Despite impressive advances in understanding cancer etiology and the development of novel therapeutic approaches, the most effective therapies for solid malignancies (carcinomas) remain surgery and radiotherapy. Although effective in removing and destroying primary tumors, most patients undergoing surgery and radiotherapy will eventually succumb to metastases that develop from residual primary cancer cells that migrate and proliferate at secondary sites. In other words, most cancer patients are killed by metastases rather than the primary tumor. Given the magnitude of this problem, research into the mechanisms that control the metastatic spread of tumors is of utmost importance and urgency This proposal is based on our preliminary results that a mutation that prevents activation of the inflammation responsive protein kinase IkappaB kinase alpha (IKKalpha) results in a dramatic decrease in the metastatic spread of prostate cancer in TRAMP mice, which express a SV40 T antigen oncogene in the prostate epithelium. This reduction in metastatic activity is associated with massive upregulation of maspin, a suppressor of metastasis whose expression is almost completely abolished in primary prostate carcinomas that express the wild type form of IKKalpha. Our preliminary results also suggest that IKKalpha activation results in inhibition of maspin expression. Given its known responsiveness to cytokines produced by stromal cells as well as by inflammatory cells, IKKalpha can provide a major conduit through which the tumor microenvironment controls the metastatic potential of prostate carcinoma cells. Our goal is to test this hypothesis and identify the molecular mechanisms through which IKKalpha controls the metastatic spread of prostate cancer and the expression of maspin in TRAMP mice. We will also examine how the tumor microenvironment modulates the activity of the IKKalpha-maspin axis and will determine the mechanisms through which maspin exerts its anti-metastatic activity in this model of prostate cancer. We will examine whether IKKalpha regulates maspin expression in human prostate cancer specimens and cell lines to control their metastatic and invasive activities. In addition to providing new and important information on the control of tumor metastasis, this work can lay the foundation to the development of novel anti-metastatic therapy based on inhibition of IKKalpha that may be applicable not only to prostate cancer but other cancers as well.
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