Scleroderma May Be Initiated By Cancer
SAN FRANCISCO, Dec 5, 2013 /PRNewswire-USNewswire/ -- The Scleroderma Research Foundation today reported that researchers at The Johns Hopkins University have discovered that some cases of scleroderma are likely to have been initiated by cancer. In a landmark paper published online on December 5 in Science, researchers focusing on a select group of patients with both scleroderma and cancer, discovered that the patients' immune response to a mutated protein in their tumors resulted in autoimmunity once the immune response spread to the non-mutated form of the protein. This major insight into the origins of autoimmunity in scleroderma may also have ramifications for other autoimmune diseases. The Scleroderma Research Foundation has provided funding for this work.
Scleroderma (also known as systemic sclerosis) is a rare autoimmune disease affecting approximately 1 in 4,000 Americans. A signature symptom is fibrosis of the skin, although the disease often affects the lungs, kidneys and other organs with life-threatening consequences. In scleroderma, like many complex autoimmune diseases, little is understood about why and how the immune system becomes dysregulated and begins to attack a patient's own tissues. This study sheds light on this "breaking of tolerance" that is at the heart of autoimmunity.
In this collaborative effort, led by Dr. Antony Rosen, Dr. Bert Vogelstein and Dr. Kenneth Kinzler, researchers looked at patients who were diagnosed with both scleroderma and cancer within a two and a half-year time frame. Rosen, M.D., a Scientific Advisor for the Scleroderma Research Foundation, is Vice Dean for Research at The Johns Hopkins University and the Mary Betty Stevens Professor of Medicine and Professor of Cell Biology and Pathology. In a previous study, also supported by the Scleroderma Research Foundation and published in Arthritis and Rheumatism in 2010, Casciola-Rosen and colleagues identified a striking group of patients with rapid onset scleroderma and auto-antibodies to RNA polymerase III large subunit (RPC1), who also had cancers diagnosed close in time to the onset of scleroderma.
The Science study, published today, provides a mechanistic basis for the earlier observational studies. In this work, Rosen's group collaborated with the research groups of renowned cancer biologists, Bert Vogelstein, M.D., Director of the Ludwig Center, Clayton Professor of Oncology and Pathology and a Howard Hughes Medical Institute investigator and Kenneth Kinzler, Ph.D., Director of the Ludwig Center and Professor of Oncology, both of The Johns Hopkins University. Sequencing of the gene for RPC1 (POLR3A) in tumors from eight patients with antibodies against RPC1 found mutations in tumors from three of the patients. Additionally, there were other genetic alterations in the POLR3A gene in the tumors from most (five of eight) of the patients with antibodies against RPC1. The researchers did not find mutations or other genetic alterations in the POLR3A gene in cancers from eight other scleroderma patients whose antibodies recognize different cellular targets. Overall, six of eight tumors from scleroderma patients with antibodies to RPC1 harbored genetic alterations affecting the POLR3A gene, while none of the tumors from scleroderma patients without RPC1 antibodies had these changes. Further, the relatively low fraction of cancer cells with these genetic alterations in the tumors from some of the patients with RPC1 antibodies also suggests that an immune response against the cancer had occurred, with cells containing these mutations selected against during tumor growth.
The researchers went on to show that the CD4+ T cell response in the patients with a mutated POLR3A gene was directed against the part of the protein that had been mutated and, in some patients had spread to the non-mutated form of the protein. One patient was found to have many T cells with different nucleic acid sequences recognizing the mutated amino acid sequence, indicating that the mutation was driving the immune response.
Other experiments showed that long-lived, immune B cell antibodies from patients with POLR3A mutations recognized RPC1 whether it was mutated or not, demonstrating that once triggered, the immune response is capable of attacking both cancerous and normal tissues.
The authors propose that in patients pre-disposed to autoimmunity, cancers harboring POLR3A mutations initiated scleroderma in most patients with the RPC1 form of the disease, but that in the majority of these patients, the immune response eradicates the cancer by the time scleroderma develops.
While this study provides new insight into disease initiation in scleroderma, "the generation of an autoreactive immune response alone may not be sufficient to generate the self-sustaining tissue injury seen in scleroderma, and additional factors (genetic, environmental, or target tissue-specific) may be required," says Rosen. He adds, "further studies are underway to understand the role of these additional factors in the development of scleroderma."
"This study is the first to show that mutation of a normal gene in a cancer can be the initiator of an autoimmune disease. This is a profound shift in our thinking about scleroderma," says Scleroderma Research Foundation Chairman and MPM Capital Managing Director, Luke Evnin, Ph.D. Patients with a short cancer-autoimmune disease interval have also been described for other autoimmune rheumatic diseases, such as myositis, vasculitis, and lupus. Evnin adds, "the biological mechanisms discovered here may, therefore, have relevance to disease initiation in other autoimmune diseases."
"Our study results could change the way many physicians evaluate and eventually treat autoimmune diseases like scleroderma," says Dr. Rosen. "Current treatment strategies that are focused on dampening down the immune response in scleroderma could instead be replaced by strategies aimed at finding, diagnosing and treating the underlying cancer," adds Rosen.
The impact of this study may be as important to cancer research as it is to autoimmune research," says Evnin. "This could be a way to begin to uncover natural anti-cancer mechanisms which have been difficult to visualize in humans."
Critical to this study were the clinical expertise, database and biorepository of Dr. Fredrick Wigley and his team at The Johns Hopkins Scleroderma Center of Excellence, one of the premier scleroderma centers in the United States, which the Scleroderma Research Foundation has supported since its inception.
[Link to Science abstract] https://www.sciencemag.org/content/early/2013/12/04/science.1246886.abstract
[Link to The Johns Hopkins University Media Release]
Additional authors on the paper included Christine Joseph, Ph.D.; Erika Darrah, Ph.D.; Ami Shah, M.D.; Andrew Skora, Ph.D.; Livia Casciola-Rosen, Ph.D.; Fredrick Wigley, M.D.; Francesco Boin, M.D.; Andrea Fava, M.D.; Christopher Thoburn, B.S.; Isaac Kinde, B.S.; Yuchen Jiao, M.D., Ph.D.; and Nickolas Papadopoulos, Ph.D.
The study was supported in part by the Scleroderma Research Foundation, America's leading nonprofit investor in research aimed at improved therapies and a cure for patients with scleroderma, with additional support from The Virginia and D.K. Ludwig Fund for Cancer Research, The Donald B. and Dorothy L. Stabler Foundation, the Rheumatology Research Foundation Career Development Bridge Funding Award, and NIH grants K23 AR061439, P30‐AR053503, CA43460, CA 57345, and CA 62924
More about Scleroderma and the Scleroderma Research Foundation:
The word scleroderma literally means "hard skin," but the disease is much more than that, often affecting the internal organs such as the lungs, heart, kidney and gastrointestinal tract with life-threatening consequences. In some cases, the joints and muscles are affected, resulting in severe pain and limited mobility. Vascular damage due to scleroderma can result in loss of digits and entire limbs.
The symptoms and severity of scleroderma vary from one person to another and the course of the disease is often unpredictable. Women are disproportionately affected by scleroderma (representing four out of five patients), and it usually strikes in the prime of their lives, between the ages of 20 and 50; however, children and men of all ages and across all ethnic boundaries can also be affected.
Today, there is no way to prevent scleroderma and there is no cure. Treatments are available for some, but not all of the most serious complications. The continued success of the Scleroderma Research Foundation is entirely dependent upon charitable gifts from individuals and corporations.
The Scleroderma Research Foundation was founded in San Francisco in 1987 by scleroderma patient Sharon Monsky who lost her battle to the disease in May of 2002. Monsky's legacy lives on through the organization she founded which is currently chaired by Luke Evnin, Ph.D., managing partner of MPM Capital, a dedicated investor in life sciences. "We continue to pursue Sharon's vision," says Evnin. "We are in business to go out of business and, thanks entirely to a growing network of thousands of supporters and generous donors, we will press forward until a cure is found."
Led by a Scientific Advisory Board of world-renowned scientists, the Foundation's collaborative research program enables scientists from leading institutions across the nation and around the world to work together and develop an understanding of how the disease begins, how it progresses and what can be done to slow, halt or reverse the disease process.
For more information, call (800) 441-CURE or visit www.sclerodermaRESEARCH.org.
SOURCE Scleroderma Research Foundation