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

Cancer Res. 2013 Jul 15;73(14):4579-4590. doi: 10.1158/0008-5472.CAN-13-0529. Epub 2013 May 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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

Substances

  • Integrin alpha5
  • Neuropilin-2