Progress in prostate cancer through research

Donald S. Coffey, Ph.D.
The Catherine Iola & J. Smith Michael
Distinguished Professor of Urology

The Brady Research Laboratories have focused the major part of their research on understanding the cause of abnormal growth of the prostate and developing improved methods for growth control. Any abnormal growth that forms a tumor is the result of an abnormal accumulation of cells. This increase in total cell number is similar to the increase in a poulation--it results from an imbalance between the birth rate minus the death rate. As cells turn over in normal organs of our body, the processes of cell replication and cell death are held in strict balance so that the organ does not increase in size. However, in prostate tumors there is an imbalance caused by both an increase in cell replication and a decrease in the rate of cell death so that the net effect is an abnormal accumulation of cells. Natural substances in the prostate that cause cells to replicate are called growth factors and there are a variety of these factors that appear to work in tandem and in sequence that signal the cells to replicate and divide. In addition to changes in replication, it is now apparent that a decrease in the rate of cell death is also of importance and this is also driven by natural factors that cause the cells to self-destrcut. These two opposing pathways of cell growth and cell death are under intensive study in the laboratory, and new pathways of cell growth and self-destruction are being delineated. Work in the laboratory by Dr. John Isaacs shows that prostate cell death involves a programmed series of timed events including the controlled influx of calcium ions into the cell which activates a calcium-dependent enzyme that destroys the DNA genetic tape of the cell. One of the natural factors invovled in cell death is tumor necrosis factor (TNF), a protein which can now be produced synthetically for drug use by applying recombitant DNA techniques. We have shown that TNF used alone is not very effective, but when combined with certain cancer chemotherapeutic agents, can greatly enhance therapeutic potential. At present, this approach is in its very early phases of study but appears to hold great potential promise for our future understanding of how cell death may be regulated.

In addition to knowing the rate of growth of the tumor, it is also important to determine the metastatic potential of the cells. As the cells spread through the tissue, they can dislodge and travel through the blood stream or the lymph fluid to distant organs and start growing in inappropriate sites, which are called metastatic lesions. Our laboratory has observed tumor cells with different malignant and metastatic potential by making time-lapse movies of their movements when grown in culture dishes. It appears that cells with increased cell motility have the ability to migrate and therefore invade adjacent tissues. In animal models, we have shown that we can quantitiate this cell motility with a new mathematical analysis of cell shape that measures the malignant potential of the cells in a quantitative manner.

We are now busy trying to determine molecular mechanisms that cause cancer cells to move. It appears that these cancer cells have a protein system containing acting and myosin molecules which are very similar to the types of proteins that are involved in our muscles that enable us to walk. We are now studying several drugs that are capable of blocking this type of cell motility and we are determining how they may be used in preventing metastatic spread of cancer cells.

Many patients, who have had localized prostate cancer and have been surgically treated by Dr. Walsh, have cooperated in a large study to determine if there is a genetic basis that might dispose on to prostate cancer. It appears that there are some families that have a higher probability of developing prostate cancer than would be expected on a random basis. Meanwhile in the laboratory, Dr. William Isaacs has been studying the DNA of prostate cancer to determine how this genetic tape has been altered. He has shown that certain chromosomes have a higher probability of being altered in specific locations in prostate cancer. He is now busy identifying the genetic information that has been altered in these areas. This is a large, long-term study requiring the most tedious and modern molecular biological techniques. His work has been recognized as being in the forefront of these types of studies. We are all enthusiastic about the information that is becoming available through these powerful new molecular tehcniques.

These and other studies contiue to provide exciting information on prostate cancer. The four basic scientists working full time in the laboratory in close collaboration with our clinical investigators are producing important new insights and inroads into the understanding and control of prostate cancer. Their continued efforts will require constant dedication and cooperation. There is much to be done and the search continues as new young investigators are being trained to join this important mission.