Gastrointestinal Neuroendocrine Tumors: A Possible Therapeutic Role for the Ras/Raf Signal Transduction Pathway
Funding:
American Surgical Association
Principal Investigator:
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Project Summary:
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 which characterize these NE lesions. 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, a component of the ras/raf-1/MAP kinase signal transduction pathway, in human carcinoid cells markedly suppresses cellular growth and causes changes in cellular morphology and adhesion in vitro. Moreover, over-expression of raf-1 also leads to a dramatic reduction in NE marker expression and serotonin secretion by carcinoid cells in vitro. However, the role of raf-1 in modulating GI NE tumor growth and hormone production in vivo has not been explored. To delineate the mechanism(s) of raf-1 mediated growth suppression seen in GI NE tumors in vitro, we will look for changes in cell cycling, induction of senescence or apoptosis, cellular differentiation, growth factor expression, and adhesion molecules in carcinoid cells. To develop potential palliative treatments for GI NE tumors, we will characterize the downstream events leading to the raf-1 induced reduction in NE markers and hormone secretion by GI NE cells. We will focus on the interplay between raf-1 and hASH1, a transcription factor essential to the NE features of these tumors as well as a known downstream target of raf-1. Finally, to determine if over-expression of raf-1 in GI NE tumors can inhibit tumor progression and metastasis in vivo, we will characterize murine carcinoid tumor models that study the effects of raf-1 on proliferation, local invasion, and adherence/organ invasion. In summary, these studies should determine if modulation of the raf-1 signal transduction pathway could play a potential role in the management of patients with carcinoid tumors. Furthermore, these finding may permit development of components of raf-1 pathway as therapeutic targets in the treatment and palliation of GI NE tumors.
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General Surgery
University of Wisconsin Department of Surgery
First published: 07/15/02 Last updated: 11/24/09 webmaster@surgery.wisc.edu
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