Cold Spring Harbor, NY -- The tumor suppressor protein p53 rids the body of abnormal, pre-cancerous cells by triggering a genetically programmed "self destruct" mechanism called apoptosis. A hallmark of many types of cancer is a defect in the function of p53 that allows pre-cancerous cells to survive and proliferate, and eventually form a tumor. Now, scientists at Cold Spring Harbor Laboratory have discovered that defects in another kind of tumor suppressor protein, p19ARF, lead to the formation of aggressive, chemotherapy-resistant lymphomas that are strikingly similar to those caused by mutations in the p53 gene. The study, carried out by Scott Lowe and his colleagues at Cold Spring Harbor Laboratory, is significant in part because it helps to explain why many human tumors are defective in p53 function despite the presence of normal p53 genes.
"Our results demonstrate the importance of understanding complete signaling pathways, rather than simply determining whether individual genes are or are not mutated in particular cancers," says Lowe. The study was published in the October 15, 1999, issue of Genes & Development along with two related studies by groups working at the University of Tennessee, St. Jude Children's Research Hospital, and the Netherlands Cancer Institute. These investigations of the role of p19ARF in safeguarding cells from the effects of uncontrolled oncogene expression have important consequences for the development of improved methods for diagnosing and treating cancer.
To create a mouse strain that is predisposed to lymphoma and in which cells lacking p19ARF arise frequently, Lowe and his colleagues first crossed a strain that expresses the myc-oncogene in B cells to a different strain that lacked one of its two chromosomal copies of the p19ARF locus. Then they determined which offspring received both genetic traits, i.e., the expression of myc in B cells and only one copy of the p19ARF locus. The presence of only one copy of the p19ARF locus in all cells of the offspring greatly increases the chance that a spontaneous mutation of the single remaining copy will give rise to cells that completely lack functional p19ARF.
"A lot of time and effort has been expended on developing therapies that are effective against cancer cells in a laboratory dish but turn out to be useless against tumors in humans," says Lowe. "We're banking on the idea that studying a genetically well-defined mouse model of tumor development will be much more relevant to cancer in humans than many of these in vitro studies."
Lowe and his colleagues-including postdoctoral fellow and lead author of the study Clemens A. Schmitt-monitored the p19ARF+/- offspring for one year to observe the development of B cell lymphoma. They also monitored control mice expressing the myc oncogene in B cells but containing the usual two chromosomal copies of the p19ARF locus. The scientists expected these control animals to develop B cell lymphoma, but at a slower rate.
They observed that the onset of lymphoma in p19ARF+/- mice was greatly accelerated compared to that in the control animals. In addition, tumors that arose in p19ARF+/- mice were remarkably similar to those that formed in p53+/- animals with respect to their time of onset, degree of invasiveness, and resistance to chemotherapy. Significantly, the scientists observed that p19ARF-/- lymphomas displayed reduced p53-mediated apoptosis despite the presence of wild-type p53 genes.
Mutations of the p19ARF locus are frequently associated with cancer in humans and in experimental mouse systems. In addition, previous studies of mouse cells cultured in vitro described the ability of p19ARF to mitigate the effect of myc oncogene expression by stimulating p53-mediated apoptosis. However, the new study provides the first evidence that mutations in the p19ARF locus reduce the effectiveness of cancer therapies that rely on p53-mediated apoptosis.
The mouse model system developed by Lowe and his colleagues should prove useful for testing new therapies directed against cancers caused by defects in p19ARF or p53 function. "One puzzling phenomenon, which unfortunately is known to many cancer patients and their families, is 'de novo' drug resistance. How can tumor cells have developed resistance to drugs they've never been exposed to?" asks Lowe. He and other scientists now believe that traditional targets of anticancer drugs (such as the p19ARF/p53-mediated apoptosis pathway) are disabled during tumor formation, allowing cells to become simultaneously drug-resistant and cancerous. "The model system we have developed allows us to begin to find ways to treat these drug-resistant tumors that lack p19ARF or p53. It gives us a powerful tool for testing new types of anticancer therapy designed to work via p53-independent pathways," says Lowe.
The central role of the p19ARF /p53 pathway in suppressing tumor formation is underscored by the fact defects in p19ARF or p53 function are associated with more than half of all human cancers.
Scott W. Lowe is an Associate Investigator at Cold Spring Harbor Laboratory. He was joined by postdoctoral fellow and lead author of the study Clemens A. Schmitt and colleagues Mila E. McCurrach (research technician), Elisa de Stanchina (graduate student), and Rachel R. Wallace-Brodeur (graduate student).
Cold Spring Harbor Laboratory is a private, non-profit basic research and educational institution with programs focusing on cancer, neurobiology, and plant biology. Its other areas of research expertise include molecular and cellular biology, genetics, structural biology, and bioinformatics. The Laboratory's new Watson School of Biological Sciences offers an innovative Ph.D. program for a small group of exceptional students. Located on the north shore of Long Island, 35 miles from Manhattan, the Laboratory was founded in 1890 as a field station for the study of evolution. Today, the Laboratory is headed by Director Bruce Stillman and President James D. Watson.
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