Gastrointestinal (GI) neuroendocrine (NE) tumors such as carcinoid and islet cell tumors are the second most common cause of isolated hepatic metastases. These tumors often cause debilitating symptoms due to excessive hormonal secretion. Besides surgery, there are limited curative and palliative treatments available to patients with GI NE tumors, emphasizing the need for development of other forms of therapy. We have recently shown that over-expression of raf-1 in human GI carcinoid cells markedly suppresses NE marker expression and serotonin secretion by these tumor cells in vitro. The exact downstream factors that mediate this effect are unknown. We will present new data suggesting that activation of raf-1 in carcinoid cells results in secretion of a soluble, autocrine factor which can independently suppress hormone production in untransduced carcinoid cells. In this proposal, we will attempt to identify the soluble, autocrine factor in the conditioned media from raf-1 transduced GI carcinoid cells utilizing several strategies such as cDNA arrays and proteomics tools. The results from this proposal may have a significant impact on patients with metastatic disease from GI NE tumors. While we have shown that raf-1 activation in human carcinoid tumor cells can suppress hormone production, methods to target raf-1 induction in tumor cells would prove to be difficult. The possibility that raf-l-mediated hormone suppression could be induced by a soluble factor would provide a plausible, therapeutic delivery method.
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