Generation of an UV-dependent Mouse Model of Melanoma

描述（由申请人提供）：黑色素细胞（色素生成细胞）的恶性转化导致黑色素瘤的产生。皮肤黑色素瘤是皮肤癌中最致命的一种，也是美国增长最快的癌症之一。黑色素瘤具有高度转移性，目前的治疗干预措施并不十分有效。众所周知，黑色素瘤的形成和发展受遗传和环境因素以及肿瘤与宿主相互作用的改变的影响。遗传学研究已经确定染色体9p21上的INK4a/ARF是黑色素瘤的易感位点。在环境因素中，暴露于紫外线（UV）光谱的太阳辐射被认为在大多数黑色素瘤中起着偶然的作用。g偶联受体内皮素受体b （Ednrb）被认为是黑色素瘤进展标志物，体外数据表明其配体内皮素3 （Edn3）可以改变黑色素瘤细胞中粘附分子的表达。本研究的目的是建立一种基于内皮素信号通路过度激活的新型紫外线依赖黑色素瘤小鼠模型，以解决紫外线、遗传因素和肿瘤-宿主相互作用在黑色素瘤发病中的功能关系。我们将使用一种诱导型转基因小鼠模型，该模型在整个发育过程中产生过量的Edn3，导致成年小鼠皮肤中大量黑色素细胞的积累，而这些黑色素细胞通常是找不到的。这种情况是前体增生急剧增加的结果，这也可能是黑色素细胞肿瘤形成的基础。我们将(1)评估新生儿紫外线暴露和内皮素信号通路的过度激活是否足以导致转移性黑色素瘤的产生；(2)在Edn3转基因小鼠中测试ink4a/arf在紫外线诱导的黑色素瘤形成和进展中的作用。这种新的黑色素瘤小鼠模型的发展有可能有助于更好地了解这种疾病的复杂民族学，并作为评估有效预防和治疗方案的工具。

DESCRIPTION (provided by applicant): The malignant transformation of melanocytes, pigment producing cells, leads to the generation of melanoma. Cutaneous melanoma is the most lethal form of skin cancer and one of the fastest increasing cancers in the U.S. Melanomas are highly metastatic and current therapeutic interventions are not very effective. It is well established that the formation and progression of melanoma are influenced by genetic and environmental factors, as well as alterations in tumor-host interactions. Genetic studies have identified INK4a/ARF at chromosome 9p21 as a melanoma susceptibility locus. Amongst the environmental factors, exposure to the ultraviolet (UV) spectrum of solar radiation is considered to have a casual role in the majority of melanomas. The G-coupled receptor Endothelin receptor b (Ednrb) is considered a melanoma progression marker, and in vitro data suggest that its ligand, Endothelin 3 (Edn3), can alter the expression of adhesion molecules in melanoma cells. The goal of this study is to create a novel UV-dependent mouse model of melanoma based on the over-activation of the endothelin signaling pathway to address the functional relationship among UV, genetic factors and tumor-host interactions in melanoma pathogenesis. We will use an inducible transgenic mouse model we generated and characterized that produces excessive Edn3 throughout development, leading to the accumulation of large numbers of melanocytes in the skin of adult mice where they are not normally found. This condition is a result of a dramatic increase in the proliferation of precursors, which could also serve as the basis for melanocytic tumor formation. We will (1) evaluate whether a combination of neonatal UV exposure and the over-activation of the endothelin signaling pathway is sufficient for the generation of metastatic melanoma and (2) test for a role of ink4a/arf in UV-induced melanoma formation and progression in the Edn3 transgenic mice. The development of this new mouse model of melanoma has the potential to contribute to a better understanding of the complex ethnology of this disease and serve as a tool for the evaluation of effective preventive and therapeutic regimens.