While some cell types, such as those that compose the skin and bone marrow, continue to proliferate throughout life, other types including bone and muscle cells cease active proliferation when a human reaches adulthood. Most normal cells remain in a non-proliferative state unless they are stimulated to divide to replace lost cells. Abnormal regulation of the cell cycle can lead to the over proliferation of cells and an accumulation of abnormal cell numbers. Cancer cells arise from one cell that becomes damaged, and when divided, the damage is passed on to the daughter cell and again to the granddaughter cells and so on. Such uncontrolled, abnormal growth of cells is a defining characteristic of cancer.7, 10-12
The total number of cells composing the human body is determined not only by the rate of proliferation of cells but also by the rate of cell loss. Excess cells and those that are aged or have sustained damage that impairs normal functioning are eliminated to prevent accumulation of abnormal numbers of cells. The mechanism for regulating the removal of excess and impaired cells is known as apoptosis. Also referred to as cell suicide or programmed cell death, apoptosis is an orderly process during which internal cellular structures are progressively dismantled, the impaired cell shrinks and finally is rapidly destroyed by immune cells.6, 8, 13
Role of key genes TP53 and RB1
A number of key genes, proteins and enzymes that regulate the cell cycle and the process of apoptosis have been identified. The TP53 gene and the regulatory protein it is responsible for producing, p53, together with the RB1 gene and its related protein, pRB, act to inhibit cell proliferation. In addition, the role of a group of proteins (cyclins and enzymes) known as cyclin-dependent kinases (CDKs) that act to stimulate a cell to progress through the cell cycle have also been identified.
It is now understood that mutations of these key genes affect the action of regulating proteins and enzymes and lead to the loss of regulation of cell proliferation that is seen in cancer. Mutations of the TP53 gene are also implicated in disturbances in apoptosis. Cells with mutated TP53 genes evade the apoptosis mechanisms normally responsible for eliminating impaired cells.4, 6, 7, 10, 13
DNA mutations may result from:
- artificial sources (pesticides, organic chemicals, alkylating agents)
- naturally occurring sources (plant toxins, viruses)
When cell cycle control checkpoints fail, the following may occur:2
- the mistake is quickly fixed
- a mutation results in the production of an abnormal protein or enzyme
- a mutation occurs near or around the proto-oncogene turning on cell division when not required
- a mutation occurs near or around tumour suppressor gene (e.g. the p53 gene that normally inhibits the growth of tumours) resulting in inability to stop uncontrolled cell division.
Access a current text. Identify examples within the following classes of genes and discuss their role in carcinogenesis:
- tumour suppressor genes
- DNA repair pathway genes.
Describe the key differences between the following types of cell proliferation patterns:
Access a current text and/or the Research Apoptosis web page14. Explain the role of apoptosis in homeostasis and the development of cancer.