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.
Highlights
Metastatic colorectal cancer (CRC) is one of the most common tumors in both men and women, and the second leading cause of cancer deaths worldwide [1]
To recapitulate the micro-environmental Hepatocyte Growth Factor (HGF)/MET signaling conditions found in those oncological patients typically addressed towards anti-angiogenic therapy, we employed human HGF knock-in (hHGF KI) severe combined immuno-deficiency syndrome (SCID) mice
The strikingly different efficacy of angiogenesis inhibitor (AI) in WT and hHGF KI SCID mice suggests that stroma-derived HGF represents a major source of resistance to antiangiogenic therapy of metastatic colorectal cancer, at least in the orthotopic models analyzed
Summary
Metastatic colorectal cancer (CRC) is one of the most common tumors in both men and women, and the second leading cause of cancer deaths worldwide [1]. More than half CRC patients, are not eligible to EGFR-targeted therapy because they bear KRAS- or BRAF-mutant tumors [3]. These patients, as well as those that have developed resistance to cetuximab or panitumumab, are typically addressed towards treatment with anti-angiogenic agents (bevacizumab, ziv-aflibercept, regorafenib) [4]. Most clinical trials testing agents targeting the vascular endothelial growth factor (VEGF) pathway in CRC provided evidence for increased www.impactjournals.com/oncotarget progression-free survival but failed to demonstrate a substantial overall survival benefit, suggesting that antiangiogenic treatment induces a biological adaptation leading to disease modification [9]
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