After recently announcing success in eliminating melanoma metastasis in laboratory experiments, scientists at Virginia Commonwealth University Massey Cancer Center have made another important discovery in understanding the process by which the gene mda-9/syntenin contributes to metastasis in melanoma (the spread of skin cancer) and possibly a variety of other cancers.
Published in the journal Cancer Research, the study demonstrated that mda-9/syntenin is a key regulator of angiogenesis, the process responsible for the formation of new blood vessels in tumors. Mda-9/syntenin was originally cloned in the laboratory of the study's lead author Paul B. Fisher, M.Ph., Ph.D., Thelma Newmeyer Corman Endowed Chair in Cancer Research and program co-leader of Cancer Molecular Genetics at Virginia Commonwealth University Massey Cancer Center, chairman of VCU's Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine.
"Our research brings us one step closer to understanding precisely how metastatic melanoma, a highly aggressive and therapy-resistant cancer, spreads throughout the body," says Fisher. "Additionally, analysis of the human genome has indicated that mda-9/syntenin is elevated in the majority of cancers, which means novel drugs that target this gene could potentially be applicable to a broad spectrum of other deadly cancers."
Fisher's team discovered that mda-9/syntenin regulates the expression of several proteins responsible for promoting angiogenesis, including insulin growth factor binding protein-2 (IGFBP-2) and interleukin-8 (IL-8). The study is the first to provide proof of the pro-angiogenic functions of IGFBP-2 in human melanoma.
In in vivo and in vitro experiments, the scientists confirmed that mda-9/syntenin binds with the extracellular matrix (ECM) to start a series of biological processes that eventually cause endothelial cells to secrete IGFBP-2. The ECM is the substance that cells secrete and in which they are embedded. Endothelial cells are the cells that line the interior surface of blood vessels throughout the entire circulatory system. The secretion of IGFBP-2, in turn, caused the endothelial cells to produce and secrete vascular endothelial growth factor-A (VEGF-A), a protein that mediates the development of and formation of new blood vessels.
The researchers also noted that IGFBP-2 could potentially serve as a novel biomarker to monitor for disease progression in melanoma patients.
"This is a major breakthrough in understanding angiogenesis and its impact in melanoma metastasis," says Fisher. "We are now focusing on developing novel small molecules that specifically target mda-9/syntenin and IGFBP-2, which could be used as drugs to treat melanoma and potentially many other cancers."
Fisher collaborated on this study with Devanand Sarkar, M.B.B.S., Ph.D., Harrison Scholar and research member of the Cancer Molecular Genetics program at VCU Massey, Blick Scholar and assistant professor in the Department of Human and Molecular Genetics and member of the VCU Institute of Molecular Medicine at VCU School of Medicine; Swadesh K. Das, Ph.D., Santanu Dasgupta, Ph.D., and Luni Emdad, M.B.B.S., Ph.D., from the Department of Human and Molecular Genetics at VCU School of Medicine, the VCU Institute of Molecular Medicine and the Cancer Molecular Genetics research program at VCU Massey; Sujit K. Bhutia, Ph.D., Belal Azab, Ph.D., Upneet K. Sokhi, Timothy P. Kegelman, Leyla Peachy, Prasanna K. Santhekadur, Ph.D., and Rupesh Dash, Ph.D., all from the Department of Human and Molecular Genetics; Paul Dent, Ph.D., Universal Corporation Distinguished Professor for Cancer Cell Signaling and Developmental Therapeutics program member at VCU Massey, and professor and vice chair of research in the Department of Neurosurgery at VCU School of Medicine; Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research, program co-leader of the Developmental Therapeutics program and Cancer Cell Signaling program member at VCU Massey; and Maurizio Pellacchia, Ph.D., from Sanford-Burnham Medical Research Institute.
This research was supported by National Institutes of Health grant CA097318, the Thelma Newmeyer Corman Endowment, the National Foundation for Cancer Research, the Goldhirsh Foundation for Brain Tumor Research, the Dana Foundation and, in part, by funding from VCU Massey Cancer Center's NIH-NCI Cancer Center Support Grant P30 CA016059.
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