More than a third of US adults will get cancer. In 2018 alone, more than 1.7 million new cancer cases will be diagnosed. Earlier detection and more precise treatment options are improving outcomes for patients, but with an estimated 14 million cancer survivors living in the US, cancer recurrence remains a sizeable threat. Cancer cells, unlike the normal cells in our bodies, can grow forever. Cancer cell immortality leads to massive tumors, metastatic spread, and potentially re-emergence. JAX postdoctoral associate Floris BarthelDeploys next-generation sequencing techniques to understand brain tumor biology and telomere mechanicsFloris Barthel, M.D. , received a Pathway to Independence Award (or “K99”) from the NIH’s National Cancer Institute to determine how cancer cells achieve immortality.
Ultimately I hope that I can contribute to developing new cancer therapies that reduce or eliminate telomerase activity without affecting non-cancer cells.
The normal cells in our bodies get old and die. The ends of the chromosomes, specialized DNA sequences called telomeres, keep track of cellular age. With each cell division, telomeres shorten until eventually they become too short to protect the chromosomes and the cell dies. Cancers become immortal by reversing the normal telomere shortening process and instead lengthen their telomeres. Barthel, who works with Professor Roel Verhaak, Ph.D.Brain tumors, sequencing, computational biology.Roel Verhaak, Ph.D., at JAX’s Genomic Medicine campus in Farmington, Conn., is discovering how cancer cells coopt the cellular processes that control telomere length.
The cellular machine mainly responsible for extending telomeres is the protein telomerase: it adds telomere DNA to the ends of chromosomes. In our bodies, telomerase is usually shut off. It is turned on when making sperm and eggs and in some very early stages of life – in cells that will have to divide a lot. And it is turned on when cells become cancerous. Cancer cells may reactivate telomerase by changing the DNA around one of the genes that makes telomerase, called TERT. Barthel is particularly focused on determining how chemical changes to the TERT DNA allow telomerase to be turned on again.
The results of Barthel’s research may identify new ways to turn telomerase off. Making cancer cells mortal — subject to the normal cellular lifespan imposed by telomere shortening — would dramatically change the potential for cures, including for cancers with as yet few effective treatment options. The grant — $230,000 over two years followed by an optional three-year phase — enables Barthel to uncover how telomerase reactivation occurs at the DNA level and to establish his independent research laboratory.
“Therapies that target telomerase directly were found to be toxic to non-cancer cells, and understanding precisely how telomerase is turned on in cancer may allow us to circumvent that,” said Barthel. “Ultimately I hope that I can contribute to developing new cancer therapies that reduce or eliminate telomerase activity without affecting non-cancer cells.”
“NIH K99 awards enable the most talented junior scientist to optimally prepare for a career as an independent researcher,” said Verhaak. “In the case of Floris Barthel, there is no doubt in my mind that he will continue to make discoveries that will ultimately lead to improved outcomes for cancer patients.”
Chapter 6: Introduction to Reproduction at the Cellular Level
By the end of this section, you will be able to:
- Explain how cancer is caused by uncontrolled cell division
- Understand how proto-oncogenes are normal cell genes that, when mutated, become oncogenes
- Describe how tumor suppressors function to stop the cell cycle until certain events are completed
- Explain how mutant tumor suppressors cause cancer
Cancer is a collective name for many different diseases caused by a common mechanism: uncontrolled cell division. 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. Even when all of the cell-cycle controls are fully functional, a small percentage of replication errors (mutations) 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.
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.
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 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 6.8). 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.
Go to this website to watch an animation of how cancer results from errors in the cell cycle.
Cancer is the result of unchecked cell division caused by a breakdown of the mechanisms regulating the cell cycle. The loss of control begins with a change in the DNA sequence of a gene that codes for one of the regulatory molecules. Faulty instructions lead to a protein that does not function as it should. Any disruption of the monitoring system can allow other mistakes to be passed on to the daughter cells. 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, resulting in tumorous growth.
oncogene: a mutated version of a proto-oncogene, which allows for uncontrolled progression of the cell cycle, or uncontrolled cell reproduction
proto-oncogene: a normal gene that controls cell division by regulating the cell cycle that becomes an oncogene if it is mutated
tumor suppressor gene: a gene that codes for regulator proteins that prevent the cell from undergoing uncontrolled division