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首页> 外文期刊>Molecular and Cellular Biology >Astrocytes derived from p53-deficient mice provide a multistep in vitro model for development of malignant gliomas.
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Astrocytes derived from p53-deficient mice provide a multistep in vitro model for development of malignant gliomas.

机译：源自p53缺陷小鼠的星形胶质细胞为恶性神经胶质瘤的发展提供了一个多步骤的体外模型。

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Loss or mutation of p53 is thought to be an early event in the malignant transformation of many human astrocytic tumors. To better understand the role of p53 in their growth and transformation, we developed a model employing cultured neonatal astrocytes derived from mice deficient in one (p53 +/-) or both (p53 -/-) p53 alleles, comparing them with wild-type (p53 +/+) cells. Studies of in vitro and in vivo growth and transformation were performed, and flow cytometry and karyotyping were used to correlate changes in growth with genomic instability. Early-passage (EP) p53 -/- astrocytes achieved higher saturation densities and had more rapid growth than EP p53 +/- and +/+ cells. The EP p53 -/- cells were not transformed, as they were unable to grow in serum-free medium or in nude mice. With continued passaging, p53 -/- cells exhibited a multistep progression to a transformed phenotype. Late-passage p53 -/- cells achieved saturation densities 50 times higher than those of p53 +/+ cells and formed large, well-vascularized tumors in nude mice. p53 +/- astrocytes exhibited early loss of the remaining wild-type p53 allele and then evolved in a manner phenotypically similar to p53 -/- astrocytes. In marked contrast, astrocytes retaining both wild-type p53 alleles never exhibited a transformed phenotype and usually senesced after 7 to 10 passages. Dramatic alterations in ploidy and karyotype occurred and were restricted to cells deficient in wild-type p53 following repeated passaging. The results of these studies suggest that loss of wild-type p53 function promotes genomic instability, accelerated growth, and malignant transformation in astrocytes.
机译：p53的丢失或突变被认为是许多人类星形细胞肿瘤恶性转化的早期事件。为了更好地了解p53在其生长和转化中的作用，我们开发了一种模型，该模型使用了培养的新生星形胶质细胞，其衍生自一个或多个（p53-/-）p53等位基因缺陷的小鼠，并将它们与野生型进行了比较（p53 + / +）细胞。进行了体外和体内生长和转化的研究，并使用流式细胞仪和核型分析将生长变化与基因组不稳定性相关联。早期传代（EP）p53-/-星形胶质细胞比EP p53 +/-和+ / +细胞具有更高的饱和密度并具有更快的生长速度。 EP p53-/-细胞未转化，因为它们无法在无血清培养基或裸鼠中生长。随着持续传代，p53-/-细胞表现出多步进展至转化表型。晚期传代的p53-/-细胞达到的饱和密度是p53 + / +细胞的50倍，并且在裸鼠中形成了血管完整的大肿瘤。 p53 +/-星形胶质细胞表现出剩余的野生型p53等位基因的早期缺失，然后以与p53-/-星形胶质细胞相似的表型进化。与之形成鲜明对比的是，保留了两个野生型p53等位基因的星形胶质细胞从未表现出转化表型，通常在传代7至10次后就会衰老。重复传代后，发生了倍性和核型的戏剧性改变，并被限制在野生型p53缺陷的细胞中。这些研究结果表明，野生型p53功能的丧失会促进星形胶质细胞的基因组不稳定，加速生长和恶性转化。

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