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, Paolo Michieli

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)38193-38213
Number of pages21
Issue number24
Publication statusPublished - Jan 1 2017


  • Anti-angiogenic therapy
  • Colorectal cancer
  • HGF
  • Resistance
  • Tumor metabolism

ASJC Scopus subject areas

  • Oncology


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