University of Pittsburgh findings published in Science illustrate how KSHV causes cancer
PITTSBURGH, Nov. 14 -- Findings published in this week's issue of the journal Science by researchers at the University of Pittsburgh Cancer Institute (UPCI) illustrate how the virus that causes Kaposi's sarcoma -- Kaposi's sarcoma-associated herpesvirus, or KSHV -- inhibits the body's immune response and causes cancer cells to grow through a technique called immune evasion. KSHV causes Kaposi's sarcoma, a cancer of the blood vessel cells that often occurs in tissues under the skin or mucous membranes, and is the most common malignancy occurring among AIDS patients. KSHV belongs to the family of herpesviruses that includes the causes of genital herpes, cold sores and chickenpox.
Patrick S. Moore, M.D., M.P.H., professor, department of molecular genetics and biochemistry, and Yuan Chang, M.D., professor, department of pathology -- the team who previously discovered KSHV -- examined the expression of a virus-derived cytokine (a hormone-like substance that regulates cells during an immune response) in KSHV. Dr. Moore and Dr. Chang found that this cytokine, viral IL-6 (vIL-6), not only inhibits immune function, but also causes cancerous cells to grow. vIL-6 protects virus-infected cells from undergoing growth arrest and apoptosis, or cell death, which is the normal way that the immune system attempts to limit viral infections.
"The importance of this finding is that it demonstrates that there is an overlap between the immune system and tumor suppressor pathways which are targeted by KSHV," said Dr. Moore, also director of the molecular virology program at UPCI. "It further demonstrates that viruses which inhibit immune functions also can, under some circumstances, induce tumor cells to grow because these viruses are attacking pathways that are important in both immunity and suppression of tumor growth."
Through a series of assays, the investigators examined how vIL-6 inhibits the signaling of antiviral factor interferon, or IFN. The signaling of IFN is a normal immune response that blocks virus-infected cells from growing. They found that KSHV has a built-in sensor mechanism that perceives an increased signaling of IFN and responds by increasing the production of vIL-6.
In effect, inhibiting the activation of the tumor-suppressor pathway during the immune response and acting like a switch by turning off the production of IFN. In addition, in some cells, vIL-6 not only stops the suppression of tumors, but also causes normal cells that are not infected with KSHV to proliferate abnormally.
"These results illustrate that tumor viruses can cause cancers because they have evolved to subvert cell defenses and make use of the same signaling pathways that are used to suppress tumors to instead cause tumors to grow," said Dr. Chang. "In other words, the virus is able to sense its environment and modify that environment to make it more habitable for the virus. By inhibiting a normal immune mechanism to evade the immune system, the virus can accidentally trigger tumor cell growth." Dr. Moore and Dr. Chang caution that this mechanism does not entirely explain how KSHV causes cancer, but it is an important principle in understanding tumor virology.
Based on these findings, added Dr. Chang, vIL-6 may be a promising target for novel therapies directed against KSHV-associated tumors often found in lymphoma and Castleman's disease, a rare disorder characterized by non-cancerous tumors that may develop in the lymph node tissue throughout the body.
The study was funded by a grant from the National Cancer Institute. The first author of this study is Malini Chatterjee, a graduate student in the Chang-Moore laboratory.