Abstract 3902: Liver cancer stem cells initiate extracellular matrix remodeling

Abstract

Abstract Extracellular matrix is one of the major components of cancer cell's niche. It is well appreciated that extracelluar matrix undergoes remodeling during the process of tumor progression,but the causal factors that initiate extracellular matrix remodeling are poorly understood. Hepatocellular carcinoma, like many other solid tumors, is thought to be hierarchically organized heterogeneous populations of cells with the cancer stem cell compartment sitting on top. We have identified a population of hepatocellular carcinoma cells, which were defined as α2δ1+ cells, exhibiting stem cell-like properties, such as increased invasiveness, expression of stem cell associated genes (OCT4, SOX2, NANOG, and BMI1), increased self-renewal, and the ability of giving rise to both α2δ1+ and α2δ1- cells with a novel monoclonal antibody, 1B50-1, using a whole-cell subtractive immunization approach that recognizes the isoform 5 of the cell surface voltage-gated calcium channel α2δ1 subunit. In order to understand the role of extracellular matrix in the regulation of α2δ1+ hepatocellular carcinoma stem cell properties, we first compared the expression of extracellular matrix components between α2δ1+ and α2δ1- cells. Comparing with α2δ1- cells, the expression of collagen isoforms such as COL6A3, COL1A2, and COL21A1 was up-regulated, while COL1A1, COL2A1, COL6A2 were down-regulated in α2δ1+ hepatocellular carcinoma cells. Interestingly, the collagen cross-linking enzyme-lysyl oxidase (LOX) was also upregulated in α2δ1+ liver cancer stem cells. Furthermore, as a direct target of microRNA-200b which was down-regulated in α2δ1+ liver cancer stem cells, LOX is sufficient to enable α2δ1− liver cancer cells to acquire cancer stem cell-like properties such as self-renewal and tumorigenicity. Knock-down of LOX in α2δ1+ liver cancer stem cells has resulted in decrease of self-renewal and tumorigenic properties. This data suggest that hepatocellular carcinoma stem cells may initiate their niche remodeling to maintain their cancer stem cell properties. Citation Format: Zhiqian Zhang, Wei Zhao, Xueying Yang, Haibo Han. Liver cancer stem cells initiate extracellular matrix remodeling. [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 3902. doi:10.1158/1538-7445.AM2014-3902