Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4R24C/R24C/TPras mice
Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4R24C/R24C/TPras mice
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DOI：
10.1158/0008-5472.can-05-3196
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发表时间：
2006-03-15
期刊：
影响因子：
11.2
通讯作者：
Walker, G
中科院分区：
文献类型：
--
作者：
Hacker, E;Muller, HK;Walker, G
人类黑色素瘤易感性通常以种系灭活CDKN2A （INK4A/ARF）突变或通过阻止CDK4与INK4A的结合和抑制来激活CDK4的突变为特征。我们之前的研究表明，对携带黑素细胞特异性激活的Hras （TPras）的小鼠进行一次新生儿紫外线辐射（UVR）剂量可使黑色素瘤的外显率从0%增加到57%。在这里，我们报告了活化的Cdk4与活化的Hras合作，增强小鼠对黑色素瘤的易感性。虽然UVR治疗未能在Cdk4（R24C/R24C）小鼠中诱导黑色素瘤，但与单独使用TPras相比，UVR治疗大大增加了Cdk4(R24C/R24C)/TPras动物的外显率并降低了黑色素瘤发展的发病年龄。这种增加的外显率依赖于Cdk4激活的阈值，因为Cdk4(R24C/+)/TPras动物与单独的TPras相比，uvr诱导的黑色素瘤外显率没有增加。此外，Cdk4(R24C/R24C)/TPras小鼠无一例外地出现多发病变，而这种情况在TPras小鼠中很少发生。这些结果表明，废除pRb途径的种系缺陷可能会增强uvr诱导的黑色素瘤。TPras和Cdk4(R24C/R24C)/TPras肿瘤在组织病理学上是相似的，但后者更大，更具侵袭性，并且来自此类黑色素瘤的培养细胞也更大，核异型性水平更高。此外，在Cdk4(R24C/R24C)/TPras小鼠中，黑色素瘤很容易转移到局部淋巴结，而在TPras小鼠中则没有。因此，在小鼠中，Hras激活启动uvr诱导的黑色素瘤发展，而突变Cdk4引入的细胞周期缺陷有助于肿瘤进展，产生更具侵袭性的转移性肿瘤。
Human melanoma susceptibility is often characterized by germ-line inactivating CDKN2A (INK4A/ARF) mutations, or mutations that activate CDK4 by preventing its binding to and inhibition by INK4A. We have previously shown that a single neonatal UV radiation (UVR) dose delivered to mice that carry melanocyte-specific activation of Hras (TPras) increases melanoma penetrance from 0% to 57%. Here, we report that activated Cdk4 cooperates with activated Hras to enhance susceptibility to melanoma in mice. Whereas UVR treatment failed to induce melanomas in Cdk4(R24C/R24C) mice, it greatly increased the penetrance and decreased the age of onset of melanoma development in Cdk4(R24C/R24C)/TPras animals compared with TPras alone. This increased penetrance was dependent on the threshold of Cdk4 activation as Cdk4(R24C/+)/TPras animals did not show an increase in UVR-induced melanoma penetrance compared with TPras alone. In addition, Cdk4(R24C/R24C)/TPras mice invariably developed multiple lesions, which occurred rarely in TPras mice. These results indicate that germ-line defects abrogating the pRb pathway may enhance UVR-induced melanoma. TPras and Cdk4(R24C/R24C)/TPras tumors were comparable histopathologically but the latter were larger and more aggressive and cultured cells derived from such melanomas were also larger and had higher levels of nuclear atypia. Moreover, the melanomas in Cdk4(R24C/R24C)/TPras mice, but not in TPras mice, readily metastasized to regional lymph nodes. Thus, it seems that in the mouse, Hras activation initiates UVR-induced melanoma development whereas the cell cycle defect introduced by mutant Cdk4 contributes to tumor progression, producing more aggressive, metastatic tumors.