PUBLICATION
A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis
- Authors
- Zhou, R., Curry, J.M., Roy, L.D., Grover, P., Haider, J., Moore, L.J., Wu, S.T., Kamesh, A., Yazdanifar, M., Ahrens, W.A., Leung, T., Mukherjee, P.
- ID
- ZDB-PUB-160126-12
- Date
- 2016
- Source
- Oncogene 35(43): 5608-5618 (Journal)
- Registered Authors
- Leung, Tin Chung
- Keywords
- none
- MeSH Terms
-
- Animals
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism*
- Carcinoma, Pancreatic Ductal/pathology*
- Cell Line, Tumor
- Disease Models, Animal
- Endothelial Cells/metabolism
- Epithelial-Mesenchymal Transition
- Gene Expression
- Heterografts
- Humans
- Mice
- Mice, Knockout
- Mucin-1/genetics
- Mucin-1/metabolism*
- Neoplasm Metastasis
- Neovascularization, Pathologic/metabolism
- Neuropilin-1/genetics
- Neuropilin-1/metabolism*
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism*
- Pancreatic Neoplasms/pathology*
- Receptors, Vascular Endothelial Growth Factor/genetics
- Receptors, Vascular Endothelial Growth Factor/metabolism
- Signal Transduction
- Vascular Endothelial Growth Factor A/metabolism
- Zebrafish
- PubMed
- 26804176 Full text @ Oncogene
Citation
Zhou, R., Curry, J.M., Roy, L.D., Grover, P., Haider, J., Moore, L.J., Wu, S.T., Kamesh, A., Yazdanifar, M., Ahrens, W.A., Leung, T., Mukherjee, P. (2016) A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: role in induction of VEGF signaling and angiogenesis. Oncogene. 35(43):5608-5618.
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, 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 VEGF165 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping