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.

Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases

“…Remarkably, the adjacent hepatocytes of co-opted lesions also expressed high levels of phosphorylated SMAD2 (S465/467) and phosphorylated p38 (T180/Y182), indicating that TGFβ1 in the adjacent hepatocytes of co-opted lesions may participate in furnishing a favorable environment for cancer cells to establish vessel co-option via multiple mechanisms. These mechanisms might include inducing hepatocyte displacement by cancer cells 14,51 or overexpression of Angiopoietin-1 (Ang1) in adjacent hepatocytes 12 . Our lab is currently examining these hypotheses.…”

High levels of serum cholesterol positively correlate with the risk of the development of vessel co-opting tumours in colorectal cancer liver metastases

“…We performed immunohistochemical staining for formalin-fixed paraffin-embedded (FFPE) specimens as described in previous publications 9,12 . We performed staining using the following antibodies: HMGCR 1:100 (Thermo Fisher, #13533-1-AP), in-house polyclonal PCSK9 antibody 29 1:1000 (was a generous gift from Dr Nabil Seideh).…”

“…Colorectal cancer liver metastases (CRCLMs) present with two common histopathological growth patterns (HGPs): Desmoplastic HGP (DHGP) and replacement HGP (RHGP) [8][9][10][11] . The fundamental histopathological feature of DHGP lesions is the presence of a desmoplastic rim at the tumour periphery that separates cancer cells from liver parenchyma 8 .…”

Angiopoietin-1 Upregulates Cancer Cell Motility in Colorectal Cancer Liver Metastases through Actin-Related Protein 2/3

“…The sections were washed, stained with Harris Modified Hematoxylin (Thermo Fisher, Saint-Laurent, QC, Canada, #SH26-4D) for 30 s, washed with distilled water, dehydrated using ethanol and xylene, and covered with a coverslip. The slides were then scanned and analyzed with Aperio ImageScope ver.11.2.0.780 software as described in previous publications [8,12,23]. The positivity values are presented in Table S2.…”