Scientists at The Rockefeller University have found, for the first time, that the persistent activation of a protein called Stat3 can, by itself, cause normal cells to behave like cancer cells. The research, reported in the August 6 issue of Cell, provides both a scientific surprise and a promising new target in the fight against cancer. Scientists already knew that Stat3 was often activated in various human cancer types, including lymphomas, leukemias, breast cancer and a high percentage of head and neck cancers, but until now no one knew whether persistent Stat3 activation could contribute directly to the development of tumors.
"In my mind, our laboratory findings on Stat3 activation in cultured cells and in cells injected into animals provide a strong basis for believing that the high levels of active Stat3 in clinical tumor samples are an important part of the cancer process. Furthermore, interruption of these high levels of active Stat3 should provide potent anti-tumor activity," says co-author James Darnell Jr., M.D., Vincent Astor Professor and head of the Laboratory of Molecular Cell Biology at Rockefeller.
The family of STAT proteins plays an important role in many normal developmental processes, but during the past several years, a growing number of scientific reports have indicated that human tumor samples contain persistently activated Stats (Stats 1, 3 and 5 most frequently). Similarly, reports have also cited a persistent activation of Stat proteins, particularly Stat3, in cell lines started from human tumors and in laboratory experiments in which oncogenes (cancer-causing genes) are used to turn normal cells into cancer cells. These observations suggested at least a supplementary role for persistently activated Stat3 in tumor development.
The new research showing that activated Stat3 could, by itself, act as the transforming agent was performed in Darnell’s laboratory, which discovered the Stats and pioneered studies of the activation of these proteins. The paper’s first author, Jacqueline F. Bromberg, M.D., Ph.D., is a postdoctoral fellow in Darnell’s lab and an assistant professor at Memorial Sloan-Kettering Cancer Center, where she conducts studies of and treats breast cancer patients with Larry Norton, M.D.
Normally, Stat proteins are inactive until cells receive an outside stimulus by such proteins as interferon, erythropoietin (Epo), growth hormone or many other proteins that circulate in the body. The active Stat then moves to the nucleus to turn quiescent genes on. After a short period of activity, the Stats become inactive again. Therefore, to study persistently active Stat3, the lab had to find a way to make a Stat3 molecule that would be constantly active. Melissa Wrzeszczynska, Ph.D., a co-author and postdoctoral fellow in the Darnell lab, suggested that a particular genetic change be made in the Stat3 gene that might cause cells with this altered gene to make Stat3 protein that would be active without any outside stimulus. The suggestion worked, and the researchers called this new, persistently active molecule Stat3-C ("C" because the new Stat3 proteins had two extra residues of the amino acid cysteine).
Cells with Stat3-C grew in a cancerous way in soft agar (a jellylike substance in which cancer cells, but not normal cells, can grow), and these cells also caused tumor development in "nude" mice (animals that accept foreign cells and can therefore be used to test the tumor-like behavior of cells in an animal). The results of these experiments demonstrate that persistently active Stat3 does indeed possess the potential to cause cancer.
The discovery is surprising because Stat3 isn’t a usual oncogene. "Most people think oncogenes depend on mutations," Darnell observes. "But the Stat3 that is persistently active in human cancers may be a normal protein; only its level of activation is abnormal. What we have shown is that if you can make Stat3 that is persistently active, it will cause tumors."
The "downstream" events of persistently active Stat3 that lead to tumor growth are still unclear, but by turning genes on, the Stat3 may enhance conditions for cell cycle progression and/or provide protection against cell death, thus allowing a cancer cell to grow unchecked.
Bromberg’s clinical interest in breast cancer led the lab to use this approach to the study of Stat3 function in cancer. (Her current, unpublished studies--and those of others, including a group headed by Richard Jove, Ph.D., at the Moffitt Cancer Center in Florida --found that more than 50 percent of fresh breast cancer samples show Stat3 activation, although a greater number of samples must be studied before this result can be considered established.)
Darnell and Bromberg suggest that persistently activated Stat3 presents an attractive target for the discovery of drugs that will inhibit the activation or action of Stat3. Such drugs should have the potential to inhibit the growth or induce the death of human cancer cells.
Rockefeller began in 1901 as The Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates. Thirty-three faculty members are elected members of the U.S. National Academy of Sciences, including President Arnold J. Levine, Ph.D.
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