Functional Role of Bone Marrow Adipocytes in Metastatic Prostate Cancer

描述(申请人提供)：骨是前列腺癌(PCa)转移的主要部位。超过80%的复发前列腺癌患者患有转移性骨病变，目前还没有可用的治疗方法可以显著改善患者的预后。为了确定这种毁灭性且无法治愈的疾病的有效治疗靶点，我们需要了解推动肿瘤细胞在骨髓利基中适应、进展和存活的分子机制。 年龄和肥胖是骨转移病变发生的重要危险因素。事实上，患有前列腺癌的肥胖和超重男性患转移性疾病的可能性是采用相同治疗方案的正常体重男性的三倍。这种关联背后的机制目前还不清楚。年龄和肥胖都会大大增加骨髓中的脂肪细胞(脂肪细胞)的数量。脂肪细胞对骨骼新陈代谢和功能产生负面影响，并加剧骨骼降解，使骨髓更支持肿瘤的生长。我们实验室的数据表明，由于高脂饮食导致骨髓肥胖症增加的小鼠，前列腺癌肿瘤生长更大，进展更快。与脂肪细胞相互作用的肿瘤细胞侵袭性更强，高表达与脂肪代谢和运输有关的蛋白(即脂肪酸结合蛋白4；FABP4)和促炎细胞因子IL-1。我们假设骨髓脂肪细胞通过FABP4/IL-1依赖的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，包括多种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，药物和遗传操作，以及脂肪组学技术，以揭示骨髓脂肪细胞在骨骼前列腺癌进展中的功能作用。我们将在三个目标下进行这些研究。我们将：1)利用来自PCa患者的独立的骨髓脂肪和骨转移样本模型，确定骨髓脂肪细胞在骨Pca细胞生长和进展中的意义；2)通过体内外对脂肪酸动员和FABP4表达的遗传和生化操作，阐明FABP4/IL-1β参与骨Pca进展的机制；以及3)利用脂质组学技术确定骨髓脂肪对转移瘤细胞脂酰脂组的影响，以确定导致肿瘤细胞侵袭行为的脂介质。综上所述，我们的发现将为骨髓脂肪细胞通过FABP4/IL-1β轴参与支持骨转移的PCA细胞的生长、适应和进展提供功能证据。这项工作将揭开新的候选治疗靶点，以改善患者的预后。这项工作的发现可能不仅与前列腺癌有关，而且还可能延伸到其他骨营养性癌症。

DESCRIPTION (provided by applicant): 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.