Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin

Ying Cao, Luke H. Hoeppner, Steven Bach, E. Guangqi, Yan Guo, Enfeng Wang, Jianmin Wu, Mark J. Cowley, David K. Chang, Nicola Waddell, Sean M. Grimmond, Andrew V. Biankin, Roger J. Daly, Xiaohui Zhang, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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 show that neuropilin-2 (NRP-2), a multifunctional nonkinase 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 patients with RCC, NRP-2 expression is positively correlated with tumor grade and is highest in metastatic tumors. In a prospectively acquired cohort of patients with pancreatic cancer, high NRP-2 expression cosegregated 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.

Original languageEnglish (US)
Pages (from-to)4579-4590
Number of pages12
JournalCancer research
Volume73
Issue number14
DOIs
StatePublished - Jul 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Cao, Y., Hoeppner, L. H., Bach, S., Guangqi, E., Guo, Y., Wang, E., Wu, J., Cowley, M. J., Chang, D. K., Waddell, N., Grimmond, S. M., Biankin, A. V., Daly, R. J., Zhang, X., & Mukhopadhyay, D. (2013). Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin. Cancer research, 73(14), 4579-4590. https://doi.org/10.1158/0008-5472.CAN-13-0529