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A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumour angiogenesis and invasion in a mouse model of multistage cancer

Joyce, Johanna A; Freeman, Craig; Meyer-Morse, Nicole; Hanahan, Douglas; Parish, Christopher

Description

Heparan sulfate proteoglycans are integral components of the extracellular matrix that surrounds all mammalian cells. In addition to providing structural integrity, they act as a storage depot for a variety of heparan sulfate (HS)-binding proteins, including growth factors and chemokines. Heparanase is a matrix-degrading enzyme that cleaves heparan sulfate side chains from the core proteoglycans, thus liberating such HS-binding proteins, as well as potentially contributing to extracellular...[Show more]

dc.contributor.authorJoyce, Johanna A
dc.contributor.authorFreeman, Craig
dc.contributor.authorMeyer-Morse, Nicole
dc.contributor.authorHanahan, Douglas
dc.contributor.authorParish, Christopher
dc.date.accessioned2015-12-13T22:34:15Z
dc.identifier.issn0950-9232
dc.identifier.urihttp://hdl.handle.net/1885/76039
dc.description.abstractHeparan sulfate proteoglycans are integral components of the extracellular matrix that surrounds all mammalian cells. In addition to providing structural integrity, they act as a storage depot for a variety of heparan sulfate (HS)-binding proteins, including growth factors and chemokines. Heparanase is a matrix-degrading enzyme that cleaves heparan sulfate side chains from the core proteoglycans, thus liberating such HS-binding proteins, as well as potentially contributing to extracellular matrix degradation. Here, we report that heparanase mRNA and protein expression are increased in the neoplastic stages progressively unfolding in a mouse model of multistage pancreatic islet carcinogenesis. Notably, heparanase is delivered to the neoplastic lesions in large part by infiltrating Gr1 + /Mac1 + innate immune cells. A sulfated oligosaccharide mimetic of heparan sulfate, PI-88, was used to inhibit simultaneously both heparanase activity and HS effector functions. PI-88 had significant effects at distinct stages of tumorigenesis, producing a reduction in the number of early progenitor lesions and an impairment of tumor growth at later stages. These responses were associated with decreased cell proliferation, increased apoptosis, impaired angiogenesis, and a substantive reduction in the number of invasive carcinomas. In addition, we show that the reduction in tumor angiogenesis is correlated with a reduced association of VEGF-A with its receptor VEGF-R2 on the tumor endothelium, implicating heparanase in the mobilization of matrix-associated VEGF. These data encourage clinical applications of inhibitors such as PI-88 for the many human cancers where heparanase expression is elevated or mobilization of HS-binding regulatory factors is implicated.
dc.publisherNature Publishing Group
dc.sourceOncogene
dc.subjectKeywords: binding protein; chemokine; growth factor; heparan sulfate; heparanase; messenger RNA; oligosaccharide; pi 88; protein; vasculotropin A; vasculotropin receptor 2; angiogenesis; animal cell; animal model; animal tissue; apoptosis; article; cancer invasion; Angiogenesis; Heparan sulfate-binding proteins; Heparanase; Invasion; Mouse model; Pancreatic neuroendocrine cancer
dc.titleA functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumour angiogenesis and invasion in a mouse model of multistage cancer
dc.typeJournal article
local.description.notesImported from ARIES
local.description.refereedYes
local.identifier.citationvolume24
dc.date.issued2005
local.identifier.absfor110709 - Tumour Immunology
local.identifier.ariespublicationMigratedxPub4949
local.type.statusPublished Version
local.contributor.affiliationJoyce, Johanna A, University of California
local.contributor.affiliationFreeman, Craig, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationMeyer-Morse, Nicole, University of California
local.contributor.affiliationParish, Christopher, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationHanahan, Douglas, University of California
local.description.embargo2037-12-31
local.bibliographicCitation.startpage4037
local.bibliographicCitation.lastpage4051
local.identifier.doi10.1038/sj.onc.1208602
dc.date.updated2015-12-11T09:19:10Z
local.identifier.scopusID2-s2.0-20444394457
CollectionsANU Research Publications

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