|
1
|
Liu Y, Yang Z, Pu JJ, Zhong J, Khoo U, Su Y, Zhang G. Proteogenomic characterisation of primary oral cancer unveils extracellular matrix remodelling and immunosuppressive microenvironment linked to lymph node metastasis. Clin Transl Med 2025; 15:e70261. [PMID: 40038875 PMCID: PMC11879901 DOI: 10.1002/ctm2.70261] [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: 12/25/2024] [Revised: 02/08/2025] [Accepted: 02/17/2025] [Indexed: 03/06/2025] Open
Abstract
Oral squamous cell carcinoma (OSCC) is an increasingly prevalent malignancy worldwide. This study aims to understand molecular alterations associated with lymph node metastasis of OSCC in order to improve treatment strategies. We analysed a cohort of 46 patients with primary OSCC, including 10 with lymph node metastasis and 36 without. Using a comprehensive multi-omics approach - encompassing genomic, transcriptomic, proteomic, epigenetic, single-cell, and spatial analyses - we integrated data to delineate the molecular landscape of OSCC in the context of lymph node metastasis. Our genomic analysis identified significant mutations in key genes within the MAPK, TGF-β and WNT signalling pathways, which are essential for tumour development. The proteogenomic analysis highlighted pathways critical for lymph node dissemination and factors contributing to an immunosuppressive tumour microenvironment. Elevated levels of POSTN were found to reorganise the extracellular matrix (ECM), interact with TGF-β, disrupt cell cycle regulation and suppress the immune response by reducing VCAM1 activity. Integrated analyses of single-cell and spatial transcriptome data revealed that cancer-associated fibroblasts (CAFs) secrete TGF-β1/2, promoting cancer cell metastasis through epithelial-mesenchymal transition (EMT). Our integrated multi-omics analysis provides a detailed understanding of molecular mechanisms driving lymph node metastasis of OSCC. These insights could lead to more precise diagnostics and targeted treatments. This article is protected by copyright. All rights reserved.
Collapse
Affiliation(s)
- Yu Liu
- Department of Thoracic Surgery/Institute of Thoracic OncologyWest China HospitalSichuan UniversityChengduChina
- Faculty of DentistryThe University of Hong KongHong KongHong Kong
| | - Zhenyu Yang
- Department of Thoracic Surgery/Institute of Thoracic OncologyWest China HospitalSichuan UniversityChengduChina
| | - Jingya Jane Pu
- Faculty of DentistryThe University of Hong KongHong KongHong Kong
| | - Jie Zhong
- Faculty of DentistryThe University of Hong KongHong KongHong Kong
| | - Ui‐Soon Khoo
- Department of PathologySchool of Clinical MedicineThe University of Hong KongHong KongHong Kong
| | - Yu‐Xiong Su
- Faculty of DentistryThe University of Hong KongHong KongHong Kong
| | - Gao Zhang
- Faculty of DentistryThe University of Hong KongHong KongHong Kong
| |
Collapse
|
|
2
|
Li W, Gao H, Liu J. Identified VCAM1 as prognostic gene in gastric cancer by co-expression network analysis. Discov Oncol 2024; 15:771. [PMID: 39692880 PMCID: PMC11655750 DOI: 10.1007/s12672-024-01603-y] [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: 07/30/2024] [Accepted: 11/19/2024] [Indexed: 12/19/2024] Open
Abstract
The diffuse gastric cancer (DGC) is a malignant tumor distinct from intestinal gastric cancer (IGC). This study aims to identify genetic variances and potential diagnostic and therapeutic approaches for diverse types of gastric cancer utilizing an extensive dataset. Data from RNA sequencing and clinical pathological details were acquired from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) dataset. Co-expression gene modules were constructed via Weighted Gene Co-Expression Network Analysis (WGCNA), followed by deciphering gene functions and protein-protein interaction networks within significantly associated modules. In total, analysis was conducted on 56,753 genes from 247 individuals with gastric cancer. Particularly, 621 genes from the green module exhibited strong associations with the Lauren type of gastric cancer. The prominent genes in the green module showed enrichment in processes such as signal transduction, immune response, and the positive regulation of GTPase activity. Noteworthy among these, VCAM1 was identified as the central gene linked to patients' prognosis. Moreover, 72 gastric cancer specimens were collected from The First Affiliated Hospital of University of Science and Technology of China. Immunohistochemical analysis demonstrated a significantly higher expression of VCAM1 in DGC compared to IGC (p = 0.019). Furthermore, it was confirmed that VCAM1 expression serves as a prognostic indicator for patients with DGC (p = 0.002), a correlation not observed in IGC (p = 0.760). In conclusion, this study identifies VCAM1 as a promising diagnostic and prognostic factor, suggesting novel avenues for diagnostic and therapeutic approaches in gastric cancer.
Collapse
Affiliation(s)
- Wenjuan Li
- Department of Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, Anhui, China
- Breast Cancer Center, Division of Life Sciences and Medicine,The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, NO. 107, West 2nd Ring Road, Hefei, Anhui, China
- Department of Oncology, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
| | - Hong Gao
- Breast Cancer Center, Division of Life Sciences and Medicine,The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, NO. 107, West 2nd Ring Road, Hefei, Anhui, China
| | - Jianjun Liu
- Breast Cancer Center, Division of Life Sciences and Medicine,The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, NO. 107, West 2nd Ring Road, Hefei, Anhui, China.
- Department of Oncology, Anhui Provincial Cancer Hospital, Hefei, Anhui, China.
| |
Collapse
|
|
3
|
Luo S, Ye D, Wang Y, Liu X, Wang X, Xie L, Ji Y. Roles of Protein S-Nitrosylation in Endothelial Homeostasis and Dysfunction. Antioxid Redox Signal 2024; 40:186-205. [PMID: 37742108 DOI: 10.1089/ars.2023.0406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/25/2023]
Abstract
Significance: Nitric oxide (NO) plays several distinct roles in endothelial homeostasis. Except for activating the guanylyl cyclase enzyme-dependent cyclic guanosine monophosphate signaling pathway, NO can bind reactive cysteine residues in target proteins, a process known as S-nitrosylation (SNO). SNO is proposed to explain the multiple biological functions of NO in the endothelium. Investigating the targets and mechanism of protein SNO in endothelial cells (ECs) can provide new strategies for treating endothelial dysfunction-related diseases. Recent Advances: In response to different environments, proteomics has identified multiple SNO targets in ECs. Functional studies confirm that SNO regulates NO bioavailability, inflammation, permeability, oxidative stress, mitochondrial function, and insulin sensitivity in ECs. It also influences EC proliferation, migration, apoptosis, and transdifferentiation. Critical Issues: Single-cell transcriptomic analysis of ECs isolated from different mouse tissues showed heterogeneous gene signatures. However, litter research focuses on the heterogeneous properties of SNO proteins in ECs derived from different tissues. Although metabolism reprogramming plays a vital role in endothelial functions, little is known about how protein SNO regulates metabolism reprogramming in ECs. Future Directions: Precisely deciphering the effects of protein SNO in ECs isolated from different tissues under different conditions is necessary to further characterize the relationship between protein SNO and endothelial dysfunction-related diseases. In addition, identifying SNO targets that can influence endothelial metabolic reprogramming and the underlying mechanism can offer new views on the crosstalk between metabolism and post-translational protein modification. Antioxid. Redox Signal. 40, 186-205.
Collapse
Affiliation(s)
- Shanshan Luo
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Danyu Ye
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Yu Wang
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Xingeng Liu
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Xiaoqian Wang
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Liping Xie
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
| | - Yong Ji
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Key Laboratory of Cardiovascular Medicine Research and Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, NHC Key Laboratory of Cell Transplantation, the Central Laboratory of the First Affiliated Hospital, Harbin Medical University, Heilongjiang, China
| |
Collapse
|
|
4
|
Salihi A, Al-Naqshabandi MA, Khudhur ZO, Housein Z, Hama HA, Abdullah RM, Hussen BM, Alkasalias T. Gasotransmitters in the tumor microenvironment: Impacts on cancer chemotherapy (Review). Mol Med Rep 2022; 26:233. [PMID: 35616143 PMCID: PMC9178674 DOI: 10.3892/mmr.2022.12749] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 04/07/2022] [Indexed: 11/23/2022] Open
Abstract
Nitric oxide, carbon monoxide and hydrogen sulfide are three endogenous gasotransmitters that serve a role in regulating normal and pathological cellular activities. They can stimulate or inhibit cancer cell proliferation and invasion, as well as interfere with cancer cell responses to drug treatments. Understanding the molecular pathways governing the interactions between these gases and the tumor microenvironment can be utilized for the identification of a novel technique to disrupt cancer cell interactions and may contribute to the conception of effective and safe cancer therapy strategies. The present review discusses the effects of these gases in modulating the action of chemotherapies, as well as prospective pharmacological and therapeutic interfering approaches. A deeper knowledge of the mechanisms that underpin the cellular and pharmacological effects, as well as interactions, of each of the three gases could pave the way for therapeutic treatments and translational research.
Collapse
Affiliation(s)
- Abbas Salihi
- Department of Biology, College of Science, Salahaddin University-Erbil, Erbil, Kurdistan Region 44001, Iraq
- Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region 44002, Iraq
- Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-17165 Stockholm, Sweden
| | - Mohammed A. Al-Naqshabandi
- Department of Clinical Biochemistry, College of Health Sciences, Hawler Medical University, Erbil, Kurdistan Region 44001, Iraq
| | - Zhikal Omar Khudhur
- Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Kurdistan Region 44001, Iraq
| | - Zjwan Housein
- Department of Medical Laboratory Technology, Technical Health and Medical College, Erbil Polytechnique University, Erbil, Kurdistan Region 44002, Iraq
| | - Harmand A. Hama
- Department of Biology, Faculty of Education, Tishk International University, Erbil, Kurdistan Region 44002, Iraq
| | - Ramyar M. Abdullah
- College of Medicine, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region 44002, Iraq
| | - Twana Alkasalias
- General Directorate of Scientific Research Center, Salahaddin University-Erbil, Erbil, Kurdistan Region 44002, Iraq
- Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden
| |
Collapse
|
|
5
|
Identification of a Genomic Instability-Related Long Noncoding RNA Prognostic Model in Colorectal Cancer Based on Bioinformatic Analysis. DISEASE MARKERS 2022; 2022:4556585. [PMID: 35711569 PMCID: PMC9197617 DOI: 10.1155/2022/4556585] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/17/2022] [Indexed: 11/17/2022]
Abstract
Background. In recent years, a growing body of research has revealed that long noncoding RNAs (lncRNAs) participate in regulating genomic instability. Materials and Methods. We obtained RNA expression profiles, somatic mutation profiles, clinical information, and pathological features of colorectal cancer (CRC) from The Cancer Genome Atlas project. We divided the cohort into two groups based on mutation frequency and identified genomic instability-related lncRNAs (GI-lncRNAs) using R software. We further analyzed the function of identified GI-lncRNAs and established a prognostic model through Cox regression. Using the established prognostic model, we divided the cohort into the high- and low-risk groups and further verified the prognostic differences between the two groups as well as the predictive power of prognosis-related lncRNAs in the genomic instability of CRC. Results. We identified a total of 143 GI-lncRNAs that were differentially expressed between the higher mutation frequency group and the lower mutation frequency group. According to Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analyses, a series of cancer-associated terms were enriched. We further constructed a prognostic model that included five GI-lncRNAs (lncRNA PTPRD-AS1, lncRNA AC009237.14, lncRNA LINC00543, lncRNA AP003555.1, and lncRNA AL109615.3). We confirmed that the expression of the five GI-lncRNAs was associated with prognosis and the mutation of critical genes in the CRC patient cohort. Conclusions. The present research further confirmed the vital function of GI-lncRNAs in the genomic instability of CRC. The five GI-lncRNAs identified in our study are potential biomarkers and need to be studied in more depth.
Collapse
|
|
6
|
Miranda KM, Ridnour LA, McGinity CL, Bhattacharyya D, Wink DA. Nitric Oxide and Cancer: When to Give and When to Take Away? Inorg Chem 2021; 60:15941-15947. [PMID: 34694129 DOI: 10.1021/acs.inorgchem.1c02434] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The mechanistic roles of nitric oxide (NO) during cancer progression have been important considerations since its discovery as an endogenously generated free radical. Nonetheless, the impacts of this signaling molecule can be seemingly contradictory, being both pro-and antitumorigenic, which complicates the development of cancer treatments based on the modulation of NO fluxes in tumors. At a fundamental level, low levels of NO drive oncogenic pathways, immunosuppression, metastasis, and angiogenesis, while higher levels lead to apoptosis and reduced hypoxia and also sensitize tumors to conventional therapies. However, clinical outcome depends on the type and stage of the tumor as well as the tumor microenvironment. In this Viewpoint, the current understanding of the concentration, spatial, and temporal dependence of responses to NO is correlated with potential treatment and prevention technologies and strategies.
Collapse
Affiliation(s)
- Katrina M Miranda
- Department of Chemistry and Biochemistry and the BIO5 Institute, University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, United States
| | - Lisa A Ridnour
- Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, Maryland 21702, United States
| | - Christopher L McGinity
- Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, Maryland 21702, United States
| | - Dana Bhattacharyya
- Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, Maryland 21702, United States
| | - David A Wink
- Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, Maryland 21702, United States
| |
Collapse
|
|
7
|
Bertrand C, Van Meerbeeck P, de Streel G, Vaherto-Bleeckx N, Benhaddi F, Rouaud L, Noël A, Coulie PG, van Baren N, Lucas S. Combined Blockade of GARP:TGF-β1 and PD-1 Increases Infiltration of T Cells and Density of Pericyte-Covered GARP + Blood Vessels in Mouse MC38 Tumors. Front Immunol 2021; 12:704050. [PMID: 34386010 PMCID: PMC8353334 DOI: 10.3389/fimmu.2021.704050] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/30/2021] [Indexed: 12/20/2022] Open
Abstract
When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP:TGF-β1 complexes induced more frequent immune-mediated rejections of CT26 and MC38 murine tumors than anti-PD-1 alone. In both types of tumors, the activity of anti-GARP:TGF-β1 mAbs resulted from blocking active TGF-β1 production and immunosuppression by GARP-expressing regulatory T cells. In CT26 tumors, combined GARP:TGF-β1/PD-1 blockade did not augment the infiltration of T cells, but did increase the effector functions of already present anti-tumor T cells. Here we show that, in contrast, in MC38, combined GARP:TGF-β1/PD-1 blockade increased infiltration of T cells, as a result of increased extravasation of T cells from blood vessels. Unexpectedly, combined GARP:TGF-β1/PD-1 blockade also increased the density of GARP+ blood vessels covered by pericytes in MC38, but not in CT26 tumors. This appears to occur because anti-GARP:TGF-β1, by blocking TGF-β1 signals, favors the proliferation of and expression of adhesion molecules such as E-selectin by blood endothelial cells. The resulting densification of intratumoral blood vasculature probably contributes to increased T cell infiltration and to the therapeutic efficacy of GARP:TGF-β1/PD-1 blockade in MC38. We conclude from these distinct observations in MC38 and CT26, that the combined blockades of GARP:TGF-β1 and PD-1 can exert anti-tumor activity via multiple mechanisms, including the densification and normalization of intratumoral blood vasculature, the increase of T cell infiltration into the tumor and the increase of the effector functions of intratumoral tumor-specific T cells. This may prove important for the selection of cancer patients who could benefit from combined GARP:TGF-β1/PD-1 blockade in the clinics.
Collapse
Affiliation(s)
| | | | | | | | - Fatima Benhaddi
- de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Loïc Rouaud
- GIGA-Cancer Research Center, University of Liège, Liège, Belgium
| | - Agnès Noël
- GIGA-Cancer Research Center, University of Liège, Liège, Belgium
| | - Pierre G Coulie
- de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Nicolas van Baren
- de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Sophie Lucas
- de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.,Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wavre, Belgium
| |
Collapse
|
|
8
|
Yin TF, Zhao DY, Zhou YC, Wang QQ, Yao SK. Identification of the circRNA-miRNA-mRNA regulatory network and its prognostic effect in colorectal cancer. World J Clin Cases 2021; 9:4520-4541. [PMID: 34222420 PMCID: PMC8223824 DOI: 10.12998/wjcc.v9.i18.4520] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/26/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The high morbidity and mortality of colorectal cancer (CRC) have posed great threats to human health. Circular RNA (CircRNA) and microRNA (miRNA), acting as competing endogenous RNAs (ceRNAs), have been found to play vital roles in carcinogenesis. However, the biological function of ceRNAs in CRC pathogenesis and prognosis remains largely unexplored. AIM To identify the CRC-specific circRNA-miRNA-mRNA regulatory network and uncover the subnetwork associated with its prognosis. METHODS CircRNAs, miRNAs and mRNAs differentially expressed (DE) in CRC tissues were selected by expression file analysis in the Gene Expression Omnibus (GEO) database, and the downstream target molecules of circRNAs and miRNAs were predicted. Then, the intersection of differentially expressed RNA molecules with the predicted targets was determined to obtain a ceRNA network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to elucidate the possible mechanism of pathogenesis. A survival analysis using the gene profiles and clinical information in The Cancer Genome Atlas (TCGA) database was performed to identify the mRNAs associated with the clinical outcome of CRC patients and construct a prognostic subnetwork. RESULTS We downloaded three datasets (GSE126095, GSE41655 and GSE41657) of large-scale CRC samples from the GEO database. There were 55 DEcircRNAs, 114 DEmiRNAs and 267 DEmRNAs in CRC tissues compared with normal tissues. After intersecting these molecules with predicted targets, 19 circRNAs, 13 miRNAs and 28 mRNAs were chosen to develop a circRNA-miRNA-mRNA network. GO and KEGG functional enrichment analyses indicated that the retinol metabolic process, leukocyte chemotaxis, extracellular matrix remodeling, endoplasmic reticulum stress, alcohol dehydrogenase activity, gastric acid secretion, nitrogen metabolism and NOD-like receptor signaling pathway might participate in the tumorigenesis of CRC. After verifying the identified mRNA effect in the TCGA database, we finally recognized 3 mRNAs (CA2, ITLN1 and LRRC19) that were significantly associated with the overall survival of CRC patients and constructed a ceRNA subnetwork including 5 circRNAs (hsa_circ_0080210, hsa_circ_0007158, hsa_circ_0000375, hsa_circ_0018909 and hsa_circ_0011536) and 3 miRNAs (hsa-miR-601, hsa-miR-671-5p and hsa-miR-765), which could contain innovative and noninvasive indicators for the early screening and prognostic prediction of CRC. CONCLUSION We proposed a circRNA-miRNA-mRNA regulatory network closely associated with the progression and clinical outcome of CRC that might include promising biomarkers for carcinogenesis and therapeutic targets.
Collapse
Affiliation(s)
- Teng-Fei Yin
- Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Dong-Yan Zhao
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yuan-Chen Zhou
- Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Qian-Qian Wang
- Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Shu-Kun Yao
- Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| |
Collapse
|
|
9
|
Identification and Verification of a 17 Immune-Related Gene Pair Prognostic Signature for Colon Cancer. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6057948. [PMID: 34124251 PMCID: PMC8166469 DOI: 10.1155/2021/6057948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 04/15/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022]
Abstract
Background Colon cancer (CC) is a malignant tumor with a high incidence and poor prognosis. Accumulating evidence shows that the immune signature plays an important role in the tumorigenesis, progression, and prognosis of CC. Our study is aimed at establishing a novel robust immune-related gene pair signature for predicting the prognosis of CC. Methods Gene expression profiles and corresponding clinical information are obtained from two public data sets: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO, GSE39582). We screened out immune-related gene pairs (IRGPs) associated with prognosis in the discovery cohort. Lasso-Cox proportional hazard regression was used to develop the best prognostic signature model. According to this, the patients in the validation cohort were divided into high immune-risk group and low immune-risk group, and the prediction ability of the signature model was verified by survival analysis and independent prognostic analysis. Results A total of 17 IRGPs composed of 26 IRGs were used to construct a prognostic-related risk scoring model. This model accurately predicted the prognosis of CC patients, and the patients in the high immune-risk group indicated poor prognosis in the discovery cohort and validation cohort. Besides, whether in univariate or multivariate analysis, the IRGP signature was an independent prognostic factor. T cell CD4 memory resting in the low-risk group was significantly higher than that in the high-risk group. Functional analysis showed that the biological processes of the low-risk group included "TCA cycle" and "RNA degradation," while the high-risk group was enriched in the "CAMs" and "focal adhesion" pathways. Conclusion We have successfully established a signature model composed of 17 IRGPs, which provides a novel idea to predict the prognosis of CC patients.
Collapse
|
|
10
|
Zhao Y, Ting KK, Coleman P, Qi Y, Chen J, Vadas M, Gamble J. The Tumour Vasculature as a Target to Modulate Leucocyte Trafficking. Cancers (Basel) 2021; 13:cancers13071724. [PMID: 33917287 PMCID: PMC8038724 DOI: 10.3390/cancers13071724] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/29/2021] [Accepted: 04/03/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Tumour blood vessels, characterised by abnormal morphology and function, create an immunosuppressive tumour microenvironment via restricting the appropriate leucocyte subsets trafficking. Strategies to trigger phenotypic alteration in tumour vascular system to resemble normal vascular system, named vascular normalisation, promote effective trafficking of leucocytes into tumours through enhancing the interactions between leucocytes and endothelial cells. This review specifically demonstrates how targeting tumour blood vessels modulates the critical steps of leucocyte trafficking. Furthermore, selective regulation of leucocyte subsets trafficking in tumours can be achieved by vasculature-targeting strategies, contributing to improved immunotherapy and thereby delayed tumour progression. Abstract The effectiveness of immunotherapy against solid tumours is dependent on the appropriate leucocyte subsets trafficking and accumulating in the tumour microenvironment (TME) with recruitment occurring at the endothelium. Such recruitment involves interactions between the leucocytes and the endothelial cells (ECs) of the vessel and occurs through a series of steps including leucocyte capture, their rolling, adhesion, and intraluminal crawling, and finally leucocyte transendothelial migration across the endothelium. The tumour vasculature can curb the trafficking of leucocytes through influencing each step of the leucocyte recruitment process, ultimately producing an immunoresistant microenvironment. Modulation of the tumour vasculature by strategies such as vascular normalisation have proven to be efficient in facilitating leucocyte trafficking into tumours and enhancing immunotherapy. In this review, we discuss the underlying mechanisms of abnormal tumour vasculature and its impact on leucocyte trafficking, and potential strategies for overcoming the tumour vascular abnormalities to boost immunotherapy via increasing leucocyte recruitment.
Collapse
Affiliation(s)
- Yang Zhao
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Correspondence: (Y.Z.); (J.G.); Tel.: +86-025-85811237 (Y.Z.); +61-02-95656225 (J.G.)
| | - Ka Ka Ting
- Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney 2050, Australia; (K.K.T.); (P.C.); (Y.Q.); (M.V.)
| | - Paul Coleman
- Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney 2050, Australia; (K.K.T.); (P.C.); (Y.Q.); (M.V.)
| | - Yanfei Qi
- Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney 2050, Australia; (K.K.T.); (P.C.); (Y.Q.); (M.V.)
| | - Jinbiao Chen
- Liver Injury and Cancer Program, Centenary Institute, The University of Sydney, Sydney 2050, Australia;
| | - Mathew Vadas
- Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney 2050, Australia; (K.K.T.); (P.C.); (Y.Q.); (M.V.)
| | - Jennifer Gamble
- Vascular Biology Program, Centenary Institute, The University of Sydney, Sydney 2050, Australia; (K.K.T.); (P.C.); (Y.Q.); (M.V.)
- Correspondence: (Y.Z.); (J.G.); Tel.: +86-025-85811237 (Y.Z.); +61-02-95656225 (J.G.)
| |
Collapse
|
|
11
|
Abou Khouzam R, Brodaczewska K, Filipiak A, Zeinelabdin NA, Buart S, Szczylik C, Kieda C, Chouaib S. Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies. Front Immunol 2021; 11:613114. [PMID: 33552076 PMCID: PMC7854546 DOI: 10.3389/fimmu.2020.613114] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/30/2020] [Indexed: 01/19/2023] Open
Abstract
The environmental and metabolic pressures in the tumor microenvironment (TME) play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition and activation. Hypoxia triggers a cascade of events that promote tumor growth, enhance resistance to the anti-tumor immune response and instigate tumor angiogenesis. During growth, the developing angiogenesis is pathological and gives rise to a haphazardly shaped and leaky tumor vasculature with abnormal properties. Accordingly, aberrantly vascularized TME induces immunosuppression and maintains a continuous hypoxic state. Normalizing the tumor vasculature to restore its vascular integrity, should hence enhance tumor perfusion, relieving hypoxia, and reshaping anti-tumor immunity. Emerging vascular normalization strategies have a great potential in achieving a stable normalization, resulting in mature and functional blood vessels that alleviate tumor hypoxia. Biomarkers enabling the detection and monitoring of tumor hypoxia could be highly advantageous in aiding the translation of novel normalization strategies to clinical application, alone, or in combination with other treatment modalities, such as immunotherapy.
Collapse
Affiliation(s)
- Raefa Abou Khouzam
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Klaudia Brodaczewska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland
| | - Aleksandra Filipiak
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland.,Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Nagwa Ahmed Zeinelabdin
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Stephanie Buart
- INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Faulty. De médecine Univ. Paris-Sud, University Paris-Saclay, Villejuif, France
| | - Cezary Szczylik
- Centre of Postgraduate Medical Education, Department of Oncology, European Health Centre, Otwock, Warsaw, Poland
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland.,Centre for Molecular Biophysics, UPR CNRS 4301, Orléans, France
| | - Salem Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates.,INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Faulty. De médecine Univ. Paris-Sud, University Paris-Saclay, Villejuif, France
| |
Collapse
|
|
12
|
Aguilar G, Koning T, Ehrenfeld P, Sánchez FA. Role of NO and S-nitrosylation in the Expression of Endothelial Adhesion Proteins That Regulate Leukocyte and Tumor Cell Adhesion. Front Physiol 2020; 11:595526. [PMID: 33281627 PMCID: PMC7691576 DOI: 10.3389/fphys.2020.595526] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 10/20/2020] [Indexed: 12/11/2022] Open
Abstract
Leukocyte recruitment is one of the most important cellular responses to tissue damage. Leukocyte extravasation is exquisitely regulated by mechanisms of selective leukocyte-endothelium recognition through adhesion proteins in the endothelial cell surface that recognize specific integrins in the activated leukocytes. A similar mechanism is used by tumor cells during metastasis to extravasate and form a secondary tumor. Nitric oxide (NO) has been classically described as an anti-inflammatory molecule that inhibits leukocyte adhesion. However, the evidence available shows also a positive role of NO in leukocyte adhesion. These apparent discrepancies might be explained by the different NO concentrations reached during the inflammatory response, which are highly modulated by the expression of different nitric oxide synthases, along the inflammatory response and by changes in their subcellular locations.
Collapse
Affiliation(s)
- Gaynor Aguilar
- Instituto de Inmunología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Tania Koning
- Instituto de Inmunología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Pamela Ehrenfeld
- Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.,Centro Interdisciplinario de Estudios del Sistema Nervioso, Universidad Austral de Chile, Valdivia, Chile
| | - Fabiola A Sánchez
- Instituto de Inmunología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.,Centro Interdisciplinario de Estudios del Sistema Nervioso, Universidad Austral de Chile, Valdivia, Chile
| |
Collapse
|
|
13
|
Bou-Dargham MJ, Sha L, Sang QXA, Zhang J. Immune landscape of human prostate cancer: immune evasion mechanisms and biomarkers for personalized immunotherapy. BMC Cancer 2020; 20:572. [PMID: 32552802 PMCID: PMC7302357 DOI: 10.1186/s12885-020-07058-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 06/10/2020] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Despite recent advances in cancer immunotherapy, the efficacy of these therapies for the treatment of human prostate cancer patients is low due to the complex immune evasion mechanisms (IEMs) of prostate cancer and the lack of predictive biomarkers for patient responses. METHODS To understand the IEMs in prostate cancer and apply such understanding to the design of personalized immunotherapies, we analyzed the RNA-seq data for prostate adenocarcinoma from The Cancer Genome Atlas (TCGA) using a combination of biclustering, differential expression analysis, immune cell typing, and machine learning methods. RESULTS The integrative analysis identified eight clusters with different IEM combinations and predictive biomarkers for each immune evasion cluster. Prostate tumors employ different combinations of IEMs. The majority of prostate cancer patients were identified with immunological ignorance (89.8%), upregulated cytotoxic T lymphocyte-associated protein 4 (CTLA4) (58.8%), and upregulated decoy receptor 3 (DcR3) (51.6%). Among patients with immunologic ignorance, 41.4% displayed upregulated DcR3 expression, 43.26% had upregulated CTLA4, and 11.4% had a combination of all three mechanisms. Since upregulated programmed cell death 1 (PD-1) and/or CTLA4 often co-occur with other IEMs, these results provide a plausible explanation for the failure of immune checkpoint inhibitor monotherapy for prostate cancer. CONCLUSION These findings indicate that human prostate cancer specimens are mostly immunologically cold tumors that do not respond well to mono-immunotherapy. With such identified biomarkers, more precise treatment strategies can be developed to improve therapeutic efficacy through a greater understanding of a patient's immune evasion mechanisms.
Collapse
Affiliation(s)
- Mayassa J Bou-Dargham
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, USA.
| | - Linlin Sha
- Department of Statistics, Florida State University, Tallahassee, Florida, USA
| | - Qing-Xiang Amy Sang
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, USA. .,Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, USA.
| | - Jinfeng Zhang
- Department of Statistics, Florida State University, Tallahassee, Florida, USA.
| |
Collapse
|
|
14
|
Cheng YC, Li YH, Hsu CY, Lee IT. Synergistic Association of Carcinoembryonic Antigen and Carbohydrate Antigen 19-9 on the Risk of Abnormal Glucose Regulation. Diabetes Metab Syndr Obes 2020; 13:1933-1942. [PMID: 32606853 PMCID: PMC7294570 DOI: 10.2147/dmso.s256223] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 05/20/2020] [Indexed: 01/08/2023] Open
Abstract
PURPOSE Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are tumor-associated antigens. An increased serum level of CEA and CA19-9 separately has been reported in diabetes. In this study, we examined the composite effect of elevated serum levels of both CEA and CA19-9 on subjects with type 2 diabetes and prediabetes. PATIENTS AND METHODS A total of 3568 adults who attended a health examination were enrolled into this cross-sectional study. Subjects were grouped into four groups according to the median serum CEA and CA19-9 levels. RESULTS Subjects with high CEA and high CA19-9 levels had the highest proportions of diabetes (43.9%) and prediabetes (33.04%). There was a statistically significant trend in the proportion of diabetes across the four groups (P < 0.001). Multivariable logistic regression analysis revealed higher risks of type 2 diabetes in subjects with high CEA and low CA19-9 levels (odds ratio [OR] = 2.10, 95% confidence interval [CI]: 1.39-3.18, P < 0.001) and in those with high CA19-9 and low CEA levels (OR = 2.18, 95% CI: 1.42-3.34, P < 0.001) than in those with low CEA and low CA19-9 levels; among these four groups, the highest risk of type 2 diabetes was observed in subjects with high CEA and high CA19-9 levels (OR = 2.65, 95% CI: 1.81-3.88, P < 0.001). The risk of prediabetes was significantly higher only in subjects with high CEA and high CA19-9 levels compared to those with low CEA and low CA19-9 levels (OR = 1.32, 95% CI: 1.08-1.61, P = 0.006). CONCLUSION CEA and CA19-9 had a synergistic ability to increase the risk of type 2 diabetes and prediabetes.
Collapse
Affiliation(s)
- Yu-Cheng Cheng
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yu-Hsuan Li
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Graduate Institute of Data Science, Taipei Medical University, Taipei, Taiwan
| | - Chiann-Yi Hsu
- Biostatistics Task Force of Taichung Veterans General Hospital, Taichung, Taiwan
| | - I-Te Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- College of Science, Tunghai University, Taichung, Taiwan
- Correspondence: I-Te Lee Email
| |
Collapse
|
|
15
|
Langsten KL, Kim JH, Sarver AL, Dewhirst M, Modiano JF. Comparative Approach to the Temporo-Spatial Organization of the Tumor Microenvironment. Front Oncol 2019; 9:1185. [PMID: 31788448 PMCID: PMC6854022 DOI: 10.3389/fonc.2019.01185] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 10/21/2019] [Indexed: 12/13/2022] Open
Abstract
The complex ecosystem in which tumor cells reside and interact, termed the tumor microenvironment (TME), encompasses all cells and components associated with a neoplasm that are not transformed cells. Interactions between tumor cells and the TME are complex and fluid, with each facet coercing the other, largely, into promoting tumor progression. While the TME in humans is relatively well-described, a compilation and comparison of the TME in our canine counterparts has not yet been described. As is the case in humans, dog tumors exhibit greater heterogeneity than what is appreciated in laboratory animal models, although the current level of knowledge on similarities and differences in the TME between dogs and humans, and the practical implications of that information, require further investigation. This review summarizes some of the complexities of the human and mouse TME and interjects with what is known in the dog, relaying the information in the context of the temporo-spatial organization of the TME. To the authors' knowledge, the development of the TME over space and time has not been widely discussed, and a comprehensive review of the canine TME has not been done. The specific topics covered in this review include cellular invasion and interactions within the TME, metabolic derangements in the TME and vascular invasion, and the involvement of the TME in tumor spread and metastasis.
Collapse
Affiliation(s)
- Kendall L Langsten
- Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, United States
| | - Jong Hyuk Kim
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN, United States.,Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, United States.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Aaron L Sarver
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN, United States.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States.,Institute for Health Informatics, University of Minnesota, Minneapolis, MN, United States
| | - Mark Dewhirst
- Radiation Oncology Department, Duke University Medical School, Durham, NC, United States
| | - Jaime F Modiano
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN, United States.,Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, United States.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States.,Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, United States.,Center for Immunology, University of Minnesota, Minneapolis, MN, United States.,Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States.,Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN, United States
| |
Collapse
|
|
16
|
Bu S, Li B, Wang Q, Gu T, Dong Q, Miao X, Lai D. Epithelial ovarian cancer stem‑like cells are resistant to the cellular lysis of cytokine‑induced killer cells via HIF1A‑mediated downregulation of ICAM‑1. Int J Oncol 2019; 55:179-190. [PMID: 31059002 DOI: 10.3892/ijo.2019.4794] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 01/10/2019] [Indexed: 11/06/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic tumors. Cancer spheroid culture is a widely used model to study cancer stem cells. Previous studies have demonstrated the effectiveness of cytokine‑induced killer (CIK) cell‑based therapies against cancer and cancer stem cells. However, it is not clear how EOC spheroid cells respond to CIK‑mediated cellular lysis, and the mechanisms involved have never been reported before. A flow cytometry‑based method was used to evaluate the anti‑cancer effects of CIK cells against adherent A2780 cells and A2780 spheroids. To demonstrate the association between hypoxia inducible factor‑1α (HIF1A) and intercellular adhesion molecule‑1 (ICAM‑1), two HIF1A short hairpin RNA (shRNA) stable transfected cell lines were established. Furthermore, the protein expression levels of hypoxia/HIF1A‑associated signaling pathways were evaluated, including transforming growth factor‑β1 (TGF‑β1)/mothers against decapentaplegic homologs (SMADs) and nuclear factor‑κB (NF‑κB) signaling pathways, comparing A2780 adherent cells and cancer spheroids. Flow cytometry revealed that A2780 spheroid cells were more resistant to CIK‑mediated cellular lysis, which was partially reversed by an anti‑ICAM‑1 antibody. HIF1A was significantly upregulated in A2780 spheroids compared with adherent cells. Using HIF1A shRNA stable transfected cell lines and cobalt chloride, it was revealed that hypoxia/HIF1A contributed to downregulation of ICAM‑1 in A2780 spheroid cells and adherent cells. Furthermore, hypoxia/HIF1A‑associated signaling pathways, TGF‑β1/SMADs and NF‑κB, were activated in A2780 spheroid cells by using western blotting. The findings indicate that EOC stem‑like cells resist the CIK‑mediated cellular lysis via HIF1A‑mediated downregulation of ICAM‑1, which may be instructive for optimizing and enhancing CIK‑based therapies.
Collapse
Affiliation(s)
- Shixia Bu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| | - Boning Li
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| | - Qian Wang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| | - Tingting Gu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| | - Qianggang Dong
- Shanghai iCELL Biotechnology Co., Ltd., Shanghai 200333, P.R. China
| | - Xiaofei Miao
- Shanghai iCELL Biotechnology Co., Ltd., Shanghai 200333, P.R. China
| | - Dongmei Lai
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200030, P.R. China
| |
Collapse
|
|
17
|
Chung S, Lee Y, Roh EY. HbA1c showed a positive association with carcinoembryonic antigen (CEA) level in only diabetes, not prediabetic or normal individuals. J Clin Lab Anal 2019; 33:e22900. [PMID: 31002428 PMCID: PMC6642291 DOI: 10.1002/jcla.22900] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 03/19/2019] [Accepted: 03/21/2019] [Indexed: 12/20/2022] Open
Abstract
Background This study was conducted to investigate the association of carcinoembryonic antigen (CEA) and glycated hemoglobin (HbA1c) in normal, prediabetic, and diabetic subjects. Methods A total of 2,911 participants who underwent general health checkups were enrolled and categorized into the normal, prediabetes, and diabetes groups. Demographic, anthropological, and clinical variables were investigated, and correlations with CEA were analyzed. For 28 diabetic subjects with CEA levels above the upper limit, the follow‐up CEA and HbA1c data were analyzed. Results Carcinoembryonic antigen levels were significantly different among the normal, prediabetes, and diabetes groups (1.7 ± 1.1 vs 2.0 ± 1.1 vs 2.5 ± 1.5; P < 0.001), and men had higher CEA levels than women in all three groups. Correlation analysis identified a significant positive correlation between serum CEA and HbA1c in the diabetes group using unadjusted and adjusted models (r = 0.189, P < 0.001 and r = 0.218, P < 0.001), and multiple linear regression analysis also revealed that HbA1c was independently and positively correlated with CEA in the diabetes group (β = 0.275, P < 0.001). However, these relationships were inconsistent in the normal and prediabetes groups. The changes in CEA and HbA1c from baseline to follow‐up (delta CEA and delta HbA1c) showed a significant positive correlation (P = 0.021). Conclusions In diabetes, the CEA level was independently and positively correlated with glycemic control status. Additionally, the change in CEA level (delta CEA) showed a positive correlation with the change in HbA1c level (delta HbA1c) in the follow‐up data analysis.
Collapse
Affiliation(s)
- Soie Chung
- Department of Laboratory Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea.,Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yunhwan Lee
- Department of Public Health Sciences, Seoul National University, Seoul, Korea
| | - Eun Youn Roh
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Laboratory Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| |
Collapse
|
|
18
|
Kwon YJ, Lee HS, Shim JY, Lee YJ. Serum carcinoembryonic antigen is positively associated with leukocyte count in Korean adults. J Clin Lab Anal 2017; 32. [PMID: 28653772 DOI: 10.1002/jcla.22291] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 06/05/2017] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Emerging evidence shows that serum carcinoembryonic antigen (CEA) levels may modestly be increased in non-neoplastic conditions such as cardiometabolic diseases, which are increasingly being seen as inflammatory diseases. Leukocyte count is widely evaluated marker of inflammation in clinical practice and a useful predictor of cardiometabolic disease. In this study, we aimed to determine the relationship between serum CEA levels and leukocyte counts in Korean adults. METHODS This cross-sectional study included a total of 19 834 individuals enrolled from a health promotion center between November 2006 and July 2010. Multiple linear regression analysis was performed to investigate the association between serum CEA levels and leukocyte counts after adjusting for confounding variables. RESULTS According to both stepwise-method and enter-method multiple linear regression analyses, serum CEA levels were positively and independently associated with leukocyte counts (P<.001) after adjusting for age, sex, body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, HDL-cholesterol, cigarette smoking, alcohol ingestion, physical activity, diabetes mellitus, and anti-inflammatory drugs. CONCLUSIONS We demonstrate a positive relationship between serum CEA levels and leukocyte counts in Korean adults. Our results suggested that an elevated serum CEA level may reflect chronic inflammation state.
Collapse
Affiliation(s)
- Yu-Jin Kwon
- Department of Family Medicine, Yong-in Severance Hospital, Yonsei University College of Medicine, Yong-in, Korea.,Department of Medicine, Gradauate School of Yonsei University College of Medicine, Seoul, Korea
| | - Hye-Sun Lee
- Biostatistics Collaboration Units, Department of Research Affairs, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Yong Shim
- Department of Family Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yong-Jae Lee
- Department of Family Medicine, Gangam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
|
19
|
Sackstein R, Schatton T, Barthel SR. T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. J Transl Med 2017; 97:669-697. [PMID: 28346400 PMCID: PMC5446300 DOI: 10.1038/labinvest.2017.25] [Citation(s) in RCA: 158] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/17/2017] [Accepted: 01/22/2017] [Indexed: 12/13/2022] Open
Abstract
Advances in cancer immunotherapy have offered new hope for patients with metastatic disease. This unfolding success story has been exemplified by a growing arsenal of novel immunotherapeutics, including blocking antibodies targeting immune checkpoint pathways, cancer vaccines, and adoptive cell therapy (ACT). Nonetheless, clinical benefit remains highly variable and patient-specific, in part, because all immunotherapeutic regimens vitally hinge on the capacity of endogenous and/or adoptively transferred T-effector (Teff) cells, including chimeric antigen receptor (CAR) T cells, to home efficiently into tumor target tissue. Thus, defects intrinsic to the multi-step T-cell homing cascade have become an obvious, though significantly underappreciated contributor to immunotherapy resistance. Conspicuous have been low intralesional frequencies of tumor-infiltrating T-lymphocytes (TILs) below clinically beneficial threshold levels, and peripheral rather than deep lesional TIL infiltration. Therefore, a Teff cell 'homing deficit' may arguably represent a dominant factor responsible for ineffective immunotherapeutic outcomes, as tumors resistant to immune-targeted killing thrive in such permissive, immune-vacuous microenvironments. Fortunately, emerging data is shedding light into the diverse mechanisms of immune escape by which tumors restrict Teff cell trafficking and lesional penetrance. In this review, we scrutinize evolving knowledge on the molecular determinants of Teff cell navigation into tumors. By integrating recently described, though sporadic information of pivotal adhesive and chemokine homing signatures within the tumor microenvironment with better established paradigms of T-cell trafficking under homeostatic or infectious disease scenarios, we seek to refine currently incomplete models of Teff cell entry into tumor tissue. We further summarize how cancers thwart homing to escape immune-mediated destruction and raise awareness of the potential impact of immune checkpoint blockers on Teff cell homing. Finally, we speculate on innovative therapeutic opportunities for augmenting Teff cell homing capabilities to improve immunotherapy-based tumor eradication in cancer patients, with special focus on malignant melanoma.
Collapse
Affiliation(s)
- Robert Sackstein
- Department of Dermatology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA,Department of Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA,Harvard Skin Disease Research Center, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA,Program of Excellence in Glycosciences, Harvard Medical School, 77 Avenue Louis Pasteur, Rm 671, Boston, MA 02115, USA
| | - Tobias Schatton
- Department of Dermatology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA,Harvard Skin Disease Research Center, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA,Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA,Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Steven R. Barthel
- Department of Dermatology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA,Harvard Skin Disease Research Center, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA,Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA,Correspondence to: Dr. Steven R. Barthel, Harvard Institutes of Medicine, Rm. 673B, 77 Avenue Louis Pasteur, Boston, MA 02115;
| |
Collapse
|
|
20
|
Bellone G, Vizio B, Scirelli T, Emanuelli G. A Xenogenic Bone Derivative as a Potential Adjuvant for Bone Regeneration and Implant Osseointegration: An In Vitro Study. Tissue Eng Regen Med 2017; 14:243-251. [PMID: 30603481 DOI: 10.1007/s13770-017-0029-2] [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: 04/01/2016] [Revised: 05/31/2016] [Accepted: 06/04/2016] [Indexed: 12/18/2022] Open
Abstract
Several clinical conditions may limit the success of bone regeneration and/or implant osseointegration. For this reason, many compounds have been tested for their ability to stimulate this biological process. Synthetic hydroxyapatite (HA), mimicking natural bone hydroxyapatite, and extra-cellular matrix proteins, such as type I collagen, are potential candidates. However, the synthetic origin of HA and the denaturing conditions required for extracting collagen from skin and derma are sources of potential drawbacks. This study examines the in vitro effects of a natural bone derivative (NBD) extracted from equine bone and containing both natural, non-synthetic bone hydroxyapatite and native, non-denatured, type I bone collagen as a possible active compound for stimulating bone regeneration and implant osseointegration. The activity of NBD was tested on bone marrow stromal cells (BMSCs), evaluating their growth/viability by the methylthiazol tetrazolium (MTT) assay and their migration potential by a scratch assay. Moreover, expression of the hyaluronic acid receptor (CD44) and the C-X-C chemokine receptor type 4 (CXCR4, CD184) on the surface of BMSCs was assessed by flow cytometry, and the release of Transforming Growth Factor (TGF)-β, Interleukin (IL)-1α and IL-6 was quantified using an enzyme-linked immunosorbent assay (ELISA). The effect of NBD-coated implants on human osteoblasts was tested by measuring alkaline phosphatase (ALP) activity with the p-nitrophenyl phosphate (pNPP) degradation test. NBD stimulated BMSC growth/viability, migration, CD184 surface expression and the release of TGF-β1. NBD-coated implants increased ALP activity of human osteoblasts. These results indicate that NBD may be an adjuvant to accelerate both bone regeneration and osseointegration.
Collapse
Affiliation(s)
- Graziella Bellone
- Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy
| | - Barbara Vizio
- Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy
| | - Tiziana Scirelli
- Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy
| | - Giorgio Emanuelli
- Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Turin, Italy
| |
Collapse
|
|
21
|
Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells. Biochem Soc Trans 2016; 44:377-85. [PMID: 27068943 PMCID: PMC5264496 DOI: 10.1042/bst20150254] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Indexed: 12/13/2022]
Abstract
The success of adoptive T-cell therapies for the treatment of cancer patients depends on transferred T-lymphocytes finding and infiltrating cancerous tissues. For intravenously transferred T-cells, this means leaving the bloodstream (extravasation) from tumour blood vessels. In inflamed tissues, a key event in extravasation is the capture, rolling and arrest of T-cells inside blood vessels which precedes transmigration across the vessel wall and entry into tissues. This depends on co-ordinated signalling of selectins, integrins and chemokine receptors on T-cells by their respective ligands which are up-regulated on inflamed blood vessels. Clinical data and experimental studies in mice suggest that tumour blood vessels are anergic to inflammatory stimuli and the recruitment of cytotoxic CD8+ T-lymphocytes is not very efficient. Interestingly, and somewhat counter-intuitively, anti-angiogenic therapy can promote CD8+ T-cell infiltration of tumours and increase the efficacy of adoptive CD8+ T-cell therapy. Rather than inhibit tumour angiogenesis, anti-angiogenic therapy ‘normalizes’ (matures) tumour blood vessels by promoting pericyte recruitment, increasing tumour blood vessel perfusion and sensitizing tumour blood vessels to inflammatory stimuli. A number of different approaches are currently being explored to increase recruitment by manipulating the expression of homing-associated molecules on T-cells and tumour blood vessels. Future studies should address whether these approaches improve the efficacy of adoptive T-cell therapies for solid, vascularized cancers in patients.
Collapse
|
|
22
|
Cheng H, Wang L, Mollica M, Re AT, Wu S, Zuo L. Nitric oxide in cancer metastasis. Cancer Lett 2014; 353:1-7. [PMID: 25079686 DOI: 10.1016/j.canlet.2014.07.014] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 07/03/2014] [Accepted: 07/04/2014] [Indexed: 12/12/2022]
Abstract
Cancer metastasis is the spread and growth of tumor cells from the original neoplasm to further organs. This review analyzes the role of nitric oxide (NO), a signaling molecule, in the regulation of cancer formation, progression, and metastasis. The action of NO on cancer relies on multiple factors including cell type, metastasis stage, and organs involved. Various chemotherapy drugs cause cells to release NO, which in turn induces cytotoxic death of breast, liver, and skin tumors. However, NO has also been clinically connected to a poor cancer prognosis because of its role in angiogenesis and intravasation. This supports the claim that NO can be characterized as both pro-metastatic and anti-metastatic, depending on specific factors. The inhibition of cell proliferation and anti-apoptosis pathways by NO donors has been proposed as a novel therapy to various cancers. Studies suggest that NO-releasing non-steroidal anti-inflammatory drugs act on cancer cells in several ways that may make them ideal for cancer therapy. This review summarizes the biological significance of NO in each step of cancer metastasis, its controversial effects for cancer progression, and its therapeutic potential.
Collapse
Affiliation(s)
- Huiwen Cheng
- Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Edison Biotechnology Institute, Konneker Research Center, Ohio University, Athens, OH 45701, USA
| | - Lei Wang
- Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Edison Biotechnology Institute, Konneker Research Center, Ohio University, Athens, OH 45701, USA
| | - Molly Mollica
- Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Edison Biotechnology Institute, Konneker Research Center, Ohio University, Athens, OH 45701, USA
| | - Anthony T Re
- School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Shiyong Wu
- Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Edison Biotechnology Institute, Konneker Research Center, Ohio University, Athens, OH 45701, USA.
| | - Li Zuo
- School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
| |
Collapse
|
|
23
|
Mikucki ME, Fisher DT, Ku AW, Appenheimer MM, Muhitch JB, Evans SS. Preconditioning thermal therapy: flipping the switch on IL-6 for anti-tumour immunity. Int J Hyperthermia 2013; 29:464-73. [PMID: 23862980 DOI: 10.3109/02656736.2013.807440] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cancer immunotherapy aims to generate long-lived, tumour-specific adaptive immunity to limit dysregulated tumour progression and metastasis. Tumour vasculature has emerged as a critical checkpoint controlling the efficacy of immunotherapy since it is the main access point for cytotoxic T cells to reach tumour cell targets. Therapeutic success has been particularly challenging to achieve because of the local, cytokine-rich inflammatory milieu that drives a pro-tumourigenic programme supporting the growth and survival of malignant cells. Here, we focus on recent evidence that systemic thermal therapy can switch the activities of the inflammatory cytokine, interleukin-6 (IL-6), to a predominantly anti-tumourigenic function that promotes anti-tumour immunity by mobilising T cell trafficking in the recalcitrant tumour microenvironment.
Collapse
Affiliation(s)
- Maryann E Mikucki
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
| | | | | | | | | | | |
Collapse
|
|
24
|
The role of the tumor endothelium in leukocyte recruitment in pancreatic cancer. Surgery 2012; 152:S89-94. [DOI: 10.1016/j.surg.2012.05.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 05/11/2012] [Indexed: 12/13/2022]
|
|
25
|
Fisher DT, Chen Q, Skitzki JJ, Muhitch JB, Zhou L, Appenheimer MM, Vardam TD, Weis EL, Passanese J, Wang WC, Gollnick SO, Dewhirst MW, Rose-John S, Repasky EA, Baumann H, Evans SS. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest 2011; 121:3846-59. [PMID: 21926464 DOI: 10.1172/jci44952] [Citation(s) in RCA: 197] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Accepted: 08/03/2011] [Indexed: 12/26/2022] Open
Abstract
Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in recruiting mediators of adaptive anticancer immunity has not been investigated. Here, we report that homeostatic trafficking of tumor-reactive CD8+ T cells across microvascular checkpoints is limited in tumors despite the presence of inflammatory cytokines. Intravital imaging in tumor-bearing mice revealed that systemic thermal therapy (core temperature elevated to 39.5°C ± 0.5°C for 6 hours) activated an IL-6 trans-signaling program in the tumor blood vessels that modified the vasculature such that it could support enhanced trafficking of CD8+ effector/memory T cells (Tems) into tumors. A concomitant decrease in tumor infiltration by Tregs during systemic thermal therapy resulted in substantial enhancement of Tem/Treg ratios. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors. Parallel increases in vascular adhesion were induced by IL-6/soluble IL-6 receptor-α fusion protein in mouse tumors and patient tumor explants. Finally, a causal link was established between IL-6-dependent licensing of tumor vessels for Tem trafficking and apoptosis of tumor targets. These findings suggest that the unique IL-6-rich tumor microenvironment can be exploited to create a therapeutic window to boost T cell-mediated antitumor immunity and immunotherapy.
Collapse
Affiliation(s)
- Daniel T Fisher
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Takeichi T, Mocevicius P, Deduchovas O, Salnikova O, Castro-Santa E, Büchler MW, Schmidt J, Ryschich E. αL β2 integrin is indispensable for CD8+ T-cell recruitment in experimental pancreatic and hepatocellular cancer. Int J Cancer 2011; 130:2067-76. [PMID: 21647874 DOI: 10.1002/ijc.26223] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Accepted: 05/23/2011] [Indexed: 12/30/2022]
Abstract
Recruitment of activated leukocytes from peripheral blood into the tumor tissue is a crucial step of the immune response, which is controlled by the interaction between specific adhesion molecules such as endothelial ICAM-1 and leukocyte β(2) -integrins. Although attenuated expression of adhesion molecules on tumor endothelium has been proposed to represent a mechanism, which suppresses the intratumoral leukocyte infiltration, the relevance of adhesion molecules for leukocyte recruitment in tumor tissue is poorly understood. The present study is the first investigation of the role of ICAM-1 and β(2) -integrins in leukocyte recruitment in pancreatic and hepatocellular cancer in vivo, which was studied using knockout mice, intravital time-lapse microscopy and immunohistochemistry. We found that tumor tissue of both pancreatic and hepatocellular cancer was infiltrated with numerous active lymphoid and myeloid leukocytes, although the leukocyte extravasation rate in tumor blood vessels was very low. The knockout of LFA-1 (also known as α(L) β(2) integrin) strongly suppressed recruitment of CD8(+) T cells whereas no significant differences of leukocyte adhesion and infiltration were found in ICAM-1(-/-) and Mac-1(-/-) mice. Analysis of the interstitial leukocyte migration demonstrated that intratumoral leukocytes used haptokinetic type of migration, however, no significant differences of leukocyte migration between any knockout strains were found. We concluded that leukocyte recruitment in pancreatic and hepatocellular cancer is a slow-going process whose dynamics clearly contrasts to a high-speed leukocyte recruitment during acute inflammation. In contrast to acute inflammatory reaction, only LFA-1 controls recruitment of CD8(+) T-cells in both pancreatic and hepatocellular cancer, whereas ICAM-1 and Mac-1 are dispensable.
Collapse
Affiliation(s)
- Takayuki Takeichi
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
27
|
TGF-β and microvessel homeostasis. Microvasc Res 2010; 80:166-73. [DOI: 10.1016/j.mvr.2010.03.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2010] [Revised: 02/23/2010] [Accepted: 03/04/2010] [Indexed: 12/17/2022]
|
|
28
|
Evans SS, Fisher DT, Skitzki JJ, Chen Q. Targeted regulation of a lymphocyte-endothelial-interleukin-6 axis by thermal stress. Int J Hyperthermia 2009; 24:67-78. [DOI: 10.1080/02656730701772498] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
|
|
29
|
Valença SS, Pimenta WA, Rueff-Barroso CR, Ferreira TS, Resende AC, Moura RSD, Porto LC. Involvement of nitric oxide in acute lung inflammation induced by cigarette smoke in the mouse. Nitric Oxide 2009; 20:175-81. [PMID: 19070674 DOI: 10.1016/j.niox.2008.11.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2008] [Revised: 11/10/2008] [Accepted: 11/23/2008] [Indexed: 02/04/2023]
Abstract
Short-term exposure to cigarette smoke (CS) leads to acute lung inflammation (ALI) by disturbing oxidant/antioxidant balance. Both CS exposure and lung inflammation are important risk factors in the pathogenesis of chronic obstructive pulmonary disease. Nitric oxide (NO) is an oxidant both present in CS and produced in the inflammatory response, but its role in the effects of CS exposure is unclear. Our aim was to study involvement of NO in a model of CS exposure. Groups of mice (male C57BL/6) exposed to CS (six cigarettes per day over five days) were simultaneously subjected to treatment with vehicle (CS), 60mg/kg/day omega-nitro-l-arginine methyl ester (CS+l-NAME), 20mg/kg/day nitroglycerine (CS+NTG), or 120mg/kg/day l-arginine (CS+l-arg). Bronchoalveolar lavage fluid was then aspirated to perform cell counts, and malondialdehyde (MDA), nitrite, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels were measured in lung homogenates. Macrophage and neutrophil counts were increased in the CS (p<0.001) and CS+l-NAME groups (p<0.05 and p<0.01, respectively); the CS+NTG and CS+l-arg groups showed no differences from the control group. MDA was increased in the CS (p<0.05) and CS+l-NAME (p<0.01) groups when compared to the control group. Nitrite levels were decreased in the CS and CS+l-NAME groups (p<0.001) and increased in the CS+NTG (p<0.001) and CS+l-arg (p<0.01) groups when compared to the control. CAT, SOD and GPx activities in the CS and CS+l-NAME groups were all significantly increased compared to the control group. Our results suggest that administration of NO donors or substrates may be a useful therapy in the treatment of ALI caused by CS.
Collapse
Affiliation(s)
- Samuel Santos Valença
- Laboratory of Tissue Repair, Department of Histology and Embryology, Rio de Janeiro State University, Brazil
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Han SU, Kwak TH, Her KH, Cho YH, Choi C, Lee HJ, Hong S, Park YS, Kim YS, Kim TA, Kim SJ. CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling. Oncogene 2007; 27:675-83. [PMID: 17653079 DOI: 10.1038/sj.onc.1210686] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The carcinoembryonic antigen (CEAs) family consists of a large group of evolutionarily and structurally divergent glycoproteins. The transforming growth factor-beta (TGF-beta) signaling pathway has been implicated in the stimulation of CEA secretion in TGF-beta-sensitive colon cells, thereby possibly modulating cell adhesion and differentiation. However, the specific CEAs targeted by TGF-beta signaling or underlying mechanism of the expression of CEAs has not yet been clarified. In this study, we investigated the specific CEAs targeted by the TGF-beta signaling pathway. In nine human gastric cancer cell lines examined, TGF-beta-responsive cell lines showed positive expression of CEAs. Expression patterns of CEA proteins correlated well with the level of CEA (CEACAM5) and CEACAM6 transcripts in these cell lines, but CEACAM1 expression was not observed in all of these cells. To investigate the role of TGF-beta signaling in CEA expression, we selected two TGF-beta unresponsive gastric cancer cell lines; SNU638 cells that contain a mutation in the TGF-beta type II receptor and SNU484 cells that express low to undetectable level of the TGF-beta pathway intermediate protein, Smad3. Restoration of TGF-beta signaling in these cells induced expression of the CEAs and increased activity of both CEA (CEACAM5) and CEACAM6 promoters. CEA expression was observed in the epithelium of the stomach of wild-type mice, but was markedly decreased in Smad3 null mice. These findings suggest that CEA (CEACAM5) and CEACAM6 are major target genes for Smad3-mediated TGF-beta signaling.
Collapse
Affiliation(s)
- S-U Han
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Mrass P, Weninger W. Immune cell migration as a means to control immune privilege: lessons from the CNS and tumors. Immunol Rev 2006; 213:195-212. [PMID: 16972905 DOI: 10.1111/j.1600-065x.2006.00433.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Certain organs, such as the brain, eye, and gonads, are particularly sensitive to damage by inflammation. Therefore, these tissues have developed unique immunological properties that curtail inflammatory responses, a phenomenon termed immune privilege. In addition, by co-opting some of the regulatory cues operant in immune privilege in normal organs, tumors can evade immunosurveillance. While many different mechanisms contribute to immune privilege, there is evidence that leukocyte migration is an important checkpoint in its control. This hypothesis is based on the fact that leukocyte entry into these organs is restricted by physical barriers and that the collapse of these obstacles marks a critical step in the development of inflammatory/autoimmune disease at these sites. Numerous studies in a variety of experimental systems have characterized the molecular and cellular mechanisms involved in leukocyte homing to immune-privileged organs. Recently, two-photon microscopy has revealed critical insights into the events occurring in the extravascular space of immune-privileged organs, including locomotion patterns and interactive behavior of leukocytes in the interstitial space. Here, we review our current understanding of immune cell migration to and within immune-privileged organs and highlight how this knowledge may be exploited for immunotherapeutic purposes.
Collapse
Affiliation(s)
- Paulus Mrass
- Immunology Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | | |
Collapse
|
|
32
|
Arenas M, Gil F, Gironella M, Hernández V, Jorcano S, Biete A, Piqué JM, Panés J. Anti-inflammatory effects of low-dose radiotherapy in an experimental model of systemic inflammation in mice. Int J Radiat Oncol Biol Phys 2006; 66:560-7. [PMID: 16965998 DOI: 10.1016/j.ijrobp.2006.06.004] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2006] [Revised: 06/04/2006] [Accepted: 06/06/2006] [Indexed: 11/29/2022]
Abstract
PURPOSE The aim of this study was to determine the effects of low-dose radiotherapy (LD-RT) on the inflammatory response and to characterize the potential mechanisms underlying these effects. METHODS AND MATERIALS Mice were irradiated with 0.1, 0.3, 0.6 Gy, or sham radiation before lipopolysaccharide (LPS) challenge. Leukocyte-endothelial cell interactions in intestinal venules were assessed using intravital microscopy. Intercellular adhesion molecule-1 (ICAM-1) expression was determined using radiolabeled antibodies 5 h after irradiation. Production of transforming growth factor-beta1 (TGF-beta1) was measured by enzyme-linked immunosorbent assay and its in vivo functional relevance by immunoneutralization. RESULTS Compared with vehicle treated animals, LPS induced a marked increase in leukocyte adhesion (0.13+/-0.59 vs. 5.89+/-1.03, p<0.0001) in intestinal venules. The number of adherent leukocytes was significantly reduced by the 3 doses of LD-RT tested; the highest inhibition was observed with 0.3 Gy (0.66+/-1.96, p<0.0001). LPS-induced ICAM-1 upregulation was not modified by LD-RT. Circulating levels of TGF-beta1 were significantly increased in response to LD-RT in controls and LPS challenged animals. Neutralization of TGF-beta1 partially restored LPS-induced adhesion (4.83+/-1.41, p<0.05). CONCLUSIONS LD-RT has a significant anti-inflammatory effect, inhibiting leukocyte recruitment, which is maximal at 0.3 Gy. This effect results in part from increased TGF-beta1 production and is not related to modulation of ICAM-1 expression.
Collapse
Affiliation(s)
- Meritxell Arenas
- Department of Radiation Oncology, Hospital Clínic de Barcelona, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12:477-479. [DOI: 10.11569/wcjd.v12.i2.477] [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] [Indexed: 02/06/2023] Open
|
|
34
|
Eichhorn ME, Strieth S, Krasnici S, Sauer B, Teifel M, Michaelis U, Naujoks K, Dellian M. Protamine enhances uptake of cationic liposomes in angiogenic microvessels of solid tumours. Angiogenesis 2004; 7:133-41. [PMID: 15516834 DOI: 10.1007/s10456-004-1428-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Cationic liposomes have been shown to target angiogenic endothelial cells of solid tumours. Supposing a charge-related mechanism might be responsible for liposome-endothelial interaction, we investigated the effect of intravenous pre-injection of the charged molecules protamine, a polycationic protein, and fucoidan, a polyanionic polysaccharide on the accumulation of cationic liposomes within the blood vessels of a solid tumour. MATERIALS AND METHODS Experiments were performed using the amelanotic hamster melanoma A-Mel-3 growing in a dorsal skinfold chamber of hamsters. Accumulation of fluorescently-labelled cationic liposomes was quantified by intravital macroscopy and digital image analysis of tumour (t) and surrounding normal host tissue (n) over an observation period of 6 h. All animals received an i.v. injection of cationic liposomes. Animals of the control group were pre-treated with an i.v. injection of 0.9% saline, while animals of group 2 received positively charged protamine and animals of group 3 negatively charged fucoidan prior to liposome injection. RESULTS In control animals i.v. injection of cationic liposomes revealed a preferential targeting of the tumour vessels, indicated by a maximal t/n ratio of 2.2 +/- 0.24 and a maximal fluorescence intensity (fmax) corresponding to the tumour of 66 +/- 12 [% standard]. While there were no significant differences of liposome accumulation within normal host tissue, accumulation of cationic liposomes within the tumour was significantly enhanced after the pre-administration of protamine (fmax: 117 +/- 12 [% standard]). The t/n ratio was significantly increased in protamine pre-treated animals (5.3 +/- 1.7) in comparison to control and fucoidan treated animals. In contrast, pre-injection of fucoidan resulted in reduced maximal fluorescence intensities in tumour (47 +/- 8 [% standard]) and normal surrounding host tissue. CONCLUSION Pre-administration of protamine increases the accumulation of cationic liposomes in a solid tumour animal model causing an increased selectivity of cationic liposomes in targeting angiogenic microvessels.
Collapse
Affiliation(s)
- M E Eichhorn
- Department of Surgery, Klinikum Grosshadern, University of Munich, Germany
| | | | | | | | | | | | | | | |
Collapse
|