Functional Role of Bone Marrow Adipocytes in Metastatic Prostate Cancer

摘要：骨是前列腺癌（PCa）转移的主要部位。超过80%的患者 复发性PCa患有转移性骨病变，目前没有可用的治疗方法可以 显著改善患者预后。为了确定有效的治疗靶点， 我们需要了解驱动肿瘤的分子机制 细胞在骨髓小生境中的适应、进展和存活。 年龄和肥胖是发生骨转移的重要危险因素。事实上，肥胖和 患有前列腺癌的超重男性发生转移性疾病的可能性是正常男性的三倍， 体重的男性有相同的治疗方案。这种关联背后的机制目前还没有 明白年龄和肥胖都大大增加了骨髓中脂肪细胞的数量。脂肪 细胞对骨代谢和功能产生负面影响，并加剧骨降解， 更有利于肿瘤生长。我们实验室的数据表明，PCa肿瘤生长更大， 在高脂肪饮食导致骨髓肥胖增加的小鼠中更快。与脂肪细胞相互作用的肿瘤细胞 更具侵袭性并具有参与脂肪代谢和转运的蛋白质的高表达（即，脂肪酸 结合蛋白4; FABP 4）和促炎细胞因子IL-1？。我们假设骨髓脂肪细胞 通过FABP 4/IL-1？依赖性机制促进和支持骨转移性前列腺癌的进展。 我们提出了一种多方面的方法，包括多个独立的骨髓肥胖小鼠模型， 骨内肿瘤生长模型，新的细胞培养技术，药理学和遗传学操作， 和脂质组学技术来揭示骨髓脂肪细胞在骨骼中PCa进展中的功能作用。 我们将在三个目标下进行这些研究。我们将：1）建立骨髓脂肪细胞在 使用骨髓肥胖和骨的独立模型的PCa细胞在骨中的生长和进展 2）阐明FABP 4/IL-1？参与PCa的机制 通过脂肪酸动员和FABP 4表达的遗传和生化操作在骨中的进展 体外和体内; 3）确定骨髓肥胖对转移性肿瘤细胞脂肪酰脂质体的影响 使用脂质组学技术鉴定导致肿瘤细胞侵袭行为的脂质介质。在一起， 我们的发现将为骨髓脂肪细胞参与支持生长提供功能证据， 通过FABP 4/IL-1轴的骨中转移性PCa细胞的适应和进展。这项工作将揭开新的 候选治疗靶点以提供患者结果的改善。这项工作的结果可能会 与前列腺癌有很高的相关性，并延伸到其他骨营养性癌症。

ABSTRACT: Bone is a primary site of metastasis from prostate cancer (PCa). More than 80% of patients with recurrent PCa suffer from metastatic bone lesions, and there are currently no available treatments that can significantly improve patient outcomes. In order to identify effective therapeutic targets for this devastating and incurable disease, we need to understand the molecular mechanisms that drive tumor cell adaptation, progression and survival in the bone marrow niche. Age and obesity are significant risk factors for development of bone metastatic lesions. In fact, obese and overweight men with PCa are three times more likely to develop metastatic disease compared to normal- weight men with same treatment regimen. The mechanisms behind this association are currently not understood. Both age and obesity greatly increase numbers fat cells (adipocytes) in the bone marrow. Fat cells negatively affect bone metabolism and function, and escalate bone degradation making the bone marrow more supportive of tumor growth. Data from our lab demonstrate that PCa tumors grow larger and progress faster in mice with increased marrow adiposity due to high fat diet. Tumor cells interacting with adipocytes are more invasive and have high expression of protein involved in fat metabolism and transport (i.e., Fatty Acid Binding Protein 4; FABP4) and proinflammatory cytokine IL-1¿. We hypothesize that bone marrow adipocytes promote and support progression of metastatic PCa in bone through the FABP4/IL-1¿-dependent mechanisms. We propose a multi-faceted approach that includes multiple independent mouse models of marrow adiposity, models of intraosseous tumor growth, novel cell culture techniques, pharmacological and genetic manipulation, and lipidomic technology to uncover functional role of bone marrow fat cells in PCa progression in skeleton. We will perform these studies in three Aims. We will: 1) Establish the significance of marrow adipocytes in growth and progression of PCa cells in bone using independent models of marrow adiposity and bone metastasis samples from PCa patients; 2) Elucidate the mechanism of FABP4/IL-1¿ involvement in PCa progression in bone by genetic and biochemical manipulation of fatty acid mobilization and FABP4 expression in vitro and in vivo; and 3) Define the effects of marrow adiposity on fatty acyl lipidome of metastatic tumor cells using lipidomics technology to identify lipid mediators that lead to invasive behavior in tumor cells. Together, our findings will provide functional evidence for involvement of bone marrow fat cells in supporting growth, adaptation and progression of metastatic PCa cells in bone via FABP4/IL-1¿ axis. This work will unravel novel candidate therapeutic targets to provide improvement in patient outcomes. Findings of this work are likely to have high relevance beyond PCa and extend to other bone-trophic cancers.