Crosstalk between Pten and Ras signaling pathways in tumor development
Crosstalk between Pten and Ras signaling pathways in tumor development
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DOI：
10.4161/cc.4.9.2039
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发表时间：
2005-09-01
期刊：
影响因子：
4.3
通讯作者：
Balmain, A
中科院分区：
文献类型：
--
作者：
To, MD;Perez-Losada, J;Balmain, A
在相当大比例的癌症中，Pten 和 Ras 通路分别被破坏或激活。经典的两阶段致癌方案诱导的皮肤肿瘤显示出一致的 H-ras 基因激活突变，但在 Pten 杂合小鼠的肿瘤中，这些突变的频率显着降低，表明这些途径之间存在一些冗余。与对照小鼠相比，Pten 杂合子小鼠会出现更多的乳头状瘤，并且癌症发病更早，但这些肿瘤的分子分析表明 Pten 的完全缺失和 H-ras 的激活是相互排斥的。然而，Pten 缺失在功能上并不等同于 H-ras 激活，因为 Pten-/- 肿瘤发生得更早并且通常更具侵袭性。 Pten 缺失或 H-ras 激活的肿瘤具有不同的生化特性，暗示了恶性肿瘤的替代途径。该小鼠模型的这些发现对于合理设计人类肿瘤新靶向疗法具有重要意义。
The Pten and Ras pathways are disrupted or activated, respectively, in a substantial proportion of cancers. Skin tumors induced by the classical two stage carcinogenesis protocols show consistent activating mutations of the H-ras gene, but in tumors from Pten heterozygous mice, the frequency of these mutations is markedly decreased, suggesting some redundancy between these pathways. Pten heterozygous mice develop more papillomas and have earlier onset of carcinomas than their control counterparts, but molecular analysis of these tumors indicated that complete loss of Pten and activation of H-ras are mutually exclusive. Pten loss is however not functionally equivalent to H-ras activation, as Pten-/- tumors occur earlier and are generally more aggressive. Tumors with Pten loss or H-ras activation have different biochemical properties, suggestive of alternative routes to malignancy. These findings in this mouse model have important implications for the rational design of new targeted therapies for human tumors.