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1
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Zhou W, Ruan H, Zhu L, Chen S, Yang M. Unveiling a Novel Glioblastoma Deep Molecular Profiling: Insight into the Cancer Cell Differentiation-Related Mechanisms. ACS OMEGA 2025; 10:10230-10250. [PMID: 40124014 PMCID: PMC11923693 DOI: 10.1021/acsomega.4c09586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/27/2025] [Accepted: 02/19/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND the sophisticated cellular heterogeneity of cell populations in glioblastoma (GBM) has been a key factor influencing tumor progression and response to therapy. The lack of more precise stratification based on cellular differentiation status poses a great challenge to therapeutic strategies. MATERIALS AND METHODS harnessing the bulk multiomics and single-nucleus RNA sequencing data available from the National Center for Biotechnology Information (NCBI) and The Cancer Genome Atlas (TCGA) Program repositories, we developed a novel and accurate GBM risk classification using an ensemble consensus clustering approach based on the junction of prognosis and trajectory analysis. Comprehensive cluster labeling and multiomics data characterization were also performed. RESULTS a novel GBM stratification model was constructed using 45 malignant cell fate genes: (a) energy metabolism-enhanced-type GBM; (b) invasion-enhanced-type GBM; (c) invasion-attenuated-type GBM; and (d) glycolysis-dominant energy metabolism-enhanced-type GBM. The biological plausibility of the model was verified through a range of comprehensive analyses of multiomics data, showing that cases with invasion-attenuated-type were the best prognosis and energy metabolism-enhanced-type the poorest. CONCLUSIONS the study has uncovered GBM complex cellular heterogeneity and a differentiated hierarchy of cell populations underlying tumorigenesis. This precise stratification system provided implications for further studies of individual therapies.
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Affiliation(s)
- Weili Zhou
- Department of Radiology, Henan Provincial People’s Hospital & the
People’s Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Hongtao Ruan
- Department of Radiology, Henan Provincial People’s Hospital & the
People’s Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Lihua Zhu
- Department of Radiology, Henan Provincial People’s Hospital & the
People’s Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Shunqiang Chen
- Department of Radiology, Henan Provincial People’s Hospital & the
People’s Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
| | - Muyi Yang
- Department of Radiology, Henan Provincial People’s Hospital & the
People’s Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
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2
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Xiao LY, Su YL, Huang SY, Chen YH, Hsueh PR. Chitinase 3-like-1 Expression in the Microenvironment Is Associated with Neutrophil Infiltration in Bladder Cancer. Int J Mol Sci 2023; 24:15990. [PMID: 37958973 PMCID: PMC10648396 DOI: 10.3390/ijms242115990] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
Bladder cancer is a common cancer with well-established therapeutic strategies. However, recurrence occurs in 50% of patients with non-muscle-invasive bladder cancer, and 20% of patients progress to muscle-invasive bladder cancer. The 5-year survival rate for muscle-invasive bladder cancer patients is disappointingly low, ranging from 36% to 48%. A molecular marker of interest is chitinase 3-like-1 (CHI3L1), which is elevated in various cancers, including bladder cancer. In addition to its role in cancer cells, CHI3L1 also has regulatory abilities in immune cells. Neutrophil infiltration has been shown to positively correlate with overall survival, progression-free survival, and relapse-free survival in bladder cancer patients. However, the relationship between CHI3L1 and neutrophils remain poorly understood. Therefore, this study investigated the relationship between CHI3L1 level and protumor neutrophil infiltration in bladder cancer. We analyzed the GSE128959 dataset and the data of a bladder cancer cohort undergoing chemotherapy. We observed higher expression of CHI3L1 in bladder cancer patients with invasive or chemotherapy-resistance. Our results revealed a positive correlation between CHI3L1 expression and protumor neutrophil infiltration. Elevated CHI3L1 expression was associated with genes which were related to the recruitment and infiltration of neutrophils. Consequently, CHI3L1 may serve as a novel evaluation factor for the degree of neutrophil infiltration in advanced bladder cancer in those scheduled for chemotherapy.
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Affiliation(s)
- Ling-Yi Xiao
- Department of Laboratory Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung 404327, Taiwan;
| | - Yu-Li Su
- Division of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung 83301, Taiwan
- Genomic & Proteomic Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Shih-Yu Huang
- Division of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung 83301, Taiwan
| | - Yi-Hua Chen
- Division of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung 83301, Taiwan
| | - Po-Ren Hsueh
- Department of Laboratory Medicine, China Medical University Hospital, School of Medicine, China Medical University, Taichung 404327, Taiwan;
- Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan
- Ph.D. Program for Aging, School of Medicine, China Medical University, Taichung 404327, Taiwan
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3
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De Robertis M, Greco MR, Cardone RA, Mazza T, Marzano F, Mehterov N, Kazakova M, Belev N, Tullo A, Pesole G, Sarafian V, Signori E. Upregulation of YKL-40 Promotes Metastatic Phenotype and Correlates with Poor Prognosis and Therapy Response in Patients with Colorectal Cancer. Cells 2022; 11:cells11223568. [PMID: 36428997 PMCID: PMC9688424 DOI: 10.3390/cells11223568] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/28/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
YKL-40 is a heparin- and chitin-binding glycoprotein that belongs to the family of glycosyl hydrolases but lacks enzymatic properties. It affects different (patho)physiological processes, including cancer. In different tumors, YKL-40 gene overexpression has been linked to higher cell proliferation, angiogenesis, and vasculogenic mimicry, migration, and invasion. Because, in colorectal cancer (CRC), the serological YKL-40 level may serve as a risk predictor and prognostic biomarker, we investigated the underlying mechanisms by which it may contribute to tumor progression and the clinical significance of its tissue expression in metastatic CRC. We demonstrated that high-YKL-40-expressing HCT116 and Caco2 cells showed increased motility, invasion, and proliferation. YKL-40 upregulation was associated with EMT signaling activation. In the AOM/DSS mouse model, as well as in tumors and sera from CRC patients, elevated YKL-40 levels correlated with high-grade tumors. In retrospective analyses of six independent cohorts of CRC patients, elevated YKL-40 expression correlated with shorter survival in patients with advanced CRC. Strikingly, high YKL-40 tissue levels showed a predictive value for a better response to cetuximab, even in patients with stage IV CRC and mutant KRAS, and worse sensitivity to oxaliplatin. Taken together, our findings establish that tissue YKL-40 overexpression enhances CRC metastatic potential, highlighting this gene as a novel prognostic candidate, a predictive biomarker for therapy response, and an attractive target for future therapy in CRC.
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Affiliation(s)
- Mariangela De Robertis
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘A. Moro’, 70125 Bari, Italy
- Correspondence: (M.D.R.); (E.S.); Tel.: +39-06-4993-4232 (E.S.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘A. Moro’, 70125 Bari, Italy
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘A. Moro’, 70125 Bari, Italy
| | - Tommaso Mazza
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Flaviana Marzano
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy
| | - Nikolay Mehterov
- Department of Medical Biology, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute at Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
| | - Maria Kazakova
- Department of Medical Biology, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute at Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
| | - Nikolay Belev
- University Hospital Eurohospital, 4000 Plovdiv, Bulgaria
- Department of Propedeutics of Surgical Diseases, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
| | - Apollonia Tullo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy
| | - Graziano Pesole
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari ‘A. Moro’, 70125 Bari, Italy
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy
| | - Victoria Sarafian
- Department of Medical Biology, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute at Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
| | - Emanuela Signori
- Laboratory of Molecular Pathology and Experimental Oncology, Institute of Translational Pharmacology, Consiglio Nazionale delle Ricerche, 00133 Rome, Italy
- Correspondence: (M.D.R.); (E.S.); Tel.: +39-06-4993-4232 (E.S.)
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4
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Wang J, Qi S, Zhu YB, Ding L. Prognostic value of YKL-40 in colorectal carcinoma patients: A meta-analysis. World J Clin Cases 2022; 10:2184-2193. [PMID: 35321165 PMCID: PMC8895163 DOI: 10.12998/wjcc.v10.i7.2184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/25/2021] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In recent years, the predictive role of YKL-40 for long-term survival in colorectal cancer patients has been gradually investigated. However, whether it is a reliable and valuable prognostic indicator for patients with colorectal carcinoma has not been verified. AIM To identify the prognostic value of serum/plasma concentration of YKL-40 or expression status of YKL-40 in tumor cells in colorectal carcinoma patients. METHODS Several electronic databases including the PubMed, EMBASE, Web of Science, CNKI, VIP and WanFang were searched for relevant studies. The hazard ratios (HR) and 95% confidence intervals (CI) were combined and the primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), respectively. All statistical analysis were conducted by STATA 15.0 software. RESULTS A total of nine studies involving 2545 patients were included. The pooled results indicated that YKL-40 was significantly associated with poor OS (HR = 1.80, 95%CI: 1.32-2.45, P < 0.001) and PFS (HR = 1.62, 95%CI: 1.22-2.16, P = 0.001). Subgroup analysis stratified by the treatment, tumor type and source of YKL-40 showed similar results. CONCLUSION Elevated serum/plasma concentration of YKL-40 or positive expression in tumor cells was related with worse prognosis of colorectal carcinoma patients. YKL-40 might serve as a novel and reliable indicator for the evaluation of prognosis in colorectal cancer.
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Affiliation(s)
- Jian Wang
- Colorectal Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Shi Qi
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Yu-Bing Zhu
- Colorectal Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Lei Ding
- Colorectal Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
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5
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Wang S, Chen S, Jin M, Hu M, Huang W, Jiang Z, Yang J, Zhang Y, Wu H, Hu Y, He W, Fu L. Diagnostic and prognostic value of serum Chitinase 3-like protein 1 in hepatocellular carcinoma. J Clin Lab Anal 2022; 36:e24234. [PMID: 35034385 PMCID: PMC8841184 DOI: 10.1002/jcla.24234] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/17/2021] [Accepted: 12/29/2021] [Indexed: 12/24/2022] Open
Abstract
The serum Chitinase 3‐like protein 1 (CHI3L1) protein level can distinguish the stages of liver fibrosis to a great extent. However, the diagnostic and prognostic significance of serum CHI3L1 in hepatocellular carcinoma (HCC) is not clarified. To evaluate the diagnostic and prognostic value of CHI3L1 in HCC, a total of 128 HCC patients treated in the HwaMei Hospital, University of Chinese Academy of Sciences, from December 2018 to April 2020 were collected retrospectively. Matched age and gender subjects, 40 patients with liver cirrhosis, 40 patients with chronic hepatitis, and 40 healthy subjects were enrolled in the control group. The relevant clinical laboratory and examination data and the overall survival time (OS) of the HCC patients were collected. The serum CHI3L1 expression level is related to α‐fetoprotein (AFP), tumor‐node‐metastasis (TNM) stage, maximum tumor diameter, liver cirrhosis, and HCC patient's OS (p < 0.05). The area under the curve (AUC) of CHI3L1 was 0.7875 with the cutoff value of 91.36 ng/ml. Combining the serum CHI3L1 and α‐fetoprotein (AFP) by a binary logistic regression model can increase the diagnostic sensitivity to 97.5%. Multivariate Cox regression analysis indicated that CHI3L1 is an independent prognostic factor in patients with HCC.
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Affiliation(s)
- Shuwei Wang
- Department of Infection and Hepatology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Medical School of Ningbo University, Ningbo, China
| | - Shixiang Chen
- Department of Hepatology, Mingzhou Hospital of Zhejiang University, Ningbo, China
| | - Ming Jin
- Medical School of Ningbo University, Ningbo, China
| | - Mengyuan Hu
- Department of Infection and Hepatology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Medical School of Ningbo University, Ningbo, China
| | - Weiguang Huang
- Department of International Health Care Center, Mingzhou Hospital of Zhejiang University, Ningbo, China
| | - Zhenluo Jiang
- Department of Emergency, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Jianuo Yang
- Medical School of Ningbo University, Ningbo, China
| | | | - Haoming Wu
- Medical School of Ningbo University, Ningbo, China
| | - Yaoren Hu
- Department of Infection and Hepatology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Medical School of Ningbo University, Ningbo, China.,Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, China.,Ningbo Clinical Research Center for Digestive System tumors, Ningbo, China
| | - Weixin He
- Department of Liver Disease and Infection, 906 Hospital of PLA, Ningbo, China
| | - Liyun Fu
- Department of Infection and Hepatology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Medical School of Ningbo University, Ningbo, China.,Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, China.,Ningbo Clinical Research Center for Digestive System tumors, Ningbo, China
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6
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Yang PS, Yu MH, Hou YC, Chang CP, Lin SC, Kuo IY, Su PC, Cheng HC, Su WC, Shan YS, Wang YC. Targeting protumor factor chitinase-3-like-1 secreted by Rab37 vesicles for cancer immunotherapy. Am J Cancer Res 2022; 12:340-361. [PMID: 34987649 PMCID: PMC8690922 DOI: 10.7150/thno.65522] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/26/2021] [Indexed: 02/07/2023] Open
Abstract
Background: Chitinase 3-like-1 (CHI3L1) is a secretion glycoprotein associated with the immunosuppressive tumor microenvironment (TME). The secretory mode of CHI3L1 makes it a promising target for cancer treatment. We have previously reported that Rab37 small GTPase mediates secretion of IL-6 in macrophages to promote cancer progression, whereas the roles of Rab37 in the intracellular trafficking and exocytosis of CHI3L1 are unclear. Methods: We examined the concentration of CHI3L1 in the culture medium of splenocytes and bone marrow derived macrophages (BMDMs) from wild-type or Rab37 knockout mice, and macrophage or T cell lines expressing wild type, active GTP-bound or inactive GDP-bound Rab37. Vesicle isolation, total internal reflection fluorescence microscopy, and real-time confocal microscopy were conducted. We developed polyclonal neutralizing-CHI3L1 antibodies (nCHI3L1 Abs) to validate the therapeutic efficacy in orthotopic lung, pancreas and colon cancer allograft models. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37 and CHI3L1, and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from cancer patients. Results: We demonstrate a novel secretion mode of CHI3L1 mediated by the small GTPase Rab37 in T cells and macrophages. Rab37 mediated CHI3L1 intracellular vesicle trafficking and exocytosis in a GTP-dependent manner, which is abolished in the splenocytes and BMDMs from Rab37 knockout mice and attenuated in macrophage or T cell lines expressing the inactive Rab37. The secreted CHI3L1 activated AKT, ß-catenin and NF-κB signal pathways in cancer cells and macrophages to foster a protumor TME characterized by activating M2 macrophages and increasing the population of regulatory T cells. Our developed nCHI3L1 Abs showed the dual properties of reducing tumor growth/metastases and eliciting an immunostimulatory TME in syngeneic orthotopic lung, pancreas and colon tumor models. Clinically, high plasma level or intratumoral expression of CHI3L1 correlated with poor survival in 161 lung cancer, 155 pancreatic cancer and 180 colon cancer patients. Conclusions: These results provide the first evidence that Rab37 mediates CHI3L1 secretion in immune cells and highlight nCHI3L1 Abs that can simultaneously target both cancer cells and tumor microenvironment.
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7
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Mehta AK, Kadel S, Townsend MG, Oliwa M, Guerriero JL. Macrophage Biology and Mechanisms of Immune Suppression in Breast Cancer. Front Immunol 2021; 12:643771. [PMID: 33968034 PMCID: PMC8102870 DOI: 10.3389/fimmu.2021.643771] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 02/17/2021] [Indexed: 12/14/2022] Open
Abstract
Macrophages are crucial innate immune cells that maintain tissue homeostasis and defend against pathogens; however, their infiltration into tumors has been associated with adverse outcomes. Tumor-associated macrophages (TAMs) represent a significant component of the inflammatory infiltrate in breast tumors, and extensive infiltration of TAMs has been linked to poor prognosis in breast cancer. Here, we detail how TAMs impede a productive tumor immunity cycle by limiting antigen presentation and reducing activation of cytotoxic T lymphocytes (CTLs) while simultaneously supporting tumor cell survival, angiogenesis, and metastasis. There is an urgent need to overcome TAM-mediated immune suppression for durable anti-tumor immunity in breast cancer. To date, failure to fully characterize TAM biology and classify multiple subsets has hindered advancement in therapeutic targeting. In this regard, the complexity of TAMs has recently taken center stage owing to their subset diversity and tightly regulated molecular and metabolic phenotypes. In this review, we reveal major gaps in our knowledge of the functional and phenotypic characterization of TAM subsets associated with breast cancer, before and after treatment. Future work to characterize TAM subsets, location, and crosstalk with neighboring cells will be critical to counteract TAM pro-tumor functions and to identify novel TAM-modulating strategies and combinations that are likely to enhance current therapies and overcome chemo- and immuno-therapy resistance.
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Affiliation(s)
- Anita K Mehta
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Sapana Kadel
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Madeline G Townsend
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Madisson Oliwa
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Jennifer L Guerriero
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
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8
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Williams MM, Spoelstra NS, Arnesen S, O'Neill KI, Christenson JL, Reese J, Torkko KC, Goodspeed A, Rosas E, Hanamura T, Sams SB, Li Z, Oesterreich S, Riggins RB, Jacobsen BM, Elias A, Gertz J, Richer JK. Steroid Hormone Receptor and Infiltrating Immune Cell Status Reveals Therapeutic Vulnerabilities of ESR1-Mutant Breast Cancer. Cancer Res 2020; 81:732-746. [PMID: 33184106 DOI: 10.1158/0008-5472.can-20-1200] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 09/17/2020] [Accepted: 11/09/2020] [Indexed: 11/16/2022]
Abstract
Mutations in ESR1 that confer constitutive estrogen receptor alpha (ER) activity in the absence of ligand are acquired by ≥40% of metastatic breast cancers (MBC) resistant to adjuvant aromatase inhibitor (AI) therapy. To identify targetable vulnerabilities in MBC, we examined steroid hormone receptors and tumor-infiltrating immune cells in metastatic lesions with or without ER mutations. ER and progesterone receptor (PR) were significantly lower in metastases with wild-type (WT) ER compared with those with mutant ER, suggesting that metastases that evade AI therapy by mechanism(s) other than acquiring ER mutations lose dependency on ER and PR. Metastases with mutant ER had significantly higher T regulatory and Th cells, total macrophages, and programmed death ligand-1 (PD-L1)-positive immune-suppressive macrophages than those with WT ER. Breast cancer cells with CRISPR-Cas9-edited ER (D538G, Y537S, or WT) and patient-derived xenografts harboring mutant or WT ER revealed genes and proteins elevated in mutant ER cells, including androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and IFN-stimulated genes (ISG). Targeting these proteins blunted the selective advantage of ER-mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard-of-care fulvestrant or other selective ER degraders when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy. SIGNIFICANCE: Targetable alterations in MBC, including AR, CHI3L1, and ISG, arise following estrogen-deprivation, and ER-mutant metastases may respond to immunotherapies due to elevated PD-L1+ macrophages.See related article by Arnesen et al., p. 539.
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Affiliation(s)
- Michelle M Williams
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Nicole S Spoelstra
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Spencer Arnesen
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Kathleen I O'Neill
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jessica L Christenson
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jordan Reese
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kathleen C Torkko
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Andrew Goodspeed
- Department of Pharmacology and University of Colorado Comprehensive Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Emmanuel Rosas
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Toru Hanamura
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Sharon B Sams
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Zheqi Li
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, Pittsburgh, Pennsylvania.,Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Steffi Oesterreich
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, Pittsburgh, Pennsylvania.,Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Rebecca B Riggins
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
| | - Britta M Jacobsen
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Anthony Elias
- School of Medicine, Division of Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jason Gertz
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Jennifer K Richer
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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9
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Zhao T, Su Z, Li Y, Zhang X, You Q. Chitinase-3 like-protein-1 function and its role in diseases. Signal Transduct Target Ther 2020; 5:201. [PMID: 32929074 PMCID: PMC7490424 DOI: 10.1038/s41392-020-00303-7] [Citation(s) in RCA: 294] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/28/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022] Open
Abstract
Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4+ T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.
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Affiliation(s)
- Ting Zhao
- Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China
| | - Zhongping Su
- Department of Biotherapy, Department of Geriatrics, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yingchang Li
- Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Xiaoren Zhang
- Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Qiang You
- Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou, China.
- Department of Biotherapy, Department of Geriatrics, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China.
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10
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Griffiths SG, Ezrin A, Jackson E, Dewey L, Doucette AA. A robust strategy for proteomic identification of biomarkers of invasive phenotype complexed with extracellular heat shock proteins. Cell Stress Chaperones 2019; 24:1197-1209. [PMID: 31650515 PMCID: PMC6882979 DOI: 10.1007/s12192-019-01041-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 10/03/2019] [Accepted: 10/09/2019] [Indexed: 12/17/2022] Open
Abstract
As an extension of their orchestration of intracellular pathways, secretion of extracellular heat shock proteins (HSPs) is an emerging paradigm of homeostasis imperative to multicellular organization. Extracellular HSP is axiomatic to the survival of cells during tumorigenesis; proportional representation of specific HSP family members is indicative of invasive potential and prognosis. Further significance has been added by the knowledge that all cancer-derived exosomes have surface-exposed HSPs that reflect the membrane topology of cells that secrete them. Extracellular HSPs are also characteristic of chronic inflammation and sepsis. Accordingly, interrogation of extracellular HSPs secreted from cell culture models may represent a facile means of identifying translational biomarker signatures for targeting in situ. In the current study, we evaluated a simple peptide-based multivalent HSP affinity approach using the Vn96 peptide for low speed pelleting of HSP complexes from bioreactor cultures of cell lines with varying invasive phenotype in xenotransplant models: U87 (glioblastoma multiforme; invasive); HELA (choriocarcinoma; minimally invasive); HEK293T (virally transformed immortalized; embryonic). Proteomic profiling by bottom-up mass spectrometry revealed a comprehensive range of candidate biomarkers including primary HSP ligands. HSP complexes were associated with additional chaperones of prognostic significance such as protein disulfide isomerases, as well as pleiotropic metabolic enzymes, established as proportionally reflective of invasive phenotype. Biomarkers of inflammatory and mechanotransductive phenotype were restricted to the most invasive cell model U87, including chitinase CHI3L1, lamin C, amyloid derivatives, and histone isoforms.
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Affiliation(s)
| | - Alan Ezrin
- NX Development Corporation, Louisville, KY, USA
| | - Emily Jackson
- David H. Murdock Research Institute, Kannapolis, NC, USA
| | - Lisa Dewey
- David H. Murdock Research Institute, Kannapolis, NC, USA
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11
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Bian B, Li L, Yang J, Liu Y, Xie G, Zheng Y, Zeng L, Zeng J, Shen L. Prognostic value of YKL-40 in solid tumors: a meta-analysis of 41 cohort studies. Cancer Cell Int 2019; 19:259. [PMID: 31624472 PMCID: PMC6785874 DOI: 10.1186/s12935-019-0983-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 09/27/2019] [Indexed: 12/24/2022] Open
Abstract
Background Serum/plasma YKL-40 can be a useful index that is associated with tumor development. However, the prognostic value of serum/plasma YKL-40 in patients with solid tumors is still unclear. We aimed to utilize the existing literature to investigate the prognostic value of serum/plasma YKL-40 in solid tumors. Methods An extensive literature search for relevant studies was conducted with the Embase, Medline and Web of Science databases. The effect on survival was measured with the hazard ratio (HR). Then, pooled HRs and 95% confidence intervals (CIs) were calculated using the random and fixed-effects models according to the heterogeneity of the included studies. Results This meta-analysis was based on 41 publications and comprised a total of 7762 patients with solid tumors. The pooled HR showed that elevated serum/plasma YKL-40 was significantly associated with poor OS (HR, 1.44; 95% CI 1.33–1.56). We also found that elevated serum/plasma YKL-40 had significant prognostic effects on OS in various cancer subgroups such as gastrointestinal tumors (HR, 1.37; 95% CI 1.18–1.58), ovarian cancer (HR, 2.27; 95% CI 1.69–3.06), melanoma (HR, 1.77; 95% CI 1.18–2.67), lung cancer (HR, 1.73; 95% CI 1.35–2.23), urologic neoplasms (HR, 1.61; 95% CI 1.08–2.40) and glioblastoma (HR, 1.23; 95% CI 1.07–1.42); in contrast, the prognostic effect of serum/plasma YKL-40 was not statistically significant in breast cancer (HR, 1.07; 95% CI 0.98–1.17). Conclusions The available evidence supports the hypothesis that elevated serum/plasma YKL-40 is associated with poor survival in patients with solid tumors and that serum/plasma YKL-40 may serve as a novel prognostic biomarker.
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Affiliation(s)
- Bingxian Bian
- 1Department of Clinical Laboratory, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Li
- 1Department of Clinical Laboratory, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junyao Yang
- 1Department of Clinical Laboratory, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Liu
- 1Department of Clinical Laboratory, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guohua Xie
- 1Department of Clinical Laboratory, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingxia Zheng
- 1Department of Clinical Laboratory, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liang Zeng
- 2Department of Engineering, Tsinghua University, Beijing, China
| | - Junxiang Zeng
- 1Department of Clinical Laboratory, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lisong Shen
- 1Department of Clinical Laboratory, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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12
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Yeo IJ, Lee CK, Han SB, Yun J, Hong JT. Roles of chitinase 3-like 1 in the development of cancer, neurodegenerative diseases, and inflammatory diseases. Pharmacol Ther 2019; 203:107394. [PMID: 31356910 DOI: 10.1016/j.pharmthera.2019.107394] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2019] [Indexed: 02/07/2023]
Abstract
Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly increased by various inflammatory and immunological conditions, including rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, and several cancers. However, its physiological and pathophysiological roles in the development of cancer and neurodegenerative and inflammatory diseases remain unclear. Several studies have reported that CHI3L1 promotes cancer proliferation, inflammatory cytokine production, and microglial activation, and that multiple receptors, such as advanced glycation end product, syndecan-1/αVβ3, and IL-13Rα2, are involved. In addition, the pro-inflammatory action of CHI3L1 may be mediated via the protein kinase B and phosphoinositide-3 signaling pathways and responses to various pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ. Therefore, CHI3L1 could contribute to a vast array of inflammatory diseases. In this article, we review recent findings regarding the roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of cancers, neurodegenerative diseases, and inflammatory diseases.
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Affiliation(s)
- In Jun Yeo
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea
| | - Chong-Kil Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea
| | - Sang-Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea
| | - Jaesuk Yun
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea.
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea.
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13
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High expression of Chitinase 3-like-1 is an unfavorable prognostic factor in urothelial carcinoma of upper urinary tract and urinary bladder. Urol Oncol 2019; 37:299.e7-299.e18. [DOI: 10.1016/j.urolonc.2019.01.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 12/27/2018] [Accepted: 01/01/2019] [Indexed: 12/24/2022]
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14
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Fuksiewicz M, Kotowicz B, Rutkowski A, Achinger-Kawecka J, Wagrodzki M, Kowalska MM. The Assessment of Clinical Usage and Prognostic Value of YKL-40 Serum Levels in Patients With Rectal Cancer Without Distant Metastasis. Technol Cancer Res Treat 2018; 17:1533033818765209. [PMID: 29642772 PMCID: PMC5900806 DOI: 10.1177/1533033818765209] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Colorectal cancer is one of the most common and significant malignancies in the world. YKL-40 (chitinase-3-like protein 1) is involved in cell proliferation, migration, inflammation, and tissue remodeling; and serum levels of YKL-40 are associated with patient outcome in various cancers. The aim of this study was to assess the potential clinical usage of YKL-40 pretreatment serum levels as a prognostic biomarker in rectal cancer. METHODS Concentrations of YKL-40 and standard tumor marker-Carcinoembryonic antigen (CEA)-were assessed in serum of 83 patients with rectal cancer without distant metastasis, and association with clinicopathological characteristics and disease-free and overall survival was evaluated. RESULTS Concentration of YKL-40 was significantly higher in serum of patients with rectal cancer compared to healthy controls ( P = .0001), and YKL-40 levels were able to predict rectal cancer (area under the Receiver Operating Characteristic [ROC] curve = .769) with higher accuracy than CEA (area under the ROC curve = .728) in patients with early stage disease. Increased YKL-40 levels were significantly associated with age ( P = .001); however, no association with other clinicopathological characteristics was observed. Finally, in patients with recurrence, the percentage of cases with increased concentration of YKL-40 was significantly higher than in patients without recurrence ( P = .041), and Kaplan-Meier analysis demonstrated that elevated YKL-40 concentration is a predictor of poor overall survival in patients with rectal cancer. CONCLUSION Pretreatment serum levels of YKL-40 may be a novel prognostic factor of overall and disease-free survival in patients with nonmetastatic colorectal cancer.
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Affiliation(s)
- Malgorzata Fuksiewicz
- 1 Laboratory of Tumor Markers, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Beata Kotowicz
- 1 Laboratory of Tumor Markers, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Andrzej Rutkowski
- 2 Department of Oncological Gastroenterology, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Joanna Achinger-Kawecka
- 3 Genomics and Epigenetics Division, Garvan Institute of Medical Research, Epigenetics Research Laboratory, Darlinghurst, New South Wales, Australia.,4 Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia
| | - Michal Wagrodzki
- 5 Laboratory of Pathology, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, Poland
| | - Maria M Kowalska
- 1 Laboratory of Tumor Markers, Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
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15
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Cavassani KA, Meza RJ, Habiel DM, Chen J, Montes A, Tripathi M, Martins GA, Crother TR, You S, Hogaboam CM, Bhowmick N, Posadas EM. Circulating monocytes from prostate cancer patients promote invasion and motility of epithelial cells. Cancer Med 2018; 7:4639-4649. [PMID: 30094958 PMCID: PMC6143932 DOI: 10.1002/cam4.1695] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 06/28/2018] [Accepted: 06/29/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Recruited myeloid cells are known to promote cancer initiation, malignant progression, metastasis, and resistance to therapy in the tumor niche. We tested the hypothesis that circulating blood monocytes from advanced prostate cancer (PCa) patients exhibit a protumor phenotype and directly influence the tumor microenvironment in response to tumor-derived signals. METHODS Blood monocytes from advanced and stable PCa patients were cultured, and the conditioned media (CM) were collected and analyzed using standard invasion and wound closure assays to measure effects on invasion and motility of PCa tumor cells. We then identified the proteome profile of these monocytes using proteome array and ELISA. RESULTS Conditioned media from circulating monocytes in patients with metastatic prostate cancer (PCa-M) increased invasion of epithelial PCa cells in vitro. Proteome Profiler Analysis revealed that monocyte-derived CM from metastatic castration-resistant (mCRPC) patients presented high levels of chitinase-3-like 1 (CHI3L1, YKL-40) when compared to patients with stable disease (PCa-N) and healthy control individuals (HC). The only described receptor for CHI3L1, interleukin-13 receptor α2 (IL-13Rα2), was significantly up-regulated in the human metastatic PCa cell line, ARCaPM . Accordingly, we observed that the activation of IL-13Rα2 from PCa-M CM increased the invasiveness of ARCaPM cells while siRNA directed against this receptor significantly reduced invasiveness of these cells in the presence of CM from PCa-M patients. CONCLUSIONS Thus, we show that circulating monocytes from metastatic PCa patients exert a tumor-promoting role via the secretion of CHI3L1, and CHI3L1 demands further exploration as a possible therapeutic target in advanced PCa.
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Affiliation(s)
- Karen A. Cavassani
- Urologic Oncology Program/Uro‐Oncology Research LaboratoriesSamuel Oschin Comprehensive Cancer InstituteCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Rebecca J. Meza
- Urologic Oncology Program/Uro‐Oncology Research LaboratoriesSamuel Oschin Comprehensive Cancer InstituteCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - David M. Habiel
- Division of Pulmonary and Critical Care MedicineDepartment of Medicine & Women's Guild Lung InstituteCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Jie‐Fu Chen
- Urologic Oncology Program/Uro‐Oncology Research LaboratoriesSamuel Oschin Comprehensive Cancer InstituteCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Alexander Montes
- Urologic Oncology Program/Uro‐Oncology Research LaboratoriesSamuel Oschin Comprehensive Cancer InstituteCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Manisha Tripathi
- Department of MedicineCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Gislâine A. Martins
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research InstituteCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Timothy R. Crother
- Department of Pediatric, Infectious diseases and ImmunologyCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Sungyong You
- Urologic Oncology Program/Uro‐Oncology Research LaboratoriesSamuel Oschin Comprehensive Cancer InstituteCedars‐Sinai Medical CenterLos AngelesCA90048USA
- Division of Hematology/OncologyDepartment of MedicineCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Cory M. Hogaboam
- Division of Pulmonary and Critical Care MedicineDepartment of Medicine & Women's Guild Lung InstituteCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Neil Bhowmick
- Department of MedicineCedars‐Sinai Medical CenterLos AngelesCA90048USA
| | - Edwin M. Posadas
- Urologic Oncology Program/Uro‐Oncology Research LaboratoriesSamuel Oschin Comprehensive Cancer InstituteCedars‐Sinai Medical CenterLos AngelesCA90048USA
- Division of Hematology/OncologyDepartment of MedicineCedars‐Sinai Medical CenterLos AngelesCA90048USA
- Translational Oncology ProgramSamuel Oschin Comprehensive Cancer InstituteLos AngelesCA90048USA
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16
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Li L, Fan J, Li D, Liu Y, Shrestha P, Zhong C, Xia X, Huang X. Influence of YKL-40 gene RNA interference on the biological behaviors of endometrial cancer HEC-1A cells. Oncol Lett 2018; 16:1777-1784. [PMID: 30008865 DOI: 10.3892/ol.2018.8814] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Accepted: 10/13/2017] [Indexed: 12/17/2022] Open
Abstract
The present study aimed to investigate the effects of chitinase-3-like protein 1 (YKL-40) gene RNA interference on the biological behaviors and enhanced chemosensitivity of endometrial cancer (EC) HEC-1A cells. YKL-40 small interfering (si)RNA was transduced into EC HEC-1A cells using a lentivirus. The experiment was divided into three groups: The experimental group was transfected with YKL-40 siRNA (si-YKL-40); the mock-treatment group was transfected with transfection reagent only; and the blank control group was left untreated. A reverse transcription-quantitative polymerase chain reaction was performed to investigate the mRNA expression levels of YKL-40. The biological behaviors, including cell proliferation, migration, invasion and apoptosis, were detected by MTT and Transwell assays, and flow cytometry (FCM) analysis, respectively. The results of the present study demonstrated that the mRNA expression levels of YKL-40 were downregulated within HEC-1A cells upon transfection with si-YKL-40 (P<0.05). The proliferative, migratory and invasive abilities of HEC-1A cells were inhibited by si-YKL-40 (P<0.05). The mRNA expression levels of YKL-40 were upregulated within HEC-1A cells following treatment with cisplatin (P<0.05). FCM analysis revealed that the average cellular apoptosis rate increased following the inhibition of YKL-40 gene expression via siRNA (P<0.05). Therefore, the YKL-40 gene may be associated with the proliferative, migratory, invasive and anti-apoptotic ability of HEC-1A cells. YKL-40 downregulation may enhance the sensitivity of human EC HEC-1A cells to chemotherapy.
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Affiliation(s)
- Lili Li
- Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jiangtao Fan
- Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Dahai Li
- Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yan Liu
- Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Poonam Shrestha
- Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Chunyan Zhong
- Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiuhong Xia
- Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiaobing Huang
- Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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17
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Luo D, Chen H, Lu P, Li X, Long M, Peng X, Huang M, Huang K, Lin S, Tan L, Zhu Y, Chen Z, Ouyang N, Li H. CHI3L1 overexpression is associated with metastasis and is an indicator of poor prognosis in papillary thyroid carcinoma. Cancer Biomark 2017; 18:273-284. [PMID: 28009325 DOI: 10.3233/cbm-160255] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE In this study, we examined the relationships between the expression level of CHI3L1 and the clinicopathological characteristics of papillary thyroid carcinoma. METHODS A total of 322 tissue samples from patients with papillary thyroid carcinoma were collected, and the CHI3L1 expression levels in tumor tissues, matched adjacent noncancerous tissues were detected using immunohistochemistry (IHC) and qRT-PCR. The relationships between CHI3L1 expression levels and the clinical characteristics were evaluated. RESULTS CHI3L1 expression was significantly increased in papillary thyroid carcinoma compared with matched adjacent noncancerous tissues (P< 0.001), tumor tissues with lymph node metastasis (LNM) compared with tumor tissues without LNM (P< 0.001) and tumor tissues with distant organ metastasis (DOM) compared with tumor tissues without DOM (P< 0.01). CHI3L1 expression was significantly associated with tumor size (P= 0.0001), lymph node metastasis (P< 0.0001), distant organ metastasis (P< 0.0001), extrathyroid invasion (P= 0.0022), vascular invasion (P= 0.0004) and TNM stage (P= 0.0001). CHI3L1 overexpression in papillary thyroid carcinoma tissues correlates with the tumor malignant potential (P< 0.01). More importantly, Cox multifactor analysis indicated that patients with high CHI3L1 expression have lower overall survival, disease-free survival, lymph node recurrence-free survival, and distant recurrence free survival rates than those with low expression (P< 0.05). And our findings were further validated by online Oncomine database. CONCLUSIONS CHI3L1 is associated with tumor metastasis and might be a prognostic biomarker for papillary thyroid carcinoma.
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Affiliation(s)
- Dingyuan Luo
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.,Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Haibo Chen
- Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.,Department of Nuclear Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Penghui Lu
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.,Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaojuan Li
- Center of Medical Research, Sun Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou, Guangdong, China.,Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Miaoyun Long
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xinzhi Peng
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Mingqing Huang
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Kai Huang
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shaojian Lin
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Langping Tan
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yue Zhu
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhibo Chen
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Nengtai Ouyang
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Honghao Li
- Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
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18
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Chen Y, Zhang S, Wang Q, Zhang X. Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. J Hematol Oncol 2017; 10:36. [PMID: 28143526 PMCID: PMC5286803 DOI: 10.1186/s13045-017-0408-0] [Citation(s) in RCA: 329] [Impact Index Per Article: 41.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 01/25/2017] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The macrophage, one of the several key immune cell types, is believed to be involved in tumorigenesis. However, the mechanism of macrophages promoting tumor progression is largely unknown. METHODS The differentially secreted proteins of M1 and M2 macrophages were analyzed by mass spectrometry. We performed GST pull-down assay for the identification of cell-membrane receptors that interact with chitinase 3-like protein 1 (CHI3L1) protein. The mouse model was used to validate the function of CHI3L1 in cancer metastasis in vivo. Protein phosphorylation and gene expression were performed to study the signaling pathway activation of cancer cells after CHI3L1 treatment. RESULTS M2 macrophage-secreted CHI3L1 promoted the metastasis of gastric and breast cancer cells in vitro and in vivo. The CHI3L1 protein functioned by interacting with interleukin-13 receptor α2 chain (IL-13Rα2) molecules on the plasma membranes of cancer cells. Activation of IL-13Rα2 by CHI3L1 triggered the activation of the mitogen-activated protein kinase signaling pathway, leading to the upregulated expression of matrix metalloproteinase genes, which promoted tumor metastasis. The results of this study indicated that the level of CHI3L1 protein in the sera of patients with gastric or breast cancer was significantly elevated compared with those of healthy donors. CONCLUSIONS Our study revealed a novel aspect of macrophages with respect to cancer metastasis and showed that CHI3L1 could be a marker of metastatic gastric and breast cancer in patients.
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Affiliation(s)
- Yulei Chen
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Siyuan Zhang
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China
| | - Qizhi Wang
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233030, People's Republic of China
| | - Xiaobo Zhang
- College of Life Sciences and Laboratory for Marine Biology and Biotechnology of Qingdao National Laboratory for Marine Science and Technology, Zhejiang University, Hangzhou, 310058, People's Republic of China.
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19
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Dendritic cells serve as a "Trojan horse" for oncolytic adenovirus delivery in the treatment of mouse prostate cancer. Acta Pharmacol Sin 2016; 37:1121-8. [PMID: 27345628 DOI: 10.1038/aps.2016.59] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 02/18/2016] [Indexed: 12/23/2022]
Abstract
AIM Adenovirus-mediated gene therapy is a novel therapeutic approach for the treatment of cancer, in which replication of the virus itself is the anticancer method. However, the success of this novel therapy is limited due to inefficient delivery of the virus to the target sites. In this study, we used dendritic cells (DCs) as carriers for conditionally replicating adenoviruses (CRAds) in targeting prostate carcinoma (PCa). METHODS Four types of CRAds, including Ad-PC (without PCa-specific promoter and a recombinant human tumor necrosis factor, rmhTNF, sequence), Ad-PC-rmhTNF (without PCa-specific promoter), Ad-PPC-NCS (without an rmhTNF sequence) and Ad-PPC-rmhTNF, were constructed. The androgen-insensitive mouse PCa RM-1 cells were co-cultured with CRAd-loading DCs, and the viability of RM-1 cells was examined using MTT assay. The in vivo effects of CRAd-loading DCs on PCa were evaluated in RM-1 xenograft mouse model. RESULTS Two PCa-specific CRAds (Ad-PPC-NCS, Ad-PPC-rmhTNF) exhibited more potent suppression on the viability of RM-1 cells in vitro than the PCa-non-specific CRAds (Ad-PC, Ad-PC-rmhTNF). In PCa-bearing mice, intravenous injection of the PCa-specific CRAd-loading DCs significantly inhibited the growth of xenografted tumors, extended the survival time, and induced T-cell activation. Additionally, the rmhTNF-containing CRAds exhibited greater tumor killing ability than CRAds without rmhTNF. CONCLUSION DCs may be an effective vector for the delivery of CRAds in the treatment of PCa.
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Hamilton G, Rath B, Burghuber O. Chitinase-3-like-1/YKL-40 as marker of circulating tumor cells. Transl Lung Cancer Res 2015. [PMID: 26207216 DOI: 10.3978/j.issn.2218-6751.2015.04.04] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ex vivo expansion of circulating tumor cells (CTCs) of small cell lung cancer (SCLC) patients enabled systematic screening of secreted cytokines. Permanent CTC cultures of different patients shared secretion of chitinase-3-like-1 (CHI3L1)/YKL-40, known to be upregulated in a range of tumor entities and to be associated with increased metastasis and decreased survival. This protein lacks enzymatic activity and its mechanism of promoting tumor dissemination has not been resolved. Results from SCLC CTC cultures suggest CHI3L1 as marker and important effector of tumor cell dissemination in the peripheral blood. Furthermore, this protein may link chronic inflammation of the lung, chronic obstructive pulmonary disease (COPD) and lung cancer.
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Affiliation(s)
- Gerhard Hamilton
- 1 Ludwig Boltzmann Cluster of Translational Oncology, A-1090 Vienna, Austria ; 2 Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, 1140 Vienna, Austria
| | - Barbara Rath
- 1 Ludwig Boltzmann Cluster of Translational Oncology, A-1090 Vienna, Austria ; 2 Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, 1140 Vienna, Austria
| | - Otto Burghuber
- 1 Ludwig Boltzmann Cluster of Translational Oncology, A-1090 Vienna, Austria ; 2 Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, 1140 Vienna, Austria
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