Flavonoids in Pancreatic Carcinogenesis & Angiogenesis/Hines, Oscar

胰腺癌是美国癌症相关死亡的第四大原因。最 据估计，美国每年32，000例新病例和欧洲每年60，000例新病例中， 一年的诊断。目前迫切需要制定新的和更好的战略来治疗 胰腺癌这将需要化学预防和化学治疗的新方法， 植物化学物质提供了这种可能性。癌细胞的细胞代谢发生改变 profile必须出现。一旦正常的胰腺细胞转化为癌细胞， 细胞必须募集额外的血液供应来生长和转移--这一过程被称为血管生成 开关.我们和其他人已经发现，染料木黄酮，类黄酮，可能是一个有用的方法，在影响 胰腺癌细胞的代谢谱，并可能抑制由血管生成刺激的因子， 开关.我们实验室的初步证据表明，染料木黄酮可以改变胰腺癌细胞 代谢谱，抑制细胞生长，诱导细胞凋亡，减少体内转移扩散，并减少 血管生成我们假设类黄酮可以阻止胰腺癌的发展， 黄酮类化合物可以作为胰腺癌的化疗药物。我们将继续努力 具体目标：具体目标I）。确定类黄酮预防胰腺癌进展的能力 使用一种新的转基因治疗上皮内瘤变（PanIN）至侵袭性胰腺导管腺癌 胰腺癌动物模型。具体目标II）。评价黄酮类化合物对永生化人的作用 在原位异种移植模型中的胰腺癌细胞系。具体目标III）。确定影响 胰腺癌的治疗方法为了完成这些目标，我们将进行实验 在转基因模型（LSL-KRAS G12 D;PDX-1-Cre）中研究染料木黄酮、槲皮素和芹菜素， 重现癌前病变和恶性胰腺病变。此外，我们将测试这些类黄酮在一个 原位鼠模型，并将这些与标准吉西他滨治疗进行比较。最后，我们将 利用我们大量的胰腺癌患者临床资料，研究大豆对胰腺癌的影响。 对患有这种疾病的患者进行补充。

Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Most of the estimated 32,000 annual new cases in the U.S. and 60,000 annual new cases in Europe will die within a year of diagnosis. There is an urgent a need to develop new and better strategies for the treatment of pancreatic cancer. This will require novel approaches to both chemoprevention and chemotherapy, and phytochemicals offer to possibilty of this. For a cancer cell to develop an alteration in the cellular metabolic profile must occur. Once the normal pancreatic cell has converted to an cancer cell, then a group of cancer cells must recruit additional blood supply to grow and metastasize - a process is termed the angiogenic switch. We and others have found that genistein, a flavonoid, may be a useful approach in impacting the metabolic profile of the pancreatic cancer cell and may inhibit the factors stimulated by the angiogenic switch. Preliminary evidence in our laboratory suggests that genistein can alter the pancreatic cancer cell metabolic profile, inhibit cell growth, induce apoptosis, diminish metastatic spread in vivo, and decrease angiogenesis. We hypothesize that flavonoids prevent the progression to pancreatic cancer, and that flavonoids may act as a chemotherapeutic in established pancreatic cancer. We will pursue the following specific aims: Specific Aim I). Determine the ability of flavonoids to prevent the progression of pancreatic intraepithelial neoplasia (PanIN) to invasive pancreatic ductal adenocarcinoma using a novel transgenic pancreatic cancer animal model. Specific Aim II). Assess the effect of flavonoids on immortalized human pancreatic cancer cell lines in an orthotopic xenograph model. Specific Aim III). Determine the impact of flavonoids in patients with pancreatic cancer. To complete these aims we will perform experiments investigating genistein, quercetin, and apigenin in a transgenic model (LSL-KRAS G12D;PDX-1-Cre) that recaputulates premalignant and malignant pancreatic lesions. Also we will test these flavonoids in an orthotopic murine model and compare these to standard gemcitabine treatment. Finally, we will take advantage our large clinical volume of patients with pancreatic cancer and study the impact of soy supplementation in patients with this disease.