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.
Highlights
OF SCIRRHOUS GC MICROENVIRONMENTGastric cancer (GC) is diagnosed with 5th frequency among all cancers and is the third-leading cause of cancer death, with one million new cases and nearly 800,000 deaths globally in 2018 [1]
We focus on the soluble factors mediating communication between cancer cells and cancer associated fibroblast (CAF) in scirrhous type GC (SGC), and consider how they are related to the modulation of tumor microenvironment (TME) and the high rate of peritoneal metastasis
CAFs communicate with SGC cells in a number of ways, and contribute to the progression of SGC mainly by fibroblast growth factors (FGFs)/FGF receptors (FGFRs) and Transforming growth factor b (TGFb)/SMAD signaling axes
Summary
Gastric cancer (GC) is diagnosed with 5th frequency among all cancers and is the third-leading cause of cancer death, with one million new cases and nearly 800,000 deaths globally in 2018 [1]. Sun et al reported that CAF-secreted and MMP7-activated FGF9 promotes apoptosis evasion and invasive ability of gastric cancer cells [22]. Naito et al investigated the miR-143 expression in SGC and non-SGC, and reported that miR-143 expression is significantly higher in SGC tissue than in non-SGC tissue They showed that miR-143 enhances the expression of collagen type III in normal gastric fibroblasts and CAFs by activation of TGFb/ SMAD signaling, suggesting that miR-143 and TGFb signaling regulate fibrosis of SGC tissue. Stromal fibroblasts increase CD44 expression of GC cells through TGFb signaling, stimulating the adhesion of SGC cells to the mesothelium [87] Another important step in peritoneal dissemination is the adhesion of cancer cells to the submesothelial components. SGC (scirrhous gastric cancer), CAF (cancer associated fibroblasts), ECM (extracellular matrix), TGFb (transforming growth factor b), TGFbR (TGFb receptor), HGF (hepatocyte growth factor), c-Met (HGF receptor), MMP (matrix metalloproteinases), uPA (urokinase-type plasminogen activator). FGF ligand traps are a fusion of an immunoglobulin Fc fragment and a soluble FGFR extracellular domain that competitively binds with FGF1, 2, 3, 7, and 10 to TABLE 3 | Drugs targeting FGFRs
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