The long-term goal of this project is to define the pathobiology of metastatic uveal melanoma to the liver. This knowledge will be used to control the metastatic process thus decreasing mortality. Uveal melanoma is the most common primary intraocular tumor and has an associated 30% mortality. This mortality rate has not decreased, despite improvements in treating the primary tumor. Uveal melanoma forms micrometastases in the liver and metastatic disease of the liver is the leading cause of death in patients with uveal melanoma. These micrometastases have the potential to grow, remain dormant, or involute, depending on intrinsic properties of the micrometastases and extrinsic properties of the host. Angiostatin promotes melanoma apoptosis and maintenance of dormancy by manipulating the intrinsic vascular endothelial growth factor (VEGF) to pigment epithelium derived factor (PEDF) ratio. Interferon alpha-2b (IFN) promotes micrometastatic melanoma apoptosis by boosting intrinsic hepatic NK cells. Angiostatin and IFN act synergistically via VEGFR1 which is expressed by melanoma cells and NK cells.
The first aim i s to manipulate the intrinsic PEDF/VEGF ratio in melanoma cell lines and within the micrometastatic environment in the liver. This is done by transfection for overexpression of VEGF or PEDF and siRNA blocking of VEGF or PEDF in melanoma cell lines, determining VEGF and PEDF mRNA levels in the micrometastases with laser capture microdissection, testing for VEGF/PEDF in co-cultures of melanoma/hepatocytes, and correlating hepatic micrometastases with hypoxic zones in the liver.
The second aim determines the role of VEGFR1 stimulation of NK cells with adherence to hepatic endothelium in a coculture system and the contribution of FAS/FAS ligand, IFNgamma, and/or perforin to NK killing in knockout mice.
The third aim determines the mechanism of combined angiostatin/IFN control of the micrometastases using methods in the first two aims. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA126447-04A1
Application #
7143472
Study Section
Special Emphasis Panel (ZRG1-BDCN-F (02))
Program Officer
Hecht, Toby T
Project Start
2001-03-05
Project End
2011-07-31
Budget Start
2006-09-12
Budget End
2007-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$235,389
Indirect Cost
Name
Emory University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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