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Modern Genetic Analysis Chapter 15. Regulation of Cell Number: Normal and Cancer Cells
Cancer and the Control of Cell Number: an Overview

Cancer is now clearly understood as a genetic disease of somatic cells. In cancer, the fail-safe mechanisms that are in place to ensure that cell number remains balanced to the needs of the whole organism are subverted, and cancerous cells proliferate out of control. To understand how cells can mutate to a cancerous state, we must first understand the basic mechanisms governing the control of normal cell numbers.

The machinery of cell proliferation.

Certain aspects of proliferation control are general to all organisms. Universally, the cell division process has numerous events that must take place sequentially to produce viable progeny cells. Moreover, the cell division cycle has evolved so that there are checks and balances to prevent a subsequent event from taking place before the prerequisite events have been achieved. For example, it would be a lethal event if mitosis occurred before DNA replication was completed. Mechanisms have evolved that prevent such cellular disasters. We shall explore the regulation of the eukaryotic cell cycle. Protein kinases, enzymes that specifically phosphorylate certain amino acid residues on target proteins, and protein phosphatases, enzymes that specifically remove phosphate groups from such amino acid residues, modulate the activities of key proteins in the cell division cycle. These phosphorylationdephosphorylation pathways ultimately converge to determine which key proteins are active for a fraction of the entire cell division cycle. Put another way, it is the cyclical variations in these key proteins that determine which parts of the cell cycle are currently being executed.

The machinery of cell death.

Some aspects of cell control appear to have evolved only in multicellular organisms. To develop and maintain themselves normally, multicellular organisms must properly balance the numbers of the cell types in their various tissues. Almost all of these cell types are somaticthat is, they do not contribute to the germ line. Loss of such somatic cells is not a problem for the organism from the point of view of propagation of the species, as long as proliferation of the remaining cells of that type in a particular tissue compensates for the cells that are eliminated. Furthermore, abnormal cells have the potential to do considerable harm. Thus, mechanisms have evolved to eliminate certain cellsthrough a process called programmed cell death or apoptosis. A cascade of enzymes called caspases kill by disrupting numerous structural and functional systems within the cell. Once the cells are dead, their carcasses are removed by scavenger cells.

Linking cell proliferation and death to the environment.

The cell proliferation and cell death machinery must be interconnected so that each is activated only under the appropriate environmental circumstances. For example, in adult organs, maintenance of proper cell number requires proper balance between the birth of new cells and the loss of existing ones. Eukaryotic cells have evolved elaborate intercellular signaling pathways to serve as status indicators of the environment. Some signals stimulate proliferation, whereas others inhibit it. Furthermore, other signals can activate apoptosis, whereas still others block activation. Intercellular signaling pathways typically consist of several components: the signals themselves, the receptors that receive the signals, and the signal transduction systems responsible for relaying the signal to various regions of the cell. Just as allosteric effectors regulate the activity of many DNA-binding proteins in bacteria, modifications to the various components of the intercellular signaling systemsprotein phosphorylation, allosteric interactions between proteins and small molecules, or interaction between protein subunitscontrol the activity of these pathways.

© 1999 by W. H. Freeman and Company. All rights reserved.