Cancer cells induce hepatocytes apoptosis in co-opted colorectal cancer liver metastatic lesions

Abstract

Vessel co-option in colorectal cancer liver metastases (CRCLM) has been recognized as one of the mechanistic pathways that contribute to resistance against anti-angiogenic therapy. In vessel co-opted CRCLM lesions, the cancer cells are highly motile that move toward and along the pre-existing sinusoidal vessels and hijack them to gain access to nutrient. The movement of cancer cells is accompanied by replacement of the hepatocytes. However, the molecular mechanisms by which this replacement occurs are unclear yet. To examine the involvement of apoptosis in hepatocytes replacement by cancer cells in co-opted lesions, we conducted immunohistochemical staining for chemonaive CRCLM specimens using pro-apoptotic markers antibody, such as cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase-1 (PARP-1). The results suggested overexpression of pro-apoptotic markers in liver parenchyma of co-opted lesions compared to angiogenic lesions, specifically the hepatocytes that are in close proximity to the cancer cells. Importantly, co-culturing hepatocytes with colorectal cancer cells induced overexpression of pro-apoptotic markers in the hepatocytes. Altogether, these results propose that cancer cells could exploit apoptosis to replace the hepatocytes and establish vessel co-option in CRCLM.