Abstract 1927: Cancer cells induce apoptosis in hepatocytes as one of the mechanisms to displace hepatocytes in vessel co-opted colorectal cancer liver metastases

Abstract

Vessel co-option in colorectal cancer liver metastases (CRCLM) has been recognized as one of the mechanistic pathways of resistance against anti-angiogenic therapy. The cancer cells are highly motile in co-opted lesions, which 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 displacement of the hepatocytes. However, the molecular mechanisms underlying this displacement are unclear yet. To examine whether apoptosis involved in hepatocytes displacement by cancer cells in co-opted lesions, we performed immunohistochemical staining for pro-apoptotic markers, such as cleaved caspase-3 and cleaved PARP-1. We observed 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. In vitro, we found that culturing hepatocytes with either colorectal cancer cells or conditioned media of co-opted CRCLM organoids induces apoptosis. Importantly, our results also suggested proprotein convertase subtilisin/kexin type 9 (PCSK-9 or PC-9) as a potential mediator of cancer cells-driven hepatocytes apoptosis. Altogether, these results confirm that cancer cells exploit apoptosis to establish vessel co-option in CRCLM. Citation Format: Miran Rada, Migmar Tsamchoe, Audrey Kapelanski-Lamoureux, Jessica Bloom, Stephanie Petrillo, Sébastien Tabariès, Diane H. Kim, Peter Younan, Alex Gregorieff, Peter Siegel, Anthoula Lazaris, Peter Metrakos. Cancer cells induce apoptosis in hepatocytes as one of the mechanisms to displace hepatocytes in vessel co-opted colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1927.