Role of GPR120 and Macrophages in Dietary Omega-3 Fatty Acid Inhibition of Prostate Cancer

项目摘要 流行病学研究和多项临床前研究表明，膳食鱼油有可能延缓前列腺增生 癌症进展我们小组进行的一项前瞻性随机前列腺切除术前试验发现， 食用鱼油（ω-3）补充饮食导致前列腺癌上皮细胞增殖较低 如通过Ki-67指数所测量的，并且与对照组相比，细胞周期进展（CCP）评分降低 西式饮食。Ki-67和CCP评分均与前列腺癌进展和死亡率相关， 提示食用鱼油补充饮食对前列腺癌患者的潜在益处。研究中 我们最近用免疫活性GPR 120敲除（KO）小鼠证明，GPR 120，一种g蛋白， 在长链多不饱和脂肪酸的转运中重要的偶联受体，是宿主 鱼油的抗癌活性。M2样免疫抑制性肿瘤相关巨噬细胞 这些特征与前列腺癌的进展和不良预后相关。我们还发现 鱼油抑制M2样肿瘤相关巨噬细胞的功能，这种作用在 GPR 120 KO小鼠。基于这些发现，我们假设补充鱼油的饮食会延迟 通过GPR 120对肿瘤微环境的依赖性作用来控制前列腺癌的进展。的目的 我们的建议是：目标1。确定饮食中的ω-3脂肪酸是否通过GPR 120抑制前列腺增生 在转基因小鼠模型中研究癌症，并研究与M2巨噬细胞功能相关的潜在机制。目的 2.确定GPR 120依赖性宿主来源的骨髓细胞和髓系细胞是否是 膳食ω-3脂肪酸的抗癌作用。目标3。确定基线前列腺活检组织中的生物标志物， 通过检查前列腺活检组织，预测对基于鱼油的饮食干预的反应， 一项正在接受鱼油补充饮食（ω-6：ω-3比例为3：1）的男性中进行的主动监测试验。我们将 通过一系列GPR 120基因敲除和转基因小鼠的机制研究， 模型喂食不同ω-3和ω-6脂肪酸含量的饲料，并对来自第一期研究的前列腺活检组织进行研究。 第二，饮食干预，积极监测试验，我们正在前列腺癌患者中进行。意义：我们的 一项提案为精准医疗方法设定了一个新的方向，该方法可以选择更有可能被 对基于GPR 120状态的饮食改变有反应。通过研究鱼油的潜在生物学 通过GPR 120和肿瘤相关的巨噬细胞/免疫细胞的抗癌作用，我们正在建立一个 新的研究领域，营养免疫疗法，这可能最终导致创新的营养疗法，为我们的 前列腺癌患者。我们的多学科研究团队拥有悠久的成功历史， 合作是唯一适合实现我们的既定目标。

PROJECT SUMMARY Epidemiologic studies and multiple preclinical studies suggest dietary fish oil has the potential to delay prostate cancer progression. A prospective randomized pre-prostatectomy trial conducted by our group found that consuming a fish oil (omega-3) supplemented diet resulted in lower proliferation of prostate cancer epithelium as measured by the Ki-67 index, and decreased Cell Cycle Progression (CCP) Score as compared to a control Western diet. Both Ki-67 and the CCP Score are associated with prostate cancer progression and mortality, suggesting potential benefits of consuming a fish oil supplemented diet for prostate cancer patients. In studies with immunocompetent GPR120 knockout (KO) mice, we recently demonstrated that GPR120, a g-protein coupled receptor important in the transport of long chain polyunsaturated fatty acids, is required in the host for the anti-cancer activity of fish oil. Immune suppressive tumor associated macrophages with M2-like characteristics have been associated with prostate cancer progression and poor prognosis. We also found that fish oil inhibits the function of M2-like tumor-associated macrophages, and this effect was reversed in the GPR120 KO mouse. Based on these findings, we hypothesize that a fish oil supplemented diet will delay the progression of prostate cancer through GPR120 dependent effects on the tumor microenvironment. The Aims of our proposal are: Aim 1. Determine if dietary omega-3 (ω-3) fatty acids act through GPR120 to inhibit prostate cancer in a transgenic mouse model and study underlying mechanisms related to M2 macrophage function. Aim 2. Determine if GPR120 dependent host-derived bone marrow cells and myeloid lineage cells are essential for the anticancer effects of dietary ω-3 FAs. Aim 3. Identify biomarkers in baseline prostate biopsy tissue that predict responsiveness to a fish oil based dietary intervention by examining prostate biopsy tissue obtained from an ongoing active surveillance trial in men receiving a fish oil supplemented diet (ω-6: ω-3 ratio of 3:1). We will accomplish these aims through a series of mechanistic studies using GPR120 knockout and transgenic mouse models fed diets varying in ω-3 and ω-6 fatty acid content, and studies on prostate biopsy tissue from a Phase II, dietary intervention, active surveillance trial we are conducting in men with prostate cancer. Significance: Our proposal sets a new direction for a precision medicine approach for selecting patients more likely to be responsive to dietary modification based on GPR120 status. By studying the underlying biology of fish oil anticancer effects through GPR120 and tumor associated macrophages/immune cells, we are establishing a new field of study, nutritional immunotherapy, that may ultimately lead to innovative nutritional therapies for our patients with prostate cancer. Our multidisciplinary team of investigators with a longstanding history of successful collaborations is uniquely suited to achieve our stated goals.