Omega-6 Fat Promotion of Mutant Kras-Induced Pancreatic Neoplasia

描述（由申请人提供）：胰腺癌是所有已知癌症中生存率最低的，目前的治疗方法不足。对抗这种疾病的一种新方法涉及化学预防，其中饮食中摄入脂肪和抑制关键酶可能会在早期癌症扩散之前减少其产生。为了测试这种方法，将给发展早期胰腺癌的小鼠喂食高脂肪饮食，其中w-3：w-6脂肪的比例不同。观察疾病进展和相关基因表达与特定的分子机制是这个项目的重点。了解w-6脂肪在突变型Kras诱导的胰腺上皮内肿瘤（PanIN）的发展和进展中的作用背后的过程和分子机制，将阐明饮食对人类胰腺癌发展的影响。胰腺癌是一个可怕的敌人，是癌症死亡的第四大原因，其中每年的发病率和死亡率约为每年约30，000人。在这个提议中，我们将讨论w-6多不饱和脂肪酸（PUFA）在胰腺癌病因学中的起始事件，Kras突变，导致5-脂氧合酶（5-LOX）和环氧合酶-2（考克斯-2）表达增加后的作用。这些酶与花生四烯酸（AA）途径相关，并利用PUFA作为生产白三烯和白藜芦醇的底物。因此，？- 6 PUFA将影响突变Kras介导细胞变化的能力，所述细胞变化通过AA代谢酶5-LOX和考克斯-2导致早期瘤形成。我们假设，与给予富含ω-3脂肪饮食（8：1 w-3：w-6比例）的EL-Kras小鼠队列相比，给予富含w-6脂肪饮食（1：8）的EL-Kras转基因小鼠将发生更高的PanIN发生率、频率和更短的发病时间。我们进一步假设这些作用是由于提供了AA代谢酶5-LOX和考克斯-2可用的底物，这将通过建立不表达5-LOX和/或考克斯-2的EL-Kras小鼠并给予具有低和高w-3：w-6脂肪比的饮食来证明。最终，我们将确定5-LOX和/或考克斯-2的缺乏是否可以抑制w-6脂肪对EL-Kras小鼠中PanIN形成的影响。此外，啮齿类动物饮食中含有高w-6脂肪会改变许多基因的表达，包括一些在胰腺癌中发现的改变。我们打算证明这些小鼠饮食中1：8 w-3：w-6的脂肪比例将增加IGF-II，IGFBP-1和GLUT-1，降低H19，FAS和RAR？表达，导致细胞分裂率更高，细胞凋亡率更低，葡萄糖代谢增加。在缺乏5LOX和/或考克斯-2的小鼠中减少的PanIN形成将为在临床中抑制这些酶提供动力。在这组基因中改变的基因表达伴随着不依赖于5-LOX和考克斯-2的细胞效应将支持使用潜在的替代和/或组合策略抑制IGF-II、IGFBP-1和/或GLUT-1。该项目将研究高脂肪饮食对早期胰腺癌进展的作用，将其与炎症介质和脂肪消耗的类型或比例联系起来。将向发展早期胰腺癌前病变的小鼠施用高脂肪饮食（w-3：w-6脂肪酸比率为1：8、1：1和8：1），并研究胰腺癌前病变发展的增强或抑制。这项工作的结果将建立潜在的途径，当药物或饮食改变时，可能会预防或延缓胰腺癌的发展。

DESCRIPTION (provided by applicant): Pancreatic cancer has the poorest survival of any known cancer, and current therapies are insufficient. A novel approach to fighting this disease involves chemoprevention, where dietary intake of fats and inhibition of key enzymes may reduce production of early cancer before it spreads. To test this approach, mice that develop early pancreatic cancer will be fed high fat diets where the ratio of w-3:w-6 fats vary. Observing disease progression and correlating gene expression with specific molecular mechanisms is the focus of this project. Understanding the process and molecular mechanisms behind the role of w-6 fat in the development and progression of mutant Kras-induced pancreatic intraepithelial neoplasms (PanINs) will illuminate dietary effects on pancreatic cancer development in the human population. Pancreatic cancer is a formidable foe and is the fourth leading cause of cancer deaths, where the annual incidence and mortality are about equal at ~30,000 people per year. In this proposal, we will address the effect of w-6 polyunsaturated fatty acids (PUFA) following an initiating event in pancreatic cancer etiology, a mutation in Kras, which leads to increased expression of 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2). These enzymes are associated with the arachidonic acid (AA) pathway and utilize PUFAs as substrates for the production of leukotrienes and prostaglandins. Hence, ?-6 PUFAs will affect the ability of mutant Kras to mediate cellular changes that lead to early neoplasia through the AA metabolic enzymes, 5-LOX and COX-2. We hypothesize that EL-Kras transgenic mice will develop greater incidence, frequency, and shorter time of onset for PanIN development when administered a diet rich in w-6 fats (1:8) when compared to cohorts of EL-Kras mice administered a diet rich in omega-3 fats (8:1 w-3:w-6 ratio). We further hypothesize that these effects are due to provision of substrates available to the AA metabolic enzymes, 5-LOX and COX-2, which will be proven by establishing EL-Kras mice with no expression of 5-LOX and/or COX-2 and administered diets with low and high w-3:w-6 ratio of fat. Ultimately, we will determine if the absence of 5-LOX and/or COX-2 can prohibit the effects of w-6 fats on PanIN formation in EL-Kras mice. In addition, rodent diets with high w-6 fats change the expression of many genes including some found altered in pancreatic cancer. We intend to demonstrate that a 1:8 w-3:w-6 fat ratio in the diet of these mice will increase IGF-II, IGFBP-1, and GLUT-1 and decrease H19, FAS, and RAR¿ expression leading to higher rates of cell division, lower rates of apoptosis, and increased glucose metabolism. Reduced PanIN formation in mice deficient for 5LOX and/or COX-2 will provide the impetus for inhibiting these enzymes in the clinic. Altered gene expression in this panel of genes with concomitant cellular effects independent of 5-LOX and COX-2 would support the use of a potential alternative and/or combined strategy with inhibition of IGF-II, IGFBP-1, and/or GLUT-1. This project will investigate the role of high fat diets on the progression of early pancreatic cancer, relating it to inflammatory mediators and the type or ratio of fat consumed. Mice that develop early pancreatic precancer will be administered high fat diets (w-3:w-6 fatty acid ratios 1:8 , 1:1, and 8:1) and studied for enhanced or suppressed development of pancreatic precancer. Results from this work will establish potential pathways that, when altered by drugs or changes in the diet, may prevent or retard the development of pancreatic cancer.