Apoptosis Cancer

Harnessing Apoptosis to Destroy Cancer Cells

In 1972, John Kerr, Andrew Wyllie, and Alistair Currie published a foresighted paper describing a little known and curious form of cell death that today is one of the most intensively studied topics in modern biology. The researchers reported on a type of cell death - a programmed cell suicide - that was distinctly different from the long-recognized process of cell death known as necrosis. Necrosis occurs when a cell becomes acutely injured and ruptures, causing inflammatory cells to rush in to clear away the debris. Programmed cell suicide, in contrast, is clean and quick and involves a predictable sequence of structural changes that cause a cell to shrink and be rapidly digested by neighboring cells.

Although biologists have long known that cell suicide plays an important role in sculpting tissue within developing embryos, Kerr, Wyllie, and Currie were the first to observe that programmed suicide - which they labeled apoptosis - also occurs in mature cells. They also were the first to hypothesize that apoptosis plays a broad role in normal life processes, and its failure contributes to a variety of diseases, including cancer.

Several years later, Nobel Prize winners John Sulston, H. Robert Horvitz, and colleagues used the microscopic roundworm C. elegans to explore how a single fertilized egg develops into an adult organism with multiple cell types. As they painstakingly followed each of the developing worm's 1,090 cells to their ultimate fate, they were surprised to see that 131 cells died via apoptosis as the worm matured into adulthood. With this observation, they substantiated the prediction made by Kerr and his colleagues that apoptosis occurred beyond embryogenesis. By 1986 Horvitz and colleagues determined that two genes - ced-3 and ced-4 - produce proteins that are required for apoptosis to proceed in C. elegans. Horvitz's work demonstrated conclusively that programmed cell suicide is genetically controlled. Horvitz's team later identified a third apoptosis gene, ced-9, which produces a protein to inhibit apoptosis. Subsequent analysis demonstrated that these genes have been broadly conserved throughout evolution, indicating the ubiquitous importance of apoptosis among animals. These findings served to heighten researcher interest in this process.

Over the last 15 years, using emerging technologies, scientists have confirmed that apoptosis plays a central role within developing organisms by shaping the neural and immune systems and molding tissue specificity. They also demonstrated that apoptosis helps to establish a natural balance between cell death and cell renewal in mature animals by destroying excess, damaged, or abnormal cells.

Additional studies have revealed that apoptosis occurs through two distinct cellular pathways. The "extrinsic" pathway is activated by the binding of death activator proteins to the cell surface. The "intrinsic" pathway is launched by signals inside the cell, such as damage caused by radiation or toxins, the withdrawal of critical survival factors (growth factors, hormones), or disturbances in the cell cycle. Both pathways converge inside the cell, turning on a central executioner family of proteins resembling ced-3 that are now known as caspases. Caspases act as knives, cutting up proteins inside the cell and digesting the cell from within. Because caspases become activated early in apoptosis and irreversibly launch a cell's death machinery, scientists realized that finding their trigger would offer the unprecedented opportunity to control cell death and survival.

More recently, scientists have been exploring the role of mitochondria (the energy-producing structures of cells) in apoptosis. In 1996, Xiaodong Wang and colleagues discovered that cytochrome c, a critical protein component of the mitochondria, is a caspase activator. With this finding, scientists began to study the mitochondria to determine how apoptosis functions in the cell, and malfunctions in disease.

National Cancer Institure