Targeting the HGF/c-MET pathway: stromal remodelling in pancreatic cancer

Abstract

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Srinivasa P. Pothula1, 2, 3, Zhihong Xu1, 2, 3, David Goldstein2, Neil Merrett2, Romano C. Pirola1, 2, 3, Jeremy S. Wilson1, 2, 3 and Minoti V. Apte1, 2, 3 1Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia 2Faculty of Medicine, The University of New South Wales, Sydney, Australia 3Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia Correspondence to: Minoti V. Apte, email: m.apte@unsw.edu.au Keywords: HGF/c-MET pathway, pancreatic cancer, stromal-tumor interactions, pancreatic stellate cells, orthotopic model Received: May 09, 2017 Accepted: August 23, 2017 Published: September 11, 2017 ABSTRACT Stromal-tumor interactions in pancreatic cancer (PC) impact on treatment outcomes. Pancreatic stellate cells (PSCs) produce the collagenous stroma of PC and interact with cancer cells to facilitate disease progression. A candidate growth factor pathway that may mediate this interaction is the hepatocyte growth factor (HGF)/c-MET pathway. HGF is produced by PSCs and its receptor c-MET is expressed on pancreatic cancer cells. We studied the effects on PC progression of inhibiting the HGF/c-MET pathway in the presence and absence of a representative chemotherapeutic agent, gemcitabine. Using an orthotopic model of PC we have shown that “triple therapy” (inhibition of both HGF and c-MET combined with gemcitabine) resulted in the greatest reduction in tumor volume compared to each of the treatments alone or in dual combinations. Importantly, metastasis was virtually eliminated in mice receiving triple therapy. Our in vivo findings were supported by in vitro studies showing that the increase in cancer cell proliferation and migration in response to PSC secretions was significantly inhibited by the triple regimen. Our studies suggest that a combined approach, that targets tumor cells by chemotherapy while inhibiting specific pathways that mediate stromal-tumor interactions, may represent a novel therapeutic strategy to improve outcomes in PC.