Role of Cancer-Associated Fibroblast in Gastric Cancer Progression and Resistance to Treatments

Abstract

Although the survival of gastric cancer (GC) patients has gradually improved, the outcomes of advanced GC patients remain unsatisfactory despite standard treatment with conventional chemotherapy or targeted agents. Several studies have shown that cancer-associated fibroblasts (CAFs), a major component of tumor stroma in GC, may have significant roles in GC progression and resistance to treatments. CAFs are a major source of various secreted molecules in the tumor microenvironment, which stimulate cancer cells and other noncancerous components of GC. Surprisingly, these factors could be involved in gastric carcinogenesis. Cytokines, including interleukin-6 and interleukin-11, or growth factors, such as fibroblast growth factor produced from CAFs, can directly activate GC cells and consequently lead to the development of an aggressive phenotype. Galectin-1 or hepatocyte growth factor can be involved in CAF-derived neovascularization in GC. In addition, recent studies showed that CAFs can affect tumor immunity through M2 polarization of tumor-associated macrophages. Finally, the current study aimed to introduce several inhibitory agents and evaluate their suppressive effects on CAFs in patients with GC progression. However, further studies are required to evaluate their safety and select appropriate patients for application in clinical settings.

Exosomal miRNAs in tumor microenvironment

“…Compared with NFs, CAFs have the characteristics of excessive proliferation and unique cytokines. This not only induces the formation of new blood vessels, but also promotes the entry of immune cells into TME, which greatly changes the physiological function of ECM to support tumor proliferation, metastasis and treatment resistance [116,117]. However, cells involved in ECM formation are not only fibroblasts, but also chondrocytes, osteoblasts, and certain epithelial cells.…”

Long-Term Helicobacter pylori Infection Switches Gastric Epithelium Reprogramming towards Cancer Stem Cell-Related Differentiation Program in Hp-Activated Gastric Fibroblast-TGFβ Dependent Manner

“…However, CSC origins still remain a matter of debate. During tumor development, CSCs cooperate with stromal fibroblasts that constitute the milieu for neoplastic loci and the barriers for immune system, concomitantly providing paracrine signals for tumor promotion [ 18 , 26 , 27 , 28 , 29 ]. We have previously reported that normal gastric epithelial RGM1 cells undergo EMT-like phenotypic shifts, accompanied by inhibition of proliferation upon short-term (96 h) exposure to the secretome from Hp -infected gastric fibroblasts ( Hp -AGFs) [ 22 ].…”

“…It also induces EMT-type II-related local fibrosis, which otherwise accompanies the inflammatory responses and tissue repair under normal conditions. Nevertheless, TGFβ1 is also overproduced in many tumors and plays a dual role in GC progression and metastasis [ 17 , 18 ]. These events are associated with the limited benefit of GC treatment regimens via the stimulatory effect on the tumor stroma, in particular on cancer-associated fibroblast formation [ 18 ].…”

“…Nevertheless, TGFβ1 is also overproduced in many tumors and plays a dual role in GC progression and metastasis [ 17 , 18 ]. These events are associated with the limited benefit of GC treatment regimens via the stimulatory effect on the tumor stroma, in particular on cancer-associated fibroblast formation [ 18 ]. CAFs represent an important element of the tumor microenvironment [ 19 , 20 , 21 ] responsible for EMT-type III initiation in epithelial cell compartments, which is a prerequisite for CAF-induced tumor promotion/progression [ 22 , 23 , 24 , 25 ].…”

MALAT1 Induces Fibroblast Activation to Promote Cancer Progression via Blunting Autophagic Flux and Instigating IL-6 Secretion in Gastric Cancer Cells

“…Increasing evidence showed that MALAT1 were aberrantly overexpressed and could act as oncogene in GC [21]. The crosstalk between CAFs and GC cells could aggravate dysregulation of gene expression [22,23]. However the mechanism of upregulation of MALAT1 within TME was rarely reported.…”