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

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.

The lncRNA MACC1-AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1

“…In our study, the MACC1-AS1/MACC1 axis functioned as a modulator of metabolic plasticity by promoting glycolysis and antioxidant production. The HGF/c-MET has been reported to drive metabolic adaptation to prevent glucose deprivation-induced apoptosis [ 19 ]. In addition, inhibition of this pathway perturbs redox homeostasis by downregulating NADPH production [ 20 ]; thus we suggest that inhibition of MACC1-AS1/MACC1 might result in synergetic anti-tumor effects, when combined with the clinical application of HGF/c-MET inhibitors, by targeting metabolic plasticity.…”

A mechanism for semaphorin-induced apoptosis: DNA damage of endothelial and myogenic cells in primary cultures from skeletal muscle

“…HGF is produced by proliferating myogenic cells (and anti-inflammatory macrophages [ 8 ]), and is a key signaling molecule in the pathway that activates metabolically and mitotically quiescent muscle satellite cells to cycle and migrate [ 35 , 36 ]. HGF from cultured myogenic cells may have influenced the differential responses by endothelial and myogenic cells to Sema3A and 3F, as found in studies of human colon cancer in a mouse transgenic strain [ 37 ]. Amplification of MET expression in some cancers [ 38 ] would affect interaction of HGF with proteins in the senescence-associated secretory phenotype [ 39 ], as would the stage of angiogenesis in the growth, carcinogenesis and metastasis of tumors in response to Sema3A signaling [ 40 , 41 ].…”

Angiogenesis: Managing the Culprits behind Tumorigenesis and Metastasis

“…Notably, angiopoietin promotes HGF and induces the recruitment of smooth muscle cells, enhancing the stabilization of angiogenesis [ 72 ]. Previous studies have proven that HGF induced c-Met activation plays a fundamental role in angiogenesis and tumour progression in colorectal cancer by avoiding anti-angiogenic therapy and maintaining the glucose uptake and utilization by inducing GLUT1 expression [ 76 ]. In addition, inhibition of HGF and c-Met signaling pathway has resulted in tumor reduction and progression in pancreatic cancer which paves the way for effective therapeutic approach [ 77 ].…”