A Mutated EGFR Is Sufficient to Induce Malignant Melanoma with Genetic Background-Dependent Histopathologies
A Mutated EGFR Is Sufficient to Induce Malignant Melanoma with Genetic Background-Dependent Histopathologies
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DOI：
10.1038/jid.2009.213
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发表时间：
2010-01-01
影响因子：
6.5
通讯作者：
Meierjohann, Svenja
中科院分区：
文献类型：
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作者：
Schartl, Manfred;Wilde, Brigitta;Meierjohann, Svenja
黑色素瘤是一种一旦转移治愈率很低的肿瘤。虽然许多基因对黑色素瘤的诱导、转化和转移都很重要，但对黑色素瘤的发生过程只有部分了解。黑色素瘤介质最容易在细胞培养模型中进行研究，但需要动物模型来评估其在整个生物体中的重要性。在这里，我们描述了一个转基因黑色素瘤模型青。致癌受体酪氨酸激酶，Xmrk，负责黑色素瘤形成的剑尾鱼，稳定表达的色素细胞特异性启动子的控制下。转基因鱼发生色素细胞瘤，有效率为100%。该模型用于监测几种细胞凋亡和分化基因的体内相关性，以及诱导黑色素瘤相关信号传导途径。我们发现，Stat 5激活，Mitf和Bcl-2水平与恶性肿瘤的更积极的阶段。有趣的是，不同类型的色素细胞肿瘤的发生取决于遗传背景，即侵袭性黑色素瘤，葡萄膜黑色素瘤，或外生性和侵略性较低的色素细胞肿瘤称为黄色红细胞瘤。此外，在p53突变的背景下，xmrk的表达导致了巨大的局灶性色素细胞肿瘤的出现，而肿瘤的发生与野生型青鳉相比没有变化。
Melanoma is a tumor with a very low cure rate once metastasized. Although many genes important for melanoma induction, transformation, and metastasis have been identified, the process of melanomagenesis is only partly understood. Melanoma mediators are easiest to investigate in cell culture models, but animal models are required to evaluate their importance in the context of the whole organism. Here, we describe a transgenic melanoma model in medaka. The oncogenic receptor tyrosine kinase, Xmrk, responsible for melanoma formation in Xiphophorus, was stably expressed under the control of a pigment cell-specific promoter. The transgenic fish developed pigment cell tumors with a penetrance of 100%. The model was used for monitoring the in vivo relevance of several apoptosis and differentiation genes, and for induction of melanoma-relevant signal transduction pathways. We found that Stat5 activation, and Mitf and Bcl-2 levels correlated with a more aggressive stage of the malignancy. Interestingly, different types of pigment cell tumors occurred depending on the genetic background, namely invasive melanoma, uveal melanoma, or exophytic and less aggressive pigment cell tumors called xanthoerythrophoroma. Furthermore, on p53 mutant background, the expression of xmrk led to the appearance of giant focal pigment cell tumors, whereas tumor onset was unchanged compared with wild-type medaka.