Prostate Cancer Switch may Yield Map of Cancer Machinery, Targets for Drugs
DURHAM, N.C. -- A team of molecular biologists has pinpointed a genetic switch in prostate cancer cells that may play a role in triggering a quiescent tumor to erupt into an invasive, deadly cancer that spreads throughout the body.
The scientists said discovery of this single genetic switch could open a research pathway that might well lead to a road map of the complex changes prostate cancer cells undergo in their progression to a deadly form. Such a road map would yield not only molecular markers that would allow physicians to better pinpoint the stage of a prostate cancer, but also new drugs to kill cancer cells at earlier stages, the researchers said.
Prostate cancers are distinguished by their tendency to linger at a relatively benign stage for many years, but to suddenly transform into a deadly form that spreads, or metastasises, throughout the body.
The scientists are Russ Carstens and Mariano Garcia-Blanco of the Duke University Medical Center department of pharmacology and cancer biology, and Wallace McKeehan of Texas A&M University. They published their findings in the April issue of Molecular and Cellular Biology. Their work is supported by the National Institutes of Health, the Duke Comprehensive Cancer Center, the American Heart Association and the Keck Foundation, which supports the Levine Science Research Center, where the work was performed.
Working with rat prostate cancer cells, the scientists discovered the molecular basis for a genetic switch that governs whether a cancer cell generates one or another form of a protein receptor molecule called FGF-R2 (Fibroblast Growth Factor Receptor 2) that festoons the surface of the cell. These receptors are molecular locks, into which fits a protein called a growth factor, secreted by another cell in the prostate. As long as the FGF-R2 receptor is of one type -- called IIIb -- the cancer cell is relatively well-behaved, like other cells growing only when stimulated by a growth factor from other prostate cells, called stroma cells. Those stroma cells, in turn, are stimulated by the male hormone androgen.
But when the cancer cell abruptly switches over to making another receptor type, called IIIc, it needs no outside stimulation to grow, and escapes all controls - becoming "androgen-independent" - to spread throughout the body. This phenomenon was originally observed by McKeehan, and the Duke medical center researchers began exploring its molecular mechanism.
The three scientists discovered the switch as a short stretch of RNA nestled in the string of "messenger RNA," a molecule which constitutes the blueprint for the receptor and which moves out of the cell's nucleus to the protein-making machinery, where it governs production of FGF-R2.
The scientists found that this string of messenger RNA actually includes the code for producing both IIIb and IIIc, with the genetic switch sitting between the two lengths of RNA code. That switch acts as a molecular "scissors" to activate one form of FGF-R2, while suppressing another. The phenomenon is called "alternative splicing," said Garcia-Blanco, an associate professor of pharmacology and cancer biology. Carstens, who initiated experiments on the alternative splicing switch, is a fellow in the Garcia-Blanco laboratory and in the division of nephrology of the department of medicine.
"Alternative splicing is quite similar to the process of editing film." Garcia-Blanco said. "An editor starting from the raw footage can decide to cut one scene and not another, possibly producing two very different films."
He emphasized that "we don't know yet for a fact whether this switch in the receptor is critical for either androgen independence or metastasis, or whether it's just a marker. But even if it is a marker, it could still be useful as a very early signal of tumor progression."
However, he said, "I would bet that this mechanism has a very good chance of being an important enabling component in the progression to metastasis and/or androgen independence."
The finding is also important, Garcia-Blanco said, because of the scant knowledge about the machinery of prostate cancer.
"The stages in prostate cancer that lead to the development of very highly metastatic and androgen-independent tumors are not well characterized," he said. "So, this finding can lead us to a better understanding of what other genetic lesions are necessary for the cancer to progress."
The finding is unique, Garcia-Blanco said, because aberrant gene expression in cancer usually arises from genetic mistakes in producing messenger RNA in the nucleus and not in alternative splicing of the RNA into one form or another.
The researchers' next aim will be to follow this initial clue to understand how the RNA switch itself is controlled, and ultimately to use this information to broadly map the deadly machinery of prostate cancer.
"While we think this switch has tremendous physiological consequences, because it affects this fundamental receptor, we now want to know why the switch is being tripped," Garcia-Blanco said. "And whatever protein is triggering this switch, we believe, could affect many other parts of the cell machinery that go awry as the tumor progresses.