Neovascularization in Pancreatic Cancer is Dependent on Neuropilin 2

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate due to lack of detection, tendency to metastasize to the liver, and the absence of effective treatments. Consequently, there is an urgent need to understand the biology of this devastating disease in order to develop drugs to inhibit PDAC progression. Neuropilin‐2 (Nrp2) is a transmembrane receptor that binds competitively to either the angiogenic ligand, Vascular Endothelial Growth Factor (VEGF), or the inhibitory protein, Semaphorin‐3F (SEMA3F). Nrp2 expression is quiescent in the normal adult blood vasculature, however the expression of Nrp2 is strongly upregulated in tumor‐associated neovessels in human and mouse xenograft models of PDAC. Nrp2‐deficient mice in the C57BL/6J background are viable with no obvious defects in the blood vascular system or signs of edema. Using immunohistochemistry to CD31, we compared the blood microvascular density (MVD) in the adult mouse pancreas of Nrp2+/+ wildtype mice and Nrp2−/− knockout (KO) mice and found no significant difference. However, when luciferase‐labeled syngeneic PDAC cells were injected orthotopically into the pancreas of Nrp2‐mutant mice, subsequent PDAC tumor growth was impeded in mice lacking Nrp2 compared to wildtype littermates. Additionally, PDAC tumors showed reduced tumor MVD in Nrp2‐deficient mice compared to PDAC tumors in Nrp2 wildtype littermates. Correspondingly, the incidence of liver metastasis was inhibited in mice lacking Nrp2 suggesting that tumor angiogenesis and metastasis is dependent on endothelial expression of Nrp2 in this PDAC model. Lastly, PDAC tumor cells do not express the VEGF Receptor 2 tyrosine kinase and therefore do not respond in vitro to VEGF stimulation. However, the Nrp2 inhibitory ligand, SEMA3F, was able to directly inhibit the migration of PDAC tumor cells in vitro. Taken together, our data suggests that Nrp2 may be an important receptor to target in both tumor cells and endothelial cells in PDAC. Our results suggest that targeted therapy to the NRP2 axis could be a potential treatment strategy to inhibit the growth and metastasis of pancreatic tumors.Support or Funding InformationNIH CA155728 (DRB)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.