title: A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis.
abstract: We report that Mucin1 (MUC1), a transmembrane glycoprotein that is overexpressed in >80% of pancreatic ductal adenocarcinoma (PDA), induced a pro-angiogenic tumor microenvironment by increasing the levels of neuropilin-1 (NRP1, a co-receptor of vascular endothelial growth factor (VEGF)) and its ligand VEGF. Expression of tumor-associated MUC1 (tMUC1) positively correlated with NRP1 levels in human and mouse PDA. Further, tMUC1hiPDA cells secreted high levels of VEGF and expressed high levels of VEGF receptor 2 (VEGFR2) and its phosphorylated forms as compared with tMUC1low/nullPDA. This enabled the tMUC1hi/NRP1hiPDA cells to (a) induce endothelial cell tube formation, (b) generate long ectopic blood vessels and (c) enhance distant metastasis in a zebrafish xenograft model. Concurrently, the proteins associated with epithelial-to-mesenchymal transition, N-cadherin and Vimentin, were highly induced in these tMUC1/NRP1hiPDA cells. Hence, blocking signaling via the NRP1-VEGF axis significantly reduced tube formation, new vessel generation and metastasis induced by tMUC1hiPDA cells. Finally, we show that blocking the interaction between VEGF165and NRP1 with a NRP1 antagonist significantly reduced VEGFR signaling and PDA tumor growth in vivo. Taken together, our data suggest a novel molecular mechanism by which tMUC1 may modulate NRP1-dependent VEGFR signaling in PDA cells.
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Curry
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: Roy
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: P
authors.initials: P
authors.lastname: Grover
authors.affiliation: Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Kannapolis, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Haider
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Moore
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: S-T
authors.initials: ST
authors.lastname: Wu
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kamesh
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yazdanifar
authors.affiliation: Section of Hepatobiliary and Pancreas Surgery, Department of Surgery, Carolinas Medical Center, Charlotte, NC, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Ahrens
authors.affiliation: Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Kannapolis, NC, USA.
authors.forename: T
authors.initials: T
authors.lastname: Leung
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: P
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish
chemical_list: D018396:Mucin-1; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040262:Receptors, Vascular Endothelial Growth Factor