Mouse models for BRAF-induced cancers.
Mouse models for BRAF-induced cancers.
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DOI：
10.1042/bst0351329
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发表时间：
2007-11
影响因子：
3.9
通讯作者：
Kamata T
中科院分区：
文献类型：
--
作者：
Pritchard C;Carragher L;Aldridge V;Giblett S;Jin H;Foster C;Andreadi C;Kamata T
BRAF基因中的致癌突变在0.7%的人类癌症样本中被检测到，其中恶性黑色素瘤中的突变频率特别高。已经发现了超过40种不同的错义BRAF突变，但绝大多数（>90%）代表单个核苷酸变化，导致残基600处的缬氨酸→谷氨酸突变（V600 EBRAF）。在体外培养的细胞中，V600 EBRAF能够刺激内源性MEK [MAPK（促分裂原活化蛋白激酶）/ERK（细胞外信号调节激酶）激酶]和ERK磷酸化，导致细胞增殖、细胞存活、转化、致瘤性、侵袭和血管发育增加。这些癌症标志中的许多可以通过用针对BRAF的siRNA（小干扰RNA）处理细胞或通过抑制MEK来逆转，这表明BRAF和MEK是具有BRAF突变的癌症样品中有吸引力的治疗靶标。为了充分理解致癌BRAF在体内癌症发展中的作用以及测试抗BRAF或抗MEK疗法的体内功效，已经产生了GEMM（基因工程小鼠模型），其中致癌BRAf的表达有条件地依赖于Cre重组酶。Cre重组酶的递送/活化可以以时间和空间方式调节，因此这些小鼠模型可用于重现在人类癌症发展中不同组织中发生的BRAF体细胞突变。到目前为止，在造血组织和肺中Cre介导的激活后获得的数据表明，V600 EBRAF突变可以驱动肿瘤的发生，其主要作用是诱导高水平的细胞周期蛋白D1介导的细胞增殖。然而，OIS（癌基因诱导的衰老）的标志是明显的，抑制了肿瘤的进一步发展。
Oncogenic mutations in the BRAF gene are detected in ∼7% of human cancer samples with a particularly high frequency of mutation in malignant melanomas. Over 40 different missense BRAF mutations have been found, but the vast majority (>90%) represent a single nucleotide change resulting in a valine → glutamate mutation at residue 600 (V600EBRAF). In cells cultured in vitro, V600EBRAF is able to stimulate endogenous MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and ERK phosphorylation leading to an increase in cell proliferation, cell survival, transformation, tumorigenicity, invasion and vascular development. Many of these hallmarks of cancer can be reversed by treatment of cells with siRNA (small interfering RNA) to BRAF or by inhibiting MEK, indicating that BRAF and MEK are attractive therapeutic targets in cancer samples with BRAF mutations. In order to fully understand the role of oncogenic BRAF in cancer development in vivo as well as to test the in vivo efficacy of anti-BRAF or anti-MEK therapies, GEMMs (genetically engineered mouse models) have been generated in which expression of oncogenic BRaf is conditionally dependent on the Cre recombinase. The delivery/activation of the Cre recombinase can be regulated in both a temporal and spatial manner and therefore these mouse models can be used to recapitulate the somatic mutation of BRAF that occurs in different tissues in the development of human cancer. The data so far obtained following Cre-mediated activation in haemopoietic tissue and the lung indicate that V600EBRAF mutation can drive tumour initiation and that its primary effect is to induce high levels of cyclin D1-mediated cell proliferation. However, hallmarks of OIS (oncogene-induced senescence) are evident that restrain further development of the tumour.