Fibulin-3 is uniquely upregulated in malignant gliomas and promotes tumor cell motility and invasion.
Fibulin-3 is uniquely upregulated in malignant gliomas and promotes tumor cell motility and invasion.
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DOI：
10.1158/1541-7786.mcr-09-0207
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Viapiano MS
中科院分区：
文献类型：
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作者：
Hu B;Thirtamara-Rajamani KK;Sim H;Viapiano MS
恶性胶质瘤是一种高度侵袭性的肿瘤，几乎总是快速和致命的结果。手术和放化疗不能去除分散在正常组织中的耐药肿瘤细胞，这是疾病进展和治疗失败的主要原因。与其他实体瘤相比，神经实质的浸润是恶性胶质瘤的一个独特性质。因此，神经胶质瘤细胞被认为产生独特的分子变化，重塑神经细胞外基质，并形成一个微环境，允许他们的运动。在这里，我们描述了fibulin-3的独特表达和促侵袭作用，fibulin-3是一种在胶质瘤中特异性上调的间充质基质蛋白。纤蛋白-3在外周肿瘤中下调，并被认为抑制肿瘤生长。然而，我们发现fibulin-3在神经胶质瘤和培养的神经胶质瘤细胞中高度上调，尽管该蛋白在正常脑或培养的星形胶质细胞中检测不到。过表达和敲低实验表明，fibulin-3似乎不影响胶质瘤细胞的形态或增殖，但增强基板特异性细胞粘附和促进细胞运动和分散在器官型培养。此外，原位植入fibulin-3过表达胶质瘤细胞导致弥漫性肿瘤体积增加和吻尾向扩展相比，控制。过表达纤蛋白-3的肿瘤和培养细胞也显示基质金属蛋白酶如MMP-2/9和ADAMTS-5的表达和活性升高。综上所述，我们的研究结果表明，fibulin-3在胶质瘤中具有独特的表达和促肿瘤作用，并且可能是对抗肿瘤进展的潜在靶点。针对这种胶质瘤特异性基质成分的策略可以破坏侵袭机制并限制这些肿瘤的传播。
Malignant gliomas are highly invasive tumors with an almost invariably rapid and lethal outcome. Surgery and chemoradiotherapy fail to remove resistant tumor cells that disperse within normal tissue, which are a major cause for disease progression and therapy failure. Infiltration of the neural parenchyma is a distinctive property of malignant gliomas compared to other solid tumors. Thus, glioma cells are thought to produce unique molecular changes that remodel the neural extracellular matrix and form a microenvironment permissive for their motility. Here we describe the unique expression and pro-invasive role of fibulin-3, a mesenchymal matrix protein specifically upregulated in gliomas. Fibulin-3 is downregulated in peripheral tumors and thought to inhibit tumor growth. However, we found fibulin-3 highly upregulated in gliomas and cultured glioma cells, although the protein was undetectable in normal brain or cultured astrocytes. Overexpression and knockdown experiments revealed that fibulin-3 did not seem to affect glioma cell morphology or proliferation, but enhanced substrate-specific cell adhesion and promoted cell motility and dispersion in organotypic cultures. Moreover, orthotopic implantation of fibulin-3-overexpressing glioma cells resulted in diffuse tumors with increased volume and rostrocaudal extension compared to controls. Tumors and cultured cells overexpressing fibulin-3 also showed elevated expression and activity of matrix metalloproteases, such as MMP-2/9 and ADAMTS-5. Taken together, our results suggest that fibulin-3 has a unique expression and pro-tumoral role in gliomas, and could be a potential target against tumor progression. Strategies against this glioma-specific matrix component could disrupt invasive mechanisms and restrict dissemination of these tumors.