Liver cancer - genetics, cell signalling, and cancer stem cells and their translational implications

Abstract

We investigated the mutational landscape of mTOR signaling cascade in hepatocellular carcinoma (HCC). W detected frequent mutations of TSC1/2 genes in HCCs, which likely disrupt the functions in suppressing the downstream mTOR activity and lead to aggressive tumor behavior. There are therapeutic benefits of the hyper-sensitivity towards Rapamycin. TSC1/2 mutations may define a molecular subset of HCC with potential significance of specific drug therapy. In addition, cancer stem cells (CSCs) are capable of selfrenewal, maintaining tumor propagation, metastasis and chemo-resistance. In HCC, we have identified CD24 and CD47, among others, as novel liver CSC markers. HCC cells positive for these markers are more chemoresistant than marker-negative cells. They are functional markers that drive hepatocarcinogenesis through specific signaling pathways. Our work using antibodies targeting these markers has shown promising data in animal models. Furthermore, tumor microenvironment plays an important role in regulating cancer cells. The potential interaction of liver CSCs and tumor microenvironment as exemplified by cancer-associated fibroblasts will be presented.