Benjamin K. Tsang, PhD
Telephone: 613-798-5555, Ext. 16040 (Office)
Telephone: 613-798-5555, Ext. 13713 (Laboratory)
Telephone: 613-798-5555, Ext. 14081/13906 (Res. Admin. Assistant)
Fax: 613-761-4403
btsang@ohri.ca
Cellular Life and Death in Infertility and Ovarian Cancer
When something as important as reproduction is at stake, Nature takes no chances. Only one sperm can fertilize an egg, yet millions make the attempt. Likewise, although many follicles begin the process of maturation at the start of the menstrual cycle, only one follows that path to completion and produces an egg (except in the case of fraternal twins), while the rest of the follicles degenerate. Dr. Benjamin Tsang is investigating the cellular and molecular mechanisms that underpin the regulation of these events, which determine which follicles will ovulate and which will degenerate.
The cellular process through which follicles not selected for ovulation degenerate is called "apoptosis," which Dr. Tsang sometimes calls "the A-word." The terms "active death" and "programmed cell death" are also used. A healthy balance between cell proliferation and cell death helps to maintain homeostasis, ensuring because, in this case, the rejected follicles degenerate that there is no accumulation of tissue, which could lead to a cancerous condition.
One of Dr. Tsang's projects is to determine what directs the cell to proliferate or to commit suicide. Both options are programmed by certain genes, either "cell death genes" or "cell survival genes." Cells proliferate when the cell survival genes are turned on and the cell death genes are turned off. Conversely, cells commit suicide when a cell death gene is turned on or overexpressed. One of the cell death genes that particularly interests Dr. Tsang involves a protein receptor called Fas that is found on the cell's surface. When another cell-surface protein called Fas ligand binds to this receptor, a signal is sent that says "die." Other factors are also at work here, some secreted by the brain (e.g., gonadotropins), while other factors are produced within the ovary to cause its cells to proliferate or die. These cell survival and cell death factors are cytokines and growth factors.
Dr. Tsang and his team suggest that infertility in some patients might result from the overexpression of cell death genes, and the suppression of cell survival genes (e.g., Inhibitor of Apoptosis Proteins). Dr. Tsang is working on the sets of survival genes involved in promoting follicle development, which act by suppressing cell death. As Dr. Tsang and his team investigate the range of expression of these genes, they may learn how new drugs might be targeted to treat infertility in these patients by causing the expression of cell survival genes and the suppression of cell death genes.
Another project engaging Dr. Tsang's attention involves human ovarian cancer. At one time, cancer was thought to result from the uncontrolled proliferation of cells. A new school of thought suggests that the suppression of cell death may be a cause, because when cells that would normally die don't, there is an abnormal accumulation of cells. A combination of both mechanisms is also a possibility. However, if the suppression of cell death plays a role, then during tumor formation a signal must be sent out that prevents cells from dying when they should. Dr. Tsang and his team are suggesting that certain cell survival genes (Inhibitor of Apoptosis Proteins) are being expressed at high levels. They also theorize that in cases where ovarian cancer patients don't respond to chemotherapy, or develop resistance to it, the chemotherapeutic agent has lost its ability to induce cell death gene expression or to inhibit the expression of cell survival genes. Therefore, Dr. Tsang is studying how to develop drugs or techniques that would work at the genetic level to suppress cell survival genes and turn on cell death genes. Dr. Tsang and his team compare the responses of ovarian cancer cells, chemo-sensitive cells, and chemo-resistant cells, while they turn specific genes on and off, and explore treatment with various chemotherapeutic agents. Dr. Tsang has established close collaboration on this project with gynecological pathologist Dr. Mary Senterman and gynecological oncologists Drs. Michael Fung Kee Fung and Wylam Faught at The Ottawa Hospital, and Dr. Barbara Vanderhyden, OHRI Cancer Therapeutics Program, who coordinates the operation of the Ottawa Ovarian Tumour Bank.
It is often hard for us to grasp that death is a necessary and even a healthy part of life. But on a cellular level, apoptosis is commonplace. Thus what Dr. Tsang and his team learn about it in the specific area of reproduction will have broad applications, helping us to understand the important function of the "A-word" in many different physiological processes.
