TGFBETA1 IN COLON CANCER PROGRESSION

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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.