PTEN Deficiency Is Fully Penetrant for Prostate Adenocarcinoma in C57BL/6 Mice via mTOR-Dependent Growth
PTEN Deficiency Is Fully Penetrant for Prostate Adenocarcinoma in C57BL/6 Mice via mTOR-Dependent Growth
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DOI：
10.2353/ajpath.2009.080055
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发表时间：
2009-05-01
影响因子：
6
通讯作者：
Walker, Cheryl Lyn
中科院分区：
文献类型：
--
作者：
Blando, Jorge;Portis, Melisa;Walker, Cheryl Lyn
肿瘤抑制磷酸酶和张力蛋白同源物 (PTEN) 经常与人类前列腺癌有关。因此，PTEN 是开发临床前动物模型的一个有吸引力的目标。前列腺上皮内瘤变病变在具有 Pten 杂合性的小鼠中发生，但据报道，疾病进展仅与其他肿瘤抑制基因改变或前列腺上皮细胞中两个 Pten 等位基因的条件性失活相结合。我们报告说，在 C57BL/6 背景下，与之前对混合 129 个遗传背景的研究相比，Metz 位点杂合性对于前列腺腺癌的发展具有完全渗透性。肉眼可见的肿瘤在 6 个月大时被发现，到 10 至 12 个月时，100% 的受检小鼠患上前前列腺腺癌。此外，携带 Pten 和 Tsc2 无效等位基因的双杂合子相对于 Pten(+/-) 杂合子在病变发展或进展方面没有表现出增加。 Pten 两侧均有病变（+/-）； Tsc2(+/-) 和 Pten(+/-) 小鼠表现出 PTEN 表达缺失和 PI3K 信号传导激活。 PI3K 激活发生在这些动物的前列腺上皮内瘤变病变形成的早期，与 PTEN 功能的丧失一致，并导致 Pten(+/-) 小鼠中发生肿瘤的病因学。此外，Pten(+/-) 小鼠中前列腺病变的生长依赖于 mTOR，雷帕霉素治疗后磷酸-S6 水平和增殖指数的降低证明了这一点。 （Am J Pathol 2009，174：1869-1879；DOI：10.2353/ajpath.2009.080055）
The tumor suppressor phosphatase and tensin homolog (PTEN) is frequently involved in human prostate carcinoma. PTEN is therefore an attractive target for the development of preclinical animal models. Prostate intraepithelial neoplasia lesions develop in mice with Pten heterozygosity, but disease progression has been reported only in combination with either other tumor suppressor gene alterations or die conditional inactivation of both Pten alleles in prostate epithelial cells. We report that on a C57BL/6 background, in contrast to previous studies on mixed 129 genetic backgrounds, Metz locus heterozygosity is fully penetrant for the development of prostate adenocarcinoma. Grossly observable tumors were detected at 6 months of age, and, by 10 to 12 months, 100% of examined mice developed adenocarcinoma of the anterior prostate. Furthermore, double heterozygotes carrying both Pten and Tsc2-null alleles showed no increase relative to Pten(+/-) heterozygotes in either lesion development or progression. Lesions in both Pten(+/-); Tsc2(+/-), and Pten(+/-) mice exhibited loss of PTEN expression and activation of PI3K signaling. PI3K activation occurred early in prostate intraepithelial neoplasia lesion formation in these animals, consistent with loss of PTEN function, and contributed to the etiology of tumors that developed in Pten(+/-) mice. Furthermore, prostate lesion growth in Pten(+/-) mice was dependent on mTOR, as evidenced by a reduction in both phospho-S6 levels and proliferative index after rapamycin treatment. (Am J Pathol 2009, 174:1869-1879; DOI: 10.2353/ajpath.2009.080055)