DYSREGULATION OF TGF-BETA ACTIONS IN PANCREATIC CANCER

描述：(改编自调查人员的摘要)细胞和 导致细菌生物侵袭性的分子机制 胰腺导管腺癌并不为人所知。然而，它是建立起来的 这些癌症K-ras癌基因突变的发生率很高， 含有多个突变的抑癌基因，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向调节器。调查人员 报道称，人类胰腺癌也高水平表达这三种 哺乳动物转化生长因子β亚型及其亚型 癌症中的存在与疾病的进展有关。转化生长因子-β 抑制上皮细胞类型的生长但促进血管生成， 有助于细胞外基质的形成，调节细胞迁移和 黏附和调节免疫功能。因此，可以想象， 转化生长因子-β通过旁分泌机制促进胰腺生长 体内的癌细胞。这意味着癌症导向的转化生长因子-b抑制物 在这种疾病中，通路可能不起作用。从理论上讲，这一损失 负增长监管可能是由于 转化生长因子-b受体或受体后缺陷。在本提案中，他们 将检验一种假说，即基因异常表达和功能改变 胰腺癌细胞中的转化生长因子-b受体导致 伴随转化生长因子-β的自分泌生长抑制机制 过表达通过旁分泌机制促进细胞生长。二 我们将使用各种方法来检验这一假设。首先，他们将确定 转化生长因子-b受体在胰腺癌中的表达是否及如何改变 并确定这些改变的临床意义。这一分析 将使用适当的特定抗体、分子 探针和寡核苷酸。对照组织将由正常人组成 通过器官捐献计划获得的胰腺样本。第二，他们 将阐明胰腺癌细胞耐药的原因 转化生长因子-β1通过检测转化生长因子-β的潜在作用而介导的生长抑制 受体和受体后缺陷。他们还将确定转化生长因子-b如何 胰腺癌中配体的过度表达与疾病的关系 进展和设计有可能恢复癌症的方法 细胞抑制性反应和抑制转化生长因子-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.