SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion
SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion
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DOI：
10.1002/ijc.23450
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发表时间：
2008-06-15
影响因子：
6.4
通讯作者：
Rempel, Sandra A.
中科院分区：
文献类型：
--
作者：
Yunker, Christopher K.;Golembieski, William;Rempel, Sandra A.
胶质母细胞瘤是异质性肿瘤，显示坏死、增殖、血管生成、凋亡和侵袭区域。在神经胶质瘤中，负调节血管生成和细胞增殖，但增强细胞从基质脱粘附的基质细胞蛋白，上调（II-IV级）。我们以前证明，ESTA促进入侵，同时伴随着减少肿瘤生长，部分通过减少肿瘤细胞的增殖。在其他类型的癌症中，已经显示出通过改变基质产生和通过干扰VEGF-VEGFR 1信号传导途径减少血管生成来影响肿瘤生长。因此，我们研究了是否SPARC诱导的神经胶质瘤肿瘤生长的减少也部分是由于基质的改变和/或血管分布减少，并评估了SPARC-VEGF相互作用。这些数据表明，β-胡萝卜素上调胶质瘤基质，胶原蛋白I是基质的成分，β-胡萝卜素促进胶原蛋白原纤维形成。此外，VEGF抑制神经胶质瘤血管生成，并伴有VEGF表达和分泌减少，这部分是由于VEGF 165转录丰度减少。这些数据表明，VEGF通过改变肿瘤微环境和通过抑制VEGF表达和分泌抑制肿瘤血管生成来调节胶质瘤生长。这些实验暗示了一种新的机制，即VEGF通过限制可用的生长因子来调节VEGF功能。由于胶质瘤被认为是神经胶质瘤的治疗靶点，因此进一步了解其复杂的信号传导机制是重要的，因为靶向胶质瘤以减少侵袭可能会不期望地导致更多血管和增殖性肿瘤的生长。(C)2008 Wiley-Liss，[tic.
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. (C) 2008 Wiley-Liss, [tic.