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

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. © 2008 Wiley-Liss, Inc.

Lymphovascular invasion of colorectal cancer is correlated to SPARC expression in the tumor stromal microenvironment

“…Recent reports showed that SPARC inhibits microvascular endothelial cell proliferation by blocking VEGF-A. 30,31,33,34 To examine the relationship between SPARC and VEGF-A, we assessed cytoplasmic expression of VEGF-A in cancer cells versus SPARC in CRC and stromal cells using IHC staining intensity. An inverse correlation between VEGF-A and stromal cell SPARC staining intensity, but not between VEGF-A and CRC cell SPARC, was demonstrated (Fig.…”

“…SPARC has been associated with reduced vascularity and hypoxia, 9 which are events linked to VEGF-A suppression in tumors. 30,31 HSP27, one of the smallest HSPs, has been associated with clinical outcomes in different solid tumors, including a positive correlation with SPARC in gliomas. 32 In our study, IHC analysis demonstrated that HSP27 expression in CRC was proportionately correlated with expression of SPARC in stromal cells but not in SPARC cancer cells.…”

The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine

“…The SPARC modulates glioma growth by altering the tumour microenvironment and suppressing tumour vascularity through suppression of VEGF expression and secretion. (Yunker et al, 2008). In this context, the suppression of angiogenesis-mediated tumour growth by SPARC in medulloblastoma seems to be the consequence of its ability to inhibit the expression of angiogenic factors such as MMP-9, bFGF and VEGF in tumour tissues, which may in turn inhibit capillary infiltration into tumours.…”

Biology of Angiogenesis and Invasion in Glioma

“…106 Expression of SPARC in the nervous system is limited to the angiogenic microvasculature, as well as the locus coeruleus and retinal astrocytes, but is not normally expressed in the cerebral cortex. [107][108][109][110] However, SPARC expression is present in both tumor cells and endothelial cells in gliomas of all grades, as well as in endothelial cells and astrocytes in the adjacent tissue. 111 Recent work indicates that SPARC suppresses tumor vascularity via suppression of VEGF expression and secretion, which is accomplished by limiting the availability of the growth factor.…”

“…111 Recent work indicates that SPARC suppresses tumor vascularity via suppression of VEGF expression and secretion, which is accomplished by limiting the availability of the growth factor. 110 In contrast to its negative effect on angiogenesis, SPARC appears to have a promoting effect on tumor invasiveness. 112,113 A better understanding of these pathways is necessary before proceeding with anti-SPARC therapies.…”