Bone metabolism and bone metastases in prostate cancer

描述(申请人提供)：骨是前列腺癌最常见的转移部位，前列腺癌伴骨转移是不治之症。我们建议研究肿瘤细胞和骨环境的哪些方面影响前列腺癌骨转移的发展，这将提高患者的风险预测，并为预防疾病进展创造新的机会。我们还将把饮食因素和肥胖与这些肿瘤和骨骼特征联系起来，以确定一级和二级预防的机会。我们将利用健康专业人员后续研究和医生健康研究中的一个独特的男性队列，他们的前列腺癌标本和长期随访数据的生物库已经存在。此外，我们将在健康专业人员的后续研究中将这些肿瘤组织数据与存储的血液样本和关于饮食和生活方式的问卷数据联系起来。我们假设，骨相关基因的原发肿瘤表达可能通过促进前列腺癌细胞在骨组织中的归宿、存活和生长能力来促进骨转移。我们计划使用已经收集的全基因组mRNA表达数据来研究骨相关基因表达如何与生存相关，以及它是否增加了超越分期和Gleason分级的预测信息。此外，我们假设，那些骨转换水平较高的男性，或所有成年人都经历的正在进行的骨重建，风险更高。 对于骨转移，因为它们的骨环境促进了播散性肿瘤细胞的生长。我们将通过测量男性癌症诊断前采集的血液样本中几种骨调节激素和骨转换标志物的水平，并将这些血液标志物与前列腺癌存活率联系起来，来研究这一假说。我们还将评估这些骨代谢的血液标记物可能如何影响骨相关基因的原代肿瘤细胞表达。最后，我们假设，一些晚期前列腺癌的危险因素，包括肥胖和饮食因素，如钙、维生素D、磷和维生素K，可能通过影响骨相关基因的肿瘤表达、对骨转换和骨骼环境的影响来影响前列腺癌的进展。健康专业人员后续研究提供了丰富的饮食和生活方式数据，使我们能够将前列腺癌诊断前的饮食和肥胖信息与肿瘤特征和循环骨代谢标记物联系起来。传统上，前列腺癌的风险因素一直被视为对前列腺癌的直接影响。我们认为，根据它们对肿瘤-骨相互作用的影响进行研究，可能会阐明潜在的机制，并增加预防前列腺癌骨转移的机会。总体而言，这项研究将提供关于促进前列腺癌进展的肿瘤和骨骼特征的丰富信息，为患者提供更好的风险预测，并为预防和治疗骨转移前列腺癌提供新的方法。

DESCRIPTION (provided by applicant): Bone is the most common site of prostate cancer metastases, and prostate cancer with bone metastases is incurable. We propose to study which aspects of the tumor cells and the bone environment affect the development of bone metastasis in prostate cancer, which will improve risk prediction for patients and create new opportunities for preventing disease progression. We will also relate dietary factors and obesity to these tumor and bone characteristics to identify opportunities for primary and secondary prevention. We will leverage a unique cohort of men in the Health Professionals Follow-up Study and Physicians' Health Study for whom a biorepository of prostate tumor specimens and long-term follow-up data already exist. In addition, we will link this tumor tissue data to stored blood samples and questionnaire data on diet and lifestyle in the Health Professionals Follow-up Study. We hypothesize that primary tumor expression of bone-related genes may promote bone metastasis by facilitating prostate cancer cells' ability to home to, survive, and grow in bone tissue. We plan to use already collected whole genome mRNA expression data to study how bone-related gene expression relates to survival, and whether it adds predictive information beyond stage and Gleason grade. In addition, we hypothesize that men who have higher levels of bone turnover, or the on-going rebuilding of bone that all adults experience, are at higher risk for bone metastases because their bone environment facilitates the growth of disseminated tumor cells. We will study this hypothesis by measuring levels of several bone-regulating hormones and markers of bone turnover in men from blood samples collected prior to their cancer diagnosis, and relating these blood markers to prostate cancer survival. We will also assess how these blood markers of bone metabolism might have affected primary tumor cell expression of bone-related genes. Finally, we hypothesize that some risk factors for advanced prostate cancer, including obesity and dietary factors like calcium, vitamin D, phosphorus, and vitamin K, may impact prostate cancer progression through their effects on tumor expression of bone-related genes and on bone turnover and the skeletal environment. Rich dietary and lifestyle data available in the Health Professionals Follow-up Study allow us to link information on diet and obesity prior to prostate cancer diagnosis with tumor characteristics and circulating bone metabolism markers. Traditionally, risk factors for prostate cancer have been viewed in light of their direct effects on the prostate. We believe that studying them in light of their effets on tumor-bone interaction might elucidate the underlying mechanisms and improve opportunities for prevention of bone metastases in prostate cancer. Overall, this study will provide a wealth of information on tumor and bone characteristics that promote prostate cancer progression, providing improved risk prediction for patients and providing new approaches to the prevention and treatment of bone metastatic prostate cancer.