Cancer Cells Promote Phenotypic Alterations in Hepatocytes at the Edge of Cancer Cell Nests to Facilitate Vessel Co-Option Establishment in Colorectal Cancer Liver Metastases

Abstract

Simple SummaryTumour cells in colorectal cancer liver metastases (CRCLM) obtain their blood supply via two major mechanisms: (i) sprouting angiogenesis, through the generation of new vessels; (ii) vessel co-option, where the cancer cells hijack the pre-existing vasculature. The current treatment for CRCLM targets angiogenesis; however, these treatments are ineffective on cancer cells utilizing vessel co-option to gain their blood supply. Our study suggests that cancer cells stimulate phenotypic alterations in the cells of surrounding liver tissue (hepatocytes) in vessel co-opting lesions. These modifications facilitate cancer cells to infiltrate through the liver tissue and hijack the pre-existing vasculature to obtain oxygen and nutrients.Vessel co-option is correlated with resistance against anti-angiogenic therapy in colorectal cancer liver metastases (CRCLM). Vessel co-opting lesions are characterized by highly motile cancer cells that move toward and along the pre-existing vessels in the surrounding nonmalignant tissue and co-opt them to gain access to nutrients. To access the sinusoidal vessels, the cancer cells in vessel co-opting lesions must displace the hepatocytes and occupy their space. However, the mechanisms underlying this displacement are unknown. Herein, we examined the involvement of apoptosis, autophagy, motility, and epithelial–mesenchymal transition (EMT) pathways in hepatocyte displacement by cancer cells. We demonstrate that cancer cells induce the expression of the proteins that are associated with the upregulation of apoptosis, motility, and EMT in adjacent hepatocytes in vitro and in vivo. Accordingly, we observe the upregulation of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase-1 (PARP-1) and actin-related protein 2/3 (ARP2/3) in adjacent hepatocytes to cancer cell nests, while we notice a downregulation of E-cadherin. Importantly, the knockdown of runt-related transcription factor 1 (RUNX1) in cancer cells attenuates the function of cancer cells in hepatocytes alterations in vitro and in vivo. Altogether, our data suggest that cancer cells exploit various mechanisms to displace hepatocytes and access the sinusoidal vessels to establish vessel co-option.