3. Sustaining proliferative signalling
One of the most defining features of cancer cells is their ability to sustain proliferation beyond what would be expected for normal cells. Healthy tissues maintain homeostasis through strict regulation of growth-promoting signalling pathways, which are responsible for driving progression of cells through the cell cycle. These signalling mechanisms are deregulated in cancerous cells. Growth-promoting signalling pathways typically involve growth factors, which are able to bind to cell surface-bound growth factor receptors. Binding of the ligand to receptors activates an intracellular tyrosine kinase-mediated signalling cascade, which ultimately leads to changes in gene expression, promoting cellular proliferation and growth. There are several different ways in which cancer cells may acquire sustained proliferative capacity:
- overproduction of growth factor ligands;
- overproduction of growth factor receptors;
- production of structurally altered receptors, which are able to signal in absence of ligand binding;
- activation of intracellular signalling pathway components so that signalling is no longer ligand-dependent
The cell cycle
The cell cycle is comprised of four ordered, strictly regulated phases referred to as G1 (gap 1), S (DNA synthesis), G2 (gap 2) and M (mitosis/meiosis). Normal cells grown in culture will stop proliferating and enter a quiescent state called G0 once they become confluent or are deprived of serum or growth factors. The first gap phase (G1) prior to the initiation of DNA synthesis, represents the period of commitment that separates M and S phases as cells prepare for DNA duplication. Cells in G0 and G1 are receptive to growth signals but once they have passed a restriction point they are committed to enter DNA synthesis (S phase). Cells demonstrate arrest at different points in G1 in response to different inhibitory growth signals. Mitogenic signals promote progression through G1 to S phase utilising phosphorylation of the retinoblastoma gene product (pRb). Following DNA synthesis there is a second gap phase (G2) prior to mitosis (M) allowing cells to repair errors that have occurred during DNA replication and thus preventing propagation of these errors to daughter cells. Although the duration of individual phases may vary, depending on cell and tissue type, most adult cells are in a G0 state at any one time.
Cell cycle regulation
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