Chapter 8: Cell Proliferation and Death

8.1 INTRODUCTION

Our cells are continuously proliferating and dying. Development from a single-celled egg into adults with approximately 10¹⁴ cells requires massive cell proliferation. However, selective cell death is also essential for development, for example, 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, more than a million blood and intestinal cells are turned over 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.

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.

8.2 MOLECULAR CONTROL OF CELL PROLIFERATION

Cell proliferation is perhaps best viewed as a combination of 2 distinct processes: the cell cycle, which replicates and segregates the genome, and cell growth, which doubles all other components of the cell. The cell cycle and cell growth are intertwined in most normal and cancerous cells, but the 2 processes can be uncoupled, both in the laboratory and as part of normal development.

8.2.1 The Mammalian Cell Cycle

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. 8–1). 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 on 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.