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促使前列腺癌从无痛性疾病进展为危及生命的疾病的一个因素，但这可能是如何发生的仍然不清楚。已经提出了几种假设，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识别其他机制在人类中将是困难的。出于这个原因，至关重要的是开发实验上易于处理的动物模型来评估这些问题。我们已经开发了一种新的小鼠模型（B6：PTEN/luc），结合了几个先前描述的元素，非常适合解决这些问题。该模型的关键特征如下：1）前列腺癌是通过使用Cre-lox技术，前列腺特异性缺失PTEN肿瘤抑制基因（在人前列腺癌中通常突变的基因）而引发的; 2）我们已经改造了该菌株，使得可以使用生物发光成像非侵入性地监测前列腺癌进展;和3）我们已经将我们的模型与C57 BL/6 J品系广泛回交，这将有助于肿瘤表型的分析，并且是肥胖研究的最佳表征的小鼠品系。在本提案中，我们寻求通过追求以下具体目标来进一步开发该模型：1）表征纯合和杂合B6：PTEN/luc小鼠中的前列腺癌进展。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在监测这些小鼠中前列腺癌进展方面的效用; 2）测量饮食诱导的肥胖对杂合B6：PTEN/luc小鼠中前列腺癌进展的影响。在此，我们将确定饮食诱导的肥胖是否加速前列腺癌从肿瘤前状态到腺癌的进展，并确定这是否与睾酮、IGF-1和瘦素的水平相关;和3）测量饮食诱导的肥胖对纯合B6：PTEN/luc小鼠中雄激素非依赖性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影响去势后雄激素非依赖性前列腺癌的发展。这些研究的成功完成将验证我们研究肥胖和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。这些研究将为进一步阐明这些机制的未来假设导向研究提供基础。公共卫生相关性：临床研究表明，肥胖可能会促进前列腺癌从无痛性疾病发展为致命性疾病，但其生物学机制尚不清楚。阐明这些机制对于改善这种疾病的诊断和治疗将是重要的。由于这些机制很难在人类中进行实验验证，因此本文提出开发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.