
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan.
| | - Koki Kato
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Rie Maki
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Akihiro Hirakawa
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Akihiro Hirata
- Laboratory of Veterinary Pathology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu, 501-1194, Japan
| | - Yasuhiro Yamada
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Haruhiko Akiyama
- Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
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14
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Zhang T, Wahib R, Zazara DE, Lücke J, Shiri AM, Kempski J, Zhao L, Agalioti T, Machicote AP, Giannou O, Belios I, Jia R, Zhang S, Tintelnot J, Seese H, Grass JK, Mercanoglu B, Stern L, Scognamiglio P, Fard-Aghaie M, Seeger P, Wakker J, Kemper M, Brunswig B, Duprée A, Lykoudis PM, Pikouli A, Giorgakis E, Stringa P, Lausada N, Gentilini MV, Gondolesi GE, Bachmann K, Busch P, Grotelüschen R, Maroulis IC, Arck PC, Nakano R, Thomson AW, Ghadban T, Tachezy M, Melling N, Achilles EG, Puelles VG, Nickel F, Hackert T, Mann O, Izbicki JR, Li J, Gagliani N, Huber S, Giannou AD. CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis. Oncoimmunology 2023; 12:2269634. [PMID: 37876835 PMCID: PMC10591777 DOI: 10.1080/2162402x.2023.2269634] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023] Open
Abstract
Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.
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Affiliation(s)
- Tao Zhang
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ramez Wahib
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dimitra E. Zazara
- Division for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pediatrics, University Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jöran Lücke
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ahmad Mustafa Shiri
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Kempski
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lilan Zhao
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Theodora Agalioti
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andres Pablo Machicote
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Olympia Giannou
- Computer Engineering & Informatics Dept, University of Patras, Patras, Greece
| | - Ioannis Belios
- Division for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rongrong Jia
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Siwen Zhang
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Joseph Tintelnot
- Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- ll. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hannes Seese
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julia Kristin Grass
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Baris Mercanoglu
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Louisa Stern
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Pasquale Scognamiglio
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mohammad Fard-Aghaie
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Philipp Seeger
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jonas Wakker
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marius Kemper
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Benjamin Brunswig
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Duprée
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Panagis M. Lykoudis
- 3rd Department of Surgery, National & Kapodistrian University of Athens, Athens, Greece
- Division of Surgery & Interventional Science, University College London (UCL), London, UK
| | - Anastasia Pikouli
- 3rd Department of Surgery, National & Kapodistrian University of Athens, Athens, Greece
| | - Emmanouil Giorgakis
- Winthrop P Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Division of Transplantation, Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Pablo Stringa
- Department General Surgery, Liver, Pancreas and Intestinal Transplantation, Hospital Universitario, Fundacion Favaloro, Buenos Aires, Argentina
| | - Natalia Lausada
- Department General Surgery, Liver, Pancreas and Intestinal Transplantation, Hospital Universitario, Fundacion Favaloro, Buenos Aires, Argentina
| | - Maria Virginia Gentilini
- Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMETTyB, CONICET, Universidad Favaloro), Laboratorio de Inmunología asociada al Trasplante, Buenos Aires, Argentina
| | - Gabriel E. Gondolesi
- Department General Surgery, Liver, Pancreas and Intestinal Transplantation, Hospital Universitario, Fundacion Favaloro, Buenos Aires, Argentina
| | - Kai Bachmann
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Philipp Busch
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rainer Grotelüschen
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Petra C. Arck
- Division for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ryosuke Nakano
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Angus W. Thomson
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Tarik Ghadban
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Tachezy
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nathaniel Melling
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike-Gert Achilles
- Department of Visceral Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Victor G. Puelles
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Felix Nickel
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Oliver Mann
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R. Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jun Li
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Gagliani
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anastasios D. Giannou
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Qin R, Ren W, Ya G, Wang B, He J, Ren S, Jiang L, Zhao S. Role of chemokines in the crosstalk between tumor and tumor-associated macrophages. Clin Exp Med 2023; 23:1359-1373. [PMID: 36173487 PMCID: PMC10460746 DOI: 10.1007/s10238-022-00888-z] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 09/07/2022] [Indexed: 11/03/2022]
Abstract
Tumor microenvironment (TME) consists of a dynamic network of non-tumoral stromal cells, including cancer-associated fibroblasts, endothelial cells, tumor-associated macrophages (TAMs), B and T cells. In the TME, TAMs support tumor initiation, progression, invasion and metastasis by promoting angiogenesis and immunosuppression of the tumor cells. There is close crosstalk between TAMs and tumor cells. Notably, chemokines are a significant messenger mediating the crosstalk between tumor cells and TAMs. TAMs can promote tumor progression via secretion of chemokines. Various chemokines secreted by tumors are involved in the generation and polarization of TAMs, the infiltration of TAMs in tumors, and the development of TAMs' suppressive function. This paper reviews CCL2-CCR2, CCL3/5-CCR5, CCL15-CCR1, CCL18-CCR8, CX3CL1/CCL26-CX3CR1, CXCL8-CXCR1/2, CXCL12-CXCR4/CXCR7 signaling pathways, their role in the recruitment, polarization and exertion of TAMs, and their correlation with tumor development, metastasis and prognosis. Furthermore, we present the current research progress on modulating the effects of TAMs with chemokine antagonists and discuss the prospects and potential challenges of using chemokine antagonists as therapeutic tools for cancer treatment. The TAMs targeting by chemokine receptor antagonists in combination with chemotherapy drugs, immune checkpoint inhibitors or radiotherapy appears to be a promising approach.
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Affiliation(s)
- Rui Qin
- The First Clinical Medical Institute, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Weihong Ren
- Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China.
| | - Guoqi Ya
- The First Clinical Medical Institute, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Bei Wang
- The First Clinical Medical Institute, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Jiao He
- The First Clinical Medical Institute, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Shaoxin Ren
- The First Clinical Medical Institute, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Lu Jiang
- Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Shuo Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
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16
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Moon HG, Kim SJ, Kim KH, Kim YM, Rehman J, Lee H, Wu YC, Lee SSY, Christman JW, Ackerman SJ, Kim M, You S, Park GY. CX 3CR 1+ Macrophage Facilitates the Resolution of Allergic Lung Inflammation via Interacting CCL26. Am J Respir Crit Care Med 2023; 207:1451-1463. [PMID: 36790376 PMCID: PMC10263139 DOI: 10.1164/rccm.202209-1670oc] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 02/15/2023] [Indexed: 02/16/2023] Open
Abstract
Rationale: The resolution of inflammation is an active process coordinated by mediators and immune cells to restore tissue homeostasis. However, the mechanisms for resolving eosinophilic allergic lung inflammation triggered by inhaled allergens have not been fully elucidated. Objectives: Our objectives were to investigate the cellular mechanism of tissue-resident macrophages involved in the resolution process of eosinophilic lung inflammation. Methods: For the study, we used the institutional review board-approved protocol for human subsegmental bronchoprovocation with allergen, mouse models for allergic lung inflammation, and novel transgenic mice, including a conditional CCL26 knockout. The samples were analyzed using mass cytometry, single-cell RNA sequencing, and biophysical and immunological analyses. Measurements and Main Results: We compared alveolar macrophage (AM) subsets in the BAL before and after allergen provocation. In response to provocation with inhaled allergens, the subsets of AMs are dynamically changed in humans and mice. In the steady state, the AM subset expressing CX3CR1 is a relatively small fraction in bronchoalveolar space and lung tissue but drastically increases after allergen challenges. This subset presents unique patterns of gene expression compared with classical AMs, expressing high C1q family genes. CX3CR1+ macrophages are activated by airway epithelial cell-derived CCL26 via a receptor-ligand interaction. The binding of CCL26 to the CX3CR1+ receptor induces CX3CR1+ macrophages to secrete C1q, subsequently facilitating the clearance of eosinophils. Furthermore, the depletion of CX3CR1 macrophages or CCL26 in airway epithelial cells delays the resolution of allergic lung inflammation displaying prolonged tissue eosinophilia. Conclusions: These findings indicate that the CCL26-CX3CR1 pathway is pivotal in resolving eosinophilic allergic lung inflammation.
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Affiliation(s)
- Hyung-Geun Moon
- Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine
| | - Seung-jae Kim
- Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine
| | - Ki-Hyun Kim
- Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine
| | | | | | - Hyun Lee
- Department of Medicinal Chemistry & Pharmacognosy, Center for Biomolecular Sciences
| | | | | | - John W. Christman
- Section of Pulmonary, Critical Care, and Sleep Medicine, Davis Heart and Lung Research Center, The Ohio State University, Columbus, Ohio
| | - Steven J. Ackerman
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois
| | - Minhyung Kim
- Departments of Surgery, Cedars-Sinai Medical Center, Los Angeles, California; and
| | - Sungyoung You
- Departments of Surgery, Cedars-Sinai Medical Center, Los Angeles, California; and
| | - Gye Young Park
- Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine
- Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois
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17
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Chen S, Saeed AFUH, Liu Q, Jiang Q, Xu H, Xiao GG, Rao L, Duo Y. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther 2023; 8:207. [PMID: 37211559 DOI: 10.1038/s41392-023-01452-1] [Citation(s) in RCA: 680] [Impact Index Per Article: 340.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 03/06/2023] [Accepted: 04/26/2023] [Indexed: 05/23/2023] Open
Abstract
Macrophages exist in various tissues, several body cavities, and around mucosal surfaces and are a vital part of the innate immune system for host defense against many pathogens and cancers. Macrophages possess binary M1/M2 macrophage polarization settings, which perform a central role in an array of immune tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about macrophage signaling and immune modulation are yet to be uncovered. In addition, the clinical importance of tumor-associated macrophages is becoming more widely recognized as significant progress has been made in understanding their biology. Moreover, they are an integral part of the tumor microenvironment, playing a part in the regulation of a wide variety of processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, and resistance to chemotherapeutic and checkpoint blockade immunotherapies. Herein, we discuss immune regulation in macrophage polarization and signaling, mechanical stresses and modulation, metabolic signaling pathways, mitochondrial and transcriptional, and epigenetic regulation. Furthermore, we have broadly extended the understanding of macrophages in extracellular traps and the essential roles of autophagy and aging in regulating macrophage functions. Moreover, we discussed recent advances in macrophages-mediated immune regulation of autoimmune diseases and tumorigenesis. Lastly, we discussed targeted macrophage therapy to portray prospective targets for therapeutic strategies in health and diseases.
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Affiliation(s)
- Shanze Chen
- Department of Respiratory Diseases and Critic Care Unit, Shenzhen Institute of Respiratory Disease, Shenzhen Key Laboratory of Respiratory Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China
| | - Abdullah F U H Saeed
- Department of Cancer Biology, Beckman Research Institute of City of Hope National Medical Center, Los Angeles, CA, 91010, USA
| | - Quan Liu
- Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen University, Shenzhen, 518052, China
| | - Qiong Jiang
- Department of Respiratory Diseases and Critic Care Unit, Shenzhen Institute of Respiratory Disease, Shenzhen Key Laboratory of Respiratory Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China
| | - Haizhao Xu
- Department of Respiratory Diseases and Critic Care Unit, Shenzhen Institute of Respiratory Disease, Shenzhen Key Laboratory of Respiratory Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China
- Department of Respiratory, The First Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Gary Guishan Xiao
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, China.
| | - Lang Rao
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
| | - Yanhong Duo
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
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18
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Zajkowska M, Mroczko B. A Novel Approach to Staging and Detection of Colorectal Cancer in Early Stages. J Clin Med 2023; 12:3530. [PMID: 37240636 PMCID: PMC10218832 DOI: 10.3390/jcm12103530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/03/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
Colorectal cancer (CRC) is a significant problem affecting patients all over the world. Since it is the fourth most common cause of cancer-related deaths, many scientists aim to expand their knowledge on the detection in early stages and treatment of this disease. Chemokines, as protein parameters involved in many processes accompanying the development of cancer, constitute a group of potential biomarkers that could also be useful in the detection of CRC. For this purpose, our research team used the results of thirteen parameters (nine chemokines, one chemokine receptor and three comparative markers, i.e., CEA, CA19-9 and CRP) to calculate one hundred and fifty indexes. Moreover, for the first time, the relationship between these parameters during the ongoing cancer process and in comparison to a control group are presented. As a result of statistical analyses using patients' clinical data and the obtained indexes, it was established that several of the indexes have a diagnostic utility that is much higher than the tumor marker that is currently the most commonly used (CEA) currently. Furthermore, two of the indexes (CXCL14/CEA and CXCL16/CEA) showed not only extremely high usefulness in the detection of CRC in its early stages, but also the ability to determine whether the stage is low (stage I and II) or high (stage III and IV).
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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19
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O’Connell F, Mylod E, Donlon NE, Heeran AB, Butler C, Bhardwaj A, Ramjit S, Durand M, Lambe G, Tansey P, Welartne I, Sheahan KP, Yin X, Donohoe CL, Ravi N, Dunne MR, Brennan L, Reynolds JV, Roche HM, O’Sullivan J. Energy Metabolism, Metabolite, and Inflammatory Profiles in Human Ex Vivo Adipose Tissue Are Influenced by Obesity Status, Metabolic Dysfunction, and Treatment Regimes in Patients with Oesophageal Adenocarcinoma. Cancers (Basel) 2023; 15:cancers15061681. [PMID: 36980567 PMCID: PMC10046380 DOI: 10.3390/cancers15061681] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/12/2023] Open
Abstract
Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and has a strong link to obesity. To better elucidate the role of visceral adiposity in this disease state, a full metabolic profile combined with analysis of secreted pro-inflammatory cytokines, metabolites, and lipid profiles were assessed in human ex vivo adipose tissue explants from obese and non-obese OAC patients. These data were then related to extensive clinical data including obesity status, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Real-time energy metabolism profiles were assessed using the seahorse technology. Adipose explant conditioned media was screened using multiplex ELISA to assess secreted levels of 54 pro-inflammatory mediators. Targeted secreted metabolite and lipid profiles were analysed using Ultra-High-Performance Liquid Chromatography coupled with Mass Spectrometry. Adipose tissue explants and matched clinical data were collected from OAC patients (n = 32). Compared to visceral fat from non-obese patients (n = 16), visceral fat explants from obese OAC patients (n = 16) had significantly elevated oxidative phosphorylation metabolism profiles and an increase in Eotaxin-3, IL-17A, IL-17D, IL-3, MCP-1, and MDC and altered secretions of glutamine associated metabolites. Adipose explants from patients with metabolic dysfunction correlated with increased oxidative phosphorylation metabolism, and increases in IL-5, IL-7, SAA, VEGF-C, triacylglycerides, and metabolites compared with metabolically healthy patients. Adipose explants generated from patients who had previously received neo-adjuvant chemotherapy (n = 14) showed elevated secretions of pro-inflammatory mediators, IL-12p40, IL-1α, IL-22, and TNF-β and a decreased expression of triacylglycerides. Furthermore, decreased secreted levels of triacylglycerides were also observed in the adipose secretome of patients who received the chemotherapy-only regimen FLOT compared with patients who received no neo-adjuvant treatment or chemo-radiotherapy regimen CROSS. For those patients who showed the poorest response to currently available treatments, their adipose tissue was associated with higher glycolytic metabolism compared to patients who had good treatment responses. This study demonstrates that the adipose secretome in OAC patients is enriched with mediators that could prime the tumour microenvironment to aid tumour progression and attenuate responses to conventional cancer treatments, an effect which appears to be augmented by obesity and metabolic dysfunction and exposure to different treatment regimes.
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Affiliation(s)
- Fiona O’Connell
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Eimear Mylod
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity College Dublin, St. James’s Hospital, D08 W9RT Dublin, Ireland
| | - Noel E. Donlon
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity College Dublin, St. James’s Hospital, D08 W9RT Dublin, Ireland
| | - Aisling B. Heeran
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Christine Butler
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Anshul Bhardwaj
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Sinead Ramjit
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Michael Durand
- Department of Radiology, St. James’s Hospital, D08 NHY1 Dublin, Ireland
| | - Gerard Lambe
- Department of Radiology, St. James’s Hospital, D08 NHY1 Dublin, Ireland
| | - Paul Tansey
- Department of Radiology, St. James’s Hospital, D08 NHY1 Dublin, Ireland
| | - Ivan Welartne
- Department of Radiology, St. James’s Hospital, D08 NHY1 Dublin, Ireland
| | - Kevin P. Sheahan
- Department of Radiology, Beaumont Hospital, D02 YN77 Dublin, Ireland
| | - Xiaofei Yin
- UCD School of Agriculture and Food Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland
| | - Claire L. Donohoe
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Narayanasamy Ravi
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Margaret R. Dunne
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
- School of Chemical & Biopharmaceutical Sciences, Technological University Dublin, Tallaght, D07 EWV4 Dublin, Ireland
| | - Lorraine Brennan
- UCD School of Agriculture and Food Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland
| | - John V. Reynolds
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
| | - Helen M. Roche
- Nutrigenomics Research Group, UCD Conway Institute, School of Public Health, Physiotherapy and Sports Science, University College Dublin, D04 C1P1 Dublin, Ireland
- Institute for Global Food Security, School of Biological Sciences, Queens University Belfast, Belfast BT9 5DL, UK
| | - Jacintha O’Sullivan
- Department of Surgery, Trinity St. James’s Cancer Institute and Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College Dublin, D08 W9RT Dublin, Ireland
- Correspondence:
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20
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Rosado-Galindo H, Domenech M. Surface roughness modulates EGFR signaling and stemness of triple-negative breast cancer cells. Front Cell Dev Biol 2023; 11:1124250. [PMID: 36968199 PMCID: PMC10030610 DOI: 10.3389/fcell.2023.1124250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/27/2023] [Indexed: 03/29/2023] Open
Abstract
Introduction: Cancer stem cells (CSC), a major culprit of drug-resistant phenotypes and tumor relapse, represent less than 2 % of the bulk of TNBC cells, making them difficult to isolate, study, and thus, limiting our understanding of the pathogenesis of the disease. Current methods for CSC enrichment, such as 3D spheroid culture, genetic modification, and stem cell conditioning, are time consuming, expensive, and unsuitable for high-throughput assays. One way to address these limitations is to use topographical stimuli to enhance CSC populations in planar culture. Physical cues in the breast tumor microenvironment can influence cell behavior through changes in the mechanical properties of the extracellular matrix (ECM). In this study, we used topographical cues on polystyrene films to investigate their effect on the proteome and stemness of standard TNBC cell lines. Methods: The topographical polystyrene-based array was generated using razor printing and polishing methods. Proteome data were analyzed and enriched bioprocesses were identified using R software. Stemness was assessed measuring CD44, CD24 and ALDH markers using flow cytometry, immunofluorescence, detection assays, and further validated with mammosphere assay. EGF/EGFR expression and activity was evaluated using enzyme-linked immunosorbent assay (ELISA), immunofluorescence and antibody membrane array. A dose-response assay was performed to further investigate the effect of surface topography on the sensitivity of cells to the EGFR inhibitor. Results: Surface roughness enriched the CSC population and modulated epidermal growth factor receptor (EGFR) signaling activity in TNBC cells. Enhanced proliferation of MDA-MB-468 cells in roughness correlated with upregulation of the epidermal growth factor (EGF) ligand, which in turn corresponded with a 3-fold increase in the expression of EGFR and a 42% increase in its phosphorylation compared to standard smooth culture surfaces. The results also demonstrated that phenotypic changes associated with topographical (roughness) stimuli significantly decreased the drug sensitivity to the EGFR inhibitor gefitinib. In addition, the proportion of CD44+/CD24-/ALDH+ was enhanced on surface roughness in both MDA-MB-231 and MDA-MB-468 cell lines. We also demonstrated that YAP/TAZ activation decreased in a roughness-dependent manner, confirming the mechanosensing effect of the topographies on the oncogenic activity of the cells. Discussion: Overall, this study demonstrates the potential of surface roughness as a culture strategy to influence oncogenic activity in TNBC cells and enrich CSC populations in planar cultures. Such a culture strategy may benefit high-throughput screening studies seeking to identify compounds with broader tumor efficacy.
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Affiliation(s)
| | - Maribella Domenech
- Bioengineering Program, University of Puerto Rico-Mayagüez, Mayagüez, Puerto Rico
- Department of Chemical Engineering, University of Puerto Rico-Mayagüez, Mayagüez, Puerto Rico
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21
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Tong J, Jiang W, Zhang X, Wang R, Qiao T, Song Y, Gao D, Yu X, Lv Z, Li D. CCL22 and CCL26 are potential biomarkers for predicting distant metastasis in thyroid carcinoma. J Int Med Res 2022; 50:3000605221139555. [PMID: 36495170 DOI: 10.1177/03000605221139555] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Chemokines have been suggested to play significant roles in the progression of malignant cancers. This study aimed to identify the chemokines related to malignant progression in thyroid carcinoma. METHODS The mRNA expression levels of 52 chemokines were compared between differentiated thyroid cancer (DTC) samples and normal thyroid tissues from The Cancer Genome Atlas database; survival analysis was then performed on the basis of differentially expressed chemokines. A retrospective study was conducted on the level of differentially expressed chemokines in 76 DTC patients. Functional pathway analysis was performed to explore chemokine-related regulatory mechanisms. RESULTS We identified 20 chemokines with differentially expressed mRNA levels through publicly available data. High levels of CCL22 and CCL26 were found to be related with metastasis in clinical DTC samples. High levels of CCL22 were found to be significantly related to poor prognosis in DTC patients. Pathway analyses revealed that cytokines might affect cancer progression through cytokine-cytokine receptor and cytokine-interleukin interactions. CONCLUSIONS CCL22 and CCL26 could serve as prognostic biomarkers in thyroid carcinoma.
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Affiliation(s)
- Junyu Tong
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Wen Jiang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Xiaoying Zhang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.,Department of Nuclear Medicine, The Affiliated Shanghai Tenth People's Hospital of Nanjing Medical University, Shanghai, P.R. China
| | - Ru Wang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Tingting Qiao
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Yingchun Song
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Dingwei Gao
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Xiaqing Yu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China
| | - Dan Li
- Department of Nuclear Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P.R. China
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22
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CCL26 silence represses colon cancer by inhibiting the EMT signaling pathway. Tissue Cell 2022; 79:101937. [DOI: 10.1016/j.tice.2022.101937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 12/24/2022]
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Cui M, Zhang H, Han S, Huo F, Shen Z, Ding D. Screening of biomarkers associated with diagnosis and prognosis of colorectal cancer. Genes Genet Syst 2022; 97:101-110. [PMID: 36104170 DOI: 10.1266/ggs.21-00072] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
We aimed to explore biomarkers associated with diagnosis and prognosis of colorectal cancer. Differentially expressed protein (DEP) genes were obtained and validated. Moreover, co-expressed genes were screened and their prognostic value was evaluated. In addition, miRNAs that were negatively correlated with DEP genes were identified and used to construct a competitive endogenous RNA network. Furthermore, a support vector machine model was built using DEP genes, and a receiver operating characteristic curve was implemented to confirm its prediction performance. The results showed that only one DEP gene, CCL26, was obtained. Moreover, 43 genes co-expressed with CCL26 were identified, among which six (AP3M2, DAPK1, ISYNA1, PPM1K, PRR4 and RNF122) were linked with the prognosis of colorectal cancer. Besides, the axis RP11-47122.2/RP11-527N22.1-hsa-miR-3192-5p-CCL26 was identified as an lncRNA-miRNA-target gene network. Support vector machine model analysis showed that the area under the curve of CCL26 reached 0.878 based on GEO data and 0.743 based on our protein data. In conclusion, AP3M2, DAPK1, ISYNA1, PPM1K, PRR4, RNF122, CCL26 and hsa-miR-3192-5p appear to be related to the progression of colorectal cancer.
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Affiliation(s)
- Mingfu Cui
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital, Jilin University
| | - Haiyan Zhang
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital, Jilin University
| | - Songyun Han
- Department of Emergency, Tonghua Central Hospital, Jilin University
| | - Feng Huo
- Department of Oncological Surgery, Changchun Tumor Hospital
| | - Zhaoming Shen
- Department of General Surgery, Changchun People's Hospital
| | - Dayong Ding
- Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital, Jilin University
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24
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Feng Y, Ye Z, Song F, He Y, Liu J. The Role of TAMs in Tumor Microenvironment and New Research Progress. Stem Cells Int 2022; 2022:5775696. [PMID: 36004381 PMCID: PMC9395242 DOI: 10.1155/2022/5775696] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/24/2022] [Accepted: 07/28/2022] [Indexed: 02/08/2023] Open
Abstract
Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment (TME) and play a key role in TME, participating in the process of tumor occurrence, growth, invasion, and metastasis. Among them, metastasis to tumor tissue is the key step of malignant development of tumor. In this paper, the latest progress in the role of TAMs in the formation of tumor microenvironment is summarized. It is particularly noteworthy that cell and animal experiments show that TAMs can provide a favorable microenvironment for the occurrence and development of tumors. At the same time, clinical pathological experiments show that the accumulation of TAMs in tumor is related to poor clinical efficacy. Finally, this paper discusses the feasibility of TAMs-targeted therapy as a new indirect cancer therapy. This paper provides a theoretical basis for finding a potentially effective macrophage-targeted tumor therapy.
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Affiliation(s)
- Yawei Feng
- Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhiqiang Ye
- Department of Emergency, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Furong Song
- Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yufeng He
- Department of Intensive Care Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jun Liu
- Department of Anesthesiology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
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Zou Q, Lei X, Xu A, Li Z, He Q, Huang X, Xu G, Tian F, Ding Y, Zhu W. Chemokines in progression, chemoresistance, diagnosis, and prognosis of colorectal cancer. Front Immunol 2022; 13:724139. [PMID: 35935996 PMCID: PMC9353076 DOI: 10.3389/fimmu.2022.724139] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 06/27/2022] [Indexed: 12/24/2022] Open
Abstract
Plenty of factors affect the oncogenesis and progression of colorectal cancer in the tumor microenvironment, including various immune cells, stromal cells, cytokines, and other factors. Chemokine is a member of the cytokine superfamily. It is an indispensable component in the tumor microenvironment. Chemokines play an antitumor or pro-tumor role by recruitment or polarization of recruiting immune cells. Meanwhile, chemokines, as signal molecules, participate in the formation of a cross talk among signaling pathways and non-coding RNAs, which may be involved in promoting tumor progression. In addition, they also function in immune escape. Chemokines are related to drug resistance of tumor cells and may even provide reference for the diagnosis, therapy, and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Qian Zou
- Department of Pathology, Guangdong Medical University, Dongguan, China
| | - Xue Lei
- Department of Pathology, Guangdong Medical University, Dongguan, China
| | - Aijing Xu
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ziqi Li
- Department of Pathology, Guangdong Medical University, Dongguan, China
| | - Qinglian He
- Department of Pathology, Guangdong Medical University, Dongguan, China
| | - Xiujuan Huang
- Department of Pathology, Guangdong Medical University, Dongguan, China
- Department of Hematology, Longgang District People’s Hospital of Shenzhen, Shenzhen, China
| | - Guangxian Xu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Institute of Clinical Laboratory, Guangdong Medical University, Dongguan, China
| | - Faqing Tian
- Department of Pathology, Guangdong Medical University, Dongguan, China
- Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
- *Correspondence: Faqing Tian, ; Yuanlin Ding, ; Wei Zhu,
| | - Yuanlin Ding
- School of Public Health, Guangdong Medical University, Dongguan, China
- *Correspondence: Faqing Tian, ; Yuanlin Ding, ; Wei Zhu,
| | - Wei Zhu
- Department of Pathology, Guangdong Medical University, Dongguan, China
- *Correspondence: Faqing Tian, ; Yuanlin Ding, ; Wei Zhu,
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Vaccaro J, Canziani KE, Guzmán L, Bernedo V, García M, Altamirano EM, Feregotti E, Curciarello R, Muglia CI, Docena GH. Type-2 Cytokines Promote the Secretion of the Eosinophil–Attractant CCL26 by Intestinal Epithelial Cells in Food-Sensitized Patients. Front Immunol 2022; 13:909896. [PMID: 35799778 PMCID: PMC9254714 DOI: 10.3389/fimmu.2022.909896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/03/2022] [Indexed: 11/29/2022] Open
Abstract
Several inflammatory processes of the bowel are characterized by an accumulation of eosinophils at inflammation sites. The mechanisms that govern mucosal infiltration with eosinophils are not fully understood. In this work, we studied the colorectal polyp-confined tissue containing eosinophils and we hypothesized that intestinal epithelial cells are the cell source of eotaxin-3 or CCL26, a potent chemoattractant for eosinophils. We analyzed colorectal polyps (n=50) from pediatric patients with rectal bleeding by H&E staining and eosin staining, and different pro-inflammatory cytokines were assessed by RT-qPCR and ELISA. IgE and CCL26 were investigated by RT-qPCR, ELISA and confocal microscopy. Finally, the intracellular signaling pathway that mediates the CCL26 production was analyzed using a kinase array and immunoblotting in human intestinal Caco-2 cell line. We found a dense cell agglomeration within the polyps, with a significantly higher frequency of eosinophils than in control adjacent tissue. IL-4 and IL-13 were significantly up-regulated in polyps and CCL26 was elevated in the epithelial compartment. Experiments with Caco-2 cells showed that the type-2 cytokine IL-13 increased STAT3 and STAT6 phosphorylation and eotaxin-3 secretion. The addition of the blocking antibody Dupilumab or the inhibitor Ruxolitinib to the cytokine-stimulated Caco-2 cells diminished the CCL26 secretion to basal levels in a dose-dependent manner. In conclusion, our findings demonstrate a high frequency of eosinophils, and elevated levels of type-2 cytokines and eotaxin-3 in the inflammatory stroma of colorectal polyps from pediatric patients. Polyp epithelial cells showed to be the main cell source of CCL26, and IL-13 was the main trigger of this chemokine through the activation of the STAT3/STAT6/JAK1-2 pathway. We suggest that the epithelial compartment actively participates in the recruitment of eosinophils to the colonic polyp-confined inflammatory environment.
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Affiliation(s)
- Julián Vaccaro
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, Asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
| | - Karina Eva Canziani
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, Asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
| | - Luciana Guzmán
- Servicio de Gastroenterología, Hospital de Niños Sor María Ludovica, La Plata, Argentina
| | - Viviana Bernedo
- Servicio de Gastroenterología, Hospital de Niños Sor María Ludovica, La Plata, Argentina
| | - Marcela García
- Sala de Alergia, Hospital de Niños Sor María Ludovica, La Plata, Argentina
| | | | - Emanuel Feregotti
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, Asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
| | - Renata Curciarello
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, Asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
| | - Cecilia Isabel Muglia
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, Asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
| | - Guillermo Horacio Docena
- Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, Asociado a CIC PBA, Facultad de Ciencias Exactas, Departamento de Ciencias Biológicas, La Plata, Argentina
- *Correspondence: Guillermo Horacio Docena,
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27
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Zhou H, Liu Z, Wang Y, Wen X, Amador EH, Yuan L, Ran X, Xiong L, Ran Y, Chen W, Wen Y. Colorectal liver metastasis: molecular mechanism and interventional therapy. Signal Transduct Target Ther 2022; 7:70. [PMID: 35246503 PMCID: PMC8897452 DOI: 10.1038/s41392-022-00922-2] [Citation(s) in RCA: 151] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.
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Affiliation(s)
- Hui Zhou
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Zhongtao Liu
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Yongxiang Wang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xiaoyong Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Eric H Amador
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA
| | - Liqin Yuan
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China
| | - Xin Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Xiong
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
| | - Yuping Ran
- Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Chen
- Department of Physics, The University of Texas, Arlington, TX, 76019, USA.
- Medical Technology Research Centre, Chelmsford Campus, Anglia Ruskin University, Chelmsford, CM1 1SQ, UK.
| | - Yu Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, China.
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28
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Meng LK, Zhu D, Zhang Y, Fang Y, Liu WZ, Zhang XQ, Zhu Y. Recurrence of sigmoid colon cancer–derived anal metastasis: A case report and review of literature. World J Clin Cases 2022; 10:1122-1130. [PMID: 35127928 PMCID: PMC8790455 DOI: 10.12998/wjcc.v10.i3.1122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/26/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Distant metastasis of colorectal cancer to the anus is very rare, with only 30 related cases published in PubMed thus far. Therefore, recurrence of colorectal cancer derived anus metastases is rarely seen and less presented.
CASE SUMMARY Here we report an 80-year-old male patient who underwent radical resection for sigmoid colon cancer in January 2010 and another surgery for anal fistula resection in December 2010. Postoperative pathology of the anal fistula revealed a metastatic moderately differentiated adenocarcinoma. The patient subsequently received chemotherapy and radiotherapy. In May 2020, after the patient reported symptoms of anal swelling and pain, computed tomography and magnetic resonance imaging revealed a perianal abscess. Perianal mass biopsy was performed, and the postoperative pathological diagnosis was metastatic moderately differentiated adenocarcinoma.
CONCLUSION This case highlights that there is a risk of recurrence of anal metastasis of colorectal cancer even after 10 years of follow-up. We also reviewed the literature and discuss potential mechanisms for anal metastasis of colorectal cancer, thus providing some suggestions for treatment of these cases.
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Affiliation(s)
- Ling-Kang Meng
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Dan Zhu
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Yu Zhang
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Yuan Fang
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Wei-Zhen Liu
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Xia-Qing Zhang
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
| | - Yong Zhu
- Department of Colorectal Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
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29
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Kou Y, Li Z, Sun Q, Yang S, Wang Y, Hu C, Gu H, Wang H, Xu H, Li Y, Kou Y, Han B. Prognostic value and predictive biomarkers of phenotypes of tumor-associated macrophages in colorectal cancer. Scand J Immunol 2021; 95:e13137. [PMID: 34964155 PMCID: PMC9286461 DOI: 10.1111/sji.13137] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 10/29/2021] [Accepted: 12/26/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND The roles of different subtypes of tumor-associated macrophages (TAMs) in predicting the prognosis of colorectal cancer (CRC) remain controversial. In this study, different subtypes of TAMs were investigated as prognostic and predictive biomarkers for CRC. METHODS Expressions of CD68, CD86 and CD163 were investigated by immunohistochemistry (IHC) and immunofluorescence (IF), and the correlation between the expression of CD86 and CD163 was calculated in colorectal cancer tissues from 64 CRC patients. RESULTS The results showed that high expressions of CD86+ and CD68+ CD86+ TAMs as well as low expression of CD163+ and CD68+ CD163+ TAMs were significantly associated with favorable overall survival (OS). The level of CD86 protein expression showed a negative correlation with CD163 protein expression. In addition, CD86 protein expression remarkably negative correlated with tumor differentiation and tumor node metastasis (TNM) stage, while CD163 protein expression significantly positive correlated with tumor differentiation and tumor size. As an independent risk factor, high expression of CD86 TAMs had prominently favorable prognostic efficacy while high expression of CD68+ CD163+ TAMs had significantly poor prognostic efficacy. CONCLUSIONS These results indicate that CD86+ and CD68+ CD163+ TAMs as prognostic and predictive biomarkers for CRC.
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Affiliation(s)
- Yu Kou
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225000, Jiangsu, China
| | - Zhuoqun Li
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Qidi Sun
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Shengnan Yang
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Yunshuai Wang
- Department of General Surgery, Luoyang Central Hospital Affiliated of Zhengzhou University, 471000, Henan, China
| | - Chen Hu
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Huijie Gu
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China
| | - Huangjian Wang
- Department of General Surgery, Luoyang Central Hospital Affiliated of Zhengzhou University, 471000, Henan, China
| | - Hairong Xu
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225000, Jiangsu, China
| | - Yan Li
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225000, Jiangsu, China
| | - Yu Kou
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medcine for Prevention and Treatment of Senile Diseases, Medical College of Yangzhou University, 225000, Jiangsu, China.,Department of Traditional Chinese Medicine Affiliated Hospital, Yangzhou University, 225000, Jiangsu, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, 225000, Jiangsu, China
| | - Baowei Han
- Department of General Surgery, Luoyang Central Hospital Affiliated of Zhengzhou University, 471000, Henan, China
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30
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Zhu S, Yi M, Wu Y, Dong B, Wu K. Roles of tumor-associated macrophages in tumor progression: implications on therapeutic strategies. Exp Hematol Oncol 2021; 10:60. [PMID: 34965886 PMCID: PMC8715617 DOI: 10.1186/s40164-021-00252-z] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/16/2021] [Indexed: 12/11/2022] Open
Abstract
Macrophages are heterogeneous cells that present as different functional phenotypes due to their plasticity. They can be classified into two categories, namely M1- and M2-like macrophages, which are involved in processes as diverse as anti-tumor activity and immunosuppressive tumor promotion. Tumor-associated macrophages (TAMs) are defined as being of an M2-type and are considered as the active component in tumor microenvironment. TAMs are involved in multiple processes of tumor progression through the expression of cytokines, chemokines, growth factors, protein hydrolases and more, which lead to enhance tumor cell proliferation, angiogenesis, and immunosuppression, which in turn supports invasion and metastasis. It is assumed that the abundance of TAMs in major solid tumors is correlated to a negative patient prognosis. Because of the currently available data of the TAMs’ role in tumor development, these cells have emerged as a promising target for novel cancer treatment strategies. In this paper, we will briefly describe the origins and types of TAMs and will try to comprehensively show how TAMs contribute to tumorigenesis and disease progression. Finally, we will present the main TAM-based therapeutic strategies currently available.
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31
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Kennedy SA, Annett SL, Dunne MR, Boland F, O'Neill LM, Guinan EM, Doyle SL, Foley EK, Elliott JA, Murphy CF, Bennett AE, Carey M, Hillary D, Robson T, Reynolds JV, Hussey J, O'Sullivan J. Effect of the Rehabilitation Program, ReStOre, on Serum Biomarkers in a Randomized Control Trial of Esophagogastric Cancer Survivors. Front Oncol 2021; 11:669078. [PMID: 34604026 PMCID: PMC8479183 DOI: 10.3389/fonc.2021.669078] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 08/17/2021] [Indexed: 11/24/2022] Open
Abstract
Background The Rehabilitation Strategies Following Esophagogastric cancer (ReStOre) randomized control trial demonstrated a significant improvement in cardiorespiratory fitness of esophagogastric cancer survivors. This follow-up, exploratory study analyzed the biological effect of exercise intervention on levels of 55 serum proteins, encompassing mediators of angiogenesis, inflammation, and vascular injury, from participants on the ReStOre trial. Methods Patients >6 months disease free from esophagogastric cancer were randomized to usual care or the 12-week ReStOre program (exercise training, dietary counselling, and multidisciplinary education). Serum was collected at baseline (T0), post-intervention (T1), and at 3-month follow up (T2). Serum biomarkers were quantified by enzyme-linked immunosorbent assay (ELISA). Results Thirty-seven patients participated in this study; 17 in the control arm and 20 in the intervention arm. Exercise intervention resulted in significant alterations in the level of expression of serum IP-10 (mean difference (MD): 38.02 (95% CI: 0.69 to 75.35)), IL-27 (MD: 249.48 (95% CI: 22.43 to 476.53)), and the vascular injury biomarkers, ICAM-1 (MD: 1.05 (95% CI: 1.07 to 1.66)), and VCAM-1 (MD: 1.51 (95% CI: 1.04 to 2.14)) at T1. A significant increase in eotaxin-3 (MD: 2.59 (95% CI: 0.23 to 4.96)), IL-15 (MD: 0.27 (95% CI: 0 to 0.54)) and decrease in bFGF (MD: 1.62 (95% CI: -2.99 to 0.26)) expression was observed between control and intervention cohorts at T2 (p<0.05). Conclusions Exercise intervention significantly altered the expression of a number of serum biomarkers in disease-free patients who had prior treatment for esophagogastric cancer. Impact Exercise rehabilitation causes a significant biological effect on serum biomarkers in esophagogastric cancer survivors. Clinical Trial Registration ClinicalTrials.gov (NCT03314311).
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Affiliation(s)
- Susan A Kennedy
- Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Stephanie L Annett
- School of Pharmacy and Biomolecular Science, Royal College of Surgeons Ireland, Dublin, Ireland
| | - Margaret R Dunne
- Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Fiona Boland
- Data Science Centre, Royal College of Surgeons Ireland, Dublin, Ireland
| | - Linda M O'Neill
- Discipline of Physiotherapy, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Emer M Guinan
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Suzanne L Doyle
- School of Biological Sciences, Dublin Institute of Technology, Dublin, Ireland
| | - Emma K Foley
- Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Jessie A Elliott
- Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Conor F Murphy
- Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Annemarie E Bennett
- Discipline of Physiotherapy, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Michelle Carey
- School of Mathematics & Statistics, University College Dublin, Dublin, Ireland
| | - Daniel Hillary
- School of Mathematics & Statistics, University College Dublin, Dublin, Ireland
| | - Tracy Robson
- School of Pharmacy and Biomolecular Science, Royal College of Surgeons Ireland, Dublin, Ireland
| | - John V Reynolds
- Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Juliette Hussey
- Discipline of Physiotherapy, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Jacintha O'Sullivan
- Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
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32
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Analysis of the signal cross talk via CCL26 in the tumor microenvironment in osteosarcoma. Sci Rep 2021; 11:18099. [PMID: 34518591 PMCID: PMC8438066 DOI: 10.1038/s41598-021-97153-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 08/20/2021] [Indexed: 11/08/2022] Open
Abstract
Interaction with surrounding healthy cells plays a major role in the growth and metastasis of osteosarcoma. In this study, we hypothesized that humoral factors, which do not require direct contact with cells, are involved in the interaction between osteosarcoma and the surrounding cells. We identified the humoral factor involved in the association between tumor cells and surrounding normal cells using a co-culture model and investigated the significance of our findings. When human osteosarcoma cells (MG63) and human mesenchymal stem cells (hMSCs) were co-cultured and comprehensively analyzed for changes in each culture group, we found that the expression of chemokine (CC motif) ligand 26 (CCL26) was significantly enhanced. We also analyzed the changes in cell proliferation in co-culture, enhanced interaction with administration of recombinant CCL26 (rCCL26), reduced interaction with administration of anti-CCL26 antibodies, changes in invasive and metastatic abilities. CCL26 levels, motility, and invasive capability increased in the co-culture group and the group with added rCCL26, compared to the corresponding values in the MG63 single culture group. In the group with added CCL26 neutralizing antibodies, CCL26 level decreased in both the single and co-culture groups, and motility and invasive ability were also reduced. In a nude mice lung metastasis model, the number of lung metastases increased in the co-culture group and the group with added rCCL26, whereas the number of tumors were suppressed in the group with added neutralizing antibodies compared to those in the MG63 alone. This study identified a possible mechanism by which osteosarcoma cells altered the properties of normal cells to favorably change the microenvironment proximal to tumors and to promote distant metastasis.
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33
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Ho WJ, Zhu Q, Durham J, Popovic A, Xavier S, Leatherman J, Mohan A, Mo G, Zhang S, Gross N, Charmsaz S, Lin D, Quong D, Wilt B, Kamel IR, Weiss M, Philosophe B, Burkhart R, Burns WR, Shubert C, Ejaz A, He J, Deshpande A, Danilova L, Stein-O'Brien G, Sugar EA, Laheru DA, Anders RA, Fertig EJ, Jaffee EM, Yarchoan M. Neoadjuvant Cabozantinib and Nivolumab Converts Locally Advanced HCC into Resectable Disease with Enhanced Antitumor Immunity. NATURE CANCER 2021; 2:891-903. [PMID: 34796337 PMCID: PMC8594857 DOI: 10.1038/s43018-021-00234-4] [Citation(s) in RCA: 217] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 06/10/2021] [Indexed: 02/07/2023]
Abstract
A potentially curative hepatic resection is the optimal treatment for hepatocellular carcinoma (HCC), but most patients are not candidates for resection and most resected HCCs eventually recur. Until recently, neoadjuvant systemic therapy for HCC has been limited by a lack of effective systemic agents. Here, in a single arm phase 1b study, we evaluated the feasibility of neoadjuvant cabozantinib and nivolumab in patients with HCC including patients outside of traditional resection criteria (NCT03299946). Of 15 patients enrolled, 12 (80%) underwent successful margin negative resection, and 5/12 (42%) patients had major pathologic responses. In-depth biospecimen profiling demonstrated an enrichment in T effector cells, as well as tertiary lymphoid structures, CD138+ plasma cells, and a distinct spatial arrangement of B cells in responders as compared to non-responders, indicating an orchestrated B-cell contribution to antitumor immunity in HCC.
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Affiliation(s)
- Won Jin Ho
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Qingfeng Zhu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jennifer Durham
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Aleksandra Popovic
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Stephanie Xavier
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James Leatherman
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Aditya Mohan
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Guanglan Mo
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shu Zhang
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nicole Gross
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Soren Charmsaz
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Dongxia Lin
- Fluidigm Corporation, San Francisco, CA, USA
| | - Derek Quong
- Fluidigm Corporation, San Francisco, CA, USA
| | - Brad Wilt
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ihab R Kamel
- Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Matthew Weiss
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Benjamin Philosophe
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Richard Burkhart
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - William R Burns
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chris Shubert
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Aslam Ejaz
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jin He
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Atul Deshpande
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ludmila Danilova
- Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Genevieve Stein-O'Brien
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elizabeth A Sugar
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Daniel A Laheru
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert A Anders
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elana J Fertig
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA
| | - Elizabeth M Jaffee
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mark Yarchoan
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Su SF, Ho H, Li JH, Wu MF, Wang HC, Yeh HY, Kuo SW, Chen HW, Ho CC, Li KC. DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a smoking-associated malignancy index. J Clin Invest 2021; 131:e139552. [PMID: 34228648 DOI: 10.1172/jci139552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 07/01/2021] [Indexed: 12/15/2022] Open
Abstract
Unlike the better-studied aberrant epigenome in the tumor, the clinicopathologic impact of DNA methylation in the tumor microenvironment (TME), especially the contribution from cancer-associated fibroblasts (CAFs), remains elusive. CAFs exhibit profound patient-to-patient tumorigenic heterogeneity. We asked whether such heterogeneity may be exploited to quantify the level of TME malignancy. We developed a robust and efficient methylome/transcriptome co-analytical system for CAFs and paired normal fibroblasts (NFs) from non-small-cell lung cancer patients. We found 14,781 CpG sites of CAF/NF differential methylation, of which 3,707 sites showed higher methylation changes in ever-smokers than in nonsmokers. Concomitant CAF/NF differential gene expression analysis pointed to a subset of 54 smoking-associated CpG sites with strong methylation-regulated gene expression. A methylation index that summarizes the β values of these CpGs was built for NF/CAF discrimination (MIND) with high sensitivity and specificity. The potential of MIND in detecting premalignancy across individual patients was shown. MIND succeeded in predicting tumor recurrence in multiple lung cancer cohorts without reliance on patient survival data, suggesting that the malignancy level of TME may be effectively graded by this index. Precision TME grading may provide additional pathological information to guide cancer prognosis and open up more options in personalized medicine.
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Affiliation(s)
- Sheng-Fang Su
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.,Graduate Institute of Oncology, National Taiwan University, College of Medicine, Taipei, Taiwan.,YongLin Institute of Health, National Taiwan University, Taipei, Taiwan
| | - Hao Ho
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Jia-Hua Li
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Ming-Fang Wu
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.,Graduate Institute of Toxicology, National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Hsu-Chieh Wang
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Hsiang-Yuan Yeh
- School of Big Data Management, Soochow University, Taipei, Taiwan
| | - Shuenn-Wen Kuo
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Huei-Wen Chen
- Graduate Institute of Toxicology, National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Chao-Chi Ho
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Ker-Chau Li
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.,Department of Statistics, UCLA, Los Angeles, California, USA
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Zhang Y, Zhao Y, Li Q, Wang Y. Macrophages, as a Promising Strategy to Targeted Treatment for Colorectal Cancer Metastasis in Tumor Immune Microenvironment. Front Immunol 2021; 12:685978. [PMID: 34326840 PMCID: PMC8313969 DOI: 10.3389/fimmu.2021.685978] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/24/2021] [Indexed: 12/16/2022] Open
Abstract
The tumor immune microenvironment plays a vital role in the metastasis of colorectal cancer. As one of the most important immune cells, macrophages act as phagocytes, patrol the surroundings of tissues, and remove invading pathogens and cell debris to maintain tissue homeostasis. Significantly, macrophages have a characteristic of high plasticity and can be classified into different subtypes according to the different functions, which can undergo reciprocal phenotypic switching induced by different types of molecules and signaling pathways. Macrophages regulate the development and metastatic potential of colorectal cancer by changing the tumor immune microenvironment. In tumor tissues, the tumor-associated macrophages usually play a tumor-promoting role in the tumor immune microenvironment, and they are also associated with poor prognosis. This paper reviews the mechanisms and stimulating factors of macrophages in the process of colorectal cancer metastasis and intends to indicate that targeting macrophages may be a promising strategy in colorectal cancer treatment.
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Affiliation(s)
- Yingru Zhang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yiyang Zhao
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qi Li
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Wang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Zajkowska M, Kulczyńska-Przybik A, Dulewicz M, Safiejko K, Juchimiuk M, Konopko M, Kozłowski L, Mroczko B. Eotaxins and Their Receptor as Biomarkers of Colorectal Cancer. J Clin Med 2021; 10:jcm10122675. [PMID: 34204490 PMCID: PMC8235018 DOI: 10.3390/jcm10122675] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/03/2021] [Accepted: 06/14/2021] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies. Despite the availability of diagnostic tests, an increasing number of new cases is observed. That is why it is very important to search new markers that would show high diagnostic utility. Therefore, we made an attempt to assess the usefulness of eotaxins, as there are few studies that investigate their significance, in patients with CRC. The study included 80 subjects (CRC patients and healthy volunteers). Serum concentrations of all eotaxins were measured using a multiplexing method (Luminex), while CCR3 was measured by immunoenzymatic assay (ELISA). CRP levels were determined by immunoturbidimetry and classical tumor marker levels (CEA and CA 19-9) and were measured using chemiluminescent microparticle immunoassay (CMIA). The highest usefulness among the proteins tested showed CCR3. Its concentrations were significantly higher in the CRC group than in healthy controls. The diagnostic sensitivity, specificity, positive and negative predictive value, and the area under the ROC curve (AUC) of CCR3 were higher than those of CA 19-9. The maximum values for sensitivity, negative predictive value, and AUC were obtained for a combination of CCR3 and CRP. Our findings suggest the potential usefulness of CCR3 in the diagnosis of CRC, especially in combination with CRP or CEA.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (M.D.); (B.M.)
- Correspondence: ; Tel.: +48-686-5168; Fax: +48-686-5169
| | - Agnieszka Kulczyńska-Przybik
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (M.D.); (B.M.)
| | - Maciej Dulewicz
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (M.D.); (B.M.)
| | - Kamil Safiejko
- Maria Sklodowska-Curie Oncology Center, Department of Oncological Surgery with Specialized Cancer Treatment Units, 15-027 Bialystok, Poland; (K.S.); (M.J.); (M.K.); (L.K.)
| | - Marcin Juchimiuk
- Maria Sklodowska-Curie Oncology Center, Department of Oncological Surgery with Specialized Cancer Treatment Units, 15-027 Bialystok, Poland; (K.S.); (M.J.); (M.K.); (L.K.)
| | - Marzena Konopko
- Maria Sklodowska-Curie Oncology Center, Department of Oncological Surgery with Specialized Cancer Treatment Units, 15-027 Bialystok, Poland; (K.S.); (M.J.); (M.K.); (L.K.)
| | - Leszek Kozłowski
- Maria Sklodowska-Curie Oncology Center, Department of Oncological Surgery with Specialized Cancer Treatment Units, 15-027 Bialystok, Poland; (K.S.); (M.J.); (M.K.); (L.K.)
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (M.D.); (B.M.)
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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Fan T, Liu Y, Liu H, Wang L, Tian H, Zheng Y, Zheng B, Xue L, Tan F, Xue Q, Gao S, Li C, He J. Comprehensive analysis of a chemokine- and chemokine receptor family-based signature for patients with lung adenocarcinoma. Cancer Immunol Immunother 2021; 70:3651-3667. [PMID: 33977344 DOI: 10.1007/s00262-021-02944-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/10/2021] [Indexed: 01/12/2023]
Abstract
The clinical significance and comprehensive features of chemokines and their receptors in lung adenocarcinoma (LUAD) have not been clarified. We aimed to characterize the expression profiles of chemokine and chemokine receptor family members and construct a chemokine- and chemokine receptor-based prognosis signature. A total of 1511 patients with LUAD from seven independent cohorts were included in the study. The training set collected from The Cancer Genome Atlas (TCGA) database containing 468 cases. The validation was performed on the basis of six different cohorts downloaded from Gene Expression Omnibus (GEO) database. A five-chemokine- and chemokine receptor-(CXCL2, CXCL13, CCL26, CCL20, CX3CR1) based prognosis signature was constructed with TCGA dataset using LASSO Cox regression and Cox proportional hazards regression analysis. A multivariate analysis verified that this signature was an independent prognostic factor. The predictive value of this signature was further verified by other six independent cohorts and multiple clinical subtypes. We performed immune cell infiltration analysis and biological pathway analysis which provided more insight into this signature-related immune and inflammatory landscape and clarified the intrinsic molecular mechanism by which this signature could be used to predict clinical prognosis. Furthermore, we explored the close relationship between this signature and tumor mutation burden (TMB), neoantigen burden, PD-1, PD-L1, CTLA4, TIDE score, T cell-inflamed score. This signature provided a robust prognostic biomarker for LUAD and could serve as a predictor for immunotherapy response, which may be used as an important supplement to immunotherapy to achieve individualized tumor treatment by optimizing the prognostic management and immunotherapy for patients with LUAD.
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Affiliation(s)
- Tao Fan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.,Department of Oncology, Renmin Hospital of Wuhan University, 238th Jiefang Road, Wuhan, 430060, China
| | - Yu Liu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hengchang Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liyu Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - He Tian
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yujia Zheng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Bo Zheng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Liyan Xue
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fengwei Tan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qi Xue
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shungeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chunxiang Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. .,Department of Oncology, Renmin Hospital of Wuhan University, 238th Jiefang Road, Wuhan, 430060, China.
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Chen X, An Y, Zhang Y, Xu D, Chen T, Yang Y, Chen W, Wu D, Zhang X. CCL26 is upregulated by nab-paclitaxel in pancreatic cancer-associated fibroblasts and promotes PDAC invasiveness through activation of the PI3K/AKT/mTOR pathway. Acta Biochim Biophys Sin (Shanghai) 2021; 53:612-619. [PMID: 33764366 DOI: 10.1093/abbs/gmab032] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Indexed: 01/05/2023] Open
Abstract
Recently, the combined use of FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine plus nab-paclitaxel has significantly improved the prognosis of patients with pancreatic cancer. However, there is still a high proportion of patients who develop metastatic pancreatic cancer in the course of chemotherapy or within a short period after chemotherapy. Previous reports have shown that chemotherapy-driven cytokine storms or the direct effects of certain chemotherapeutics on stromal and/or immune cells collectively change the microenvironment of the primary tumor, thus indirectly promoting metastasis. However, the mechanism underlying chemotherapy-induced metastasis in the course of chemotherapy, and afterwards, remains elusive in pancreatic cancer. In the present study, we aimed to determine the expression of CCL26 in the pancreatic cancer-associated fibroblasts (CAFs) after nab-paclitaxel treatment and to explore the role of CCL26 in the pancreatic adenocarcinoma (PDAC) invasion. Our results showed that nab-paclitaxel increased CCL26 mRNA and protein expression levels in a dose- and time-dependent manner. Subsequently, PDAC cell lines were treated with recombinant CCL26 for 48 h. The transwell migration assay showed that recombinant CCL26 enhanced the invasion of PDAC cells. Western blot analysis showed that the protein expression levels of phospho-(p-)PI3K, p-AKT, and p-mTOR were increased by CCL26 in PDAC cells. CCL26 expressions in 95 PDAC tissues and adjacent normal tissues were evaluated using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. CCL26 was found to be overexpressed in PDAC samples, and upregulated CCL26 expression was significantly associated with advanced perineural invasion, lymph node metastasis, and poor differentiation. In summary, our results showed that nab-paclitaxel increased the expression of CCL26 in CAFs, and CCL26 enhanced the invasive potential of pancreatic cancer cells by activating the PI3K/AKT/mTOR axis. Thus, CCL26 may be a potential prognostic biomarker for pancreatic cancer.
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Affiliation(s)
- Xuemin Chen
- Department of Hepato-Pancreato-Biliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China
| | - Yong An
- Department of Hepato-Pancreato-Biliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China
| | - Yue Zhang
- Department of Hepato-Pancreato-Biliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China
| | - Dong Xu
- Department of General Surgery, Gaochun Branch, Drum Tower Hospital Affiliated to Nanjing University, Nanjing 211300, China
| | - Tongbing Chen
- Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China
| | - Yue Yang
- Department of Hepato-Pancreato-Biliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China
| | - Weibo Chen
- Department of Hepato-Pancreato-Biliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China
| | - Di Wu
- Department of Hepato-Pancreato-Biliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China
| | - Xiaoying Zhang
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China
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Han C, Zhang C, Wang H, Zhao L. Exosome-mediated communication between tumor cells and tumor-associated macrophages: implications for tumor microenvironment. Oncoimmunology 2021; 10:1887552. [PMID: 33680573 PMCID: PMC7901554 DOI: 10.1080/2162402x.2021.1887552] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Exosomes are extracellular vesicles released from numerous types of cells that are involved in multiple tumors development. Exosomes contribute to the modulation of tumor microenvironment (TME) through intercellular communication. As essential immune stromal cells in the TME, tumor-associated macrophages (TAMs) participate in tumor development by mediating angiogenesis, metastasis, chemoresistance, and immune escape. Due to communication with multiple cells in the TME, they exhibit plasticity and heterogeneity during the progress of polarization from monocytes to macrophages. Previous studies suggest that targeting TAMs is a promising therapeutic strategy; however, the detailed mechanism by which TAMs regulate tumor development still remains unclear. In this review, we provide an overview of the roles of exosomes as messengers in the communication between tumor cells and polarization of TAMs; we also describe the effects of their interaction on tumor development. Finally, we comprehensively discussed the potential application of exosomes as the promising tumor immunotherapy strategy.
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Affiliation(s)
- Chen Han
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China.,Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Cong Zhang
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hengxiao Wang
- Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Lianmei Zhao
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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40
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Tezcan G, Garanina EE, Alsaadi M, Gilazieva ZE, Martinova EV, Markelova MI, Arkhipova SS, Hamza S, McIntyre A, Rizvanov AA, Khaiboullina SF. Therapeutic Potential of Pharmacological Targeting NLRP3 Inflammasome Complex in Cancer. Front Immunol 2021; 11:607881. [PMID: 33613529 PMCID: PMC7887322 DOI: 10.3389/fimmu.2020.607881] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/17/2020] [Indexed: 12/19/2022] Open
Abstract
Introduction Dysregulation of NLRP3 inflammasome complex formation can promote chronic inflammation by increased release of IL-1β. However, the effect of NLRP3 complex formation on tumor progression remains controversial. Therefore, we sought to determine the effect of NLRP3 modulation on the growth of the different types of cancer cells, derived from lung, breast, and prostate cancers as well as neuroblastoma and glioblastoma in-vitro. Method The effect of Caspase 1 inhibitor (VX765) and combination of LPS/Nigericin on NLRP3 inflammasome activity was analyzed in A549 (lung cancer), MCF-7 (breast cancer), PC3 (prostate cancer), SH-SY5Y (neuroblastoma), and U138MG (glioblastoma) cells. Human fibroblasts were used as control cells. The effect of VX765 and LPS/Nigericin on NLRP3 expression was analyzed using western blot, while IL-1β and IL-18 secretion was detected by ELISA. Tumor cell viability and progression were determined using Annexin V, cell proliferation assay, LDH assay, sphere formation assay, transmission electron microscopy, and a multiplex cytokine assay. Also, angiogenesis was investigated by a tube formation assay. VEGF and MMPs secretion were detected by ELISA and a multiplex assay, respectively. Statistical analysis was done using one-way ANOVA with Tukey’s analyses and Kruskal–Wallis one-way analysis of variance. Results LPS/Nigericin increased NRLP3 protein expression as well as IL-1β and IL-18 secretion in PC3 and U138MG cells compared to A549, MCF7, SH-SY5Y cells, and fibroblasts. In contrast, MIF expression was commonly found upregulated in A549, PC3, SH-SY5Y, and U138MG cells and fibroblasts after Nigericin treatment. Nigericin and a combination of LPS/Nigericin decreased the cell viability and proliferation. Also, LPS/Nigericin significantly increased tumorsphere size in PC3 and U138MG cells. In contrast, the sphere size was reduced in MCF7 and SH-SY5Y cells treated with LPS/Nigericin, while no effect was detected in A549 cells. VX765 increased secretion of CCL24 in A549, MCF7, PC3, and fibroblasts as well as CCL11 and CCL26 in SH-SY5Y cells. Also, VX765 significantly increased the production of VEGF and MMPs and stimulated angiogenesis in all tumor cell lines. Discussion Our data suggest that NLRP3 activation using Nigericin could be a novel therapeutic approach to control the growth of tumors producing a low level of IL-1β and IL-18.
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Affiliation(s)
- Gulcin Tezcan
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,Department of Fundamental Sciences, Faculty of Dentistry, Bursa Uludag University, Bursa, Turkey
| | - Ekaterina E Garanina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Mohammad Alsaadi
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Zarema E Gilazieva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Ekaterina V Martinova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Maria I Markelova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Svetlana S Arkhipova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Shaimaa Hamza
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Alan McIntyre
- Centre for Cancer Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Svetlana F Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.,Department of Microbiology and Immunology, University of Nevada, Reno, NV, United States
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Su P, Lai W, Liu L, Zeng Y, Xu H, Lan Q, Chu Z, Chu Z. Mesenchymal and Phosphatase of Regenerating Liver-3 Status in Circulating Tumor Cells May Serve as a Crucial Prognostic Marker for Assessing Relapse or Metastasis in Postoperative Patients With Colorectal Cancer. Clin Transl Gastroenterol 2020; 11:e00265. [PMID: 33512811 PMCID: PMC7743843 DOI: 10.14309/ctg.0000000000000265] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Circulating tumor cells (CTCs) and phosphatase of regenerating liver-3 (PRL-3) have been considered to be significant prognostic indicators in metastatic colorectal cancer (CRC). This study discusses the prognostic significance of mesenchymal CTCs with PRL-3 (M+ PRL-3+ CTCs) in postoperative patients with CRC. METHODS We detected CTC subtypes (including epithelial CTCs, biphenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs) and PRL-3 in CTCs from the peripheral blood samples of 156 patients. Receiver operating characteristic curve analysis, Kaplan-Meier analysis, and Cox proportional hazards regression analysis were performed to identify the prognostic value of mesenchymal CTCs with PRL-3+. Immunohistochemistry was used to detect the expression of PRL-3 in tumor tissues from some of the patients to explore the connection between CTCs and tissues. RESULTS All CTCs were positive in all samples, both mesenchymal CTCs and PRL-3-positive cells. The count of mesenchymal and PRL-3+ CTCs was significantly associated with recurrence, and the optimal cutoff value was 2 (area under the curve = 0.690, P < 0.001). In addition, these patients had a significantly shorter median disease-free survival than those who did not fulfill the criteria (8.5 vs 24 months, P < 0.001) according to multivariable and multinomial logistic regression. Immunohistochemistry was applied to explore the associations between PRL-3 expression and significant prognostic risk factors, including recurrence (R = 0.566; P < 0.001), and M+ PRL-3+ status in CTCs (R = 0.452; P = 0.001). DISCUSSION The status of M+ PRL-3+ in CTCs may serve as a crucial prognostic marker for assessing clinical outcomes in CRC.
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Affiliation(s)
- PengWei Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Lai
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lu Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yujie Zeng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Heyang Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiusheng Lan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ziqiang Chu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhonghua Chu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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Zhao XT, Zhu Y, Zhou JF, Gao YJ, Liu FZ. Development of a novel 7 immune-related genes prognostic model for oral cancer: A study based on TCGA database. Oral Oncol 2020; 112:105088. [PMID: 33220636 DOI: 10.1016/j.oraloncology.2020.105088] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/16/2020] [Accepted: 10/31/2020] [Indexed: 12/24/2022]
Abstract
Oral squamous cell carcinoma (OSCC) is an aggressive tumor whose prognosis has little improvement in the last three decades. Various immune-related genes have been suggested as significant roles in the development and progression of malignant cancers. In this study, we acquired and integrated differentially expressed genes of OSCC patients, including immune-related genes and transcription factors (TFs), from The Cancer Genome Atlas (TCGA) database. TF-mediated network was established to exploring the regulatory mechanisms of prognostic immune-related genes. A 7 immune-related genes prognostic model for OSCC was obtained, including CGB8, CTLA4, TNFRSF19, CCL26, NRG1, TPM2 and PLAU, which was further proved to be an independent prognostic indicator after adjusting for other clinical factors. The immune-related genes prognostic index was significantly negatively correlated to the infiltration abundances of B cells (P < 0.05) and CD8+ T cells (P < 0.05). The novel proposed immune-based prognostic model not only provided a promising biomarker and a way to monitor the long-term treatment of OSCC, but also gave a new insight into a potential immunotherapy strategy.
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Affiliation(s)
- Xiao-Tong Zhao
- Department of Otorhinolaryngology and Head and Neck Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
| | - Yan Zhu
- Department of Pathology, the People's Hospital of Jiangsu Province (The First Affiliated Hospital of Nanjing Medial University), Nanjing, Jiangsu 210029, China
| | | | | | - Fang-Zhou Liu
- Department of Head & Neck Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210029, China.
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Donlon NE, Sheppard A, Davern M, O’Connell F, Phelan JJ, Power R, Nugent T, Dinneen K, Aird J, Greene J, Nevins Selvadurai P, Bhardwaj A, Foley EK, Ravi N, Donohoe CL, Reynolds JV, Lysaght J, O’Sullivan J, Dunne MR. Linking Circulating Serum Proteins with Clinical Outcomes in Esophageal Adenocarcinoma-An Emerging Role for Chemokines. Cancers (Basel) 2020; 12:3356. [PMID: 33202734 PMCID: PMC7698106 DOI: 10.3390/cancers12113356] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/10/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023] Open
Abstract
Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis and incidence is increasing rapidly in the Western world. Multi-modal treatment has improved survival outcomes but only for a minority of patients. Currently no markers have been identified to predict treatment response. This study investigated the association between clinical outcomes and pre-treatment levels of 54 serum proteins in n = 80 patients with EAC. Low tumor regression grade (TRG), corresponding to a favorable treatment response, was linked to prolonged overall survival (OS). CCL4 was higher in patients with a favorable treatment response, while Tie2 and CRP were higher in poor responders. Elevated CCL22 and CCL26 was associated with improved OS, while elevated IL-10 showed a negative association. CCL3, CCL4, IL-1α and IL-12/IL23p40 were highest in individuals with no adverse features of tumor biology, whereas levels of Tie2 and VEGF were lowest in this cohort. CCL4 was also elevated in patients with high tumor lymphocyte infiltration. Comparison of matched pre- and post-treatment serum (n = 28) showed a large reduction in VEGFC, and a concomitant increase in other cytokines, including CCL4. These data link several serum markers with clinical outcomes, highlighting an important role for immune cell trafficking in the EAC antitumor immune response.
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Affiliation(s)
- Noel E. Donlon
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Andrew Sheppard
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Maria Davern
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Fiona O’Connell
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - James J. Phelan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Robert Power
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Timothy Nugent
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Kate Dinneen
- Department of Histopathology, St James’s Hospital, Dublin 8, Ireland; (K.D.); (J.A.)
| | - John Aird
- Department of Histopathology, St James’s Hospital, Dublin 8, Ireland; (K.D.); (J.A.)
| | - John Greene
- Department of Medical Oncology, St James’s Hospital, Dublin 8, Ireland; (J.G.); (P.N.S.)
| | - Paul Nevins Selvadurai
- Department of Medical Oncology, St James’s Hospital, Dublin 8, Ireland; (J.G.); (P.N.S.)
| | - Anshul Bhardwaj
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Emma K. Foley
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Narayanasamy Ravi
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Claire L. Donohoe
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - John V. Reynolds
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Joanne Lysaght
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Jacintha O’Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
| | - Margaret R. Dunne
- Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James’s Hospital, Dublin 8, Ireland; (N.E.D.); (A.S.); (M.D.); (F.O.); (J.J.P.); (R.P.); (T.N.); (A.B.); (E.K.F.); (N.R.); (C.L.D.); (J.V.R.); (J.L.); (J.O.)
- Trinity St James’s Cancer Institute, St James’s Hospital, Dublin 8, Ireland
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Leiphrakpam PD, Lazenby AJ, Smith LM, Brattain MG, Black JD, Wang J, Are C. Correlation of PRL3 expression with colorectal cancer progression. J Surg Oncol 2020; 123:42-51. [PMID: 33179291 DOI: 10.1002/jso.26253] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 08/19/2020] [Accepted: 09/27/2020] [Indexed: 01/13/2023]
Abstract
OBJECTIVES To evaluate the relationship between phosphatase of regenerating liver 3 (PRL3) expression and clinical outcome in colorectal cancer (CRC). BACKGROUND PRL3, a protein tyrosine phosphatase functions as one of the key regulatory enzymes of various signal transduction pathways. PRL3 is highly expressed in a majority of cancers and is a novel potential therapeutic target. METHODS PRL3 expression was evaluated by immunohistochemistry in 167 patients with CRC, 37 patients with no disease, and 26 patients with metastatic CRC (mCRC). Phosphorylated Akt at serine 473 (p-Akt S473) expression was also evaluated by immunohistochemistry in mCRC patients. RESULTS High expression of PRL3 was correlated with CRC progression, and every one unit increase in PRL3 level contributed to an increase in the rate of death by 1%-1.7%. PRL3 expression was significantly higher in liver metastases compared with primary tumors and showed a significant positive correlation with the expression level of p-Akt S473. CONCLUSION PRL3 expression levels associated with CRC progression and metastasis, and positively correlated with activated Akt level in mCRC. Together, these findings indicated that PRL3 might be a potential marker for increased risk of CRC-specific tumor burden and identify PRL3 as an attractive therapeutic target for mCRC treatment.
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Affiliation(s)
- Premila D Leiphrakpam
- Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Audrey J Lazenby
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Lynette M Smith
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Michael G Brattain
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Jennifer D Black
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Jing Wang
- Department of Cancer Biology and Genetics, College of Medicine, Ohio State University, Columbus, Ohio, USA
| | - Chandrakanth Are
- Division of Surgical Oncology, Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
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CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4. Int J Mol Sci 2020; 21:ijms21218412. [PMID: 33182504 PMCID: PMC7665155 DOI: 10.3390/ijms21218412] [Citation(s) in RCA: 249] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/06/2020] [Accepted: 11/08/2020] [Indexed: 12/14/2022] Open
Abstract
CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all known human CC chemokines in the hallmarks of cancer, and this paper aims at filling this gap. The first part of this review discusses the importance of CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 in cancer. Here, we discuss the significance of CCL2 (MCP-1), CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL22, CCL23, CCL24, and CCL26. The presentation of each chemokine includes its physiological function and then the role in tumor, including proliferation, drug resistance, migration, invasion, and organ-specific metastasis of tumor cells, as well as the effects on angiogenesis and lymphangiogenesis. We also discuss the effects of each CC chemokine on the recruitment of cancer-associated cells to the tumor niche (eosinophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), regulatory T cells (Treg)). On the other hand, we also present the anti-cancer properties of CC chemokines, consisting in the recruitment of tumor-infiltrating lymphocytes (TIL).
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Karin N. The Development and Homing of Myeloid-Derived Suppressor Cells: From a Two-Stage Model to a Multistep Narrative. Front Immunol 2020; 11:557586. [PMID: 33193327 PMCID: PMC7649122 DOI: 10.3389/fimmu.2020.557586] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells. Under normal conditions, they differentiate into macrophages, dendritic cells, and granulocytes. Under pathological conditions, such as chronic inflammation, or cancer, they tend to maintain their immature state as immature myeloid cells that, within the tumor microenvironment, become suppressor cells and assist tumor escape from immune eradication. MDSC are comprised of two major subsets: monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC). Monocytic myeloid cells give rise to monocytic cells, whereas PMN-MDSC share similarities with neutrophils. Based on their biological activities, a two-stage model that includes the mobilization of the periphery as myeloid cells and their activation within the tumor microenvironment converting them into suppressor cells was previously suggested by D. Gabrilovich. From the migratory viewpoint, we are suggesting a more complex setup. It starts with crosstalk between the tumor site and the hematopoietic stem and progenitor cells (HSPCs) at the bone marrow (BM) and secondary lymphatic organs, resulting in rapid myelopoiesis followed by mobilization to the blood. Although myelopoiesis is coordinated by several cytokines and transcription factors, mobilization is selectively directed by chemokine receptors and may differ between M-MDSC and PMN-MDSC. These myeloid cells may then undergo further expansion at these secondary lymphatic organs and then home to the tumor site. Finally, selective homing of T cell subsets has been associated with retention at the target organs directed by adhesion molecules or chemokine receptors. The possible relevance to myeloid cells is still speculative but is discussed.
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Affiliation(s)
- Nathan Karin
- Department of Immunology, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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Korbecki J, Kojder K, Barczak K, Simińska D, Gutowska I, Chlubek D, Baranowska-Bosiacka I. Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor-A Literature Review. Int J Mol Sci 2020; 21:ijms21165647. [PMID: 32781743 PMCID: PMC7460668 DOI: 10.3390/ijms21165647] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023] Open
Abstract
Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we have gathered all the available data about the impact of hypoxia on β chemokines. In the introduction, we present the chronic (continuous, non-interrupted) and cycling (intermittent, transient) hypoxia together with the mechanisms of activation of hypoxia inducible factors (HIF-1 and HIF-2) and NF-κB. Then we describe the effect of hypoxia on the expression of chemokines with the CC motif: CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 together with CC chemokine receptors: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10. To better understand the effect of hypoxia on neoplastic processes and changes in the expression of the described proteins, we summarize the available data in a table which shows the effect of individual chemokines on angiogenesis, lymphangiogenesis, and recruitment of eosinophils, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and tumor-associated macrophages (TAM) to a tumor niche.
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Affiliation(s)
- Jan Korbecki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
| | - Klaudyna Kojder
- Department of Anaesthesiology and Intensive Care, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-281 Szczecin, Poland;
| | - Katarzyna Barczak
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Donata Simińska
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
- Correspondence: ; Tel.: +48-914661515; Fax: +48-914661516
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Zajkowska M, Mroczko B. Eotaxins and Their Receptor in Colorectal Cancer-A Literature Review. Cancers (Basel) 2020; 12:cancers12061383. [PMID: 32481530 PMCID: PMC7352276 DOI: 10.3390/cancers12061383] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/19/2020] [Accepted: 05/27/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies in the world, with a global incidence of almost 2 million new cases every year. Despite the availability of many diagnostic tests, including laboratory tests and molecular diagnostics, an increasing number of new cases is observed. Thus, it is very important to search new markers that would show high diagnostic sensitivity and specificity in the detection of colorectal cancer in early stages of the disease. Eotaxins are proteins that belong to the cytokine group-small molecules with a variety of applications. Their main role is the activation of basophils and eosinophils involved in inflammatory processes. Therefore, we performed an extensive search of the literature pertaining to our investigation via the MEDLINE/PubMed database. On the basis of available literature, we can assume that eotaxins accumulate in cancer cells in the course of CRC. This leads to a decrease in the chemotaxis of eosinophils, which are effector immune cells with anti-tumor activity. This may explain a decrease in their number as a defense mechanism of cancer cells against their destruction and may be useful when attempting anti-tumor therapy with the use of chemokines.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
- Correspondence: ; Tel.: +48-686-5168; Fax: +48-686-5169
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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Fractalkine/CX3CL1 in Neoplastic Processes. Int J Mol Sci 2020; 21:ijms21103723. [PMID: 32466280 PMCID: PMC7279446 DOI: 10.3390/ijms21103723] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023] Open
Abstract
Fractalkine/CX3C chemokine ligand 1 (CX3CL1) is a chemokine involved in the anticancer function of lymphocytes-mainly NK cells, T cells and dendritic cells. Its increased levels in tumors improve the prognosis for cancer patients, although it is also associated with a poorer prognosis in some types of cancers, such as pancreatic ductal adenocarcinoma. This work focuses on the 'hallmarks of cancer' involving CX3CL1 and its receptor CX3CR1. First, we describe signal transduction from CX3CR1 and the role of epidermal growth factor receptor (EGFR) in this process. Next, we present the role of CX3CL1 in the context of cancer, with the focus on angiogenesis, apoptosis resistance and migration and invasion of cancer cells. In particular, we discuss perineural invasion, spinal metastasis and bone metastasis of cancers such as breast cancer, pancreatic cancer and prostate cancer. We extensively discuss the importance of CX3CL1 in the interaction with different cells in the tumor niche: tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC) and microglia. We present the role of CX3CL1 in the development of active human cytomegalovirus (HCMV) infection in glioblastoma multiforme (GBM) brain tumors. Finally, we discuss the possible use of CX3CL1 in immunotherapy.
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50
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Li L, Wang XL, Lei Q, Sun CZ, Xi Y, Chen R, He YW. Comprehensive immunogenomic landscape analysis of prognosis-related genes in head and neck cancer. Sci Rep 2020; 10:6395. [PMID: 32286381 PMCID: PMC7156482 DOI: 10.1038/s41598-020-63148-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancer is the sixth most common malignancy around the world, and 90% of cases are squamous cell carcinomas. In this study, we performed a systematic investigation of the immunogenomic landscape to identify prognostic biomarkers for head and neck squamous cell carcinoma (HNSCC). We analyzed the expression profiles of immune-related genes (IRGs) and clinical characteristics by interrogating RNA-seq data from 527 HNSCC patients in the cancer genome atlas (TCGA) dataset, including 41 HPV+ and 486 HPV- samples. We found that differentially expressed immune genes were closely associated with patient prognosis in HNSCC by comparing the differences in gene expression between cancer and normal samples and performing survival analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to annotate the biological functions of the differentially expressed immunogenomic prognosis-related genes. Two additional cohorts from the Oncomine database were used for validation. 65, 56 differentially expressed IRGs was associated with clinical prognosis in total and HPV- samples, respectively. Furthermore, we extracted 10, 11 prognosis-related IRGs from 65, 56 differentially expressed IRGs, respectively. They were significantly correlated with clinical prognosis and used to construct the prognosis prediction models. The multivariable ROC curves (specifically, the AUC) were used to measure the accuracy of the prognostic models. These genes were mainly enriched in several gene ontology (GO) terms related to immunocyte migration and receptor and ligand activity. KEGG pathway analysis revealed enrichment of pathways related to cytokine-cytokine receptor interactions, which are primarily involved in biological processes. In addition, we identified 63 differentially expressed transcription factors (TFs) from 4784 differentially expressed genes, and 16 edges involving 18 nodes were formed in the regulatory network between differentially expressed TFs and the high-risk survival-associated IRGs. B cell and CD4 T cell infiltration levels were significantly negatively correlated with the expression of prognosis-related immune genes regardless of HPV status. In conclusion, this comprehensive analysis identified the prognostic IRGs as potential biomarkers, and the model generated in this study may enable an accurate prediction of survival.
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Affiliation(s)
- Lei Li
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Xiao-Li Wang
- Radiation Therapy Center, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Qian Lei
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Chuan-Zheng Sun
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Yan Xi
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Ran Chen
- Department of Head and Neck Surgery Section II, the Third Affiliated Hospital of Kunming Medical University, 519 Kunzhou Road, Kunming, China
| | - Yong-Wen He
- Department of Dental Research, The Affiliated Stomatological Hospital of Kunming Medical University, Yunnan, China.
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