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。多数 据估计，美国每年新增病例32,000例，欧洲每年新增病例60,000例，其中 一年的诊断。迫切需要制定新的更好的治疗策略。 胰腺癌。这将需要化学预防和化疗的新方法，以及 植物化学物质为这一点提供了可能性。使癌细胞在细胞代谢方面发生变化 必须进行配置文件。一旦正常的胰腺细胞转化为癌细胞，那么一组癌症 细胞必须招募额外的血液供应才能生长和转移--这个过程被称为血管生成 换个位置。我们和其他人发现，染料木素，一种类黄酮类，可能是一种有用的方法来影响 胰腺癌细胞的代谢特征及其对血管生成刺激因子的抑制作用 换个位置。我们实验室的初步证据表明，金雀异黄素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。我们假设类黄酮类化合物可以防止胰腺癌的进展，而且 类黄酮类化合物可作为已确诊的胰腺癌的化疗药物。我们将致力于以下工作 具体目标：具体目标一)。测定类黄酮类化合物预防胰腺癌进展的能力 应用一种新的转基因技术从上皮内瘤变(Panin)转化为侵袭性胰腺导管腺癌 胰腺癌动物模型。具体目标二)。评价黄酮类化合物对永生化人体的影响 原位异种移植模型中的胰腺癌细胞系。具体目标三)。确定以下方面的影响 胰腺癌患者的类黄酮类化合物。为了实现这些目标，我们将进行实验 在转基因模型(LSL-KRAS G12D；PDX-1-CRE)中研究染料木素、栎素和芹菜素 切除胰腺癌前病变和恶性病变。此外，我们还将在一个 建立小鼠原位模型，并与标准吉西他滨治疗进行比较。最后，我们将带着 利用我们临床上大量的胰腺癌患者和研究大豆的影响 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.