John T. Isaacs, Ph.D., Johns Hopkins University School of Medicine, Baltimore, MD
J. Carl Barrett, Ph.D., National Institute of Environmental Health and Science, Research Triangle Pk., NC
John Cidlowski, Ph.D., National Institute of Environmental Health and Science, Research Triangle Pk., NC
Caroline Dive, Ph.D., University of Manchester, Manchester, England
Alan R. Eastman, Ph.D., Dartmouth Medical School, Dartmouth Medical School, Hanover, NH
Michael Kasten, MD, Ph.D., Johns Hopkins University School of Medicine, Baltimore, MD
Yuri Lazebnik, Ph.D., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Ruth Muschel, MD, Ph.D., University of Pennsylvania School of Medicine, Baltimore, MD
William Nelson, MD, Ph.D., Johns Hopkins University School of Medicine, Baltimore, MD
Moshe Oren, Ph.D., Weizman Institute of Science, Rehovot, Israel
Andrew H. Wyllie, Ph.D., University Medical School, Edinburgh, Scotland
Layout and Goals
- Overview, Cellular Interactions, DNA Damage
- Biochemistry of Apoptosis (Proteases, Nucleases, Immune Consequences, p53)
- Implications for the Therapeutic Activation of Apoptosis Induced by: Radiation,Alkylating Agents, Topoisomerase Inhibitors
- Cell Kinetics, Cell Senescence, Summary
The Forum focused on Apoptosis or Programmed Cell Death. Dr. Isaacs organized a group of participants from all over the USA as well as from England, Scotland and Israel. The topic was very pertinent as it was only recently realized there is more than one way for a cell to die. Programmed cell death means that when cells in your body receive a particular signal they start up machinery which leads to their death – a cell suicide brought about by a particular stress. A cancer cell is one that has gone wrong by continuing to divide within the body. Programmed cell death occurs to rid the body of cells that behaving in the “wrong way.” If the mechanism that leads to this form of cell death becomes faulty then a cancer could result. Further, we know when the majority of cancer cells are exposed to either chemotherapeutic drugs or radiation they die by programmed cell death. This was only realized a few years before this Forum took place. Once it is understood how programmed cell death occurs, we may find ways to selectively turn the mechanism back on again, causing cancer cells to die.
The subject of the eleventh annual Forbeck Forum was programmed (apoptotic) cell death in the development and treatment of cancers. The number of cell in a tissue, whether normal or cancerous, depends upon the relationship between the rate of cell proliferation (production) and cell death (cell loss). In normal tissues, these rates are balanced such that neither overgrowth of the tissue nor regression occurs with time.
A fundamental characteristic of cancer cells is that, unlike their normal counterparts, their rate of cell proliferation exceeds their rate of death, thus producing continuous net growth of the cancer. Therefore, malignant conversion results in a dysfunction in the regulation of cell proliferation and/or cell death. Remarkable progress has occurred over the last twenty years in understanding what normally regulates the rates of cell proliferation. Indeed, last year’s forum focused on cell cycle checkpoints in cancer. In the present forum, the focus was on what regulates the rates of cell death. It is becoming increasingly clear that cells possess, within their repertoire, the ability not only to proliferate and to be functionally active, but to activate and undergo a process of self-induced suicide. This process, termed ‘programmed cell death’, involves a reprogramming of the cell resulting in an energy-dependent cascade of biochemical and morphological changes within the cell which in turn result in death and elimination.
The morphological pathway for programmed cell death is rather stereotypical and has been given the name apoptosis. Activation of this programmed cell death process is controlled by a series of endogenous cell type specific signals. In addition, a variety of exogenous cell damaging treatments (i.e. radiation, chemicals or viruses) can activate this pathway if sufficient injury to the cell occurs. Because a cell must undergo a series of molecular changes to acquire the malignant phenotype to become cancer, and because these changes are often induced by agents or treatments that damage the cell over an extended period of time, anything which enhances the survival of initiated/damaged cells will promote the carcinogenic process. In addition, once the cancer has developed, therapy is focused on shifting the balance between cell proliferation and cell death such that cell death exceeds proliferation so that tumors will regress. Therefore, an understanding of the controlling pathways for programmed cell death is critical in both attempting to prevent the initial development of cancer, and in finding new approaches for more effective treatment of established cancers.
Dr. Andrew Wyllie, one of the original authors of the paper defining the term apoptosis, presented an overview of apoptosis and the genetic pathways controlling this process. Dr. Caroline Dive discussed the importance of cellular interactions between both the surrounding environment of the cancer cell, and its interaction with other cancer cells as modifiers of whether a cell does or does not undergo cell death. The ability of a cancer cell to leave the original tissue of origin and go to distinct parts of the body (metastasize) is critical for the lethality of cancer. As Dr. Dive pointed out, this ability requires the cancer cell to be able to live and survive in a foreign environment. Therefore, the importance of cellular environment for the prevention of metastases, as well as for the development of new therapies for cancer, is an exciting area of research.
Dr. Michael Kasten and Dr. Moshe Oren discussed the role of a variety of genes (p53, Rb, etc.) in regulating the sensitivity of cancer cells undergoing apoptotic cell death. This area is critical since a variety of presently utilized chemotherapeutic agents have the ability to activate programmed cell death in cancer cells. Because there is a wide disparity in the sensitivity of cancer cells to these agents, Drs. Kasten and Oren centered discussion on an explanation for some of the differences in sensitivity as this information could be extremely helpful in attempts to optimize the use of established chemotherapeutic agents.
The role of specific proteins in the programmed cell death pathway was discussed by Dr. Yuri Lazebnik and Dr. John Cidlowski. Dr. Lazebnik focused on the role of proteases in both activating and completing apoptotic cell death, and Dr. Cidlowski highlighted the role of various endonucleases involved in degrading the DNA of cancer cells. Likewise, Dr. Allen Eastman discussed the mechanics of activation of endonuclease activity involved in degrading the DNA of cancer cells (a critical step in the apoptotic process). Resolving both the pathways for initiating apoptotic cell death, as well as the enzymology of completing the process, is important since this information will identify new therapeutic approaches to enhance these activities as well as allow specific targeting of programmed cell death in cancer cells (as opposed to normal cells).
Dr. Ruth Muschel led a discussion concerning the role of radiation and how it can activate cell death in cancer cells. She pointed out several interesting differences in how cells undergo radiation-induced death (immediate vs. delayed cell death). Dr. William nelson discussed the possibility that programmed cell death occurs in such an orderly fashion that it rarely induces an inflammatory reaction. While this is useful during normal activities, therapeutically there may be some advantage in attempting to kill cells in a way other than through a programmed mechanism. Cells undergoing programmed cell death do not shed molecules recognized by the host immune system as foreign. Dr. Nelson depicted an interesting prospect: the possibility of using different forms of cell killing that would liberate proteins from the cancer cell which would now be recognized by the host immune system as foreign. In this way, it might be possible to induce an autoimmune type reaction against the cancerous tissue. For certain cancers in which the normal tissue of origin is not vital (i.e. breast, prostate), such an approach could be highly promising.
Dr. J. Carl Barrett described the various steps that a normal cell must undergo in order to become a malignant cell. A normal cell has only a limited number of times that it may divide, producing daughter cells. Since transformation of a normal cell to a malignant involves multiple genetic changes, anything that allows a normal cell to give rise to more daughter cells (more rounds of proliferation) increases the likelihood of producing genetic errors. Dr. Barrett focused on what allows cells to escape the normal limited life span, thus increasing their likelihood for malignant transformation. He pointed out the similarities and dissimilarities between this acquisition of an extended proliferation, and escape of the cells from undergoing normal programmed cell death.
Dr. John Isaacs led a discussion concerning the fact that many presently utilized chemotherapeutic agents disrupt cells during their cell proliferation; and that such disruption activates the programmed cell death pathway explaining why these agents are highly effective against rapidly proliferating cells. However, many cancers of solid tissue (breast, colon, prostate) do not have high rates of cell proliferation or sensitivity to such chemotherapeutic activation of cell death. He focused on the possibility of identifying pathways and agents which can lead to programmed death of cells not proliferating, but in a metabolically active proliferative quiescent state. Ample opportunity was provided for general discussion to define both what information is presently known concerning the control of pathways of apoptotic cell death, and more importantly, which areas need to be resolved.
The camaraderie and frank discussion at this unique meeting allowed substantial progress to be made in the identification of key areas for future studies. The Forbeck Forum provided a catalyst to accelerate progress in the critical area of understanding the control, activation, and targeting of programmed cell death. This information is critical in helping to design new strategies for both the prevention of cancer development, as well as the treatment of established disease.