Low-Fat/Fish Oil Diet and prostate Cancer Outcomes in Human Cohorts and Mouse Mo

流行病学和临床前研究支持低脂饮食和鱼油摄入对预防和治疗前列腺癌的作用。我们小组进行的一项前瞻性前列腺切除术前试验发现，含鱼油的低脂饮食可减少根治性前列腺切除术标本中前列腺癌上皮细胞的增殖，我们发现RBC膜omega-6/omega-3（n-6/n-3）脂肪酸比率与前列腺组织增殖水平相关。我们的合作者Olefsky博士最近在巨噬细胞上发现了一种G蛋白偶联受体（GPR 120），它介导EPA和DHA（鱼油中的omega-3脂肪酸）的抗炎作用，我们在前列腺癌基质、中性粒细胞和巨噬细胞中发现了GPR 120。基于这些发现，我们假设，低脂饮食与鱼油可能会通过前列腺基质GPR 120通过调节肿瘤微环境赋予其抗炎/抗增殖作用的前列腺癌。基于我们先前的临床前和临床研究，我们预期低脂鱼油（LF/FO）饮食将抑制处于主动监测的男性中的前列腺癌增殖，RBC n-6/n-3比率将是监测前列腺癌增殖水平的有用的基于血液的替代生物标志物，并且前列腺组织中具有较高GPR 120水平的受试者将对鱼油摄入产生更大的抗增殖作用。因此，我们的建议的目的是（1）确定GPR 120对存档标本中前列腺癌增殖的贡献（2）通过使用PTEN和GPR 120敲除小鼠模型确定LF/FO饮食是否部分地通过GPR 120受体延迟前列腺癌的发展，和（3）确定LF/FO干预在积极监测的男性中的功效，并鉴定前列腺癌增殖的潜在替代生物标志物。我们将测量GPR 120的基因表达和相关的炎症通路在激光捕获的基质组织从我们以前的临床试验，并将这些发现与增殖。将在100名接受主动监测的男性中进行前瞻性试验，随机分配至低脂饮食和鱼油补充剂或对照组，并将在基线和1年时分析前列腺活检的增殖（Ki-67指数）和GPR 120受体水平。

Epidemiologic and preclinical studies support the role of a low fat diet and fish oil intake for the prevention and treatment of prostate cancer. A prospective pre-prostatectomy trial conducted by our group found that a low-fat diet with fish oil reduced proliferation in prostate cancer epithelium in radical prostatectomy specimens and we found that the RBC membrane omega-6/omega-3 (n-6/n-3) fatty acid ratio correlated with prostate tissue proliferation levels. Our collaborator, Dr. Olefsky, recently identified a G protein coupled receptor (GPR120) on macrophages that mediates the anti-inflammatory effects of EPA and DHA (omega-3 fatty acids in fish oil) and we identified GPR120 in prostate cancer stroma, in neutrophils, and macrophages. Based on these findings, we hypothesize that a low-fat diet with fish oil may confer its anti-inflammatory/anti-proliferative effects on prostate cancer through prostatic stromal GPR120 by modulating the tumor microenvironment. Based on our prior preclinical and clinical studies, we anticipate that a low-fat fish oil (LF/FO) diet will inhibit prostate cancer proliferation in men on active surveillance, that the RBC n-6/n-3 ratio will be a useful blood-based surrogate biomarker to monitor prostate cancer proliferation levels, and that subjects with higher GPR120 levels in prostate tissue will have greater antiproliferative effects in response to fish oil intake. Thus the Aims of our proposal are (1) To determine the contribution of GPR120 to prostate cancer proliferation in archived specimens (2) To determine if a LF/FO diet delays the development of prostate cancer, in part, through the GPR120 receptor by using PTEN and GPR120 knockout mouse models, and (3) to determine the efficacy a LF/FO intervention in men on active surveillance and identify potential surrogate biomarkers for prostate cancer proliferation. We will measure gene expression of GPR120 and related inflammatory pathways in laser captured stromal tissue from our previous clinical trial and correlate these findings with proliferation. A prospective trial will be conducted in 100 men on active surveillance randomized to a low-fat diet with fish oil supplements or to a control group and prostate biopsies will be analyzed for proliferation (Ki-67 index) and GPR120 receptor levels at baseline and 1-year.