Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer.

Abstract

At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.

• Authors: Kristen S Hill, Ivana Gaziova, Lindsay Harrigal, Yvette A Guerra, Suimin Qiu, Sarita K Sastry, Thiruvengadam Arumugam, Craig D Logsdon, Lisa A Elferink
• Journal: PloS one (PLoS One) Vol. 7 Issue 7 Pg. e40420 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22815748 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-8
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Blood Vessels (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic
• Gene Knockdown Techniques
• Humans
• Interleukin-8 (metabolism)
• Male
• Mice
• Mice, Nude
• Neovascularization, Pathologic
• Pancreatic Neoplasms (blood supply, metabolism, pathology)
• Paracrine Communication
• Proto-Oncogene Proteins c-met (deficiency, genetics, metabolism)
• RNA Interference
• Signal Transduction