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9.1 INTRODUCTION

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Our cells are continuously proliferating and dying. Our development from a single-celled egg into adults with approximately 1014 cells requires intense cell proliferation. But our development also requires cell death; for instance, to prune excess neurons in the brain and to sculpt the fingers. As adults, most of our organs exist in a dynamic steady state, being constantly renewed by cell proliferation and death. For example, our bodies generate and destroy more than a million blood and intestinal cells every second. In the extreme, cells live for only a few days before dying, as is the case for neutrophils and the cells that line the small intestine. In the midst of this continual and profuse cell renewal lies the constant threat of cancer. Cancerous cells invariably contain alterations to genes encoding regulators of cell proliferation and cell death and are generally thought to arise from actively proliferating cell types.

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This chapter discusses the molecular control of the cell cycle and of the processes that lead to cell death, many of which are modified in the processes of malignant transformation and tumor progression. Chapter 12 discusses the growth of tumors and the patterns of cell proliferation and cell death that influence tumor growth, together with the tumor microenvironment and metabolism with which they are closely linked. Chapter 13 discusses the properties of tumor stem cells with high proliferative potential.

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9.2 MOLECULAR CONTROL OF CELL PROLIFERATION

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Cell proliferation is perhaps best viewed as a combination of two distinct processes: the cell cycle, which replicates and segregates the genome, and cell growth, which doubles all the other components of the cell. The cell cycle and cell growth are intertwined in most normal and cancerous cells, but the two processes can be uncoupled, both in the laboratory and as part of normal development.

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9.2.1 The Mammalian Cell Cycle

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The cell cycle is partitioned into 4 phases: G1, S, G2, and M. This organization reflects the 2 primary goals of the cell cycle: to replicate the genome of the mother cell during DNA synthesis or S-phase, and to segregate the replicated genome into 2 daughter cells during mitosis or M-phase (Fig. 9–1). Two gap phases (G1, G2) separate these fundamental events. The combined G1, S, and G2-phases are frequently referred to as interphase. When cells cease proliferating because of insufficient nutrients, lack of growth factors, or upon differentiation, they exit the cell cycle from G1-phase and enter a quiescent state called G0. Most cells in the body are in the G0 state. If cells in G0 are instructed to start proliferating, they must transition back into G1-phase before starting another cell cycle.

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FIGURE 9–1

The key events of the cell cycle. In cells, ...

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