This discovery, reported in the June 24 on-line issue of Nature Cell Biology, could provide scientists with a promising new target for the development of a drug to halt tumor invasion and metastasis, the spread of cancer from its primary site to other areas of the body.
Metastasis occurs when cancer cells penetrate the boundaries of the tumor's tissue and infiltrate the walls of blood vessels or lymph vessels, gaining a means of transport to other parts of the body - far from the original tumor site - where they can then grow anew. This process is unique to cancer cells and is what makes the disease so dangerous - and so feared.
"A primary [cancerous] tumor can be removed," explains the study's senior author Alex Toker, Ph.D., of the department of pathology at Beth Israel Deaconess Medical Center (BIDMC) and assistant professor at Harvard Medical School. "But once the cancer has metastasized, it becomes intractable." In fact, the goal of early cancer detection is to remove the primary carcinoma before it has a chance to spread.
Scientists have known that in order for a tumor to metastasize, certain genes had to be "turned on" so that they could produce enzymes necessary to invade blood vessel walls and penetrate other tissues. Toker and his coauthors at BIDMC and at the Center for Blood Research at Harvard Medical School, set out to identify how this was happening, and began by focusing on the actions of a group of proteins known as transcription factors, including NFAT (nuclear factor of activated T cells).
NFAT, which is critical for efficient immune cell responses, was first identified in the cells of the immune system about 20 years ago. It subsequently became the target for cyclosporin A, a drug used to suppress the immune systems of patients undergoing organ transplants in order to prevent their bodies from rejecting their new organs. NFAT has also been shown to be important for heart development during embryogenesis.
In this new study, lead author Sebastien Jauliac, Ph.D., was surprised to find high levels of NFAT in cancer cells. In order to evaluate the contribution of NFAT to tumor metastasis, the authors used laboratory models of cancer cell invasion. Their results showed that the protein NFAT was indeed contributing to the aggressive, invasive behavior of cancer cells.
Because there was no information indicating NFAT expression in human metastatic cancer, the researchers evaluated the presence of NFAT in tissue samples from five breast cancer patients with aggressive grade III ductal carcinoma, who had positive lymph node metastases at the time of diagnosis.
Besides showing a high correlation between tumor aggression and NFAT levels, the researchers showed that NFAT is found in association with another protein, the alpha 6 beta 4 integrin. This integrin has been linked with several hallmarks of metastatic tumors, including epithelial cell motility, cellular survival and carcinoma invasion.
According to Toker, the next step for researchers will be to attempt to determine the subset of genes that are induced by the NFAT proteins in invasive tumors, and to assess the importance of these genes to the process of metastasis.
"Cancer has been attacked from a large number of fronts, but this discovery presents a previously unappreciated role for NFAT in human cancer," says Toker. "If we pursue this avenue, and add NFAT to the growing list of proteins that have been shown to be important for disease progression, we could be offering a novel target for drug discovery to block this aspect of cancer progression. We may be providing another weapon in our arsenal in the fight against cancer."
Study co-authors include Sebastien Jauliac, Ph.D., Leslie Shaw, Ph.D., and Lawrence Brown, M.D., of Beth Israel Deaconess Medical Center; and Cristina Lopez-Rodriguez, Ph.D., and Anjana Rao, Ph.D., of the Department of Pathology and Center for Blood Research, Harvard Medical School.
This research was funded by grants from the National Institutes of Health (NIH) and the U.S. Department of Defense, and by fellowships from the Association Pour la Recherche Contre le Cancer, the Cancer Research Institute and the Leukemia and Lymphoma Society.
Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. Beth Israel Deaconess is the third largest recipient of NIH Research funding among independent U.S. teaching hospitals.