9/6/2023 0 Comments Prognostic factor![]() We comprehensively analyzed four gastric cancer GEO gene expression datasets using a network-based approach and identified key markers for CAF infiltration. In this study, we aim to identify the poor prognostic gene signature for CAF infiltration targeting which may increase the therapeutic efficacy in a large group of gastric cancer patients. However, the poor prognostic markers for CAF infiltration in gastric cancer are not clear and drugs that target CAF-mediated processes are lacking in the clinic. Therefore, addressing CAFs is essential for the treatment of gastric cancer. CAFs were identified as the greatest risk factor in tumor microenvironment phenotype with the poorest overall survival in gastric cancer patients. CAF infiltration is associated with a dismal prognosis in gastric cancer. Moreover, CAFs remodel the ECM to form a protective barrier against immune surveillance and the diffusion of anti-cancer agents. They secrete various ECM proteins and soluble mediators that potentiate pro-tumorigenic signaling pathways via activation of transmembrane receptors – mainly integrins. They originate from activated fibroblasts and the endothelial or epithelial cells undergoing epithelial-mesenchymal transition (EMT). ![]() Cancer-associated fibroblasts (CAFs) are critical components in the cellular compartment of the tumor microenvironment that assemble and remodel the ECM. Dynamic interactions with the extracellular matrix (ECM) and cellular components in the tumor microenvironment potentiate the aggressiveness of cancer cells and limit their response to anti-cancer agents. The tumor microenvironment is a great challenge for the treatment of cancer. Unfortunately, they have limited efficacy on the overall survival of a limited group of advanced-stage patients with target positivity. Currently, molecular-targeted agents, nivolumab (anti-PD-1), pembrolizumab (anti-PD-1), ramucirumab (anti-VEGFR2), and trastuzumab (anti-HER2), are approved in gastric cancer treatment. However, similar success is not achieved in gastric cancer yet. Molecular-targeted agents against tumor-specific biomarkers and immunotherapy increased the treatment efficacy in certain cancers such as breast cancer, lung cancer, and melanoma. At this stage, complete resection is impossible, and currently available chemotherapeutics fail due to chemoresistance. However, the tumors are commonly metastatic at the time of diagnosis. The mainstay of treatment in localized stomach adenocarcinoma is gastrectomy with total lymphadenectomy and chemotherapy. Stomach adenocarcinomas (STAD) constitute almost 95% of all gastric cancer cases. More than one million people were diagnosed with gastric cancer, and more than 750,000 deaths occurred due to gastric cancer in 2020. Gastric cancer is the fifth most common cancer worldwide and the fourth leading cause of cancer-related deaths, the GLOBOCAN 2020 statistics report. Elucidating the mechanisms by which the signature genes contribute to poor patient outcomes can lead to the discovery of more potent molecular-targeted agents and increase the therapeutic success in gastric cancer. The gene signature we identified in this study carries high potential as a predictive tool for poor prognosis in gastric cancer patients. Our study demonstrated the central role of extracellular matrix components secreted and remodeled by CAFs in gastric cancer. The search on drug databases revealed collagenase clostridium histolyticum, ocriplasmin, halofuginone, natalizumab, firategrast, and BIO-1211 as the potential drugs for further investigation. The stepwise multivariate Cox regression elucidated COL1A1 and COL5A1, together with ITGA4, Emilin1, and TSPAN9 as poor prognostic signature genes for CAF infiltration. Analysis of the TCGA and ACRG cohorts validated their upregulation and poor prognostic significance. Our study revealed the COL1A1, COL1A2, CO元A1, COL5A1, FN1, and SPARC as the key CAF markers in gastric cancer. Lastly, we conducted a database search for drugs targeting the signature genes. We implemented stepwise multivariate Cox regression guided by a pan-cancer analysis in TCGA to identify a poor prognostic gene signature for CAF infiltration in gastric cancer. ![]() We analyzed four GEO datasets with a network-based approach and validated key CAF markers in The Cancer Genome Atlas (TCGA) and The Asian Cancer Research Group (ACRG) cohorts. In this study, we aim to identify a poor prognostic gene signature for CAFs, targeting which may increase the therapeutic success in gastric cancer. The poor prognostic signature for CAFs is not clear in gastric cancer, and drugs that target CAFs are lacking in the clinic. Cancer-associated fibroblasts (CAFs) are pivotal cells in the stroma of gastric tumors posing a great risk for progression and chemoresistance. Gastric cancer is one of the deadliest cancers, currently available therapies have limited success. ![]()
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