New York, September 23 - Although it has been known that a mutation in both copies of the PTEN tumor suppressor gene impairs a cell's ability to program its death, researchers have found that losing function of only one of the pair is enough to disrupt this vital signaling mechanism. Their findings, published in the September 24 issue of the journal Science, show that inactivation of just one PTEN gene allows some white blood cells to accumulate unchecked and "attack" their own organs. This process, studied in mice, eventually results in the development of chronic fatal conditions that may include cancer and an autoimmune disease.
"The mutation of the PTEN gene is clearly linked with the cell's inability to die -- a process called apoptosis. As a result of our research, we have seen that it is the gene most highly implicated in malignant tumors," said Pier Paolo Pandolfi, M.D., Ph.D., senior author of the study and Head of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering. "Our study shows that the loss of just one PTEN gene is enough to interrupt cell signaling and begin the process of uncontrolled cell growth."
Mutations of the PTEN gene are found in a large number of human tumors. These include cancers of the breast, prostate, endometrium, ovary, and colon, as well as melanoma, glioblastoma. and lymphoma. The inherited inactivation of one copy of the PTEN gene also results in three syndromes associated with an increased susceptibility to develop tumors.
In mice, the complete disruption of PTEN function leads to early embryonic death. Mice with a mutation in one PTEN copy (PTEN+/-) were found to have a high incidence of tumors. The most commonly occurring tumors were cancers of the colon, prostate, and thyroid. The scientists also found that the mouse immune system was unable to signal the white blood cells called lymphocytes to arrest their growth and die. Instead, the cells proliferated until they were fatal to the entire organism. In addition, most of the PTEN +/- mice developed a lupus-like autoimmune disease in which lymphocytes attack their own organs.
"Despite the commonly held belief that both pairs of the PTEN tumor suppressor gene must be mutated to inhibit apoptosis, our laboratory studies showed something different," explains Antonio Di Cristofano, Ph.D., of the Molecular and Developmental Biology Laboratory and first author of the study. "Loss of just one copy of PTEN is enough to initiate a progressive accumulation of lymphocytes which are unable to commit suicide after their job is done, and are thus prone to start attacking the organism itself. These cells can accumulate further damage in their genes, which then results in the development of malignant tumors. For all these reasons, the life expectancy of the PTEN+/- mice is cut in half," said Dr. Di Cristofano.
Dr. Pandolfi said the findings are likely to have clinical implications for persons with cancer and certain autoimmune disorders because tests for PTEN mutations already exist. It may be possible, he noted, to make specific recommendations for screening, early detection and treatment for these individuals based on whether mutations are detected in one copy of the PTEN gene. Further research is required in this area, however, before definitive clinical recommendations can be made. Dr. Pandolfi and his colleagues plan additional research to explore the relationship between autoimmune disorders and PTEN mutations in humans.
The study published in Science is the work of Drs. Pier Paolo Pandolfi, Antonio Di Cristofano, Parasevki Kotsi, and Carlos Cordon-Cardo, of Memorial Sloan-Kettering, and Drs. Keith B. Elkon and Yu Feng Peng, of the Hospital for Special Surgery, Weill Medical College of Cornell University.
Memorial Sloan-Kettering Cancer Center is the world's oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Throughout its long distinguished history, the Center has played a leadership role in defining the standard of care for patients with cancer. In 1999, Memorial Sloan-Kettering was named the nation's best cancer care center for the seventh consecutive year by U.S. News & World Report.
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