<p>Cancer-associated fibroblasts endow stem-like qualities to liver cancer cells by modulating autophagy</p>

Abstract

Purpose Both cancer-associated fibroblasts (CAFs) and liver cancer stem cells (LCSCs) play an important part in the tumorigenesis, development and metastasis of hepatocellular carcinoma (HCC). Moreover, the stem-like properties in HCC cells could be promoted by CAFs. However, the mechanism remains largely unknown. Patients and methods We used conditioned medium (CM) of CAFs to culture Huh7 cells. Stemness of the cells was then examined mainly by sphere formation assay while stemness-associated genes including Nanog, Sox2 and Oct4 were measured by Western blotting. Immunofluorescence staining, Transmission Electron Microscope as well as Western blotting were performed to detect the level of autophagy in Huh7 cells. Results Increased level of stemness and autophagy was observed in HCC cells cultured in CAFs-CM compared to the control group. Activation of CAFs-induced autophagic flux could be inhibited by Chloroquine (CQ), which can accumulate LC3-II protein and increase punctate distribution of LC3 localization. Treatment of HCC cells with CQ effectively reversed the CAF-induced stemness, invasion, and metastasis ability in these cells. In vivo, Huh7 cells inoculated together with CAFs developed significantly larger tumors than Huh7 cells injected alone. Moreover, blockage of autophagy in Huh7 cells by CQ greatly reduced the growth of xenografted tumors of Huh7 cells combined with CAFs. Conclusion These results reveal that CAFs are capable of promoting stemness and metastasis of HCC cells and blocking autophagy could markedly attenuate the stemness enhanced by CAFs, suggesting that targeting autophagy in HCC could be an effective strategy in HCC treatment.

Cancer stemness in hepatocellular carcinoma: mechanisms and translational potential

“…Previous studies have demonstrated that CAFs increase the tumorigenicity of HCC cells. Conditioned medium from CAFs promotes sphere formation, 69 , 90 , 91 the expression of stemness-related genes, such as CD24, 90 CD44, 69 CD47, 69 CD90, 69 Nanog, 90 , 91 Oct4 90 , 91 and Sox2, 90 , 91 and chemoresistance to cisplatin and doxorubicin. 69 It was further demonstrated that CAF-induced cancer stemness in HCC cells was stimulated by HGF 69 , 90 via the c-MET/FRA1/HEY1 signalling axis (see above) or the c-MET/STAT3 axis or by IL-6 via STAT3 in CD24-positive HCC cells.…”

Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma

“…demonstrated that CAFs-derived cartilage oligomeric matrix protein (COMP) endowed HCC cells with stem-like properties, accelerating the invasion and metastasis of HCC cells [ 30 ]. Furthermore, CAFs could also activate Notch3/LSD1 signaling and autophagy-related mTOR pathway of HCC cells, subsequently driving their self-renewal in CSCs [ 77 , 78 ]. Interestingly, there might be a potential positive loop between CSCs and CAFs.…”

Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance

“…Liver hepatocellular carcinoma is one of the most vascularised tumor types, with reports linking CAFs to enhanced tumor angiogenesis and invasion [159,160]. Other studies link CAFs to induction of stem-cell like behaviour in cancer cells, leading to chemoresistance and metastasis [161,162]. Below, the expression of CAF markers in liver hepatocellular carcinoma versus normal samples based on TCGA samples was evaluated.…”