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.
Highlights
Around 338000 new cases of pancreatic cancer (PC) are diagnosed worldwide each year and this devastating disease is set to become the second leading cause of cancer related deaths in the decade [1]
hepatocyte growth factor (HGF) is produced by Pancreatic stellate cells (PSCs) and its receptor c-MET is expressed on pancreatic cancer cells
A candidate factor that has received some attention in recent years is the hepatocyte growth factor (HGF), which has been shown to have a role in the progression of PC [16, 17], with respect to stromal-tumor interactions [14, 18]
Summary
Around 338000 new cases of pancreatic cancer (PC) are diagnosed worldwide each year and this devastating disease is set to become the second leading cause of cancer related deaths in the decade [1]. Several preclinical studies have reported a close bidirectional interaction between pancreatic cancer cells and PSCs [6,7,8,9,10] which facilitates pancreatic cancer progression as evidenced by increased tumor growth as well as metastasis [7, 10,11,12,13,14,15]. A candidate factor that has received some attention in recent years is the hepatocyte growth factor (HGF), which has been shown to have a role in the progression of PC [16, 17], with respect to stromal-tumor interactions [14, 18]. Binding of HGF to its transmembrane cell surface receptor c-MET, which is expressed on cancer cells activates several intracellular cell-signalling pathways that play a pivotal role in cancer cell proliferation and migration. Our recent www.impactjournals.com/oncotarget work has shown that this pathway plays a critical role in cancer cell and endothelial cell functions [14, 19]
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