Dankort David, Curley David P, Cartlidge Robert A, Nelson Betsy, Karnezis Anthony N, Damsky William E, You Mingjian J, DePinho Ronald A, McMahon Martin, Bosenberg Marcus
Cancer Research Institute & Department of Cell and Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA.
Nat Genet. 2009 May;41(5):544-52. doi: 10.1038/ng.356. Epub 2009 Mar 12.
Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRaf(V600E). Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) 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. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease.
BRAF的突变激活是人类黑色素瘤中最早且最常见的基因改变。为构建人类黑色素瘤模型，我们培育了具有条件性黑素细胞特异性表达BRaf（V600E）的小鼠。在诱导BRaf（V600E）表达后，小鼠出现良性黑素细胞增生，在15至20个月内未发展为黑色素瘤。相比之下，BRaf（V600E）的表达与Pten肿瘤抑制基因沉默相结合引发了黑色素瘤的发展，其发生率为100%，潜伏期短，且在淋巴结和肺部观察到转移。mTorc1抑制剂（雷帕霉素）或MEK1/2抑制剂（PD325901）可预防黑色素瘤，但在停止给药后，小鼠会发展为黑色素瘤，表明该系统中存在长寿的黑色素瘤起始细胞。值得注意的是，雷帕霉素和PD325901联合治疗导致已形成的黑色素瘤缩小。这些具有与人类黑色素瘤相同遗传特征的小鼠，为研究黑色素瘤转移的主要特征以及对旨在预防或治疗转移性疾病的药物进行临床前评估提供了一个系统。
