DYSREGULATION OF TGF-BETA ACTIONS IN PANCREATIC CANCER

描述：（改编自研究者摘要）细胞和 分子机制，有助于生物侵略性， 胰腺导管腺癌是未知的。 然而， 这些癌症中K-ras癌基因突变的发生率很高， 携带许多突变的肿瘤抑制基因，并过表达几个 生长因子及其相应的跨膜酪氨酸激酶 受体是细胞生长的正调节剂。 调查人员 报道，人类胰腺癌也表达高水平的三种 哺乳动物转化生长因子β（TGF-β）同种型及其 在癌症中的存在与疾病进展有关。 TGF-β 抑制上皮细胞类型的生长但增强血管生成， 有助于细胞外基质形成，调节细胞迁移， 粘附和调节免疫功能。 因此，可以想象， TGF-β通过旁分泌机制促进胰腺癌细胞的生长， 体内的癌细胞。 这意味着癌症导向的TGF-β抑制剂 在这种疾病中可能会出现通路紊乱。 从理论上讲， 负增长调节可能是由于水平的变化， TGF-β受体或受体后缺陷。 在本提案中， 将测试的假设，异常表达和改变功能的 胰腺癌细胞中的TGF-β受体导致胰腺癌细胞中的 自分泌生长抑制机制，同时伴随TGF-β 过表达通过旁分泌机制增强细胞生长。 两 我们将使用各种方法来检验这一假设。 首先，他们将决定 胰腺癌中TGF-β受体表达是否以及如何改变 并确定这些改变的临床意义。 该分析 将使用适当的特异性抗体、分子 探针和寡核苷酸。 对照组织将由正常人 通过器官捐赠计划获得的胰腺样本。 二是 将阐明胰腺癌细胞抵抗 TGF-β 1介导的生长抑制，通过检查TGF-β的潜在作用 受体和受体后缺陷。 他们还将确定TGF-b 胰腺癌中配体过度表达有助于疾病 发展和设计有可能恢复癌症的方法 细胞抑制反应性和抑制TGF-β的旁分泌作用。

DESCRIPTION: (adapted from the investigator's abstract) The cellular and molecular mechanisms that contribute to the biological aggressiveness of pancreatic ductal adenocarcinomas are not known. However, it is established that these cancers have a high incidence of mutations in the K-ras oncogene, harbor a number of mutated tumor suppressor genes, and overexpress several growth factors and their corresponding transmembrane tyrosine kinase receptors that are positive modulators of cell growth. The investigators reported that human pancreatic cancers also express high levels of the three mammalian transforming growth factor beta (TGF-b) isoforms and that their presence in the cancers is associated with disease progression. TGF-bs inhibit the growth of epithelial cell types but enhance angiogenesis, contribute to extracellular matrix formation, regulate cell migration and adhesion and modulate immune functions. It is conceivable, therefore, that TGF-bs act via paracrine mechanisms to enhance the growth of pancreatic cancer cells in vivo. This implies that cancer-directed TGF-b inhibitor pathways may be inoperative in this disorder. In theory, this loss of negative growth regulation could be due to alterations at the level of the TGF-b receptors or to post-receptor defects. In the present proposal they will test the hypothesis that aberrant expression and altered function of TGF-b receptors in pancreatic cancer cells results in perturbations in autocrine growth suppressive mechanisms while concomitant TGF-b overexpression enhances cell growth via paracrine mechanisms. Two approaches will be used to test this hypothesis. First, they will determine whether and how TGF-b receptor expression is altered in pancreatic cancer and establish the clinical significance of these alterations. This analysis will be performed using the appropriate specific antibodies, molecular probes and oligonucleotides. Control tissues will consist of normal human pancreatic samples obtained through an organ donor program. Second, they will elucidate the reasons for pancreatic cancer cell resistance to TGF-b1-mediated growth inhibition by examining the potential roles of TGF-b receptor and post-receptor defects. They will also determine how TGF-b ligand overexpression in pancreatic cancer contributes to disease progression and devise approaches that have the potential to restore cancer cell inhibitory responsiveness and suppress the paracrine actions of TGF-bs.