SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion

Christopher K. Yunker, William Golembieski, Nancy Lemke, Chad R. Schultz, Simona Cazacu, Chaya Brodie, Sandra A. Rempel

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Glioblastomas are heterogeneous tumors displaying regions of necrosis, proliferation, angiogenesis, apoptosis and invasion. SPARC, a matricellular protein that negatively regulates angiogenesis and cell proliferation, but enhances cell deadhesion from matrix, is upregulated in gliomas (Grades II-IV). We previously demonstrated that SPARC promotes invasion while concomitantly decreasing tumor growth, in part by decreasing proliferation of the tumor cells. In other cancer types, SPARC has been shown to influence tumor growth by altering matrix production, and by decreasing angiogenesis via interfering with the VEGF-VEGFR1 signaling pathway. We therefore examined whether the SPARC-induced decrease in glioma tumor growth was also, in part, due to alterations in matrix and/or decreased vascularity, and assessed SPARC-VEGF interactions. The data demonstrate that SPARC upregulates glioma matrix, collagen I is a constituent of the matrix and SPARC promotes collagen fibrillogenesis. Furthermore, SPARC suppressed glioma vascularity, and this was accompanied by decreased VEGF expression and secretion, which was, in part, due to reduced VEGF165 transcript abundance. These data indicate that SPARC modulates glioma growth by altering the tumor microenvironment and by suppressing tumor vascularity through suppression of VEGF expression and secretion. These experiments implicate a novel mechanism, whereby SPARC regulates VEGF function by limiting the available growth factor. Because SPARC is considered to be a therapeutic target for gliomas, a further understanding of its complex signaling mechanisms is important, as targeting SPARC to decrease invasion could undesirably lead to the growth of more vascular and proliferative tumors.

Original languageEnglish
Pages (from-to)2735-2743
Number of pages9
JournalInternational Journal of Cancer
Volume122
Issue number12
DOIs
StatePublished - 15 Jun 2008
Externally publishedYes

Keywords

  • Collagen I
  • Gliomas
  • Matrix
  • SPARC
  • VEGF(R1/2)
  • Vascularity

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