Gastrointestinal (GI) neuroendocrine (NE) tumors such as carcinoids are the second most common cause of isolated hepatic metastases. These tumors often cause debilitating symptoms due to excessive hormonal production. Besides surgery, there are limited curative and palliative treatments available to patients with GI NE tumors. We have recently shown that overexpression of Notch1, a transmembrane receptor protein that plays an essential role in development of the GI tract, markedly suppresses cellular growth of human carcinoid cells in vitro. Moreover, overexpression of Notch1 also leads to a dramatic reduction in NE marker expression and serotonin secretion by carcinoid cells in vitro. However, the role of Notch1 in modulating GI NE tumor growth and hormone production in vivo has not been explored. To determine the mechanisms that lead to Notch1-mediated growth suppression, we will test our hypothesis that overexpression of Notch1 leads to cell cycle arrest through increased expression of cell cycle inhibitors such as p21. To develop potential palliative treatments for GI NE tumors, we will characterize the downstream events leading to the Notch1-induced reduction in NE markers and hormone secretion by GI NE cells. We will focus on the interplay between Notch1 and hASH1, a transcription factor essential to the NE features of these tumors as well as a known downstream target of Notch1. Finally, to determine if overexpression of Notch1 in GI NE tumors can inhibit tumor progression and metastasis in vivo, we will characterize distinct mouse models that study the effects of Notch1 on proliferation, tumor invasion, and liver metastasis by carcinoid tumors. In summary, these studies should determine if modulation of the Notch1 signaling pathway could play a potential role in the management of patients with carcinoid tumors. Furthermore, these finding may permit development of components of Notch1 pathway as therapeutic targets in the treatment and palliation of GI NE tumors.
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