Scleroderma May Be Initated By Cancer PDF Print E-mail
Friday, 06 December 2013 13:45
The Scleroderma Research Foundation has 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 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.

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. 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 RNA polymerase III large subunit or 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."

Source: Digital Journal
 
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