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
-
- Cell Movement/genetics
- Kidney Neoplasms/blood supply
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism*
- Kidney Neoplasms/pathology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Integrin alpha5/genetics
- Integrin alpha5/metabolism*
- Human Umbilical Vein Endothelial Cells
- Male
- Prognosis
- Zebrafish
- Mice, Nude
- Cell Adhesion/genetics
- Neoplasm Invasiveness
- Carcinoma, Renal Cell/blood supply
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism*
- Carcinoma, Renal Cell/pathology
- Prospective Studies
- Cell Line, Tumor
- Mice
- Neuropilin-2/genetics
- Neuropilin-2/metabolism*
- Female
- Endothelial Cells/metabolism
- Endothelial Cells/pathology*
- Animals
- Neoplastic Cells, Circulating/metabolism*
- Neoplastic Cells, Circulating/pathology*
- Humans
- Adenocarcinoma/blood supply
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Neoplasm Metastasis
- 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.