Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.
Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.
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DOI：
10.1038/ng.356
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发表时间：
2009-05
期刊：
影响因子：
30.8
通讯作者：
Bosenberg, Marcus
中科院分区：
文献类型：
--
作者：
Dankort, David;Curley, David P.;Cartlidge, Robert A.;Nelson, Betsy;Karnezis, Anthony N.;Damsky, William E., Jr.;You, Mingjian J.;DePinho, Ronald A.;McMahon, Martin;Bosenberg, Marcus
BRAF的突变激活是人类黑色素瘤中最早和最常见的基因改变。因此，为了构建人类黑色素瘤模型，我们产生了条件黑色素细胞特异性表达BRafV600E的小鼠。诱导BRafV600E表达后，小鼠出现良性黑色素细胞增生，在15-20个月内未进展为黑色素瘤。相比之下，BRafV600E的表达联合Pten抑癌基因沉默可诱导黑色素瘤的发展，其外显率为100%，潜伏期短，并在淋巴结和肺部观察到转移。mTorc1（雷帕霉素）或MEK1/2 （PD325901）抑制剂可预防黑色素瘤，但在停止给药后，小鼠发生黑色素瘤，表明该系统中存在长寿命的黑色素瘤起始细胞。重要的是，雷帕霉素和PD325901联合治疗可使已形成的黑色素瘤缩小。这些小鼠具有与人类黑色素瘤相同的基因特征，为研究黑色素瘤转移的主要特征和预防或治疗转移性疾病的药物的临床前评估提供了一个很好的系统。
Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. Hence, to build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRafV600E. Upon induction of BRafV600E expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRafV600E combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (Rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma indicating the presence of long-lived melanoma-initiating cells in this system. Importantly, combined treatment with Rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide an excellent system to study melanoma’s cardinal feature of metastasis and for pre-clinical evaluation of agents designed to prevent or treat metastatic disease.
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影响因子：
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作者：
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