Stroma-derived HGF Drives Metabolic Adaptation of Colorectal Cancer to Angiogenesis Inhibitors

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Apr 27

PMID 28445144

Citations 13

Authors

Alessia Mira

Virginia Morello

Maria Virtudes Cespedes

Timothy Perera

Paolo M Comoglio

Ramon Mangues

Paolo Michieli

Affiliations

Soon will be listed here.

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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References

Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M . Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2012; 381(9863):303-12. DOI: 10.1016/S0140-6736(12)61900-X. View

Luraghi P, Reato G, Cipriano E, Sassi F, Orzan F, Bigatto V . MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res. 2014; 74(6):1857-69. DOI: 10.1158/0008-5472.CAN-13-2340-T. View

Jahangiri A, De Lay M, Miller L, Carbonell W, Hu Y, Lu K . Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance. Clin Cancer Res. 2013; 19(7):1773-83. PMC: 3618605. DOI: 10.1158/1078-0432.CCR-12-1281. View

Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor R, Williamson C, Bhagwandin V . Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012; 2(3):270-87. PMC: 3354652. DOI: 10.1158/2159-8290.CD-11-0240. View

Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen R, Hagmann J . Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy. Cell Rep. 2016; 15(6):1161-74. PMC: 4870473. DOI: 10.1016/j.celrep.2016.04.028. View

Goos J, de Cuba E, Coupe V, Diosdado B, Delis-van Diemen P, Karga C . Glucose Transporter 1 (SLC2A1) and Vascular Endothelial Growth Factor A (VEGFA) Predict Survival After Resection of Colorectal Cancer Liver Metastasis. Ann Surg. 2015; 263(1):138-45. DOI: 10.1097/SLA.0000000000001109. View

Strickler J, Hurwitz H . Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer. Oncologist. 2012; 17(4):513-24. PMC: 3336830. DOI: 10.1634/theoncologist.2012-0003. View

Tabernero J, Elez M, Herranz M, Rico I, Prudkin L, Andreu J . A pharmacodynamic/pharmacokinetic study of ficlatuzumab in patients with advanced solid tumors and liver metastases. Clin Cancer Res. 2014; 20(10):2793-804. DOI: 10.1158/1078-0432.CCR-13-1837. View

Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio P . Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003; 3(4):347-61. DOI: 10.1016/s1535-6108(03)00085-0. View

10.

Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G . Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012; 12(2):89-103. DOI: 10.1038/nrc3205. View

11.

Liu Y, Cao Y, Zhang W, Bergmeier S, Qian Y, Akbar H . A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther. 2012; 11(8):1672-82. DOI: 10.1158/1535-7163.MCT-12-0131. View

12.

Stein U, Walther W, Arlt F, Schwabe H, Smith J, Fichtner I . MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med. 2008; 15(1):59-67. DOI: 10.1038/nm.1889. View

13.

Cowey C . Profile of tivozanib and its potential for the treatment of advanced renal cell carcinoma. Drug Des Devel Ther. 2013; 7:519-27. PMC: 3693745. DOI: 10.2147/DDDT.S31442. View

14.

Heijmen L, ter Voert E, Punt C, Heerschap A, Oyen W, Bussink J . Monitoring hypoxia and vasculature during bevacizumab treatment in a murine colorectal cancer model. Contrast Media Mol Imaging. 2014; 9(3):237-45. DOI: 10.1002/cmmi.1564. View

15.

Vander Heiden M . Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011; 10(9):671-84. DOI: 10.1038/nrd3504. View

16.

Rapisarda A, Melillo G . Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat. 2009; 12(3):74-80. PMC: 2696589. DOI: 10.1016/j.drup.2009.03.002. View

17.

Jimenez-Valerio G, Martinez-Lozano M, Bassani N, Vidal A, Ochoa-de-Olza M, Suarez C . Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients. Cell Rep. 2016; 15(6):1134-43. PMC: 4870515. DOI: 10.1016/j.celrep.2016.04.015. View

18.

Samame Perez-Vargas J, Biondani P, Maggi C, Gariboldi M, Gloghini A, Inno A . Role of cMET in the development and progression of colorectal cancer. Int J Mol Sci. 2013; 14(9):18056-77. PMC: 3794769. DOI: 10.3390/ijms140918056. View

19.

Cecchi F, Lih C, Lee Y, Walsh W, Rabe D, Williams P . Expression array analysis of the hepatocyte growth factor invasive program. Clin Exp Metastasis. 2015; 32(7):659-76. PMC: 7709798. DOI: 10.1007/s10585-015-9735-0. View

20.

Wang C, Hu Q, Shen H . Pharmacological inhibitors of autophagy as novel cancer therapeutic agents. Pharmacol Res. 2016; 105:164-75. DOI: 10.1016/j.phrs.2016.01.028. View