The peroxisome proliferator-activated receptor-γ agonist troglitazone inhibits transforming growth factor-β-mediated glioma cell migration and brain invasion
The peroxisome proliferator-activated receptor-γ agonist troglitazone inhibits transforming growth factor-β-mediated glioma cell migration and brain invasion
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DOI：
10.1158/1535-7163.mct-06-0763
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发表时间：
2007-06-01
影响因子：
5.7
通讯作者：
Hahnen, Eric
中科院分区：
文献类型：
--
作者：
Coras, Roland;Hoelsken, Annett;Hahnen, Eric
胶质瘤是中枢神经系统最常见的原发肿瘤，恶性程度最高。这些肿瘤的快速增殖和弥漫性脑侵袭可能决定了不良的预后。考虑到转化生长因子-β信号通路的趋化特性，转化生长因子-β信号通路已成为治疗的主要靶点。对切除的胶质瘤组织的分析发现，肿瘤分级与转化生长因子-β(1-3)及其受体I和II的表达存在有趣的相关性。在这里，我们分析了过氧化体增殖物激活受体γ(PPAR-γ)激动剂对胶质瘤增殖、迁移和脑侵袭的影响。使用器质性胶质瘤侵袭模型，我们发现微摩尔剂量的PPAR-γ激活剂曲格列酮阻止了胶质瘤的进展，而没有观察到对器质性神经环境的神经毒性损害。曲格列酮这种耐人寻味的抗胶质瘤特性似乎只是部分基于其适度的细胞抑制作用。我们发现曲格列酮是一种有效的胶质瘤细胞迁移和脑侵袭的抑制剂，这种抑制作用是以PPAR-γ非依赖性的方式发生的。曲格列酮的抗迁移作用与其对转化生长因子-β(1-3)及其受体I、II转录的抑制作用一致，并与减少转化生长因子-β的释放有关。由于曲格列酮能够抑制转化生长因子-β的释放和胶质瘤细胞在低微摩尔剂量下的运动和侵袭性，因此有望成为胶质瘤和其他高迁移肿瘤的辅助治疗药物。
Gliomas are the most common primary tumors of the central nervous system, with glioblastomas as the most malignant entity. Rapid proliferation and diffuse brain invasion of these tumors are likely to determine the unfavorable prognosis. Considering its promigratory properties, the transforming growth factor-beta (TGF-beta) signaling pathway has become a major therapeutic target. Analyses of resected glioma tissues revealed an intriguing correlation between tumor grade and the expression of TGF-beta(1-3) as well as their receptors I and II. Here, we analyzed the effects of peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists on glioma proliferation, migration, and brain invasion. Using an organotypic glioma invasion model, we show that micromolar doses of the PPAR-gamma activator troglitazone blocked glioma progression without neurotoxic damage to the organotypic neuronal environment observed. This intriguing antiglioma property of troglitazone seems to be only partially based on its moderate cytostatic effects. We identified troglitazone as a potent inhibitor of glioma cell migration and brain invasion, which occurred in a PPAR-gamma - independent manner. The antimigratory property of troglitazone was in concordance with the transcriptional repression of TGF-beta(1-3) and their receptors I and II and associated with reduced TGF-beta release. Due to its capacity to counteract TGF-beta release and glioma cell motility and invasiveness already at low micromolar doses, troglitazone represents a promising drug for adjuvant therapy of glioma and other highly migratory tumor entities.