Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial alpha5 integrin
- Authors
- Cao, Y., Hoeppner, L., Bach, S., E, G., Guo, Y., Wang, E., Wu, J., Cowley, M.J., Chang, D.K., Waddell, N., Grimmond, S.M., Biankin, A.V., Daly, R.J., Zheng, X., and Mukhopadhyay, D.
- ID
- ZDB-PUB-130702-5
- Date
- 2013
- Source
- Cancer research 73(14): 4579-4590 (Journal)
- Registered Authors
- Cao, Ying, Hoeppner, Luke, Mukhopadhyay, Debabrata
- Keywords
- none
- MeSH Terms
-
- Adenocarcinoma/blood supply
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Animals
- Carcinoma, Renal Cell/blood supply
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism*
- Carcinoma, Renal Cell/pathology
- Cell Adhesion/genetics
- Cell Line, Tumor
- Cell Movement/genetics
- Endothelial Cells/metabolism
- Endothelial Cells/pathology*
- Female
- Human Umbilical Vein Endothelial Cells
- Humans
- Integrin alpha5/genetics
- Integrin alpha5/metabolism*
- Kidney Neoplasms/blood supply
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism*
- Kidney Neoplasms/pathology
- Male
- Mice
- Mice, Nude
- Neoplasm Invasiveness
- Neoplasm Metastasis
- Neoplastic Cells, Circulating/metabolism*
- Neoplastic Cells, Circulating/pathology*
- Neuropilin-2/genetics
- Neuropilin-2/metabolism*
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Prognosis
- Prospective Studies
- Zebrafish
- PubMed
- 23689123 Full text @ Cancer Res.
Metastasis, the leading cause of cancer death, requires tumor cell intravasation, migration through the bloodstream, arrest within capillaries, and extravasation to invade distant tissues. Few mechanistic details have been reported thus far regarding the extravasation process or re-entry of circulating tumor cells at metastatic sites. Here, we demonstrate that neuropilin-2 (NRP-2), a multi-functional non-kinase receptor for semaphorins, vascular endothelial growth factor (VEGF), and other growth factors, expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular extravasation and metastasis in zebrafish and murine xenograft models of clear cell renal cell carcinoma (RCC) and pancreatic adenocarcinoma. In tissue from RCC patients, NRP-2 expression is positively correlated with tumor grade and highest in metastatic tumors. In a prospectively acquired cohort of patients with pancreatic cancer, high NRP-2 expression co-segregated with poor prognosis. Through biochemical approaches as well as Atomic Force Microscopy (AFM), we describe a unique mechanism through which NRP-2 expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular adhesion and extravasation. Taken together, our studies reveal a clinically significant role of NRP-2 in cancer cell extravasation and promotion of metastasis.