- Self-sufficiency in growth signals (positive cell-cycle regulators): Cancer cells have an unregulated ability to proliferate. This uncontrolled mitosis often occurs via the activation of oncogenes (literally, a gene that can cause cancer). Many of these genes code for enzymes, such as the protein kinase known as Cdk (see below) or Src, which become hyperactive when mutated; this hyperactivity drives unregulated cell proliferation (see below).
- Insensitivity to growth-inhibitory signals (negative cell cycle regulators): Cancer cells inactivate so-called tumor suppressor genes, such as RB1 or p53 (see below), that normally act at certain points in the cell cycle to inhibit mitosis (see below).
- Evasion of programmed cell death ( apoptosis ): cancer cells suppress and inactivate genes and pathways that normally cause cells to die.
- Unlimited replication potential: Cancer cells activate specific gene pathways that render them immortal even after generations of growth. HeLa cells, a human cancer cell derived from a cervical carcinoma in the 1950's, are busily proliferating in labs around the world today, long after the cancer victim passed away.
- Sustained angiogenesis (ability to make new blood vessels and obtain nutrients via increased blood flow): Many cancer cells acquire the capacity to induce growth of blood vessels into the tumor; this is known as tumor angiogenesis.
- Tissue invasion and metastasis: Most normal cells do not migrate, nor do they invade surrounding tissues; cancer cells acquire the capacity to migrate to other organs, invade other tissues, and colonize these organs, resulting in their spread throughout the body. This process is called metastasis .
Proto-oncogenes
The genes that code for the positive cell-cycle regulators are called proto-oncogenes . Proto-oncogenes are normal genes that, when mutated, become oncogenes —genes that cause a cell to become cancerous. Consider what might happen to the cell cycle in a cell with a recently acquired oncogene. In most instances, the alteration of the DNA sequence will result in a less functional (or non-functional) protein. The result is detrimental to the cell and will likely prevent the cell from completing the cell cycle; however, the organism is not harmed because the mutation will not be carried forward. If a cell cannot reproduce, the mutation is not propagated and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator. For example, a mutation that allows Cdk, a protein involved in cell-cycle regulation, to be activated before it should be could push the cell cycle past a checkpoint before all of the required conditions are met. If the resulting daughter cells are too damaged to undertake further cell divisions, the mutation would not be propagated and no harm comes to the organism. However, if the atypical daughter cells are able to divide further, the subsequent generation of cells will likely accumulate even more mutations, some possibly in additional genes that regulate the cell cycle.
The Cdk example is only one of many genes that are considered proto-oncogenes. 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. Once a proto-oncogene has been altered such that there is an increase in the rate of the cell cycle, it is then called an oncogene.
Tumor suppressor genes
Like proto-oncogenes, many of the negative cell-cycle regulatory proteins were discovered in cells that had become cancerous. Tumor suppressor genes are genes that code for the negative regulator proteins, the type of regulator that—when activated—can prevent the cell from undergoing uncontrolled division. The collective function of the best-understood tumor suppressor gene proteins, retinoblastoma protein (RB1), p53, and p21, is to put up a roadblock to cell-cycle progress until certain events are completed. A cell that carries a mutated form of a negative regulator might not be able to halt the cell cycle if there is a problem.
Mutated p53 genes have been identified in more than half of all human tumor cells. This discovery is not surprising in light of the multiple roles that the p53 protein plays at the G 1 checkpoint. The p53 protein activates other genes whose products halt the cell cycle (allowing time for DNA repair), activates genes whose products participate in DNA repair, or activates genes that initiate cell death when DNA damage cannot be repaired. A damaged p53 gene can result in the cell behaving as if there are no mutations ( [link] ). This allows cells to divide, propagating the mutation in daughter cells and allowing the accumulation of new mutations. In addition, the damaged version of p53 found in cancer cells cannot trigger cell death.