Generation of an UV-dependent Mouse Model of Melanoma

描述(申请人提供)：黑素细胞的恶性转化，产生色素的细胞，导致黑色素瘤的产生。皮肤黑色素瘤是最致命的皮肤癌，也是美国增长最快的癌症之一。黑色素瘤是高度转移性的，目前的治疗干预措施并不是很有效。众所周知，黑色素瘤的形成和发展受到遗传和环境因素的影响，以及肿瘤与宿主相互作用的改变。遗传学研究证实染色体9p21上的INK4a/ARF是黑色素瘤的易感基因。在环境因素中，暴露于太阳辐射的紫外线(UV)光谱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的标志物，体外实验数据表明其配体内毒素3(Edn3)可以改变黑色素瘤细胞中黏附分子的表达。本研究的目的是建立一种新的紫外线依赖的黑色素瘤小鼠模型，该模型基于内皮素信号通路的过度激活，以研究紫外线、遗传因素和肿瘤-宿主相互作用在黑色素瘤发病机制中的功能关系。我们将使用我们生成并鉴定的可诱导转基因小鼠模型，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素细胞的积累，而成年小鼠的皮肤中通常没有黑素细胞。这种情况是前体细胞增殖急剧增加的结果，这也可能是黑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产生转移性黑色素瘤，以及(2)测试Ink4a/arf在紫外线诱导的Edn3转基因小鼠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.