Mouse model of obesity and prostate cancer progression.

描述（由申请人提供）：流行病学研究表明，肥胖是导致前列腺癌从无痛发展为危及生命疾病的一个因素，但这是如何发生的仍不清楚。已经提出了几种假说，包括睾酮水平降低，胰岛素样生长因子1 （IGF-1）水平升高或脂肪因子特别是瘦素水平升高。确定这些机制的相对重要性或确定其他机制在人类身上将是困难的。出于这个原因，开发实验上易于处理的动物模型来评估这些问题是至关重要的。我们开发了一种新的小鼠模型（B6: PTEN/luc），结合了前面描述的几个元素，非常适合解决这些问题。该模型的主要特点是：1)前列腺癌是通过Cre- lox技术，通过前列腺特异性缺失PTEN肿瘤抑制基因而引发的，PTEN是人类前列腺癌中常见的突变基因；2)我们已经设计了这种菌株，因此可以使用生物发光成像无创地监测前列腺癌的进展；3)我们将我们的模型与C57BL/6J菌株进行了广泛的回交，这将有助于分析肿瘤表型，并且是肥胖研究中最具特征的小鼠菌株。在本提案中，我们寻求通过追求以下具体目标来进一步发展该模型：1)在纯合子和杂合子B6: PTEN/luc小鼠中表征前列腺癌的进展。在这里，我们将进行必要的基线分析，以表征变异性并验证生物发光成像监测这些小鼠前列腺癌进展的效用；2)测量饮食性肥胖对杂合B6: PTEN/luc小鼠前列腺癌进展的影响。在这里，我们将确定饮食诱导的肥胖是否会加速前列腺癌从肿瘤前状态向腺癌的进展，并确定这是否与睾酮、IGF-1和瘦素水平相关；3)在纯合子B6: PTEN/luc小鼠中测量饮食诱导的肥胖对雄激素不依赖型前列腺癌进展的影响。在这里，我们将确定饮食引起的肥胖是否会影响去势后雄激素不依赖型前列腺癌的发展。这些研究的成功完成将验证我们研究肥胖与前列腺癌进展之间联系的模型，并开始评估与此相关的生物学机制。这些研究将为未来旨在进一步阐明这些机制的假设导向研究提供基础。公共卫生相关性：临床研究表明，肥胖可能促进前列腺癌从无痛发展为致命疾病，但其生物学机制尚不清楚。阐明这些机制对改善该病的诊断和治疗具有重要意义。由于这些机制很难在人类身上进行实验验证，因此我们建议建立一种新的小鼠模型来探索肥胖与前列腺癌进展之间的关系。

DESCRIPTION (provided by applicant): Epidemiologic studies have implicated obesity as a factor driving the progression of prostate cancer from an indolent to a life-threatening disease but how this may occur remains obscure. Several hypotheses have been advanced including reduced levels of testosterone, elevated levels of insulin-like growth factor 1 (IGF-1) or elevated levels of adipokines particularly leptin. Determining the relative importance of these mechanisms or identifying others will be difficult in humans. For this reason, it is critical to develop experimentally tractable animal models with which to evaluate these questions. We have developed a new mouse model (B6: PTEN/luc), combining several previously described elements, which is ideally suited to address these questions. The key features of this model are the following: 1) Prostate cancer is initiated by prostate-specific deletion of the PTEN tumor suppressor gene, a gene commonly mutated in human prostate cancer, using Cre- lox technology; 2) We have engineered this strain so that prostate cancer progression can be monitored non- invasively using bioluminescence imaging; and 3) We have extensively backcrossed our model to the C57BL/6J strain which will facilitate analysis of the tumor phenotype and is the best characterized mouse strain for obesity research. In this proposal we seek to further the development of this model by pursuing the following specific aims: 1) Characterize prostate cancer progression in both homozygous and heterozygous B6: PTEN/luc mice. Here we will perform the baseline analysis necessary to characterize the variability and validate the utility of bioluminescence imaging to monitor prostate cancer progression in these mice; 2) Measure the effects of diet-induced obesity on prostate cancer progression in heterozygous B6: PTEN/luc mice. Here we will determine whether diet-induced obesity accelerates the progression of prostate cancer from a pre-neoplastic state to adenocarcinoma and determine whether this is correlated with levels of testosterone, IGF-1 and leptin; and 3) Measure the effects of diet-induced obesity on progression to androgen- independent prostate cancer in homozygous B6: PTEN/luc mice. Here we will determine whether diet-induced obesity affects the development of androgen-independent prostate cancer following castration. The successful completion of these studies will validate our model for the study of the linkage between obesity and prostate cancer progression and begin to evaluate the biological mechanisms associated with this. These studies will provide the basis for future hypothesis-directed studies aimed at further elucidation of these mechanisms. PUBLIC HEALTH RELEVANCE: Clinical studies suggest that obesity may promote the progression of prostate cancer from an indolent to a lethal disease, but the biological mechanisms for this are unclear. Elucidating these mechanisms will be important for the improved diagnosis and treatment of this disease. Because these mechanisms will be difficult to experimentally validate in humans, here propose to develop a novel mouse model to explore the relationship between obesity and prostate cancer progression.