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，即饮食中摄入脂肪和抑制关键酶可能在癌症扩散之前减少早期癌症的产生。为了测试这种方法，患有早期胰腺癌的老鼠将被喂食高脂肪饮食，其中w-3:w-6脂肪的比例不同。观察疾病进展并将基因表达与特定分子机制联系起来是本项目的重点。了解w-6脂肪在突变型kras诱导的胰腺上皮内肿瘤（PanINs）发生和发展中的作用及其分子机制，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，每年的发病率和死亡率大约相等，约为每年30 000人。在本提案中，我们将讨论w-6多不饱和脂肪酸（PUFA）在胰腺癌病因中的启动事件（Kras突变）的影响，该突变导致5-脂氧合酶（5-LOX）和环氧合酶-2 （COX-2）的表达增加。这些酶与花生四烯酸（AA）途径相关，并利用PUFAs作为底物生产白三烯和前列腺素。因此,?-6 PUFAs会影响突变体Kras通过AA代谢酶、5-LOX和COX-2介导导致早期肿瘤的细胞变化的能力。我们假设EL-Kras转基因小鼠在给予富含w-6脂肪的饮食（1:8）时，与给予富含ω -3脂肪的饮食（8:1 w-3:w-6比例）的EL-Kras小鼠相比，会出现更高的发生率、频率和更短的PanIN发病时间。我们进一步假设，这些影响是由于提供了可用于AA代谢酶，5-LOX和COX-2的底物，这将通过建立没有5-LOX和/或COX-2表达的EL-Kras小鼠和给予低和高w-3:w-6脂肪比的饮食来证明。最终，我们将确定5-LOX和/或COX-2的缺失是否可以阻止w-6脂肪对EL-Kras小鼠PanIN形成的影响。此外，含有高w-6脂肪的啮齿动物饮食改变了许多基因的表达，包括一些在胰腺癌中发现的改变。我们打算证明，在这些小鼠的饮食中，1:8 w-3:w-6的脂肪比例会增加IGF-II， IGFBP-1和GLUT-1，并降低H19， FAS和RAR¿的表达，从而导致更高的细胞分裂率，更低的凋亡率，并增加葡萄糖代谢。在缺乏5LOX和/或COX-2的小鼠中，PanIN的形成减少将为临床抑制这些酶提供动力。这组基因表达的改变具有独立于5-LOX和COX-2的伴随细胞效应，这将支持使用潜在的替代和/或联合策略来抑制IGF-II、IGFBP-1和/或GLUT-1。该项目将研究高脂肪饮食在早期胰腺癌进展中的作用，以及它与炎症介质和摄入脂肪的类型或比例之间的关系。研究人员将给早期胰腺癌前病变小鼠喂食高脂肪饮食（w-3:w-6脂肪酸比例为1:8、1:1和8:1），并研究其促进或抑制胰腺癌前病变的发展。这项工作的结果将建立潜在的途径，当被药物或饮食改变时，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.