Remodeling Of The Tumor Stroma Contributes To Hepatocellular Carcinoma Progression.

Abstract

Hypoxia, oxygen deprivation, is a common finding in hepatocellular carcinoma (HCC) due to abnormal vasculature. Hypoxia stabilizes hypoxia-inducible factor-1α (HIF-1α) which drives transcription of genes that are essential to tumor progression. Our study reported that HIF-1α remodeled the stroma of HCC by two mechanisms: (1) HIF-1α enhanced collagen cross-linking in the stroma of HCC through transcriptional activation of lysyl oxidase-like 2, (2) HIF-1α recruited myeloid-derived suppressor cells (MDSCs) to stroma of HCC through transcriptional activation of chemokine C-C motif ligand 26 (CCL26). LOXL2-mediated collagen cross-linking promoted intra-and extra-hepatic metastasis HCC while CCL26-mediated MDSC recruitment promoted angiogenesis in HCC. Our data highlighted the imperative roles of HIF-1α in HCC development and suggested HIF-1α as an attractive therapeutic target in HCC treatment.