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.
Highlights
The marked influence of tumor stroma on the growth of malignant cancer cells has been demonstrated and investigated with enthusiasm in this era of targeted therapy [1,2]
HCAFs showed high-level expression of a-smooth muscle actin (a-SMA), fibroblast activation protein (FAP), fibroblast surface protein (FSP), vimentin and fibronectin according to the immunofluorescence analysis (Fig. 1A), which was confirmed by Western blotting (Fig. 1B)
peri-tumor fibroblasts (PTFs) expressed a similar level of a-SMA, FAP, FSP, vimentin and fibronectin to H-cancer-associated fibroblasts (CAFs) in vitro (Fig. 1A), which was further confirmed by Western blotting (Fig. 1B)
Summary
The marked influence of tumor stroma on the growth of malignant cancer cells has been demonstrated and investigated with enthusiasm in this era of targeted therapy [1,2]. As a major component of the tumor stroma, increasing evidence has shown that cancer-associated fibroblasts (CAFs) are a significant modifier of cancer evolution[3], and they promote the tumorigenesis [4], progression [5], invasion [6] and chemoresistance [7] of cancer cells by various mechanisms. This is especially true for hepatocellular carcinoma (HCC) [8,9] because most HCC cases may derive from liver cirrhosis [10]. More studies are needed to obtain the full view of crosstalk between H-CAFs and HCC in the host
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