TGFBETA1 IN COLON CANCER PROGRESSION

在结肠癌发生后，TGF β 1可以增强其 发展到更具侵略性的状态。 我们发现结肠癌 TGF β 1蛋白水平高的患者的发病率是正常人的18倍（p 小于0.0013）比低浓度的癌症进展为转移 TGF β 1水平。 研究人员发现， 原发肿瘤保留在淋巴结和转移灶中。 这种选择的一种机制是自分泌TGF β 1起作用， 作为一个增长因素。 我们将测试假设， 在侵袭性和转移性肿瘤中观察到TGF β 1生长刺激 结肠癌细胞是由于诱导低水平的CDK 抑制剂p21 cip 1，其稳定cdk 2/细胞周期蛋白E复合物， 增加它们的激酶活性，并确定 控制这些细胞中的p21 cip 1水平。 TGF β 1信号传导 随着结肠癌细胞进展到更大的恶性程度而变化。 Ras在TGF β 1启动信号传导时被瞬时激活 导致分化和生长停滞的途径，而不是当 TGF β 1刺激细胞生长和侵袭。 我们将确定 是否通过稳定转染显性的 阴性N17 rasH将阻断TGF β 1诱导的成熟和/或 生长抑制 杯状细胞产生粘蛋白， 第二丰富的结肠上皮细胞类型。 我们将 确定结肠杯状细胞不敏感的机制是否 转化为TGF β 1是由于β聚糖形式的水平降低， TbetaRIII通过转染研究。

After colon cancer have developed, TGFbeta1 can enhance their progression to more invasive states. We found that colon cancers with high levels of TGFbeta1 protein were 18 times more likely (p less than 0.0013) to progress to metastases than cancers with low TGFbeta 1 levels. Elevated levels of TGFbeta 1 found in the primary tumor were maintained in lymph nodes and metastases. One mechanism for this selection is that autocrine TGFbeta 1 acts as a growth factor. We will test the hypothesis that the TGFbeta1-growth stimulation seen in aggressive and metastatic colon carcinoma cells is due to induction of low levels of the CDK inhibitor p21cip1 which stabilize cdk2/cyclin E complexes and increase their kinase activity, and determine the mechanisms for controlling p21cip1 levels in these cells. TGFbeta1 signaling changes as colon carcinoma cells progress to greater malignancy. Ras is transiently activated when TGFbeta1 initiates a signaling pathway leading to differentiation and growth arrest, not when TGFbeta1 stimulates cell growth the invasion. We will determine whether blocking ras by stable transfection of the dominant negative N17rasH will block TGFbeta1-induced maturation and/or growth inhibitition. Goblet cells produce mucins and are the second most abundant colon epithelial cell-type. We will determine whether the mechanism of colon goblet cell insensitivity to TGFbeta 1 is due to reduced levels of the betaglycan form of TbetaRIII by transfection studies.