Cancer comprises many different diseases caused by a common mechanism: uncontrolled cell growth. Despite the redundancy and overlapping levels of cell cycle control, errors do occur.  During the S phase, the most critical checkpoint occurs in determining proper DNA replication.  Even when all controls are fully functional, a small percentage of replication errors (mutations) will be passed on to the daughter cells. If changes are not corrected, a gene mutation results. All cancers start from a gene mutation giving rise to a faulty protein.  The change in the cell that results from the malformed protein may be minor or detrimental.   But even minor mistakes may allow further mistakes to readily occur.  Small, uncorrected errors are passed from the parent cell to the daughter cells and amplified.  Eventually, the pace of the cell cycle increases, as the control and repair mechanisms decreases. Uncontrolled growth of the mutated cells outpaces the growth of normal cells in the area and a tumor (“-oma”) can occur.

Proto-oncogenes

The genes coding for the positive cell cycle regulators are called proto-oncogenes. Proto-oncogenes are normal genes when mutated, become oncogenes.  Oncogenes cause a cell to become cancerous.  What might happen should an oncogene develop?  The alteration of the DNA sequence will result in a less functional protein. This would be detrimental to the cell and likely prevent the cell from completing the cell cycle.  The organism, as a whole, is not harmed because the mutation will not be carried forward. If a cell cannot reproduce, the mutation is not passed and the damage is minimal.  But sometimes, a gene mutation causes a change that increases the activity of a positive regulator. A mutation could push the cell cycle past a checkpoint before all required conditions are met. If the resulting daughter cells undergo further cell divisions, the mutation would be propagated and harm could come to the organism.

In addition to the cell cycle regulatory proteins, any protein that influences the cycle can be altered in such a way as to override cell cycle checkpoints. An oncogene is any altered gene that leads to an increase in the rate of cell cycle progression.

Tumor Suppressor Genes

Tumor suppressor genes are segments of DNA that code for negative regulator proteins.  Negative regulator proteins, when activated, can prevent the cell from undergoing uncontrolled division.  The best understood tumor suppressor gene proteins, Rb, p53, and p21, puts up a roadblock to cell cycle progression until certain events are completed. A cell that carries a mutated form of a negative protein regulator might not be able to halt the cell cycle if there is a problem.

Mutated p53 genes have been identified in more than one-half of all human tumor cells.  A cell with a faulty p53 may fail to detect errors present in the genomic DNA (Figure 1).  If a partially functional p53 does identify the mutations, the enzymes needed for DNA repair may not be produced.   Damaged DNA will remain uncorrected. A functional p53 will deem the cell unsalvageable and trigger programmed cell death (apoptosis).  Damaged versions of p53 in cancer cells cannot trigger apoptosis.

Art Connection

Figure 1. The role of normal p53 is to monitor DNA and the supply of oxygen (hypoxia is a condition of reduced oxygen supply). If damage is detected, p53 triggers repair mechanisms. If repairs are unsuccessful, p53 signals apoptosis. A cell with an abnormal p53 protein cannot repair damaged DNA and thus cannot signal apoptosis. Cells with abnormal p53 can become cancerous. (credit: modification of work by Thierry Soussi)

Other issues occur for the cell cycle due to mutated  p53 function.  Without a fully functional p53, the G₁ checkpoint is severely compromised and the cell proceeds directly from G₁ to S regardless of internal and external conditions. At the completion of this shortened cell cycle, two daughter cells are produced with the mutated p53 gene. It is likely that the daughter cells will have acquired other mutations.  Cells such as these quickly accumulate both oncogenes and non-functional tumor suppressor genes.  The result is tumor growth.

Section Summary

Cancer is the result of unchecked cell division by a breakdown cell cycle regulation.  The loss of control begins with a change in the DNA  coding for one of the regulatory molecules. Faulty instructions lead to a faulty protein.  Any disruption of the monitoring system can allow other mistakes to be passed on. Each successive cell division will give rise to daughter cells with even more accumulated damage. Eventually, all checkpoints become nonfunctional, and rapidly reproducing cells crowd out normal cells.  Cancerous tumors result.