Virginia Commonwealth University Institute of Molecular Medicine and VCU Massey Cancer Center researchers have discovered how a gene, melanoma differentiation associated gene-9/syntenin (mda-9/syntenin), interacts with an important signaling protein to promote metastasis in human melanoma cells, a discovery that could one day lead to the development of the next generation of anti-metastatic drugs for melanoma and other cancers.
Metastatic disease is one of the primary challenges in cancer therapy. When cancer cells are localized in the body, specialists may be able to surgically remove the diseased area. However, when cancer metastasizes or spreads to sites remote from the primary tumor through the lymph system and blood vessels to new target sites, treatment becomes more difficult and in many instances ineffective.
Previous studies have shown that mda-9/syntenin regulates cell motility and can alter certain biochemical and signaling pathways leading to acquisition of metastatic ability. However, the exact mechanisms involved with these processes have not been well understood until now.
In the study, published online the week of Sept. 29 in the Early Edition of the Proceedings of the National Academy of Sciences, researchers report on the molecular mechanisms by which mda-9/syntenin is able to mediate invasion, migration, anchorage-independent growth and metastasis by physically interacting with c-Src, a key signaling protein involved with tumor cell growth and metastasis.
The team examined human cancer cells in the laboratory using a relevant human melanoma metastasis model and discovered how mda-9/syntenin was able to activate, or switch-on, the expression of c-Src. The expression of c-Src led to an increase in the formation of an active FAK/c-Src signaling complex. According to the researchers, this interaction triggers a signaling cascade resulting in increased cancer cell motility, invasion and metastasis.
"Mda-9/syntenin may represent a potential new molecular target for melanoma therapy that could be used to develop therapeutic reagents for treating this cancer as well as other cancers originating in the breast and stomach," said Paul B. Fisher, M.Ph., Ph.D., professor and chair of the Department of Human and Molecular Genetics and director of the VCU Institute of Molecular Medicine in the VCU School of Medicine.
"By disrupting the interaction between mda-9/syntenin and c-Src, it may be possible to prevent metastasis by blocking those signaling changes necessary for this process," he said.
According to Fisher, using this strategy it may be possible to identify compounds that serve this function and are effective therapeutic molecules for counteracting this final and frequently lethal stage of tumor progression.
The team will conduct further investigations to determine if small molecule drugs can be identified and developed to prevent metastasis by targeting this critical interaction between mda-9/syntenin and c-Src. Further studies are also in progress to determine how general these interactions are in mediating metastasis of other human tumors in addition to melanoma.
This work was supported by grants from the National Institutes of Health, National Cancer Institute and the Samuel Waxman Cancer Research Foundation.
Fisher, who is the first incumbent of the Thelma Newmeyer Corman Endowed Chair in Cancer Research and researcher with the VCU Massey Cancer Center and the VCU Institute of Molecular Medicine, worked with a team that included VCU School of Medicine researchers Habib Boukerche, Ph.D., a visiting scientist from INSERM in Lyon, France working in the Department of Human and Molecular Genetics and VCU Institute of Molecular Medicine; Zaozhong Su, Ph.D., associate professor in the VCU Department of Human and Molecular Genetics; Devanand Sarkar, Ph.D., assistant professor at the VCU Massey Cancer Center, VCU Institute of Molecular Medicine and Department of Human and Molecular Genetics; Célia Prévot with the University Lyon in France.
About VCU and the VCU Medical Center: Virginia Commonwealth University is the largest university in Virginia and ranks among the top 100 universities in the country in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls nearly 32,000 students in 205 certificate and degree programs in the arts, sciences and humanities. Sixty-five of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 15 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see www.vcu.edu.
About the VCU Massey Cancer Center: The VCU Massey Cancer Center is one of 64 National Cancer Institute-designated institutions that leads and shapes America's cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It offers more clinical trials than any other institution in Virginia, serving patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at www.massey.vcu.edu or call 1-877-4-MASSEY.
Journal
Proceedings of the National Academy of Sciences