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Middha P, Kachuri L, Nierenberg JL, Graff RE, Cavazos TB, Hoffmann TJ, Zhang J, Alexeeff S, Habel L, Corley DA, Van Den Eeden S, Kushi LH, Ziv E, Sakoda LC, Witte JS. Unraveling the genetic landscape of susceptibility to multiple primary cancers. HGG ADVANCES 2025; 6:100413. [PMID: 39910817 PMCID: PMC11910107 DOI: 10.1016/j.xhgg.2025.100413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/29/2025] [Accepted: 01/29/2025] [Indexed: 02/07/2025] Open
Abstract
With advances in cancer screening and treatment, there is a growing population of cancer survivors who may develop subsequent primary cancers. While hereditary cancer syndromes account for only a portion of multiple cancer cases, we sought to explore the role of common genetic variation in susceptibility to multiple primary tumors. We conducted a cross-ancestry genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) of 10,983 individuals with multiple primary cancers, 84,475 individuals with single cancer, and 420,944 cancer-free controls from two large-scale studies. Our GWAS identified six lead variants across five genomic regions that were significantly associated (p < 5 × 10-8) with the risk of developing multiple primary tumors (overall and invasive) relative to cancer-free controls (at 3q26, 8q24, 10q24, 11q13.3, and 17p13). We also found one variant significantly associated with multiple cancers when compared with single cancer cases (at 22q13.1). Multi-tissue TWAS detected associations with genes involved in telomere maintenance in two of these regions (ACTRT3 in 3q26 and SLK and STN1 in 10q24) and the development of multiple cancers. Additionally, the TWAS also identified several novel genes associated with multiple cancers, including two immune-related genes, IRF4 and TNFRSF6B. Telomere maintenance and immune dysregulation emerge as central, common pathways influencing susceptibility to multiple cancers. These findings underscore the importance of exploring shared mechanisms in carcinogenesis, offering insights for targeted prevention and intervention strategies.
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Affiliation(s)
- Pooja Middha
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Linda Kachuri
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA
| | - Jovia L Nierenberg
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Rebecca E Graff
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Taylor B Cavazos
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Thomas J Hoffmann
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
| | - Jie Zhang
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Stacey Alexeeff
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Laurel Habel
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Douglas A Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | | | - Lawrence H Kushi
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Elad Ziv
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
| | - Lori C Sakoda
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA; Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
| | - John S Witte
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
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Middha P, Kachuri L, Nierenberg JL, Graff RE, Cavazos TB, Hoffmann TJ, Zhang J, Alexeeff S, Habel L, Corley DA, Van Den Eeden S, Kushi LH, Ziv E, Sakoda LC, Witte JS. Unraveling the genetic landscape of susceptibility to multiple primary cancers. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.10.29.24316326. [PMID: 39574869 PMCID: PMC11581075 DOI: 10.1101/2024.10.29.24316326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2024]
Abstract
With advances in cancer screening and treatment, there is a growing population of cancer survivors who may develop subsequent primary cancers. While hereditary cancer syndromes account for only a portion of multiple cancer cases, we sought to explore the role of common genetic variation in susceptibility to multiple primary tumors. We conducted a cross-ancestry genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) of 10,983 individuals with multiple primary cancers, 84,475 individuals with single cancer, and 420,944 cancer-free controls from two large-scale studies. Our GWAS identified six lead variants across five genomic regions that were significantly associated (P<5×10-8) with the risk of developing multiple primary tumors (overall and invasive) relative to cancer-free controls (at 3q26, 8q24, 10q24, 11q13.3, and 17p13). We also found one variant significantly associated with multiple cancers when comparing to single cancer cases (at 22q13.1). Multi-tissue TWAS detected associations with genes involved in telomere maintenance in two of these regions (ACTRT3 in 3q26 and SLK and STN1 in 10q24) and the development of multiple cancers. Additionally, the TWAS also identified several novel genes associated with multiple cancers, including two immune-related genes, IRF4 and TNFRSF6B. Telomere maintenance and immune dysregulation emerge as central, common pathways influencing susceptibility to multiple cancers. These findings underscore the importance of exploring shared mechanisms in carcinogenesis, offering insights for targeted prevention and intervention strategies.
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Affiliation(s)
- Pooja Middha
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Linda Kachuri
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
| | - Jovia L Nierenberg
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Rebecca E Graff
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Taylor B Cavazos
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Thomas J Hoffmann
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Jie Zhang
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Stacey Alexeeff
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Laurel Habel
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Douglas A Corley
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
- Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Stephen Van Den Eeden
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Lawrence H Kushi
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Elad Ziv
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Lori C Sakoda
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
- Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
| | - John S Witte
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
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Duan Y, Fang H, Wang J, Ruan B, Yang J, Liu J, Gou S, Li Y, Cheng Z. DcR3-associated risk score: correlating better prognosis and enhanced predictive power in colorectal cancer. Discov Oncol 2024; 15:233. [PMID: 38890197 PMCID: PMC11189376 DOI: 10.1007/s12672-024-01082-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 06/05/2024] [Indexed: 06/20/2024] Open
Abstract
Decoy receptor 3 (DcR3), a novel soluble protein belonging to the tumor necrosis factor receptor (TNFR) family, has been previously associated with tumorigenesis in various cancers. However, in our study, we unexpectedly found that DcR3 may promote patient survival time in colorectal cancer (CRC). Through an analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, we discovered that high levels of DcR3 are associated with improved overall survival (OS) and disease-free survival (DFS) in CRC patients. Further investigation revealed that DcR3 is correlated with favorable clinical features in Metastasis 0 (M0) and stage I/II CRC patients, suggesting it may act as a suppressive factor in CRC. Gene Set Enrichment Analysis (GSEA) demonstrated that the high DcR3 group is enriched in the IL-17 signaling pathway and other immune-related pathways, and Single Sample Gene Set Enrichment Analysis (ssGSEA) revealed a higher abundance of Tumor Infiltrating Lymphocytes (TIL) in the DcR3 high group. To better understand the function of DcR3, we constructed a DcR3-associated riskscore (DARS) model using machine learning, comprising three genes (DPP7, KDM3A, and TMEM86B). The DARS model indicated that high riskscore patients have an unfavorable prognosis, and it is associated with advanced stages (III/IV), T3/4 tumors, and N1/2 lymph node involvement. Additionally, high riskscore group exhibited more frequent gene mutations, such as TTN, MUC16, and SYNE1, with SYNE1 mutation being related to poor prognosis. Intriguingly, DcR3 showed higher expression in the low riskscore group. These results suggest that DcR3 could serve as a potential prognostic biomarker in CRC and may play a crucial role in favorably modulating the immune response in this malignancy.
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Affiliation(s)
- Ying Duan
- Department of Pathology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 710018, Shaanxi, People's Republic of China.
| | - Hangrong Fang
- Department of Pathology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 710018, Shaanxi, People's Republic of China
| | - Juanhong Wang
- Department of Pathology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 710018, Shaanxi, People's Republic of China
| | - Banlai Ruan
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Advanced Technology, Shenzhen Institute of Synthetic Biology, Chinese Academy of Sciences, Shenzhen, China
| | - Juan Yang
- Department of Pathology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 710018, Shaanxi, People's Republic of China
| | - Jie Liu
- Medical Research Center, Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Siqi Gou
- Department of Pathology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 710018, Shaanxi, People's Republic of China
| | - Yijie Li
- Department of Pathology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 710018, Shaanxi, People's Republic of China
| | - Zhengyi Cheng
- Department of Pathology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 710018, Shaanxi, People's Republic of China
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Lagou S, Grapsa D, Syrigos N, Bamias G. The Role of Decoy Receptor DcR3 in Gastrointestinal Malignancy. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:411-421. [PMID: 35813013 PMCID: PMC9254098 DOI: 10.21873/cdp.10124] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/19/2022] [Indexed: 06/15/2023]
Abstract
Malignancies are among the leading causes of mortality worldwide. Early detection and treatment are the primary targets of clinical and translational research, and may be facilitated by the recognition of novel diagnostic and prognostic biomarkers. Decoy receptor 3 (DcR3) is a soluble receptor of the tumor necrosis factor receptor superfamily of proteins (TNFRSF), which associates with its respective TNF-like ligands, Fas-L, LIGHT, and TL1A. DcR3 has been recognised as a significant anti-apoptotic factor with prominent involvement in various inflammatory and neoplastic conditions. Increased intratumor expression of DcR3 and elevated soluble DcR3 protein content in the sera of patients has been reported for various malignancies. Recent published work has suggested that monitoring of local and systemic DcR3 may provide an attractive biomarker, mainly for defining subgroups of patients with aggressive tumor behaviour and poor prognosis. The aim of the present review is to summarize and critically present existing evidence regarding the potential clinical importance of monitoring DcR3 expression in patients with malignancies of the gastrointestinal tract, as well as liver and pancreatic cancer. We also present a detailed description of the pathophysiological basis that may underlie the involvement of DcR3 in gastrointestinal carcinogenesis. Based on these data, we comment on the potential applicability of DcR3 monitoring in the diagnosis and, most importantly, the prognostic stratification of patients.
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Affiliation(s)
- Styliani Lagou
- Oncology Unit, 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitra Grapsa
- Oncology Unit, 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Syrigos
- Oncology Unit, 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Bamias
- GI Unit, 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Hu L, Zhu M, Shen Y, Zhong Z, Wu B. The prognostic value of intratumoral and peritumoral tumor-infiltrating FoxP3+Treg cells in of pancreatic adenocarcinoma: a meta-analysis. World J Surg Oncol 2021; 19:300. [PMID: 34654443 PMCID: PMC8520308 DOI: 10.1186/s12957-021-02420-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 10/07/2021] [Indexed: 12/11/2022] Open
Abstract
Background Tumor-infiltrating lymphocytes (TILs) are major participants in the tumor microenvironment. The prognostic value of TILs in patients with pancreatic cancer is still controversial. Methods The aim of our meta-analysis was to determine the impact of FoxP3+Treg cells on the survival of pancreatic cancer patients. We searched for related studies in PubMed, EMBASE, Ovid, and Cochrane Library from the time the databases were established to Mar 30, 2017. We identified studies reporting the prognostic value of FoxP3+Treg cells in patients with pancreatic cancer. Overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS) were investigated by pooling the data. The pooled hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to evaluate the association between FoxP3+Treg cells and survival outcomes of pancreatic cancer patients. A total of 972 pancreatic cancer patients from 8 studies were included in our meta-analysis. Results High levels of infiltration with FoxP3+Treg cells were significantly associated with poor OS (HR=2.13; 95% CI 1.64–2.77; P<0.05) and poor DFS/PFS/RFS (HR=1.70; 95% CI 1.04 ~ 2.78; P< 0.05). Similar results were also observed in the peritumoral tissue; high levels of FoxP3+Treg cells were associated with poor OS (HR =2.1795% CI, CI 1.50–3.13). Conclusion This meta-analysis indicated that high levels of intratumoral or peritumoral FoxP3+Treg cell infiltration could be recognized as a negative factor in the prognosis of pancreatic cancer.
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Affiliation(s)
- Lingyu Hu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of JiaXing University, Jiaxing, 314000, Zhejiang, China
| | - Mingyuan Zhu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of JiaXing University, Jiaxing, 314000, Zhejiang, China
| | - Yiyu Shen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of JiaXing University, Jiaxing, 314000, Zhejiang, China
| | - Zhengxiang Zhong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of JiaXing University, Jiaxing, 314000, Zhejiang, China.
| | - Bin Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of JiaXing University, Jiaxing, 314000, Zhejiang, China.
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Apoptosis-Inducing TNF Superfamily Ligands for Cancer Therapy. Cancers (Basel) 2021; 13:cancers13071543. [PMID: 33801589 PMCID: PMC8036978 DOI: 10.3390/cancers13071543] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/21/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is a complex disease with apoptosis evasion as one of its hallmarks; therefore, apoptosis induction in transformed cells seems a promising approach as a cancer treatment. TNF apoptosis-inducing ligands, which are naturally present in the body and possess tumoricidal activity, are attractive candidates. The most studied proteins are TNF-α, FasL, and TNF-related apoptosis-inducing ligand (TRAIL). Over the years, different recombinant TNF family-derived apoptosis-inducing ligands and agonists have been designed. Their stability, specificity, and half-life have been improved because most of the TNF ligands have the disadvantages of having a short half-life and affinity to more than one receptor. Here, we review the outlook on apoptosis-inducing ligands as cancer treatments in diverse preclinical and clinical stages and summarize strategies of overcoming their natural limitations to improve their effectiveness.
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Skeate JG, Otsmaa ME, Prins R, Fernandez DJ, Da Silva DM, Kast WM. TNFSF14: LIGHTing the Way for Effective Cancer Immunotherapy. Front Immunol 2020; 11:922. [PMID: 32499782 PMCID: PMC7243824 DOI: 10.3389/fimmu.2020.00922] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 04/21/2020] [Indexed: 12/21/2022] Open
Abstract
Tumor necrosis factor superfamily member 14 (LIGHT) has been in pre-clinical development for over a decade and shows promise as a modality of enhancing treatment approaches in the field of cancer immunotherapy. To date, LIGHT has been used to combat cancer in multiple tumor models where it can be combined with other immunotherapy modalities to clear established solid tumors as well as treat metastatic events. When LIGHT molecules are delivered to or expressed within tumors they cause significant changes in the tumor microenvironment that are primarily driven through vascular normalization and generation of tertiary lymphoid structures. These changes can synergize with methods that induce or support anti-tumor immune responses, such as checkpoint inhibitors and/or tumor vaccines, to greatly improve immunotherapeutic strategies against cancer. While investigators have utilized multiple vectors to LIGHT-up tumor tissues, there are still improvements needed and components to be found within a human tumor microenvironment that may impede translational efforts. This review addresses the current state of this field.
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Affiliation(s)
- Joseph G Skeate
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Mikk E Otsmaa
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Ruben Prins
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Daniel J Fernandez
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Diane M Da Silva
- Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
| | - W Martin Kast
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
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Lafaro KJ, Melstrom LG. The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:44-57. [PMID: 30558722 DOI: 10.1016/j.ajpath.2018.09.009] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 08/28/2018] [Accepted: 09/25/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is projected to become the second leading cause of cancer death in the United States. Despite significant advances in understanding the disease, there has been minimal increase in PDAC patient survival. PDAC tumors are unique in the fact that there is significant desmoplasia. This generates a large stromal compartment composed of immune cells, inflammatory cells, growth factors, extracellular matrix, and fibroblasts, comprising the tumor microenvironment (TME), which may represent anywhere from 15% to 85% of the tumor. It has become evident that the TME, including both the stroma and extracellular component, plays an important role in tumor progression and chemoresistance of PDAC. This review will discuss the multiple components of the TME, their specific impact on tumorigenesis, and the multiple therapeutic targets.
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Affiliation(s)
- Kelly J Lafaro
- Department of Surgery, City of Hope National Medical Center, Duarte, California
| | - Laleh G Melstrom
- Department of Surgery, City of Hope National Medical Center, Duarte, California.
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Chang WC, Yeh YC, Ho HL, Hsieh SL, Chou TY. Decoy Receptor 3 Expression Is Associated With Wild-Type EGFR Status, Poor Differentiation of Tumor, and Unfavorable Patient Outcome. Am J Clin Pathol 2019; 152:207-216. [PMID: 31077284 DOI: 10.1093/ajcp/aqz035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVES The role of decoy receptor 3 (DcR3) in lung cancer, particularly adenocarcinoma, has not been well studied. In this study, we aim to investigate the expression profile and the clinicopathologic implications of DcR3 expression in lung adenocarcinoma. METHODS Immunohistochemistry was used to examine DcR3 expression in 461 lung adenocarcinomas. The differences in DcR3 expression among the various histopathologic patterns were analyzed. The relationship between DcR3 expression and clinicopathologic parameters, including epidermal growth factor receptor (EGFR) mutation, was also investigated. RESULTS DcR3 expression was more frequently expressed in solid, micropapillary, and acinar patterns (P < .0001) and in tumors with wild-type EGFR status (P = .018). In addition, DcR3 expression portends a less favorable disease-free survival in stage I patients (P = .012). CONCLUSIONS The expression of DcR3 might be involved in the differentiation and progression of lung adenocarcinoma. Therefore, DcR3 may be applied clinically for prediction of tumor progression in stage I lung adenocarcinoma.
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Affiliation(s)
- Wei-Chin Chang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Pathology, MacKay Memorial Hospital and MacKay Medical College, Taipei, Taiwan
- MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Yi-Chen Yeh
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsiang-Ling Ho
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shie-Liang Hsieh
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Teh-Ying Chou
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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10
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Cheng SH, Cheng YJ, Jin ZY, Xue HD. Unresectable pancreatic ductal adenocarcinoma: Role of CT quantitative imaging biomarkers for predicting outcomes of patients treated with chemotherapy. Eur J Radiol 2019; 113:188-197. [PMID: 30927946 DOI: 10.1016/j.ejrad.2019.02.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 02/04/2019] [Accepted: 02/10/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The primary aim of this study was to determine if computed tomographic (CT) texture analysis measurements of the tumor are independently associated with progression-free survival (PFS) and overall survival (OS) in patients with unresectable pancreatic ductal adenocarcinoma (PDAC), including both unresectable locally advanced and metastatic PDAC, who were treated with chemotherapy. METHODS After an institutional review board waiver was obtained, contrast material-enhanced CT studies in 41 patients with unresectable PDAC who underwent contrast-enhanced CT before chemotherapy between 2014 and 2017 were analyzed in terms of tumor texture, with quantification of mean gray-level intensity (Mean), entropy, mean of positive pixels (MPP), kurtosis, standard deviation (SD), and skewness for fine to coarse textures (spatial scaling factor (SSF) 0-6, respectively). The association between pretreatment and posttreatment texture parameters, as well as Δ value (difference between posttreatment and pretreatment texture parameters), and survival time was assessed by using Cox proportional hazards models and Kaplan-Meier analysis. RESULTS Findings from the multivariate Cox model indicated that tumor size, tumor SD (HR, 0.942; 95% CI: 0.898, 0.988) and skewness (HR, 0.407; 95% CI: 0.172, 0.962) measurements with SSF = 3, and tumor SD (HR, 0.958; 95% CI: 0.92, 0.997) measurements with SSF = 4 were significantly and independently associated with PFS, while tumor size and tumor SD (HR, 0.928; 95% CI: 0.882, 0.976) measurements with SSF = 3 were significantly and independently associated with OS. None of the post-therapy texture parameters or Δ value had a significant association with OS or PFS in multivariate Cox regression models. Medium SD (SSF = 3) of more than 38.38 and coarse SD (SSF = 4) of more than 40.67 were associated with longer PFS after chemotherapy (for SSF = 3, median PFS was 10.0 vs 6.0 months [P = 0.024], and for SSF = 4, median PFS was 12.0 vs 6.0 months [P = 0.003]). SD of 38.38 or greater (SSF = 3) as a dichotomized variable was a significant positive prognostic factor for OS (median OS, 20.0 vs 9.0 months [P = 0.04]). Survival models that included a combination of pretreatment SD (SSF = 3) with tumor size, had the potential to perform better than SD alone, while having no statistical significance in this study (area under the ROC curve, 0.756 vs 0.715 [P = 0.066]). CONCLUSIONS Pretreatment CT quantitative imaging biomarkers from texture analysis are associated with PFS and OS in patients with unresectable PDAC who were treated with chemotherapy, and the combination of pretreatment texture parameters and tumor size have the potential to perform better in survival models than imaging biomarker alone.
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Affiliation(s)
- Si-Hang Cheng
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yue-Juan Cheng
- Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Zheng-Yu Jin
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Hua-Dan Xue
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
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Ge H, Liang C, Ren S, Yue C, Wu J. Prognostic value of DcR3 in solid tumors: A meta-analysis. Clin Chim Acta 2018; 481:126-131. [PMID: 29499202 DOI: 10.1016/j.cca.2018.02.038] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 02/27/2018] [Accepted: 02/27/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Decoy receptor 3 (DcR3) has been reported to be overexpressed in a wide range of solid tumors, suggesting that DcR3 plays a crucial role in the development and progression of cancer. The present meta-analysis assesses the association between DcR3 expression and prognosis in patients with solid tumors. METHODS Eligible studies were identified by searching the PubMed, Web of Science, Cochrane Library, EMBASE, Chinese CNKI, and Wan Fang databases. The pooled hazard ratios (HRs) for overall survival (OS) and recurrence-free survival (RFS) were calculated using fixed effects models and random effects models, respectively. RESULTS Data from the 16 included studies, with 2209 patients, were reviewed and analyzed. DcR3 overexpression was significantly associated with worse OS in patients with solid tumors, but its expression might not be related to RFS in malignancies. CONCLUSIONS Current evidence demonstrates that increased DcR3 expression correlates with a poor prognosis in cancer patients, which suggests that the expression status of DcR3 is a useful biomarker for the prediction of prognosis in patients with solid tumors.
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Affiliation(s)
- Hua Ge
- Department of general surgery, Beijing Tongren hospital, Capital Medical University, Beijing, People's Republic of China
| | - Chaojie Liang
- Department of general surgery, Beijing Tongren hospital, Capital Medical University, Beijing, People's Republic of China
| | - Shulin Ren
- Department of general surgery, Beijing Tongren hospital, Capital Medical University, Beijing, People's Republic of China
| | - Chaosen Yue
- Department of general surgery, Beijing Tongren hospital, Capital Medical University, Beijing, People's Republic of China
| | - Jixiang Wu
- Department of general surgery, Beijing Tongren hospital, Capital Medical University, Beijing, People's Republic of China.
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12
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DcR3 induces epithelial-mesenchymal transition through activation of the TGF-β3/SMAD signaling pathway in CRC. Oncotarget 2018; 7:77306-77318. [PMID: 27764793 PMCID: PMC5363587 DOI: 10.18632/oncotarget.12639] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 09/28/2016] [Indexed: 12/11/2022] Open
Abstract
Decoy receptor 3 (DcR3), a novel member of the tumor necrosis factor receptor (TNFR) family, was recently reported to be associated with tumorigenesis and metastasis. However, the role of DcR3 in human colorectal cancer (CRC) has not been fully elucidated. In this study, we found that DcR3 expression was significantly higher in human colorectal cancer tissues than in paired normal tissues, and that DcR3 expression was strongly correlated with tumor invasion, lymph node metastases and poor prognoses. Moreover, DcR3 overexpression significantly enhanced CRC cell proliferation and migration in vitro and tumorigenesis in vivo. Conversely, DcR3 knockdown significantly repressed CRC cell proliferation and migration in vitro, and DcR3 deficiency also attenuated CRC tumorigenesis and metastasis in vivo. Functionally, DcR3 was essential for TGF-β3/SMAD-mediated epithelial-mesenchymal transition (EMT) of CRC cells. Importantly, cooperation between DcR3 and TGF-β3/SMAD-EMT signaling-related protein expression was correlated with survival and survival time in CRC patients. In conclusion, our results demonstrate that DcR3 may be a prognostic biomarker for CRC and that this receptor facilitates CRC development and metastasis by participating in TGF-β3/SMAD-mediated EMT of CRC cells.
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13
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Li J, Xie N, Yuan J, Liu L, Zhou Q, Ren X, Chen Q, Zhang G, Ruan Q, Chen YH, Wan X. DcR3 combined with hematological traits serves as a valuable biomarker for the diagnosis of cancer metastasis. Oncotarget 2017; 8:107612-107620. [PMID: 29296192 PMCID: PMC5746094 DOI: 10.18632/oncotarget.22544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 10/30/2017] [Indexed: 11/25/2022] Open
Abstract
Decoy receptor 3 (DcR3) is abnormally up-regulated in many cancer cells. It may help cancer cells to escape from immune surveillance and establish metastatic lesions. However, whether DcR3 can be used as a biomarker for the diagnosis of cancer metastasis is unclear. In this study, sera from healthy controls and patients with different cancers were collected, and tested for their DcR3 levels by ELISA. Significantly elevated DcR3 levels were observed in the sera of patients with gastric cancer (2.04 ± 1.01, P = 0.0061), lymphoma (1.62 ± 0.75, P = 0.041), and breast cancer (1.53 ± 0.51, P = 0.023). DcR3 was found to be a suitable biomarker for identifying gastric cancer patients. Importantly, DcR3 was positively associated with platelet distribution width (PDW) (P = 2.45 × 10−6, R = 0.63) in metastatic cancers but negatively associated with hemoglobin (HGB) (P = 0.002, R = −0.59) and hematocrit (HCT) (P = 0.001, R = −0.62) in non-metastatic cancers. Combined with PDW, HGB and HCT, serum DcR3 could be used to predict the occurrence of cancer metastasis. These findings indicate that DcR3 could be used as a biomarker for the diagnosis of gastric cancer, and for cancer metastasis in combination with hematological traits.
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Affiliation(s)
- Junxin Li
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, University City of Shenzhen, Xili Nanshan, Shenzhen, 518055, P.R. China.,University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Ni Xie
- Institute of Translation Medicine, Shenzhen Second People's Hospital, Shenzhen, 518035, P.R. China
| | - Jianhui Yuan
- Institute of Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, P.R. China
| | - Lvyan Liu
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, University City of Shenzhen, Xili Nanshan, Shenzhen, 518055, P.R. China
| | - Qiming Zhou
- Department of Oncology, Nanshan Hospital of Shenzhen, Shenzhen, 518055, P.R. China
| | - Xiaohu Ren
- Institute of Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, P.R. China
| | - Qian Chen
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, University City of Shenzhen, Xili Nanshan, Shenzhen, 518055, P.R. China.,University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Guizhong Zhang
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, University City of Shenzhen, Xili Nanshan, Shenzhen, 518055, P.R. China
| | - Qingguo Ruan
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, University City of Shenzhen, Xili Nanshan, Shenzhen, 518055, P.R. China
| | - Youhai H Chen
- Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
| | - Xiaochun Wan
- Shenzhen Laboratory of Fully Human Antibody Engineering, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, University City of Shenzhen, Xili Nanshan, Shenzhen, 518055, P.R. China
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Abstract
Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor (TNFR) superfamily member 6b (TNFRSF6B), is a soluble decoy receptor which can neutralize the biological functions of three members of tumor necrosis factor superfamily (TNFSF): Fas ligand (FasL), LIGHT, and TL1A. In addition to ‘decoy’ function, recombinant DcR3.Fc is able to modulate the activation and differentiation of dendritic cells (DCs) and macrophages via ‘non-decoy’ action. DcR3-treated DCs skew T cell differentiation into Th2 phenotype, while DcR3-treated macrophages behave M2 phenotype. DcR3 is upregulated in various cancer cells and several inflammatory tissues, and is regarded as a potential biomarker to predict inflammatory disease progression and cancer metastasis. However, whether DcR3 is a pathogenic factor or a suppressor to attenuate inflammatory reactions, has not been discussed comprehensively yet. Because mouse genome does not have DcR3, it is not feasible to investigate its physiological functions by gene-knockout approach. However, DcR3-mediated effects in vitro are determined via overexpressing DcR3 or addition of recombinant DcR3.Fc fusion protein. Moreover, CD68-driven DcR3 transgenic mice are used to investigate DcR3-mediated systemic effects in vivo. Upregulation of DcR3 during inflammatory reactions exerts negative-feedback to suppress inflammation, while tumor cells hijack DcR3 to prevent apoptosis and promote tumor growth and invasion. Thus, ‘switch-on’ of DcR3 expression may be feasible for the treatment of inflammatory diseases and enhance tissue repairing, while ‘switch-off’ of DcR3 expression can enhance tumor apoptosis and suppress tumor growth in vivo.
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Affiliation(s)
- Shie-Liang Hsieh
- Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 115, Taiwan. .,Institute of Clinical Medicine & Immunology Research Center, National Yang-Ming University, Taipei, Taiwan. .,Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan. .,Institute of Immunology, College of Medicine, National Taiwan University Taipei, Taipei, Taiwan. .,Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
| | - Wan-Wan Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, No. 1 Section 1, Jen Ai Road, Taipei, 10001, Taiwan.
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15
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Chen J, Guo XZ, Li HY, Zhao JJ, Xu WD. Dendritic cells engineered to secrete anti-DcR3 antibody augment cytotoxic T lymphocyte response against pancreatic cancer in vitro. World J Gastroenterol 2017; 23:817-829. [PMID: 28223726 PMCID: PMC5296198 DOI: 10.3748/wjg.v23.i5.817] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 11/04/2016] [Accepted: 12/21/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the enhanced cytotoxic T lymphocyte responses against pancreatic cancer (PC) in vitro induced by dendritic cells (DCs) engineered to secrete anti-DcR3 monoclonal antibody (mAb).
METHODS DCs, T lymphocytes and primary PC cells were obtained from PC patients. DCs were transfected with a designed humanized anti-DcR3 monoclonal antibody heavy and light chain mRNA and/or total tumor RNA (DC-tumor-anti-DcR3 RNA or DC-total tumor RNA) by using electroporation technology. The identification, concentration and function of anti-DcR3 mAb secreted by DC-tumor-anti-DcR3 RNA were determined by western blotting and enzyme-linked immunosorbent assay. After co-culturing of autologous isolated PC cells with target DCs, the effects of secreting anti-DcR3 mAb on RNA-DCs’ viability and apoptosis were assessed by MTT assay and flow cytometry. Analysis of enhanced antigen-specific immune response against PC induced by anti-DcR3 mAb secreting DCs was performed using a 51Cr releasing test. T cell responses induced by RNA-loaded DCs were analyzed by measuring cytokine levels, including IFN-γ, IL-10, IL4, TNF-α and IL-12.
RESULTS The anti-DcR3 mAb secreted by DCs reacted with recombinant human DcR3 protein and generated a band with 35 kDa molecular weight. The secreting mAb was transient, peaking at 24 h and becoming undetectable after 72 h. After co-incubation with DC-tumor-anti-DcR3 RNA for designated times, the DcR3 level in the supernatant of autologous PC cells was significantly down-regulated (P < 0.05). DCs secreting anti-DcR3 mAb could improve cell viability and slow down the apoptosis of RNA-loaded DCs, compared with DC-total tumor RNA (P < 0.01). The anti-DcR3 mAb secreted by DC-tumor-anti-DcR3 RNA could enhance the induction of cytotoxic T lymphocytes (CTLs) activity toward RNA-transfected DCs, primary tumor cells, and PC cell lines, compared with CTLs stimulated by DC-total tumor RNA or control group (P < 0.05). Meanwhile, the antigen-specific CTL responses were MHC class I-restricted. The CD4+ T cells and CD8+ T cells incubated with anti-DcR3 mAb secreting DCs could produce extremely higher level IFN-γ and lower level IL4 than those incubated with DC-total tumor RNA or controls (P < 0.01).
CONCLUSION DCs engineered to secrete anti-DcR3 antibody can augment CTL responses against PC in vitro, and the immune-enhancing effects may be partly due to their capability of down-regulating DC apoptosis and adjusting the Th1/Th2 cytokine network.
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16
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Liang DY, Hou YQ, Lou XL. Effect of silencing decoy receptor 3 on biological features of hepatoma cells. Shijie Huaren Xiaohua Zazhi 2017; 25:234-240. [DOI: 10.11569/wcjd.v25.i3.234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To detect the expression of decoy receptor 3 (DcR3) in hepatoma cells, and to investigate its role in the biological features of hepatoma cells.
METHODS Real-time PCR and Western blot were used to detect the expression of DcR3 mRNA and protein in human hepatoma cell lines HepG2 and Huh7 and normal hepatocytes (HL-7702 and Chang liver). ELISA was used to detect the level of DcR3 protein in the supernatant of these four cell lines. A lentiviral vector carrying shRNA against DcR3 (LV-shDcR3) was synthesized and used to infect HepG2 and Huh7 cells, with the empty lentiviral vector as a control. After infection, the interference effects were determined by Western blot, cell proliferation was assessed by CCK-8 assay and colony forming assay, cell apoptosis was examined by flow cytometry, and the expression of apoptosis related protein like PARP was detected by Western blot. The expression of TRAIL, FasL and LIGHT before and after infection was also detected by Western blot.
RESULTS The expression of DcR3 was significantly increased in hepatoma cell lines HepG2 and Huh7 both at the mRNA and protein levels compared with normal hepatocytes. The levels of DcR3 in the supernatants of HepG2 and Huh7 cells were also increased. Compared with the mock group and empty lentiviral vector infected group, the LV-shDcR3 infected group showed reduced expression of DcR3, lower cell viability rate, and higher cell apoptosis rate. The expression of TRAIL and FasL was increased after infection with LV-shDcR3 in HepG2 and Huh7 cells.
CONCLUSION The expression of DcR3 is elevated in hepatoma cells. Down-regulation of the expression of DcR3 inhibits cell proliferation and induces cell apoptosis in hepatoma cells, via mechanisms that may be related with the TRAIL and FasL apoptosis pathway.
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17
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Fu Z, Chen S, Liu S, Han S, Gao X, Li D, Li D. DcR3 gene polymorphisms are associated with sporadic breast infiltrating ductal carcinoma in Northeast Chinese women. Oncotarget 2016; 7:57970-57977. [PMID: 27517320 PMCID: PMC5295404 DOI: 10.18632/oncotarget.11153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 07/26/2016] [Indexed: 01/31/2023] Open
Abstract
Decoy Receptor 3 (DcR3), also called TNFRSF6β, is a member of the tumor necrosis factor receptor superfamily and is a soluble receptor for FasL. DcR3 is overexpressed in cancers and contributes to tumorigenesis through immune suppression and promotion of angiogenesis. We found that DcR3 is overexpressed in breast infiltrating ductal carcinoma (IDC) cells as compared with normal controls. We also conducted a case-control study analyzing associations of DcR3 polymorphisms with breast IDC risk. Subjects included 531 females with breast IDC and 592 age-matched healthy controls. Four DcR3 single nucleotide polymorphism loci with minor frequencies of more than 5% (rs3208008, rs41309931, rs2297441 and rs1291207) were genotyped using polymerase chain reaction restriction fragment length polymorphism and sequencing. Our results revealed significant differences in rs41309931genotypes and alleles (P < 0.01). Based on Haploview software analysis, the haplotype block Ars3208008 Grs41309931 Grs2297441 Ars1291207 exhibited the highest frequency, but, haplotype blocks Ars3208008 Trs41309931 Grs2297441 Ars1291207 and Crs3208008 Grs41309931 Grs2297441 Ars1291207 were associated with breast IDC risk. This study also detected associations between DcR3 gene polymorphisms and the clinicopathological features of breast IDC, including lymph node metastasis and C-erbB2, P53, estrogen receptor and progesterone receptor status. These data indicate that DcR3 gene polymorphisms are associated with sporadic breast IDC risk in Northeast Chinese females.
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Affiliation(s)
- Zhenkun Fu
- Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081 Harbin, China
| | - Shuang Chen
- Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081 Harbin, China.,Department of Immunology, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081 Harbin, China
| | - Shengwei Liu
- Department of Immunology, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081 Harbin, China
| | - Shaoli Han
- Department of Immunology, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081 Harbin, China
| | - Xiang Gao
- Department of Immunology, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081 Harbin, China
| | - Dalin Li
- Department of Breast Surgery, The Third Affiliated Hospital of Harbin Medical University, 150081 Harbin, China
| | - Dianjun Li
- Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081 Harbin, China.,Department of Immunology, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081 Harbin, China
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18
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Zhang Y, Luo J, He R, Huang W, Li Z, Li P, Dang Y, Chen G, Li S. Expression and clinicopathological implication of DcR3 in lung cancer tissues: a tissue microarray study with 365 cases. Onco Targets Ther 2016; 9:4959-68. [PMID: 27570459 PMCID: PMC4986681 DOI: 10.2147/ott.s105225] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Decoy receptor 3 (DcR3) has been reported to be involved in different cancers. However, few related researches have been accomplished on the role of DcR3 in lung cancer. OBJECTIVE To explore the expression level and clinicopathological implication of DcR3 protein in lung cancer tissues. MATERIALS AND METHODS Immunohistochemistry was used to examine DcR3 protein expression in lung cancer (n=365) and normal lung tissues (n=26). The relationships between DcR3 expression and clinical parameters were further investigated. Furthermore, the diagnostic and clinicopathological value of DcR3 mRNA was analyzed based on The Cancer Genome Atlas database in lung cancer patients. RESULTS Compared to normal lung tissues, DcR3 expression was significantly higher in lung cancer (P=0.007) tissues, including small-cell lung cancer (P=0.001) and non-small-cell lung cancer (P=0.008). In addition, DcR3 expression was related to tumor-node-metastasis (TNM) stage (P<0.001), tumor diameter (P=0.007), distant metastasis (P<0.001), and lymph node metastasis (P<0.001) in lung cancers. When concerning non-small-cell lung cancer, consistent correlations between DcR3 expression and TNM stage (P<0.001), tumor diameter (P=0.019), distant metastasis (P<0.001), and lymph node metastasis (P<0.001) were found. Simultaneously, in small-cell lung cancer, TNM stage (P=0.004) and lymph node metastasis (P=0.005) were also associated with DcR3 expression. Additionally, receiver operator characteristic curve revealed that the area under curve (AUC) of DcR3 was 0.637 (95% confidence interval [CI] 0.531-0.742) for lung cancer. Furthermore, DcR3 was overexpressed in both adenocarcinoma and squamous cell carcinoma tissues than in noncancerous lung tissues (all P<0.0001) based on the data from The Cancer Genome Atlas. AUC of DcR3 was 0.726 (95% CI 0.644-0.788) for lung adenocarcinoma patients and 0.647 (95% CI 0.566-0.728) for squamous cell carcinoma patients. DcR3 expression was also related to the overall survival (P<0.001) and disease-free survival (P<0.001) of lung adenocarcinoma according to the data from The Cancer Genome Atlas. CONCLUSION Our study confirms that DcR3 might be involved in the tumorigenesis and deterioration of lung cancer. Therefore, the detection of DcR3 gains the potential to be applied in the clinic for screening and progression prediction of lung cancer.
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Affiliation(s)
| | - Jie Luo
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University
| | - Rongquan He
- Center for Genomic and Personalized Medicine, Guangxi Medical University
| | | | | | | | | | | | - Shikang Li
- Department of Thoracic and Cardiovascular Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China
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Jiang YQ, Zhong TF, Dang YW, Zou LS, Yang L, Yang X, Chen G. Overexpression and clinicopathological contribution of DcR3 in bladder urothelial carcinoma tissues. Asian Pac J Cancer Prev 2015; 15:9137-42. [PMID: 25422191 DOI: 10.7314/apjcp.2014.15.21.9137] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To explore the expression of DcR3 protein and its clinicopathological significance in bladder urothelial carcinomas (BUC). MATERIALS AND METHODS Immunohistochemistry was performed to detect the expression of DcR3, caspase-3, Bcl-2, VEGF, Ki-67, PCNA and P53 in 166 BUC and 56 normal bladder tissues. Western blotting was used to detect the expression of DcR3 in the supernatants of cultured BUC cells. RESULTS Overexpression of DcR3 was found in BUC tissues and cell lines, with significant elevation as compared to normal bladder tissues (p<0.0001). Higher DcR3 expression was related to the status of invasion, lymph node metastasis and recurrence. Furthermore, DcR3 expression was negatively correlated with caspase-3 and positively associated with Bcl-2, VEGF, Ki-67 labeling index (LI), PCNA LI and P53 (all p<0.0001), respectively. CONCLUSIONS DcR3 may play a crucial role as an oncogene in tumorigenesis, deterioration and progress of BUC via influencing related pathways of apoptosis, proliferation and angiogenesis. The detection of DcR3 protein in the formalin- fixed and paraffin-embedded samples could assist to predict in prognosis of BUC patients.
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Affiliation(s)
- Yi-Qiang Jiang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, China E-mail :
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Decoy receptor 3 suppresses FasL-induced apoptosis via ERK1/2 activation in pancreatic cancer cells. Biochem Biophys Res Commun 2015; 463:1144-51. [PMID: 26102031 DOI: 10.1016/j.bbrc.2015.06.074] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 06/10/2015] [Indexed: 12/31/2022]
Abstract
Resistance to Fas Ligand (FasL) mediated apoptosis plays an important role in tumorigenesis. Decoy receptor 3 (DcR3) is reported to interact with FasL and is overexpressed in some malignant tumors. We sought to investigate the role of DcR3 in resistance to FasL in pancreatic cancer. We compared expression of apoptosis related genes between FasL-resistant SW1990 and FasL-sensitive Patu8988 pancreatic cell lines by microarray analysis. We explored the impact of siRNA knockdown of, or exogenous supplementation with, DcR3 on FasL-induced cell growth inhibition in pancreatic cancer cell lines and expression of proteins involved in apoptotic signaling. We assessed the level of DcR3 protein and ERK1/2 phosphorylation in tumor and non-tumor tissue samples of 66 patients with pancreatic carcinoma. RNAi knockdown of DcR3 expression in SW1990 cells reduced resistance to FasL-induced apoptosis, and supplementation of Patu8988 with rDcR3 had the opposite effect. RNAi knockdown of DcR3 in SW1990 cells elevated expression of caspase 3, 8 and 9, and reduced ERK1/2 phosphorylation (P < 0.05), but did not alter phosphorylated-Akt expression. 47 tumor tissue specimens, but only 15 matched non-tumor specimens stained for DcR3 (χ(2) = 31.1447, P < 0.001). The proliferation index of DcR3 positive specimens (14.26 ± 2.67%) was significantly higher than that of DcR3 negative specimens (43.58 ± 7.88%, P < 0.01). DcR3 expression positively correlated with p-ERK1/2 expression in pancreatic cancer tissues (r = 0.607, P < 0.001). DcR3 enhances ERK1/2 phosphorylation and opposes FasL signaling in pancreatic cancer cells.
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