Cancer is a collective name for many different diseases caused by a common mechanism: uncontrolled cell division. In cancer cells, mutations modify the control of the cell cycle and cells don’t stop growing as they normally would. Mutations can also alter the growth rate or the progression of the cell through the cell cycle. For cells to move through each phase of the cell cycle, the cell must pass through checkpoints. This ensures that the cell has properly completed the step and has not encountered any mutation that will alter its function. Despite the redundancy and overlapping levels of cell cycle control, errors occur. One of the critical processes monitored by the cell cycle checkpoint surveillance mechanism is the proper replication of DNA during the S phase (synthesis).
One example of gene modification that alters the growth rate is the increased phosphorylation of cyclin B, a protein that controls the progression of a cell through the cell cycle and serves as a cell-cycle checkpoint protein. As a result, cells can progress through the cell cycle unimpeded, even if mutations exist in the cell and its growth should be terminated. This post-translational change of cyclin B prevents it from controlling the cell cycle and contributes to the development of cancer.
Even when all of the cell cycle controls are fully functional, a small percentage of replication errors will be passed on to the daughter cells. If one of these changes to the DNA nucleotide sequence occurs within a gene, a gene mutation results. All cancers begin when a gene mutation gives rise to a faulty protein that participates in the process of cell reproduction.
The change in the cell that results from the malformed protein may be minor. Even minor mistakes, however, may allow subsequent mistakes to occur more readily. Over and over, small, uncorrected errors are passed from parent cell to daughter cells and accumulate as each generation of cells produces more non-functional proteins from uncorrected DNA damage. Eventually, the pace of the cell cycle speeds up as the effectiveness of the control and repair mechanisms decreases. Uncontrolled growth of the mutated cells outpaces the growth of normal cells in the area, and a tumor can result.
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, i.e. 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.
Anti-oncogenes or 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 protein, and p21 protein, 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 G1 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 (Figure 1). 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.
Figure 1: (a) The role of p53 is to monitor DNA. If damage is detected, p53 triggers repair mechanisms. If repairs are unsuccessful, p53 signals apoptosis. (b) A cell with an abnormal p53 protein cannot repair damaged DNA and cannot signal apoptosis. Cells with abnormal p53 can become cancerous (credit: modification of work by Thierry Soussi).
Brief history of the discovery of cancer-associated genes
In the editorial of Medical Practice, volume 13, no. 1 (54), from 2018, Prof. Dr. Adrian Restian, full member of the Romanian Academy of Medical Sciences, presents a chronology of the discovery of cancer-associated genes. An adaptation of this chronology is presented below.
- In 1975, Harold Varnus and Michael Bishop discovered that the human genome has a SRC gene similar to the chicken sarcoma virus gene, which was described by Rous in 1910. This gene is an oncogenic or proto-oncogenic gene. If such a gene is altered or amplified by epigenetic mechanisms, then cancer can occur. This discovery led Harold Varnus to say that “the enemy is in us.”
- In 1986, Stephen Friend discovered the RB gene, whose mutation can cause retinoblastoma.
- In 1989, Bert Vogelstein discovered the p53 gene, whose mutation is found in more than 50% of cancerous tumors.
- In 1990, Mary-Claire King discovered that the BRCA1 gene, whose mutation can cause breast cancer, is located on chromosome 17.
- In 1991, the APC (adenomatous polyposis coli) gene, whose mutation could lead to colon cancer, was discovered.
- In 1994, Mark Skolnick succeeded in isolating the BRCA1 gene, which is located on chromosome 17, and in 1995 he isolated the BRCA2 gene, which is located on chromosome 13. These genes are involved in breast cancer, ovarian cancer, and pancreatic cancer.
The idea that genes play a role in reducing cell growth was solidified by the hybridization experiments that used somatic cells, which were performed in 1969 by Dr. Henry Harris. In these experiments, tumor cells were fused with normal somatic cells to produce hybrid cells. A large proportion of mature hybrid cells did not have the ability to develop tumors in animals. Suppressing the tumorigenicity of these hybrid cells has led researchers to hypothesize that some genes in the normal somatic cell act as inhibitors for tumor growth.
This initial hypothesis led later to the discovery of the first classic tumor suppressor gene by Dr. Alfred Knudson. This gene, known as the RB gene, encodes the retinoblastoma tumor suppressor protein. Other suppressive or anti-oncogenic genes currently known are: APC gene in colonic epithelium, NF1 gene in Schwann cells, VHL gene in kidney cells, MEN1 gene which is involved in endocrine cancers, BRCA1 and BRCA2 genes which are involved in breast cancer, ovarian cancer, and pancreatic cancer. Decommissioning of the BRCA1 and BRCA2 genes, which are involved in DNA repair, or the p53 gene, which facilitates the apoptosis of cancer cells, can lead to cancer.
This means that the health of a cell depends on the balance between its oncogenic genes and its anti-oncogenic genes.
Final thoughts
Instead of sharing my thoughts, I will quote an excerpt from the same editorial by Prof. Dr. Adrian Restian, where the professor explains how cancer cells develop:
Obviously, in order to grow much faster, cancer cells need enough plastic and energetic substances. And to get these substances, they need proper vascularization. Therefore, with the development of the tumor, there is a process of angiogenesis, which ensures that the cancer cells are supplied. Once they have received the necessary substances, the cancer cells process them anaerobically, i.e. with a very low yield, which leads to the gradual depletion of the body. Cancer cells would not be able to grow so fast if they did not manage to escape the control of immune mechanisms, which have the role of detecting and removing all structures that are foreign or altered from normal.
Even though all these conditions, i.e. mutation of genes involved in cell division, decommissioning of control mechanisms, ensuring sufficient vascularity, preferential feeding, and immune tolerance of cancer cells, seem very difficult to achieve, the reality shows that these conditions are met quite often as the incidence of cancer continues to rise.
And this cannot be explained by changes in the human genome, which occur very slowly, but by changes in the external environment and lifestyle, which have changed much faster. Therefore, most mutations involved in carcinogenesis are not even genetically inherited, but 95% are acquired during life under the action of internal and external risk factors. So, we are victims of our own lifestyle.
References:
- Fowler, Samantha, et al. Concepts of Biology. OpenStax College, Rice University, 2013. Download for free at: https://openstax.org/details/books/concepts-biology.
- Clark, Mary, Jung Choi, and Matthew Douglas. Biology 2E. 2018. Access for free at https://openstax.org/details/books/biology-2e.
- RESTIAN, Adrian. „Mecanismele epigenetice ale cancerului.” Practica Medicală 1 (2018): 5-11.