Abstract 3044: Cancer associated fibroblasts-derived HGF regulates cancer stem cell-like properties in hepatocellular carcinoma

Abstract

Abstract Cancer stem cells (CSCs) play pivotal roles in tumor growth and therapeutic response; hence it is of fundamental importance to understand how CSCs is regulated inside the tumor mass. Similar to the regulation of normal stem cells by their ‘niche’, CSCs are also regulated by cells within the tumor microenvironment. Although most cases of HCC develop within a background of cirrhosis in which liver tissue is enriched in activated myofibroblasts, the role of cancer associated fibroblasts (CAFs) on liver CSCs within the tumor microenvironment has not yet studied. In order to achieve the goal of developing an effective therapy for HCC by specifically eliminating liver CSCs, we aim to dissect the cross-talks between HCC cells and CAFs. To study this, CAFs from fresh HCC tissues was successfully isolated, cultured and characterized by α-SMA immunoreactivity. Conditioned medium from CAFs enriched the populations of liver CSCs as reflected by an increased ability of self-renewal, chemoresistance, invasiveness and expression of stemness-associated genes and markers CD44 and CD47; and its CSC- stimulating effect was further enhanced when CAFs was stimulated with the conditioned medium of HCC cells. Using cytokine antibody array, hepatocyte growth factor (HGF) was found to be preferentially secreted by CAFs and increased upon stimulation by HCC cells. To verify whether the effect of CAFs on regulation of liver CSCs is due to HGF, the effect of recombinant HGF on regulation of liver CSCs was examined. Recombinant HGF at the physiological levels of CAFs (2ng/mL and 10ng/mL) promoted stem-like properties of HCC cells, and the effect of CAFs on CSC properties was alleviated with addition of HGF neutralizing antibody and c-met inhibitor (PHA665-752). In a cohort of HCC patient’s samples, HGF expression was significantly correlated with α-SMA (p=0.0003), suggesting the paracrine effect of CAFs on HCC cells. Further experiments showed that HCC cells induced proliferation and migration of CAFs to tumor-associated stroma; and CAFs in turn secretes HGF to regulate the CSC plasticity by activating NF-κB-mediated EMT transition. This study potentially dissects the signaling cross-talks between HCC cells and CAFs within the tumor microenvironment which may potentially open a new avenue to develop targeted therapy against this deadly disease. Citation Format: Yuen Ting Lau, Jessica Lo, Irene Oi Lin Ng, Terence Kin Wah Lee. Cancer associated fibroblasts-derived HGF regulates cancer stem cell-like properties in hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3044. doi:10.1158/1538-7445.AM2014-3044