Scientists have found evidence that cancer triggers the autoimmune disease scleroderma, a finding that could reshape the treatment of other autoimmune diseases.
A report on the discovery, published in the journal Science, also suggests that a normal immune system is critical for preventing the development of cancer.
“Our study results could change the way many physicians evaluate and eventually treat autoimmune diseases like scleroderma,” says study investigator Antony Rosen, MD, vice dean for research, director of rheumatology and a professor at the Johns Hopkins University School of Medicine.
“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.”
Scleroderma is a connective tissue disease characterized by the hardening of skin tissue in the hands, arms, or face due to increased collagen deposits. It can also take a more aggressive form and attack internal organs.
According to Johns Hopkins researchers, patients with scleroderma often make immune proteins or antibodies to another protein, called RPC1. These antibodies are believed to cause the organ damage, but the reason behind this antibody production was unknown until now.
In the study, researchers found that half of the patients with severe scleroderma had a mutation in a gene that codes for RPC1. These alterations created a “foreign” form of the RPC1 protein, which appeared to trigger the immune response. The study used blood and tumor samples from 16 patients with scleroderma and different kinds of cancer.
Eight of those patients had antibodies to RPC1. All eight were diagnosed with cancer between five months prior to their scleroderma diagnosis and two and a half years after it. The close timing of the patients’ cancer and scleroderma diagnoses suggests that the two are linked, according to scientists.
Rosen says the team’s findings should spur research into the possible cancerous origins of other autoimmune diseases, including lupus and myositis, and whether immune responses to antigens other than RPC1 are involved.
Autoimmune diseases are difficult to diagnose and their cause is largely unproven. Scientists have speculated that infections, chemical exposures and inherited genes could be triggers, although hard evidence is lacking.
Previous research has found that some patients with scleroderma have a higher incidence of cancer. In the most severe cases, patients with antibodies against RPC1 develop cancers around the time of their diagnosis more frequently than patients who have other antibodies.
“As early cancers grow, the body is exposed to novel proteins caused by the mutations in the cancer and potentially opens a window to development of autoimmune disease,” says Bert Vogelstein, MD, a professor of Oncology at the Johns Hopkins Kimmel Cancer Center and a Howard Hughes Medical Institute investigator.
Scientists found no gene mutations in tumor samples from the eight scleroderma patients lacking antibodies against RPC1. These patients also developed cancers, but most long after their diagnosis with scleroderma, with half getting cancer more than 14 years after their scleroderma diagnosis.
The findings revive a decades-old theory that everyone develops mutation-laden cells with the potential to morph into cancer. Through a process called immunosurveillance, the immune system detects and kills these cancer-prone cells. Full-blown cancers arise when immunosurveillance fails.
Evidence supporting and refuting this theory has been found in mice, but the John Hopkins study provides the first evidence that immunosurveillance may be important in human tumors, such as breast, colon, ovary and lung.
The study results may also help explain why, in some cases, people cured of cancer have also seen their scleroderma disappear.
“This study speaks to the power of the immune system and the emerging picture of harnessing the immune system to treat cancer, adding support to the notion that the immune system may be keeping cancers in check naturally,” says Kenneth Kinzler, PhD, a professor of oncology at the Kimmel Cancer Center.
The American College of Rheumatology estimates that about 49,000 Americans have scleroderma. African-Americans have a significantly higher risk of developing scleroderma than Americans of European descent.