Mayo Clinic researchers have discovered a new and deadly player in the most common form of kidney cancer. They've shown that the molecule B7-H4 helps renal cell carcinoma (RCC) grow and spread by blocking the immune system. The Mayo researchers found that when B7-H4 is active, RCC patients are three times as likely to die from their cancer as RCC patients whose tumors don't express B7-H4.
The findings may one day help physicians predict patient outcome and direct treatment, as well as serve as a target at which to aim new and better therapies for this most lethal urologic malignancy. The findings appear in the current early online edition of Proceedings of the National Academy of Science (http://www.pnas.org/papbyrecent.shtml).
Renal cell carcinoma accounts for 85 percent of all kidney cancers. In the United States, an estimated 35,000 patients are diagnosed with kidney cancer and about 12,000 die from this disease every year. It most commonly occurs in people who are between 50 and 70 years old, and is the eighth most common cancer in men and the 10th most common cancer in women.
Significance of the Mayo Clinic Research
The Mayo researchers uncovered three potentially useful roles for B7-H4:
* As a biomarker for RCC -- A biomarker is an indicator that communicates a consistent message to scientists that they can use to plot a course of action. In this case, the message is that cells with active B7-H4 are the most aggressive cancers and need immediate and powerful treatment. Cancer specialists can use this information to quickly match patients with the best form of therapy. Many different biomarkers have been explored; however, few show this type of diagnostic power.
* As a target for future therapies -- Mayo Clinic discovered that nearly 82 percent of RCC tumors have active B7-H4 on the blood vessels that nourish tumors, compared to only 6.5 percent of nearby normal renal tissues showing B7-H4. If researchers can design cancer-killing drugs that can target B7-H4 on the tumor vessel, they could cut off the tumor's lifeline.
* As a deadly collaborator -- With other members of the B7 family, notably B7-H1, B7-H4 combines forces to block the immune system. The Mayo Clinic team showed that RCC tumors expressing both B7-H4 and B7-H1 pose an even greater threat of death than tumors that express one or the other alone.
"Based on these findings, we conclude that B7-H4 has the potential to be a useful prognostic biomarker for patients with RCC," says investigator Amy Krambeck, M.D. "In addition, B7-H4 represents a new target to attack tumor cells as well as tumor vessels, thus improving treatment options for patients with RCC."
"For years, researchers have wondered how kidney cancer can disable an attack by the body's immune system," adds co-investigator R. Houston Thompson, M.D. "Our data help explain how kidney tumors shut down the immune system, which may lead to enhanced targeted therapies for this refractory tumor."
About the Study
The Mayo Clinic team examined 250 fresh-frozen tumor specimens removed from renal cell carcinoma patients. They sorted the tumors into two groups: those that showed active B7-H4 and those that did not. They then matched this data with information about the clinical outcomes of all the patients. From this comparison of laboratory and clinical data, the pattern emerged associating active B7-H4 with fatal, spreading cancers, compared to tumors lacking B7-H4. The current investigation builds on the Mayo Clinic team's 2004 and 2005 discoveries concerning B7-H1, another immune system blocker, which also may be a useful target at which to aim new therapies.
About the Immune System
The immune system has "stop and go" molecules to regulate it. When it is in "go" mode, it generates an immune attack. Both B7-H1 and B7-H4 stop the attack -- and when regulated properly, are necessary to maintaining good health because they keep the immune system from attacking the healthy body. But the Mayo Clinic research shows that in kidney cancer, B7-H1 and B7-H4 are present in high amounts in the most aggressive tumors and the vessels that feed these tumors. This abnormality suggests that these concentrations may actually keep the immune system from doing its normal job, thus allowing the cancer to grow and spread.
Collaborators and Support
Other members of the Mayo Clinic research team included: Haidong Dong, M.D., Ph.D.; Christine Lohse; Eugene Park; Susan Kuntz; Bradley Leibovich, M.D.; Michael Blute, M.D.; John Cheville, M.D.; and Eugene Kwon, M.D. Their work was supported by The Richard M. Schulze Family Foundation, The Commonwealth Foundation for Cancer Research, the Helen and Martin Kimmel Foundation, and Mayo Clinic.
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