Oncotarget

Research Papers: Autophagy and Cell Death:

Stroma-derived HGF drives metabolic adaptation of colorectal cancer to angiogenesis inhibitors

Alessia Mira, Virginia Morello, Maria Virtudes Céspedes, Timothy Perera, Paolo M. Comoglio, Ramon Mangues and Paolo Michieli _

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Oncotarget. 2017; 8:38193-38213. https://doi.org/10.18632/oncotarget.16942

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Abstract

Alessia Mira1, Virginia Morello1,2, Maria Virtudes Céspedes3,4, Timothy Perera5, Paolo M. Comoglio1, Ramon Mangues3,4 and Paolo Michieli1,2

1 Candiolo Cancer Institute, FPO, IRCCS, Candiolo, Turin, Italy

2 Department of Oncology, University of Torino Medical School, Candiolo, Turin, Italy

3 Biomedical Research Institute Sant Pau, Hospital de Sant Pau, Barcelona, Spain

4 Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain

5 OCTIMET Oncology Ltd., Oxford, United Kingdom

Correspondence to:

Paolo Michieli, email:

Keywords: colorectal cancer, HGF, anti-angiogenic therapy, resistance, tumor metabolism

Received: March 03, 2017 Accepted: March 28, 2017 Published: April 07, 2017

Abstract

The role of paracrine Hepatocyte Growth Factor (HGF) in the resistance to angiogenesis inhibitors (AIs) is hidden in xenograft models because mouse HGF fails to fully activate human MET. To uncover it, we compared the efficacy of AIs in wild-type and human HGF knock-in SCID mice bearing orthotopic human colorectal tumors. Species-specific HGF/MET signaling dramatically impaired the response to anti-angiogenic agents and boosted metastatic dissemination. In cell-based assays mimicking the consequences of anti-angiogenic therapy, colorectal cancer cells were completely resistant to hypoxia but extremely sensitive to nutrient deprivation. Starvation-induced apoptosis could be prevented by HGF, which promoted GLUT1-mediated glucose uptake, sustained glycolysis and activated autophagy. Pharmacological inhibition of GLUT1 in the presence of glucose killed tumor cells as effectively as glucose deprivation, and this effect was antagonized by HGF. Concomitant targeting of GLUT1 and HGF potently suppressed growth and dissemination of AI-resistant human tumors in human HGF knock-in SCID mice without exacerbating tumor hypoxia. These data suggest that stroma-derived HGF protects CRC cells against glucose starvation-induced apoptosis, promoting resistance to both AIs and anti-glycolytic agents. Combined inhibition of glucose metabolism and HGF/MET signaling (‘anti-METabolic therapy’) may represent a more effective CRC treatment compared to utterly blocking tumor blood supply.


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