Cancer-Associated Fibroblasts from Hepatocellular Carcinoma Promote Malignant Cell Proliferation by HGF Secretion

Abstract

Cancer-associated fibroblasts (CAFs) are reported to support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion in most solid tumors. However, the roles of CAFs in the liver cancer microenvironment have not been thoroughly studied. In our previous study, we successfully isolated CAFs from hepatocellular carcinoma (HCC) (H-CAFs) and proved that H-CAFs suppressed the activation of NK cells and thereby created favorable conditions for HCC progression. In our present study, we found that the proliferation of MHCC97L and Hep3B cells was significantly promoted by treatment with conditioned medium from H-CAFs. Pathological analysis also revealed that H-CAFs increased the proportion of Ki-67 (+) malignant cells and prevented them from undergoing necrosis. Moreover, the concentration of hepatocyte growth factor (HGF) cytokine in the conditioned medium of H-CAFs was higher than conditioned medium from normal skin fibroblasts (NSFs). Anti-HGF significantly reduced the proliferation-promoting capability of H-CAFs. In addition, we found that the abundance of H-CAFs correlated positively with tumor size. These results indicate that H-CAFs are an important factor for promoting the growth of HCC in vitro and in vivo, and that HGF plays a key role in HCC proliferation induced by H-CAFs.

Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling

“…However, different types of growth factors and cytokines, such as SDF-1, HGF, epidermal growth factor (EGF), interleukin (IL)-6, and transforming growth factor (TGF)-β, implicated as autocrine and paracrine mediators of stromal-epithelial interactions are involved in tumor progression. 12,13,21,22 In this study, we observed that the CAFs secrete FGF-1 at a higher level than NFs. The function of FGF-1 was subsequently investigated in our study.…”

“…[10][11][12][13][14] FGF is one of the growth factors secreted by CAFs, which execute diverse functions by binding to and activating members of the fibroblast growth factor receptor 4 (FGFR4) family, such as cell survival, proliferation, and migration in a variety of cell types. 15,16 To date, 22 FGF genes have been identified in human, which are differentially expressed in many tissues.…”

Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment

“…HGF from CAFs regulates tumor growth, invasion, and proliferation of cancer cells in a variety of tumors[26][27][28][29].Exosomes are secreted microvesicles that are emerging as potent mediators of cell-cell communication. Luga et al revealed that CAFs-secreted exosomes promote breast cancer cell protrusive activity, motility, and metastasis via Wnt-planar cell polarity signaling[30].Some studies have demonstrated direct interactions between CAFs and cancer cells for proliferation, migration, cancer survival, and metastasis.…”

Oxidative stress induced autophagy in cancer associated fibroblast enhances proliferation and metabolism of colorectal cancer cells

“…Olumi et al found that CAFs could induce formation of tumors when simian virus 40-transformed prostate epithelial cells BPH-1 were coinjected with either CAFs or normal fibroblasts, indicating that CAFs can initiate tumorigenesis. [27][28][29] Similarly, neighboring CAFs could promote proliferation, migration and growth of oral cancer cells (OCCs) through enhancing the expression of cell cycle-driven proteins. 30 However, the involvement of CAFs in CRCs has not been well addressed.…”