Oncotarget

Research Papers:

Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma

Pratiek N. Matkar, Krishna Kumar Singh, Dmitriy Rudenko, Yu Jin Kim, Michael A. Kuliszewski, Gerald J. Prud’homme, David W. Hedley and Howard Leong-Poi _

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Oncotarget. 2016; 7:69489-69506. https://doi.org/10.18632/oncotarget.11060

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Abstract

Pratiek N. Matkar1,6, Krishna Kumar Singh2,3,6, Dmitriy Rudenko1, Yu Jin Kim1, Michael A. Kuliszewski1, Gerald J. Prud’homme4, David W. Hedley5, Howard Leong-Poi1,6

1Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada

2Division of Vascular Surgery, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada

3Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada

4Division of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada

5Division of Medical Oncology and Hematology, Ontario Cancer Institute, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, Toronto, Canada

6Institute of Medical Science, University of Toronto, Toronto, Canada

Correspondence to:

Howard Leong-Poi, email: leong-poih@smh.ca

Krishna Kumar Singh, email: singhk@smh.ca

Keywords: endothelial cell, neuropilin-1, endothelial-to-mesenchymal transition, fibrosis, pancreatic cancer

Received: January 21, 2016     Accepted: July 18, 2016     Published: August 11, 2016

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an intense fibrotic reaction termed tumor desmoplasia, which is in part responsible for its aggressiveness. Endothelial cells have been shown to display cellular plasticity in the form of endothelial-to-mesenchymal transition (EndMT) that serves as an important source of fibroblasts in pathological disorders, including cancer. Angiogenic co-receptor, neuropilin-1 (NRP- 1) actively binds TGFβ1, the primary mediator of EndMT and is involved in oncogenic processes like epithelial-to-mesenchymal transition (EMT). NRP-1 and TGFβ1 signaling have been shown to be aberrantly up-regulated in PDAC. We report herein a positive correlation between NRP-1 levels, EndMT and fibrosis in human PDAC xenografts. Loss of NRP-1 in HUVECs limited TGFβ1-induced EndMT as demonstrated by gain of endothelial and loss of mesenchymal markers, while maintaining endothelial cell architecture. Knockdown of NRP-1 down-regulated TGFβ canonical signaling (pSMAD2) and associated pro-fibrotic genes. Overexpression of NRP-1 exacerbated TGFβ1-induced EndMT and up-regulated TGFβ signaling and expression of pro-fibrotic genes. In vivo, loss of NRP-1 attenuated tumor perfusion and size, accompanied by reduction in EndMT and fibrosis. This study defines a previously unrecognized role of NRP-1 in regulating TGFβ1-induced EndMT and fibrosis, and advocates NRP-1 as a therapeutic target to reduce tumor fibrosis and PDAC progression.


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