Biology subjects

Rada, M.

Publications and source records attributed to Rada, M..

3 recordsLinked to original sources

bioRxiv2023

Inhibition of proprotein convertase subtilisin-like kexin type 9 (PCSK9) potentiates anti-angiogenic therapy in colorectal cancer liver metastases

Colorectal cancer liver metastatic (CRCLM) tumours present as two main histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours obtain their blood supply by sprouting angiogenesis, whereas the RHGP tumours utilize an alternative vascularisation known as vessel co-option. In vessel co-option, the cancer cells hijack the mature sinusoidal vessels to obtain blood supply. Vessel co-option has been reported as an acquired mechanism of resistance to anti-angiogenic treatment in CRCLM. Herein, we showed that inhibiting proprotein convertase subtilisin-like kexin type 9 (PCSK9) via clinically approved PCSK9-neutralizing antibody (Evolocumab) can boost the response of vessel co-opting tumours to anti-angiogenic therapy. Mechanistically, we found that PCSK9 inhibition downregulates runt related transcription factor-1 (RUNX1) expression levels in CRCLM cancer cells in vivo, which its expression positively correlates with the development of vessel co-option. Collectively, these results suggest that inhibiting PCSK9 is a promising way to improve the efficacy of anti-angiogenic therapy against vessel co-opting tumours in CRCLM.

molecular biology↗

bioRxiv2022

Disruption of integrin alpha-5/beta-1-dependent transforming growth factor beta-1signaling pathway attenuates vessel co-option in colorectal cancer liver metastases

Colorectal cancer liver metastases (CRCLM) have two major histopathological growth patterns (HGPs) including angiogenic desmoplastic HGP (DHGP) and non-angiogenic replacement HGP (RHGP). The RHGP lesions obtain their blood supply through vessel co-option, where the cancer cells hijack the pre-existing blood vessels of the surrounding liver tissue. Consequently, anti-angiogenic therapies are less efficacious in CRCLM patients with RHGP lesions. Recently, we identified a positive correlation between the expression of Angiopoietin1 (Ang1) and the development of vessel co-opted CRCLM lesions in vivo. However, the mechanisms underlying Ang1 upregulation in vessel co-opting CRCLM lesions are unclear. Herein, we demonstrated that transforming growth factor {beta}1 (TGF{beta}1) modulates the expression of Ang1 in hepatocytes in vitro. Significantly, pharmaceutical inhibition of integrin alpha-5/beta-1 (ITG5{beta}1) through ATN-161 impaired TGF{beta}1-dependent Ang1 expression in vitro and in vivo. Moreover, blocking ITG5{beta}1 attenuated the formation of vessel co-opting lesions. Furthermore, treatment with ATN-161 significantly improved survival in tumour-bearing mice. Taken together, our results suggest the molecular mechanism of Ang1 upregulation in vessel co-opting CRCLM and targeting this pathway may serve as promising therapeutic strategy to overcome the development of vessel co-option in CRCLM.

cancer biology↗

bioRxiv2021

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

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.

cancer biology↗