The recent discovery of KSHV, the virus responsible for causing the neovascular tumor, KS, has prompted renewed interest into the genesis of this enigmatic neoplasm. Nonetheless, despite a greater understanding of its patho-genesis, KS remains an incurable disease. Examination of the molecular mechanisms whereby KSHV latent and lytic genes contribute to Kaposi's sarcomagenesis may ultimately expose novel therapeutic targets for the treatment of KS and may further provide insight into the complex relationship between tumorigenesis and angiogenesis.
Neoplasia: The pathological process that results in the formation and growth of a tumor.
Sarcoma: A usually malignant tumor arising from connective tissue (bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue); one of the four major types of cancer.
Transformation: Conversion of normal eukaryotic cells to a cancerlike state of uncontrolled division.
Tumor suppressor gene: Gene that suppresses the formation of tumors. Deletion or inactivation of this gene is believed to be a necessary prerequisite for tumor development.
Viral oncogene: A viral gene that contributes to cancer development in vertebrate hosts. Otherwise normal cells expressing a viral oncogene change into cancerous tumor cells.
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9. Montaner, S., Sodhi, A., Molinolo, A., Bugge, T. H., Sawai, E. T., He, Y., Li, Y., Ray, P. E., and Gutkind, J. S. (2003). Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sar-comagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3, 23-36. The authors engineered a novel transgenic mouse line expressing the avian retroviral receptor, TVA, under the endothelial cell—specific, TIE2, promoter, enabling endothelial-specific infection with avian leucosis virus-derived vectors expressing candidate KSHV oncogenes in vivo. They found that a single KSHV lytic gene, vGPCR, was able to induce angioproliferative tumors in mice that were strikingly similar to human KS. However, expression of vGPCR was limited to only a subset of cells, and paracrine mechanisms were found to be responsible for the survival of neighboring endothelial cells, suggesting that vGPCR transformation of endothelial cells, similar to KSHV, may be mediated by paracrine mechanisms. Using a KS allograft model, the authors further demonstrate that endothelial cells expressing vGPCR were able to promote tumor formation by cells expressing KSHV latent genes, suggestive of a cooperative role among latent and lytic genes in the promotion of Kaposi's sarcomagenesis.
10. Sodhi, A., Montaner, S., Patel, V, Gomez-Roman, J. J., Li, Y., Sausville, E. A., Sawai, E. T., and Gutkind, J. S. (2004). Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma her-pesvirus-encoded G protein-coupled receptor. Akt plays a central role in vGPCR-induced sarcomagenesis: a novel therapeutic target for Kaposi's sarcoma. Proc. Natl. Acad. Sci. USA 14, 4821-4826.
Dr. Akrit Sodhi is a research fellow in the Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, at the National Institutes of Health. Dr. Sodhi helped develop a novel high-throughput vascular endothelial-specific, retroviral gene transfer system. He is currently conducting research examining the molecular pathogenesis of the Kaposi's sarcoma-associated herpesvirus vGPCR in the laboratory of Dr. J. Silvio Gutkind.
Dr. J. Silvio Gutkind has been the Branch Chief in the Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial
Research, at the National Institutes of Health since 1997. His lab has elucidated key signaling pathways by which cellular and viral receptors, coupled to heterotrimeric G proteins, can regulate gene expression. His pioneering discoveries provided novel insights into the biochemical routes by which these membrane receptors control normal and aberrant cell growth.
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