Crosstalk Between Cancer Associated Fibroblasts and Cancer Cells in Scirrhous Type Gastric Cancer

Abstract

Gastric cancer (GC) is the third leading cause among all cancer deaths globally. Although the treatment outcome of GC has improved, the survival of patients with GC at stages III and IV remains unsatisfactory. Among several types of GC, scirrhous type GC (SGC) shows highly aggressive growth and invasive activity, leading to frequent peritoneal metastasis. SGC is well known to accompany abundant stromal cells that compose the tumor microenvironment (TME) along with the produced extracellular matrix (ECM) and secreted factors. One of the main stromal components is cancer associated fibroblast (CAF). In the SGC microenvironment, CAFs are a source of various secreted factors, including fibroblast growth factors (FGFs), which mediate prominent tumor-stimulating activity. In turn, cancer cells also secrete numerous factors, which can activate and educate CAFs. Current findings suggest that cancer cells and stromal cells communicate interactively via the soluble factors, the ECM, and likely also by exosomes. In this review, we focus on the soluble factors mediating communication between cancer cells and CAFs in SGC, and consider how they are related to the modulation of TME and the high rate of peritoneal metastasis. At last, we discuss the perspectives on targeting these communication pathways for improved future treatment.

SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling

“…Although the involvement of SHP2 in hematogenous metastasis has been reported in several cancer types [52][53][54], this is the first study to demonstrate the importance of SHP2 in peritoneal dissemination. DGC cells dispersed in the abdominal cavity must attach to and migrate across the mesothelium, invade the underlying stroma, and regrow to form peritoneal tumors [23,55,56]. Based on our results, SHP2 is likely to participate in the migration, invasion, and growth of DGC cells during peritoneal dissemination.…”

“…Therefore, Met and FGFR2 were proposed as potential therapeutic targets for DGC [16,17]. Indeed, other groups and we demonstrated that Met and FGFR inhibitors have therapeutic efficacy in preclinical models [18][19][20][21][22]; as a result, some of them were tested in clinical trials [23]. However, acquired resistance to Met and FGFR inhibitors inevitably occurs in DGC [22,24], which will be problematic in clinical practice.…”

Cancer-associated fibroblast infiltration in gastric cancer: the discrepancy in subtypes pathways and immunosuppression

“…To our knowledge, we are the first to point out CAF infiltration is higher in DGC and GS tumor that both are poorer survival subtypes in their corresponding classification system [ 25 , 28 ]. This difference might be explained by the overlapping of DGC and GS with scirrhous gastric cancer characterized as rapid expansion and invasion of poorly differentiated or signet‐ring cancer cells with extremely surrounding fibrosis [ 48 ]. Our result also reveals CAF infiltration is generally higher in stage III and IV patients implying the involvement of CAF in disease progression.…”

PLEKHA5 regulates the survival and peritoneal dissemination of diffuse-type gastric carcinoma cells with Met gene amplification

“…DGC is characterized by rapid invasive growth and frequent peritoneal dissemination. The process of peritoneal dissemination includes attachment of DGC cells to the mesothelium, invasion into the submesothelial connective tissue, and subsequent growth to form tumors 33 , 34 . Our results demonstrate that PLEKHA5 silencing markedly blocked the peritoneal dissemination of DGC cells.…”