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Homeobox genes in tumor biology. angiogenesis inhibition in tumor therapyHomeobox genes encode a class of transcription factors that are very important in pattern formation and organogenesis during embryogenesis. as well as in controlling cell growth and differentiation. I am interested in the roles of individual homeobox genes in regulating endothelial cell phenotype during angiogenesis and how these roles might be exploited for a therapeutic approach to cancer using antiangiogenic approaches. Specifically. I have been studying the role of the growth arrest-specific homeobox gene Gax in cell cycle control in cancer as well as its role in angiogenesis. Gax was initially isolated from a vascular smooth muscle cDNA library and has a number of important biological effects in vascular myocytes. including G1 cell cycle arrest. induction of apoptosis. inhibition of cell migration. and modulation of integrin expression. I have detected its expression in vascular endothelial cells. and its overexpression in human umbilical vein endothelial cells (HUVECs) results in inhibition of cell cycle progression. migration towards proangiogenic cytokines. and cytokine-induced tube formation on Matrigel. These observations strongly suggest that Gax has a role in the negative regulation of the initial steps by which endothelial cells convert to the angiogenic phenotype. Present studies utilize cDNA microarray technology to identify downstream targets of Gax and real time quantitative RT-PCR to measure regulation of Gax expression in endothelial cells in response to stimulation with cytokines. and Western blotting to identify downstream signaling pathways activated by Gax expression. Also. I am beginning studies of other homeobox genes that have been implicated by other groups in regulating the angiogenic phenotype. including HOXD3. which appears to promote angiogenesis. both in cancer and wound healing; HOXB3. which appears to play a different. complementary role in regulating the angiogenic phenotype. Finally. some homeobox genes function in tumors to increase the secretion of pro-angiogenic peptides. and we are beginning to study these. The long term goal of these projects is to determine the specific roles of these homeobox genes in tumor growth and angiogenesis and. more broadly. to determine if homeobox genes can be used as prognostic indicators or as targets for cancer therapy. either pharmacologic or gene-based. In collaboration with Dr. James Goydos. my second area of interest involves studying levels of VEGF and other proangiogenic factors at different stages in melanoma progression. including the role of pro-lymphangiogenic factors. such as VEGF-C. in lymph node metastases in melanoma and breast cancer. Finally. a homeobox transcription factor. Prox1. has been shown to be a master regulatory gene that promotes endothelial cell differentiation into the lymphatic phenotype. and we are beginning to examine its role in promoting lymph node metastases. Selected PublicationsChen Y, Gorski DH. (2008) Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5. Blood. 111(3):1217-26. Chen Y, Leal AD, Patel S, Gorski DH. (2007) The homeobox gene GAX activates p21WAF1/CIP1 expression in vascular endothelial cells through direct interaction with upstream AT-rich sequences. J Biol Chem. 282(1):507-17. Goydos JS. Mann B. Kim HJ. Gabriel EM. Alsina J. Germino FJ. Shih W. Gorski DH. (2005) Detection of B-RAF and N-RAS mutations in human melanoma. J Am Coll Surg. 200(3):362-70. Patel S. Leal AD. Gorski DH. (2005) The homeobox gene Gax inhibits angiogenesis through inhibition of nuclear factor-kappaB-dependent endothelial cell gene expression. Cancer Res. 65(4):1414-24. Gorski. D. H.. Mauceri. H.. Beckett. M.. Salloum. R.. Halpern. A. and Weichselbaum. R. (2003). Prolonged treatment with angiostatin reduces metastatic burden during radiation therapy. Cancer Res. 63:308-311. Salloum. R. M.. Mauceri. H. J.. Hanna. N.. Gorski. D. H. and Weichselbaum. R. R. (2003). Dual induction of the Epo-Egr-TNF- plasmid in hypoxic human colon adenocarcinoma produces tumor growth delay. Am. Surg 69:24-27. Gorski. D. H.. and Leal. A. D. (2003). Inhibition of endothelial cell activation by the homeobox gene Gax. J. Surg. Res. 111:91-99. Gorski. D. H.. and Walsh. K. (2003). Control of vascular cell differentiation by homeobox transcription factors. Trends Cardiovasc. Med. 13:213-220. Gorski. D. H.. Leal. A. D. and Goydos. J. S. (2003). Differential expression of vascular endothelial growth factor A (VEGF-A) isoforms at different stages of melanoma progression. J. Am. Coll. Surg. 197:408-18. Goydos. J. S.. and Gorski. D. H. (2003) Level of expression of vascular endothelial growth factor C (VEGF-C) correlates with stage of local/regional progression in patients with melanoma. Clin. Cancer Res. 9:5962-5967. Alsina. J.. Gorski. D. H.. Germino. F. J.. Shih. W.. Lu. S.-E.. Zhang. Z.-G.. Yang. J.-M.. Hait. W. N. and Goydos. J. S. (2003). Detection of mutations in the mitogen-activated protein kinase (MAPK) pathway in human melanoma. Clin. Cancer Res. 9:6419-6425. Gorski. D. H.. and K. Walsh (2000). The role of homeobox genes in vascular remodeling and angiogenesis. Circ. Res. 87: 865-872. Gorski. D. H.. M. A. Beckett. N. T. Jaskowiak. D. P. Calvin. H. J. Mauceri. R. M. Salloum. S. Seetharam. A. Koons. D. M. Hari. D. W. Kufe. and R. R. Weichselbaum (1999). Blockade of the VEGF stress response increases the antitumor effects of ionizing radiation. Cancer Res. 59:3374-3378. |
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