Researchers at Jefferson Medical College have found an unusual relationship between HIV and a rare head and neck cancer found primarily in Africa. Scientists, led by Antonio Giordano, M.D., Ph.D., associate professor of pathology, anatomy and cell biology, at Thomas Jefferson University in Philadelphia, discovered that HIV appears to inactivate a normally protective anti-cancer gene, contributing to the development of Burkitt's lymphoma. The work may enable scientists to better understand and devise improved treatments for the disease.
The researchers found that the retinoblastoma-related gene Rb2/p130, normally a "tumor suppressor," can become deactivated by two different mechanisms. "In two different Burkitt's lymphoma tumors, the same Rb2 gene is inactive, but it can have two different backgrounds," Dr. Giordano explains. "One may be linked with HIV, and the other one may be linked to genetic damage in Burkitt's lymphoma. There appears to be a causal relationship with HIV and there seems to be a causal relationship with an environmental factor responsible for the genetic damage."
The report appears in the March issue of the American Journal of Pathology. "This suggests a new, unknown mechanism that needs careful consideration," Dr. Giordano says. "It can help clinicians in every stage of the disease of Burkitt's lymphoma. Medical oncologists can tailor the proper therapy according to the gene. By knowing the different origins of the disease, we'll know better how to treat it."
Most cases of Burkitt's lymphoma, which is endemic in central Africa, are believed to be caused by environmental factors, and have been associated with exposure to the Epstein-Barr virus. Burkitt's lymphoma often is caused by a genetic alteration -- an exchange of genes in chromosomes. It predominantly affects young children.
Dr. Giordano and his colleagues at Jefferson and at the University of Siena, Italy, Nairobi Hospital, and at the Institute of Normal and Pathologic Cytomorphology, CNR, in Bologna, Italy, examined the expression of Rb2 in 29 Burkitt's lymphoma patients. Some of the patients had been exposed to HIV, while others had not.
The scientists found the Rb2-made protein is misplaced within the cell. It is usually found in the cell nucleus but was instead sitting outside in the cell cytoplasm. In Burkitt's, the "nuclear localization signals sequence (NLS)" has gone awry, Dr. Giordano explains. As a result, the protein was inactive and unable to help prevent tumor growth. However, "In Burkitt's lymphoma related to AIDS," he says, "the protein is in the nucleus where it should be and is not mutated. HIV somehow inhibits the protein.
"There are two different mechanisms in the same tumor," he says. "In one, the virus blocks the protein, making it inactive. In the other situation, it is the NLS. The normal sequence is usually all over the cell. In cancer, this sequence is mutated. The Rb2-encoded protein isn't working.
"We know there is a small region of Rb2 that is damaged in Burkitt's lymphoma," Dr. Giordano says. "The idea is try to see how the exposure to HIV affects Rb2. If we can understand this, others may be able to devise more specific therapy."
The National Cancer Institute and the Sbarro Institute for Cancer Research and Molecular Medicine funded the research.
Journal
American Journal Of Pathology