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bioRxiv · 10.1101/2022.05.24.493291

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

Rada, M.·Kapelanski-Lamoureux, A.·Zlotnik, O.·Petrillo, S.·Lazaris, A.·Metrakos, P.
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Abstract

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.

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Rada, M., Kapelanski-Lamoureux, A., Zlotnik, O., Petrillo, S., Lazaris, A., Metrakos, P.. 2022-05-25. Disruption of integrin alpha-5/beta-1-dependent transforming growth factor beta-1signaling pathway attenuates vessel co-option in colorectal cancer liver metastases. https://doi.org/10.1101/2022.05.24.493291

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