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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: Luke H
authors.initials: LH
authors.lastname: Hoeppner
authors.affiliation: Bioengineering Program & Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA 18015.
authors.forename: Steven
authors.initials: S
authors.lastname: Bach
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: Guangqi
authors.initials: G
authors.lastname: E
authors.affiliation: Bioengineering Program & Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA 18015.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: Enfeng
authors.initials: E
authors.lastname: Wang
authors.affiliation: The Kinghorn Cancer Centre, Cancer Research Division, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.affiliation: The Kinghorn Cancer Centre, Cancer Research Division, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.affiliation: The Kinghorn Cancer Centre, Cancer Research Division, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.|Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW 2200, Australia.|South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool NSW 2170, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Chang
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: The Kinghorn Cancer Centre, Cancer Research Division, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.|Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW 2200, Australia.|South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool NSW 2170, Australia.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: The Kinghorn Cancer Centre, Cancer Research Division, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.affiliation: Bioengineering Program & Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA 18015.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism* / Q000473:pathology*; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D015027:Zebrafish
chemical_list: D039482:Integrin alpha5; D039943:Neuropilin-2