Impact of MET targeting on tumor-associated angiogenesis and growth of MET mutations-driven models of liver cancer

Piguet, Anne-Christine; Medova, Michaela; Keogh, Adrian; Glück, Astrid Andreina; Aebersold, Daniel; Dufour, Jean-François; Dufour, Jean-François; Zimmer, Yitzhak (2015). Impact of MET targeting on tumor-associated angiogenesis and growth of MET mutations-driven models of liver cancer. Genes & cancer, 6(7-8), pp. 317-327. Impact Journals

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Deregulated expression of the MET receptor tyrosine kinase has been reported in up to 50% of patients with hepatocellular carcinoma, the most abundant form of liver cancers, and is associated with decreased survival. Consequently, MET is considered as a molecular target in this malignancy, whose progression is highly dependent on extensive angiogenesis. Here we studied the impact of MET small molecule inhibitors on angiogenesis-associated parameters and growth of xenograft liver models consisting of cells expressing MET-mutated variants M1268T and Y1248H, which exhibit constitutive kinase activity. We demonstrate that MET mutations expression is associated with significantly increased production of vascular endothelial growth factor, which is blocked by MET targeting only in cells expressing the M1268T inhibitor-sensitive but not in the Y1248H inhibitor-resistant variant. Decrease in vascular endothelial growth factor production is also associated with reduction of tyrosine phopshorylation of the vascular endothelial growth factor receptor 2 expressed on primary liver sinusoidal endothelial cells and with inhibition of vessel formation. Furthermore, MET inhibition demonstrated an efficient anti-tumor activity and considerable reduction in microvessel density only against the M1268T-derived intrahepatic tumors. Collectively, our data support the role of targeting MET-associated angiogenesis as a major biological determinant for liver tumor growth control.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology

UniBE Contributor:

Medova, Michaela; Keogh, Adrian; Glück, Astrid Andreina; Aebersold, Daniel; Dufour, Jean-François; Dufour, Jean-François and Zimmer, Yitzhak

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1947-6019

Publisher:

Impact Journals

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

06 Apr 2016 16:36

Last Modified:

07 Apr 2016 22:24

PubMed ID:

26413215

Uncontrolled Keywords:

MET; activating mutations; angiogenesis; liver cancer; small molecule inhibitors

BORIS DOI:

10.7892/boris.75363

URI:

https://boris.unibe.ch/id/eprint/75363

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