Hepatitis C virus–induced tumor‐initiating cancer stem–like cells activate stromal fibroblasts in a xenograft tumor model

Abstract

Hepatitis C virus (HCV) often causes persistent infection, and is an increasingly important factor in the etiology of fibrosis/cirrhosis and hepatocellular carcinoma (HCC), although the mechanisms for the disease processes remain unclear. We have shown previously that HCV infection generates epithelial mesenchymal transition state (EMT) and tumor initiating cancer stem-like cells (TISCs) in human hepatocytes. In this study, we investigated whether HCV induced TISC when implanted into mice activate stromal fibroblasts. A number of fibroblast activation markers, including metalloproteinase (MMP) 2 were significantly increased at the mRNA or protein level in the xenograft tumors, suggesting the presence of tumor-associated fibroblasts (TAFs). Fibroblast activation markers of murine origin were specifically increased in tumor, suggesting that fibroblasts are migrated to form stroma. Next, we demonstrated that the conditioned medium (CM) from HCV infected human hepatocytes activates fibrosis related markers in hepatic stellate cells. We further observed that these HCV infected hepatocytes express TGF-β which activates stromal fibroblast markers. Subsequent analysis suggest anti-TGF-β neutralizing antibody, when incubated with CM from HCV infected hepatocytes, inhibits fibrosis marker activation in primary human hepatic stellate cells (HSCs). Conclusion HCV infected hepatocytes induce local fibroblast activation by secretion of TGF-β, and preneoplastic or tumor state of the hepatocytes influences the network for TAF environment.

Transforming Growth Factor β Acts as a Regulatory Molecule for Lipogenic Pathways among Hepatitis C Virus Genotype-Specific Infections

“…Both TGF-␤1 and TGF-␤2 play roles in immune tolerance and induce fibrosis, while TGF-␤3 counteracts tissue fibrosis and has an opposite effect of TGF-␤1 in wound healing (16). We have previously shown TGF-␤1 or ␤2 is significantly upregulated in HCV-infected hepatocytes (17). We investigated TGF-␤1 and ␤2 expression, phospho-Akt (p-Akt) (Ser473) activation, and PPAR␣ status as the important regulatory molecules.…”

Establishment of a Patient‐Derived Xenograft Tumor From Hepatitis C–Associated Liver Cancer and Evaluation of Imatinib Treatment Efficacy

“…1B). However, tumors grown in mice exhibited mouse fibrosis markers, as observed, (23) suggesting species-specific tumor-associated fibroblast migration in the respective tumor regions.…”

Hepatitis C Virus Manipulates Humans as its Favorite Host for a Long‐Term Relationship

“…HCV infection initiates an epithelial–mesenchymal transition state and tumor‐initiating cancer stem–like cells (TISCs) in human hepatocytes . HCV‐induced TISCs, when implanted into immunodeficient mice, activate stromal fibroblasts . TGF‐β, a multifunctional cytokine, secreted in conditioned medium from HCV‐infected human hepatocytes, activates fibrosis‐related markers in HSCs, further suggesting its role in fibrosis activation.…”

“…(63) HCV-induced TISCs, when implanted into immunodeficient mice, activate stromal fibroblasts. (63,64) TGF-β, a multifunctional cytokine, secreted in conditioned medium from HCV-infected human hepatocytes, activates fibrosis-related markers in HSCs, (32) further suggesting its role in fibrosis activation. Exosomes are extracellular vesicles which are considered important mediators of cell-cell communication by delivering the information they carry to neighboring cells.…”