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A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis
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A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis
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A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis
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Journal Article
A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis
2016
Overview
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, tMUC1
hi
PDA cells secreted high levels of VEGF and expressed high levels of VEGF receptor 2 (VEGFR2) and its phosphorylated forms as compared with tMUC1
low/null
PDA. This enabled the tMUC1
hi
/NRP1
hi
PDA 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/NRP1
hi
PDA cells. Hence, blocking signaling via the NRP1–VEGF axis significantly reduced tube formation, new vessel generation and metastasis induced by tMUC1
hi
PDA cells. Finally, we show that blocking the interaction between VEGF
165
and 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Cancer
/ Carcinoma, Pancreatic Ductal - genetics
/ Carcinoma, Pancreatic Ductal - metabolism
/ Carcinoma, Pancreatic Ductal - pathology
/ Endothelial Cells - metabolism
/ Epithelial-Mesenchymal Transition
/ Humans
/ Medicine
/ Mice
/ Neovascularization, Pathologic - metabolism
/ Oncology
/ Pancreas
/ Pancreatic Neoplasms - genetics
/ Pancreatic Neoplasms - metabolism
/ Pancreatic Neoplasms - pathology
/ Receptors, Vascular Endothelial Growth Factor - genetics
/ Receptors, Vascular Endothelial Growth Factor - metabolism
/ Tumors
/ Vascular endothelial growth factor
/ Vascular Endothelial Growth Factor A - metabolism
/ Vascular endothelial growth factor receptors
/ Vimentin
