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Xin H, Chen Y, Niu H, Li X, Gai X, Cui G. Integrated Analysis Construct a Tumor-Associated Macrophage Novel Signature with Promising Implications in Predicting the Prognosis and Immunotherapeutic Response of Gastric Cancer Patients. Dig Dis Sci 2024; 69:2055-2073. [PMID: 38573378 DOI: 10.1007/s10620-024-08365-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 02/09/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND Gastric cancer (GC) remains one of the most prevalent malignant tumors worldwide. At present, tumor-associated macrophages (TAMs) are essential in the progression, metastasis, and drug resistance of tumors. Therefore, TAMs can be a crucial target for tumor treatment. AIMS We intended to investigate the TAM characteristics in GC and develop a risk signature based on TAM to predict the prognosis of GC patients. METHODS The single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data were acquired from a publicly available database. We utilized the Seurat pipeline to process the scRNA-seq data and determine TAM cell types using marker genes. Univariate Cox regression analysis was utilized to examine TAM-related prognostic genes, and then we employed Lasso-Cox regression analysis, and Multivariate Cox regression analysis established a novel risk profile to forecast the clinical value of the model with a new nomogram combining risk profiles and clinicopathological characteristics. RESULTS The current study employed scRNA-seq data to identify five TAM clusters in GC, among which four were significantly associated with GC prognosis. Accordingly, we further developed a TAM-related risk signature utilizing nine genes. After evaluation, our model accurately predicted the prognosis of gastric cancer. Generally, GC patients with low TAMS scores exhibited a more favorable prognosis, greater benefits from immunotherapy, and higher levels of immune cell infiltration. CONCLUSIONS The prognosis of GC can be effectively predicted by TAM-based risk signatures, and the signature may provide a new perspective for comprehensively guiding clinical diagnosis, prediction, and immunotherapy for gastric cancer.
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Affiliation(s)
- Hua Xin
- Laboratory Medicine, The First Affiliated Hospital of Jiamusi University, Jiamusi, 154000, Heilongjiang Province, China
| | - Yu Chen
- Clinical Medicine Department, Jiamusi University, Jiamusi, 154000, Heilongjiang Province, China
| | - Honglin Niu
- Clinical Medicine Department, Jiamusi University, Jiamusi, 154000, Heilongjiang Province, China
| | - Xuebin Li
- Clinical Medicine Department, Jiamusi University, Jiamusi, 154000, Heilongjiang Province, China
| | - Xuejie Gai
- Clinical Medicine Department, Jiamusi University, Jiamusi, 154000, Heilongjiang Province, China
| | - Guoli Cui
- Laboratory Medicine, The First Affiliated Hospital of Jiamusi University, Jiamusi, 154000, Heilongjiang Province, China.
- Clinical Medicine Department, Jiamusi University, Jiamusi, 154000, Heilongjiang Province, China.
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Wang B, Zhou B, Chen J, Sun X, Yang W, Yang T, Yu H, Chen P, Chen K, Huang X, Fan X, He W, Huang J, Lin T. Type III interferon inhibits bladder cancer progression by reprogramming macrophage-mediated phagocytosis and orchestrating effective immune responses. J Immunother Cancer 2024; 12:e007808. [PMID: 38589249 PMCID: PMC11015199 DOI: 10.1136/jitc-2023-007808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Interferons (IFNs) are essential for activating an effective immune response and play a central role in immunotherapy-mediated immune cell reactivation for tumor regression. Type III IFN (λ), related to type I IFN (α), plays a crucial role in infections, autoimmunity, and cancer. However, the direct effects of IFN-λ on the tumor immune microenvironment have not been thoroughly investigated. METHODS We used mouse MB49 bladder tumor models, constructed a retroviral vector expressing mouse IFN-λ3, and transduced tumor cells to evaluate the antitumor action of IFN-λ3 in immune-proficient tumors and T cell-deficient tumors. Furthermore, human bladder cancer samples (cohort 1, n=15) were used for immunohistochemistry and multiplex immunoflurescence analysis to assess the expression pattern of IFN-λ3 in human bladder cancer and correlate it with immune cells' infiltration. Immunohistochemistry analysis was performed in neoadjuvant immunotherapy cohort (cohort 2, n=20) to assess the correlation between IFN-λ3 expression and the pathological complete response rate. RESULTS In immune-proficient tumors, ectopic Ifnl3 expression in tumor cells significantly increased the infiltration of cytotoxic CD8+ T cells, Th1 cells, natural killer cells, proinflammatory macrophages, and dendritic cells, but reduced neutrophil infiltration. Transcriptomic analyses revealed significant upregulation of many genes associated with effective immune response, including lymphocyte recruitment, activation, and phagocytosis, consistent with increased antitumor immune infiltrates and tumor inhibition. Furthermore, IFN-λ3 activity sensitized immune-proficient tumors to anti-PD-1/PD-L1 blockade. In T cell-deficient tumors, increased Ly6G-Ly6C+I-A/I-E+ macrophages still enhanced tumor cell phagocytosis in Ifnl3 overexpressing tumors. IFN-λ3 is expressed by tumor and stromal cells in human bladder cancer, and high IFN-λ3 expression was positively associated with effector immune infiltrates and the efficacy of immune checkpoint blockade therapy. CONCLUSIONS Our study indicated that IFN-λ3 enables macrophage-mediated phagocytosis and antitumor immune responses and suggests a rationale for using Type III IFN as a predictive biomarker and potential immunotherapeutic candidate for bladder cancer.
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Affiliation(s)
- Bo Wang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Bingkun Zhou
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Junyu Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Xi Sun
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Wenjuan Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Tenghao Yang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Hao Yu
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Peng Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Ke Chen
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Xiaodong Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Xinxiang Fan
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Wang He
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Jian Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
| | - Tianxin Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen (Zhongshan) University, Guangzhou, China
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Privitera G, Williams JJ, De Salvo C. The Importance of Th2 Immune Responses in Mediating the Progression of Gastritis-Associated Metaplasia to Gastric Cancer. Cancers (Basel) 2024; 16:522. [PMID: 38339273 PMCID: PMC10854712 DOI: 10.3390/cancers16030522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Gastric cancer is one of the leading causes of cancer deaths worldwide, with chronic gastritis representing the main predisposing factor initiating the cascade of events leading to metaplasia and eventually progressing to cancer. A widely accepted classification distinguishes between autoimmune and environmental atrophic gastritis, mediated, respectively, by T cells promoting the destruction of the oxyntic mucosa, and chronic H. pylori infection, which has also been identified as the major risk factor for gastric cancer. The original dogma posits Th1 immunity as a main causal factor for developing gastritis and metaplasia. Recently, however, it has become evident that Th2 immune responses play a major role in the events causing chronic inflammation leading to tumorigenesis, and in this context, many different cell types and cytokines are involved. In particular, the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages and eosinophils, are intertwined in the process, promoting chronic gastritis-dependent and more diffuse metaplasia. Herein, we provide an overview of the critical events driving the pathology of this disease, focusing on the most recent findings regarding the importance of Th2 immunity in gastritis and gastric metaplasia.
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Affiliation(s)
- Giuseppe Privitera
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; (G.P.); (J.J.W.)
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142 Milan, Italy
| | - Joseph J. Williams
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; (G.P.); (J.J.W.)
| | - Carlo De Salvo
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; (G.P.); (J.J.W.)
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Gao Y, Wan L, Li M, Wang B, Ma Y. NRF2/HO-1 axis, BIRC5, and TP53 expression in ESCC and its correlation with clinical pathological characteristics and prognosis. Int J Biol Markers 2023; 38:174-184. [PMID: 37312528 DOI: 10.1177/03936155231176571] [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] [Indexed: 06/15/2023]
Abstract
BACKGROUND Many types of cancer exhibit high nuclear factor erythroid 2-related factor 2 (NRF2), which is effective in resisting drugs and radiation. However, the role of NRF2 gene expression in predicting the prognosis of esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS The association between NRF2, heme oxygenase-1 (HO-1), baculovirus IAP repeat 5 (BIRC5), P53 gene expression levels and their relationship to immune-infiltrating cells were assessed using the Cancer Genome Atlas dataset, the Human Protein Atlas and the TISDB database. The expression of NRF2, HO-1, BIRC5, and TP53 in 118 ESCC patients was detected by immunohistochemistry, and the relationship between their expression level and clinicopathological parameters and prognosis was analyzed. RESULTS In ESCC, NRF2 overexpression was significantly associated with Han ethnicity, lymph node metastasis, and distant metastasis. HO-1 overexpression was significantly associated with differentiation, advanced clinical staging, lymph node metastasis, nerve invasion, and distant metastasis. BIRC5 overexpression was significantly associated with Han ethnicity and lymph node metastasis. TP53 overexpression was significantly associated with Han ethnicity and T staging. The NRF2/HO-1 axis expression was positively correlated with BIRC5 and TP53. Kaplan-Meier and multivariate Cox regression analysis showed that NRF2, BIRC5, and TP53 genes co-expression was an independent prognostic risk factor. TISIDB dataset analysis showed that immune-infiltrating cells were significantly negatively correlated with NRF2 and BIRC5. CONCLUSION NRF2, BIRC5, and TP53 axis gene expressions are predictors of poor prognosis for ESCC. The overexpression of the NRF2/HO-1/BIRC5 axis may not be related to immune-infiltrating cells.
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Affiliation(s)
- Yongmei Gao
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Li Wan
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Mengyan Li
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Bo Wang
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yuqing Ma
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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Wang JB, Gao YX, Ye YH, Lin TX, Li P, Lin JX, Chen QY, Cao LL, Lin M, Tu RH, Lin JL, Huang ZN, Zheng HL, Xie JW, Zheng CH, Huang CM. CDK5RAP3 acts as a tumour suppressor in gastric cancer through the infiltration and polarization of tumour-associated macrophages. Cancer Gene Ther 2023; 30:22-37. [PMID: 35999359 PMCID: PMC9842504 DOI: 10.1038/s41417-022-00515-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 07/05/2022] [Accepted: 07/21/2022] [Indexed: 01/21/2023]
Abstract
We have demonstrated that CDK5RAP3 exerts a tumour suppressor effect in gastric cancer, but its role in regulating tumour-associated macrophages (TAMs) has not yet been reported. Here, we show that CDK5RAP3 is related to the infiltration and polarization of macrophages. It inhibits the polarization of TAMs to M2 macrophages and promotes the polarization of the M1 phenotype. CDK5RAP3 reduces the recruitment of circulating monocytes to infiltrate tumour tissue by inhibiting the CCL2/CCR2 axis in gastric cancer. Blocking CCR2 reduces the growth of xenograft tumours and the infiltration of monocytes. CDK5RAP3 inhibits the nuclear transcription of NF-κB, thereby reducing the secretion of the cytokines IL4 and IL10 and blocking the polarization of M2 macrophages. In addition, the absence of CDK5RAP3 in gastric cancer cells allows macrophages to secrete more MMP2 to promote the epithelial-mesenchymal transition (EMT) process of gastric cancer cells, thereby enhancing the invasion and migration ability. Our results imply that CDK5RAP3 may be involved in the regulation of immune activity in the tumour microenvironment and is expected to become a potential immunotherapy target for gastric cancer.
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Affiliation(s)
- Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - You-Xin Gao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Yin-Hua Ye
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Tong-Xing Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Ru-Hong Tu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Ju-Li Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Ze-Ning Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Hua-Long Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China.
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
- Fujian Key Laboratory of Tumour Microbiology, Fujian Medical University, Fuzhou, China.
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Aisa A, Weng S, Li X, Zhang D, Yuan Y. Immune Checkpoint Inhibitors combined with HER-2 targeted therapy in HER-2 positive Gastroesophageal cancer. Crit Rev Oncol Hematol 2022; 180:103864. [DOI: 10.1016/j.critrevonc.2022.103864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/25/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022] Open
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Ma M, Sun J, Liu Z, Ouyang S, Zhang Z, Zeng Z, Li J, Kang W. The Immune Microenvironment in Gastric Cancer: Prognostic Prediction. Front Oncol 2022; 12:836389. [PMID: 35574386 PMCID: PMC9096124 DOI: 10.3389/fonc.2022.836389] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Although therapeutic methods have been developed, gastric cancer (GC) still leads to high rates of mortality and morbidity and is the fourth leading cause of cancer-associated death and the fifth most common cancer worldwide. To understand the factors associated with the prognostic prediction of GC and to discover efficient therapeutic targets, previous studies on tumour pathogenesis have mainly focused on the cancer cells themselves; in recent years, a large number of studies have shown that cancer invasion and metastasis are the results of coevolution between cancer cells and the microenvironment. It seems that studies on the tumour microenvironment could help in prognostic prediction and identify potential targets for treating GC. In this review, we mainly introduce the research progress for prognostic prediction and the immune microenvironment in GC in recent years, focusing on cancer-associated fibroblasts (CAFs), tumour-associated macrophages (TAMs), and tumour-infiltrating lymphocytes (TILs) in GC, and discuss the possibility of new therapeutic targets for GC.
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Affiliation(s)
- Mingwei Ma
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Juan Sun
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Zhen Liu
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Siwen Ouyang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Zimu Zhang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Ziyang Zeng
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Jie Li
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Weiming Kang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
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Gowhari Shabgah A, Amir A, Gardanova ZR, Olegovna Zekiy A, Thangavelu L, Ebrahimi Nik M, Ahmadi M, Gholizadeh Navashenaq J. Interleukin-25: New perspective and state-of-the-art in cancer prognosis and treatment approaches. Cancer Med 2021; 10:5191-5202. [PMID: 34128588 PMCID: PMC8335817 DOI: 10.1002/cam4.4060] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/27/2021] [Accepted: 05/27/2021] [Indexed: 12/16/2022] Open
Abstract
Cancer is a leading cause of death which imposes a substantial financial burden. Among the several mechanisms involved in cancer progression, imbalance of immune cell-derived factors such as cytokines and chemokines plays a central role. IL-25, as a member of the IL-17 cytokine subfamily, exerts a paradoxical role in cancer, including tumor supportive and tumor suppressive. Hence, we have tried to clarify the role of IL-25 and its receptor in tumor progression and cancer prognosis. It has been confirmed that IL-25 exerts a tumor-suppressive role through inducing infiltration of eosinophils and B cells into the tumor microenvironment and activating the apoptotic pathways. In contrast, the tumor-supportive function has been implemented by activating inflammatory cascades, promoting cell cycle, and inducing type-2 immune responses. Since IL-25 has been dysregulated in tumor tissues and this dysregulation is involved in cancer development, its examination can be used as a tumor diagnostic and prognostic biomarker. Moreover, IL-25-based therapeutic approaches have shown promising results in cancer inhibition. In cancers in which IL-25 has a tumor-suppressive function, employing IL-25-enhancing approaches, such as Virulizin® and dihydrobenzofuran administration, has potentially inhibited tumor cell growth. On the other hand, in the case of IL-25-dependent tumor progression, using IL-25 blocking methods, including anti-IL-25 antibodies, might be a complementary approach to the other anticancer agent. Collectively, it is hoped, IL-25 might be a promising target in cancer treatment.
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Affiliation(s)
- Arezoo Gowhari Shabgah
- School of MedicineBam University of Medical SciencesBamIran
- Student Research CommitteeBam University of Medical SciencesBamIran
| | - Azwar Amir
- Wahidin Sudirohusodo Hospital MakassarMakassarTamalanreaIndonesia
| | - Zhanna R. Gardanova
- Department of PsychotherapyPirogov Russian National Research Medical UniversityMoscowRussia
| | - Angelina Olegovna Zekiy
- Department of Prosthetic DentistrySechenov First Moscow State Medical UniversityMoscowRussia
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of medical and Technical SciencesSaveetha UniversityChennaiIndia
| | - Maryam Ebrahimi Nik
- Nanotechnology Research Center, Pharmaceutical Technology InstituteMashhad University of Medical SciencesMashhadIran
| | - Majid Ahmadi
- Stem Cell Research CenterTabriz University of Medical SciencesTabrizIran
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Zhang Z, He T, Huang L, Li J, Wang P. Immune gene prognostic signature for disease free survival of gastric cancer: Translational research of an artificial intelligence survival predictive system. Comput Struct Biotechnol J 2021; 19:2329-2346. [PMID: 34025929 PMCID: PMC8111455 DOI: 10.1016/j.csbj.2021.04.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 04/09/2021] [Accepted: 04/09/2021] [Indexed: 12/13/2022] Open
Abstract
The progress of artificial intelligence algorithms and massive data provide new ideas and choices for individual mortality risk prediction for cancer patients. The current research focused on depict immune gene related regulatory network and develop an artificial intelligence survival predictive system for disease free survival of gastric cancer. Multi-task logistic regression algorithm, Cox survival regression algorithm, and Random survival forest algorithm were used to develop the artificial intelligence survival predictive system. Nineteen transcription factors and seventy immune genes were identified to construct a transcription factor regulatory network of immune genes. Multivariate Cox regression identified fourteen immune genes as prognostic markers. These immune genes were used to construct a prognostic signature for gastric cancer. Concordance indexes were 0.800, 0.809, and 0.856 for 1-, 3- and 5- year survival. An interesting artificial intelligence survival predictive system was developed based on three artificial intelligence algorithms for gastric cancer. Gastric cancer patients with high risk score have poor survival than patients with low risk score. The current study constructed a transcription factor regulatory network and developed two artificial intelligence survival prediction tools for disease free survival of gastric cancer patients. These artificial intelligence survival prediction tools are helpful for individualized treatment decision.
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Key Words
- AJCC, the American Joint Committee on Cancer
- CI, confidence interval
- DCA, decision curve analysis
- DFS, disease free survival
- Disease free survival
- GC, gastric cancer
- GEO, the Gene Expression Omnibus
- Gastric cancer
- HR, hazard ratio
- Immune gene
- Prognostic signature
- ROC, receiver operating characteristic
- SD, standard deviation
- TCGA, The Cancer Genome Atlas
- Transcription factor
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Affiliation(s)
- Zhiqiao Zhang
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Shunde, Guangdong, China
| | - Tingshan He
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Shunde, Guangdong, China
| | - Liwen Huang
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Shunde, Guangdong, China
| | - Jing Li
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Shunde, Guangdong, China
| | - Peng Wang
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Shunde, Guangdong, China
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10
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Kaewsarabhumi S, Proungvitaya T, Limpaiboon T, Tippayawat P, Tummanatsakun D, Titapun A, Sa-Ngaimwibool P, Proungvitaya S. Interleukin 25 (IL-25) expression in cholangiocarcinoma. Mol Clin Oncol 2020; 13:84. [PMID: 33163180 PMCID: PMC7642803 DOI: 10.3892/mco.2020.2154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 06/02/2020] [Indexed: 12/15/2022] Open
Abstract
Various cytokines are involved in carcinogenesis and tumor progression. Some tumor cells produce cytokines by themselves. Using secretome analysis, a high expression of APEX-1 was found in cholangiocarcinoma (CCA) cell lines. During this secretome analysis, it was found that CCA cell lines overexpressed some cytokines and related molecules, including interleukin 25 (IL-25). In the present study, we first performed precise secretome analysis on cytokines and related molecules in CCA cell lines and identified that IL-25 was overexpressed in CCA cell lines. Then, using immunohistochemical methods, we investigated the expression of IL-25 in the cancer tissues from 20 CCA patients in Northeast Thailand. Correlation between IL-25 expression levels and patients' clinical parameters were analyzed. The results showed that IL-25 expression was significantly (P<0.0001) higher in cancerous tissues than in the normal bile ducts and in the adjacent tissues. Overexpression of IL-25 protein in CCA tissue was confirmed using western blot analysis. Moreover, IL-25 expression in cancerous tissues was significantly (P<0.0015) higher in CCA patients with metastasis than in CCA patients without metastasis. Survival analysis revealed that a high expression of IL-25 was correlated with shorter survival time of CCA patients (P=0.0260). Aberrant expression of IL-25 in CCA tissue was associated with tumor metastasis and poor prognosis, suggesting that IL-25 is a potential prognostic biomarker. Biological roles of IL-25 in CCA genesis and progression should be explored in future.
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Affiliation(s)
- Supakit Kaewsarabhumi
- Centre of Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Tanakorn Proungvitaya
- Centre of Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Temduang Limpaiboon
- Centre of Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Patcharaporn Tippayawat
- Centre of Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Doungdean Tummanatsakun
- Centre of Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute (CARI), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Prakasit Sa-Ngaimwibool
- Cholangiocarcinoma Research Institute (CARI), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.,Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Siriporn Proungvitaya
- Centre of Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.,Cholangiocarcinoma Research Institute (CARI), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
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11
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Liu JY, Peng CW, Yang GF, Hu WQ, Yang XJ, Huang CQ, Xiong B, Li Y. Distribution pattern of tumor associated macrophages predicts the prognosis of gastric cancer. Oncotarget 2017; 8:92757-92769. [PMID: 29190953 PMCID: PMC5696219 DOI: 10.18632/oncotarget.21575] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 09/08/2017] [Indexed: 12/12/2022] Open
Abstract
Purpose As mayor biomarkers in tumor microenvironment (TME), tumor associated macrophages (TAMs) of gastric cancer (GC) still needs further studies in terms of the number and distribution pattern. Methods Herein, tissue microarrays (TMA) incorporating 494 GC surgical samples in duplicate were stained for TAMs infiltration analysis. TAMs number was counted according to the locations, including infiltrating macrophages in cancer nest (MC), in invasive front (MF) and in stroma (MS). Correlations between TAMs number, distribution pattern and clinic-pathological features and survival analyses were performed. Results Infiltrating macrophages number in GC tissues was much higher than that in peritumoral tissues. TAMs number was not significantly correlated with the overall survival (OS). TAMs distribution pattern could be categorized into MC or MF/MS dominant pattern, and correlated with histological grade (P =0.001). The median OS of MF/MS dominant pattern (22.1, 95%CI: 23.5-28.9) was significantly shorter than that of MC dominant pattern (25.6, 95%CI: 28.5-35.6) (P =0.002). By receiver operating characteristic curve (ROC) analysis, the predictive value of TAMs distribution pattern was superior to histological grade and pM stage, but inferior to pN and TNM stage. Conclusions TAMs distribution pattern could be an independent prognostic factor for the OS of GC patients, and patients with MF/MS dominant pattern had worse outcomes.
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Affiliation(s)
- Jiu-Yang Liu
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, China
| | - Chun-Wei Peng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, China
| | - Gui-Fang Yang
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wen-Qing Hu
- Department of Surgery, The First Affiliated Hospital of Shanxi Medical University, Taiyuan, 030001, PR China
| | - Xiao-Jun Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, China
| | - Chao-Qun Huang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, China
| | - Yan Li
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, China.,Department of Peritoneal Cancer Surgery, Cancer Center of Beijing Shijitan Hospital Affiliated to the Capital Medical University, Beijing, China
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12
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Martinez-Marin D, Jarvis C, Nelius T, de Riese W, Volpert OV, Filleur S. PEDF increases the tumoricidal activity of macrophages towards prostate cancer cells in vitro. PLoS One 2017; 12:e0174968. [PMID: 28403150 PMCID: PMC5389654 DOI: 10.1371/journal.pone.0174968] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 03/19/2017] [Indexed: 12/23/2022] Open
Abstract
Background Although inflammation and prostate cancer (PCa) have been linked, the molecular interactions between macrophages and PCa cells are poorly explored. Pigment Epithelium-Derived Factor (PEDF) is an anti-angiogenic and anti-tumor factor. We previously showed that PEDF induces macrophages recruitment in vitro, correlates with macrophages density in human prostate, and stimulates macrophages polarization towards the classically activated pathway. Here, we demonstrate that PEDF modulates the interaction between macrophages and PCa cells through a bidirectional signalling leading to tumor cell apoptosis and phagocytosis. Methods RAW 264.7 and THP-1 cells, and BMDMs were grown in vitro as mono- or co-cultures with PC3 or CL1 tumor cells. The effects of PEDF and its derived P18 peptide were measured on macrophages differentiation, migration, and superoxide production, and tumor cell apoptosis and phagocytosis. PEDF receptors (ATP5B, PNPLA2, and LRP6) and CD47 mRNA and protein expression were quantified in macrophages and tumor cells by quantitative RT-PCR, western blot, immunofluorescence and flow cytometry. Results We found that PEDF induced the migration of macrophages towards tumor 3D spheroids and 2D cultures. In co-culture, PEDF increased PCa cells phagocytosis through an indirect apoptosis-dependent mechanism. Moreover, PEDF stimulated the production of superoxide by macrophages. Conditioned media from macrophages exposed to PEDF induced tumor cells apoptosis in contrast to control conditioned media suggesting that ROS may be involved in tumor cells apoptosis. ATP5B and PNPLA2 PEDF receptors on macrophages and CD47 on tumor cells were respectively up- and down-regulated by PEDF. As PEDF, blocking CD47 induced phagocytosis. Inhibiting ATP5B reduced phagocytosis. Inversely, PNPLA2 inhibition blocks differentiation but maintains phagocytosis. CD47-induced phagocytosis was partially reverted by ATP5B inhibition suggesting a complementary action. Similar effects were observed with P18 PEDF-derived peptide. Conclusions These data established that modulating the molecular interactions between macrophages and PCa cells using PEDF may be a promising strategy for PCa treatment.
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Affiliation(s)
- Dalia Martinez-Marin
- Department of Urology, Texas Tech University-Health Sciences Center, Lubbock, Texas, United States of America
| | - Courtney Jarvis
- Department of Urology, Texas Tech University-Health Sciences Center, Lubbock, Texas, United States of America
- Department of Immunology and Molecular Microbiology, Texas Tech University-Health Sciences Center, Lubbock, Texas, United States of America
| | - Thomas Nelius
- Department of Urology, Texas Tech University-Health Sciences Center, Lubbock, Texas, United States of America
| | - Werner de Riese
- Department of Urology, Texas Tech University-Health Sciences Center, Lubbock, Texas, United States of America
| | - Olga V. Volpert
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Stéphanie Filleur
- Department of Urology, Texas Tech University-Health Sciences Center, Lubbock, Texas, United States of America
- Department of Immunology and Molecular Microbiology, Texas Tech University-Health Sciences Center, Lubbock, Texas, United States of America
- * E-mail:
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13
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Gelaleti GB, Borin TF, Maschio-Signorini LB, Moschetta MG, Hellmén E, Viloria-Petit AM, Zuccari DAPC. Melatonin and IL-25 modulate apoptosis and angiogenesis mediators in metastatic (CF-41) and non-metastatic (CMT-U229) canine mammary tumour cells. Vet Comp Oncol 2017; 15:1572-1584. [PMID: 28322030 DOI: 10.1111/vco.12303] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Revised: 11/04/2016] [Accepted: 12/11/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND Melatonin has oncostatic actions and IL-25 is active in inflammatory processes that induce apoptosis in tumor cells AIM: The aim of this study was to evaluate melatonin and IL-25 in metastatic (CF-41) and non-metastatic (CMT-U229) canine mammary tumor cells cultured as monolayers and tridimensional structures. MATERIALS AND METHODS The cells were treated with melatonin, IL-25 and IL-17B silencing gene and performed cell viability, gene and protein expression of caspase-3 and VEGFA (Vascular endothelial growth factor A) and an apoptosis membrane protein array. RESULTS Treatment with 1 mM of melatonin reduced cell viability of both tumor cell lines, all treatments alone and combined significantly increased caspase-3 cleaved and proteins involved in the apoptotic pathway and reduced pro-angiogenic VEGFA, confirming the effectiveness of these potential promising treatments. CONCLUSION This is the first study evaluating the potential use of these strategies in CF-41 and CMT-U229 cell lines and together encourages subsequent in vitro and in vivo studies for further exploration of clinical applications.
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Affiliation(s)
- G B Gelaleti
- Programa de Pós-Graduação em Genética, Universidade Estadual Paulista 'Júlio de Mesquita Filho' (UNESP/IBILCE), São José do Rio Preto, Brazil.,Faculdade de Medicina de São José do Rio Preto (FAMERP), Laboratório de Investigação Molecular do Câncer (LIMC), São José do Rio Preto, Brazil
| | - T F Borin
- Georgia Cancer Center, Tumor Imaging Angiogenesis Laboratory, Augusta University, Augusta, Georgia
| | - L B Maschio-Signorini
- Faculdade de Medicina de São José do Rio Preto (FAMERP), Laboratório de Investigação Molecular do Câncer (LIMC), São José do Rio Preto, Brazil
| | - M G Moschetta
- Faculdade de Medicina de São José do Rio Preto (FAMERP), Laboratório de Investigação Molecular do Câncer (LIMC), São José do Rio Preto, Brazil
| | - E Hellmén
- Department of Anatomy, Physiology and Biochemistry, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - A M Viloria-Petit
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Canada
| | - D A P C Zuccari
- Programa de Pós-Graduação em Genética, Universidade Estadual Paulista 'Júlio de Mesquita Filho' (UNESP/IBILCE), São José do Rio Preto, Brazil.,Faculdade de Medicina de São José do Rio Preto (FAMERP), Laboratório de Investigação Molecular do Câncer (LIMC), São José do Rio Preto, Brazil
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14
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Ma HY, Liu XZ, Liang CM. Inflammatory microenvironment contributes to epithelial-mesenchymal transition in gastric cancer. World J Gastroenterol 2016; 22:6619-6628. [PMID: 27547005 PMCID: PMC4970470 DOI: 10.3748/wjg.v22.i29.6619] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/12/2016] [Accepted: 07/06/2016] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori (H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition (EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.
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