
In this review, we summarize multiple utilities of tetraspanins in the progression of gastric cancer and the underlying molecular mechanisms. They interact with other membrane proteins to form tetraspanin-enriched microdomains and serve a variety of functions including cell adhesion, invasion, motility, cell fusion, virus infection, and signal transduction. The tetraspanins belong to a protein superfamily with four hydrophobic transmembrane domains and 33 mammalian tetraspanins are ubiquitously distributed in various cells and tissues. However, patients with an advanced stage of gastric cancer still have a poor prognosis and low overall survival rate. Gastric cancer is the fourth and fifth most common cancer worldwide in men and women, respectively. 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 cancer-associated fibroblast gene signature we identified in this study carries a high potential as a predictive tool for poor prognosis in gastric cancer patients. Conclusions: Our study demonstrated the central role of extracellular matrix components secreted and remodeled by the cancer-associated fibroblasts in gastric cancer. The search on drug databases revealed: collagenase clostridium histolyticum, ocriplasmin, and halofuginone which target collagen subunits and natalizumab, firategrast, and BIO-1211 which target ITGA4 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 the cancer-associated fibroblast infiltration. We demonstrated the substantial correlation between these genes and the cancer-associated fibroblast infiltration in gastric cancer. These genes were overexpressed and displayed poor prognostic significance in TCGA stomach adenocarcinoma samples. Results: Our network-based approach revealed the extracellular matrix components COL1A1, COL1A2, CO元A1, COL5A1, FN1, and SPARC as the central genes in gastric cancer.

Lastly, we searched the drug databases for drugs that target the signature genes. Since all the hub genes indicated the cancer-associated fibroblast infiltration in gastric tumors, we performed a stepwise multivariate Cox regression analysis to identify a poor prognostic gene signature for cancer-associated fibroblast infiltration.

We used The Cancer Genome Atlas (TCGA) stomach adenocarcinoma data as the validation set. Methods: We analyzed four GEO gene expression datasets with a network-based approach. Therefore, we aimed to identify new prognostic markers and therapeutic targets in gastric cancer. The lack of prognostic markers and efficient molecular targets limits the success of current therapies. Background: Gastric cancer is one of the deadliest cancers in the world.
