A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis.
A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis.
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DOI：
10.1038/onc.2015.516
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发表时间：
2016-10-27
期刊：
影响因子：
8
通讯作者：
Mukherjee P
中科院分区：
文献类型：
--
作者：
Zhou R;Curry JM;Roy LD;Grover P;Haider J;Moore LJ;Wu ST;Kamesh A;Yazdanifar M;Ahrens WA;Leung T;Mukherjee P
We report that 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 VEGF) and its ligand, VEGF. Expression of tumor-associated MUC1 (tMUC1) positively correlated with NRP1 levels in human and mouse PDA. Further, tMUC1hi PDA cells secreted high levels of VEGF and expressed high levels of VEGF receptor 2 and its phosphorylated forms as compared to tMUC1low/null PDA. This enabled the tMUC1hi/NRP1hi 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/NRP1hi PDA cells. Hence, blocking signaling via the NRP1-VEGF axis significantly reduced tube formation, new vessel generation, and metastasis induced by tMUC1hi PDA cells. Finally, we show that blocking the interaction between VEGF165 and NRP1 with a NRP1 antagonist significantly reduced VEGFR signaling and PDA tumor growth in vivo. Taken together, our data suggests a novel molecular mechanism by which tMUC1 may modulate NRP1-dependent VEGFR signaling in PDA cells.
