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

40 Citations (Scopus)

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

Fingerprint

Neuropilin-2
Integrins
Neoplasm Metastasis
Neoplasms
Renal Cell Carcinoma
Blood Vessels
Endothelial Cells
Semaphorins
Circulating Neoplastic Cells
Vascular Endothelial Growth Factor Receptor
Atomic Force Microscopy
Zebrafish
Pancreatic Neoplasms
Heterografts
Cell Movement
Cause of Death
Intercellular Signaling Peptides and Proteins
Adenocarcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin. / Cao, Ying; Hoeppner, Luke H.; Bach, Steven; Guangqi, E.; Guo, Yan; Wang, Enfeng; Wu, Jianmin; Cowley, Mark J.; Chang, David K.; Waddell, Nicola; Grimmond, Sean M.; Biankin, Andrew V.; Daly, Roger J.; Zhang, Xiaohui; Mukhopadhyay, Debabrata.

In: Cancer Research, Vol. 73, No. 14, 15.07.2013, p. 4579-4590.

Research output: Contribution to journalArticle

Cao, Y, Hoeppner, LH, Bach, S, Guangqi, E, Guo, Y, Wang, E, Wu, J, Cowley, MJ, Chang, DK, Waddell, N, Grimmond, SM, Biankin, AV, Daly, RJ, Zhang, X & Mukhopadhyay, D 2013, 'Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin', Cancer Research, vol. 73, no. 14, pp. 4579-4590. https://doi.org/10.1158/0008-5472.CAN-13-0529
Cao, Ying ; Hoeppner, Luke H. ; Bach, Steven ; Guangqi, E. ; Guo, Yan ; Wang, Enfeng ; Wu, Jianmin ; Cowley, Mark J. ; Chang, David K. ; Waddell, Nicola ; Grimmond, Sean M. ; Biankin, Andrew V. ; Daly, Roger J. ; Zhang, Xiaohui ; Mukhopadhyay, Debabrata. / Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin. In: Cancer Research. 2013 ; Vol. 73, No. 14. pp. 4579-4590.
@article{6662d80ae85a487f90e0e8296de881a6,
title = "Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin",
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.",
author = "Ying Cao and Hoeppner, {Luke H.} and Steven Bach and E. Guangqi and Yan Guo and Enfeng Wang and Jianmin Wu and Cowley, {Mark J.} and Chang, {David K.} and Nicola Waddell and Grimmond, {Sean M.} and Biankin, {Andrew V.} and Daly, {Roger J.} and Xiaohui Zhang and Debabrata Mukhopadhyay",
year = "2013",
month = "7",
day = "15",
doi = "10.1158/0008-5472.CAN-13-0529",
language = "English (US)",
volume = "73",
pages = "4579--4590",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

TY - JOUR

T1 - Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial α5 integrin

AU - Cao, Ying

AU - Hoeppner, Luke H.

AU - Bach, Steven

AU - Guangqi, E.

AU - Guo, Yan

AU - Wang, Enfeng

AU - Wu, Jianmin

AU - Cowley, Mark J.

AU - Chang, David K.

AU - Waddell, Nicola

AU - Grimmond, Sean M.

AU - Biankin, Andrew V.

AU - Daly, Roger J.

AU - Zhang, Xiaohui

AU - Mukhopadhyay, Debabrata

PY - 2013/7/15

Y1 - 2013/7/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84880867496&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880867496&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-13-0529

DO - 10.1158/0008-5472.CAN-13-0529

M3 - Article

C2 - 23689123

AN - SCOPUS:84880867496

VL - 73

SP - 4579

EP - 4590

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 14

ER -