The second leading cause of death in the United States, after heart diseases, is cancer, claiming around half a million lives every year.(1) People today are concerned more than ever about cancer and its terrible consequences. However, in the light of recent scientific findings, a very different picture can be seen: In an environment with increasing carcinogens, it is actually surprising to find most populations are cancer-free. This is because our bodies are equipped with systems to prevent cancer formation.
Cancer research over the last two decades has shown that cancer is a disease of the genome.(2) Changes in the DNA, called mutations, disrupt the regular cellular networks that control a state of delicate balance. People are continuously exposed to varying amounts of chemicals that have been shown to cause mutations in the genome which may lead to cancer formation. Exposure to harmful chemicals can occur due to being in an environment where these agents are present in the food, air or water, and also due to our own metabolism which may produce these chemicals. It has been estimated that exposure to environmental chemical carcinogens may contribute significantly to the formation of the majority of human cancers.(3)
Even though some of the mutations caused by these agents hit cancercritical genes, cancer does not immediately develop. Furthermore, cancer is mostly seen in old age, when many mutations have accumulated in the genome. The reason why we are protected from developing cancer, even though our DNA is under numerous types of attacks everyday, is that our cells are equipped with several lines of defense against cancer formation. These built-in defenses include DNA damage repair systems, external and internal controls of cell division rate, and the programmed death of cells. All of these defenses have been given to our cells in order to protect us from getting cancer. If we were not to have these defenses, cancer would be a daily occurrence for every one.
It is possible to say that a cell’s first defense against cancer is similar to the regular maintenance of a car. One has to replace the brake pads, change the oil, etc., so that the aging of the parts will not cause failure that may lead to an accident. Similarly, chemical carcinogens from environmental pollution, ultraviolet rays from the sun, radiation from various sources, etc. all cause multiple types of damage in the DNA molecule. Therefore, our cells and genome need maintenance as well. This function is carried out by groups of proteins called DNA repair complexes. DNA repair mechanisms have been designed to correct the DNA damage before it can lead to inheritable mutations.(4)
If the DNA damage repair systems are intact, most of the damages to the genome are dealt with before they can cause problems. We observe the extent of attacks that can damage the DNA on our genome in many types of cancer where the DNA repair mechanisms are known to have been inactivated. In these cancer cells, mutations accumulate at a very fast rate, leading to more aberrant behavior. Also, individuals with defective DNA repair systems are more susceptible to developing various types of cancer.(4,5) Therefore, the first line of defense given to our cells against cancer is the ability to check and correct the integrity of our genome.
Every cell type in our body has been designed to proliferate at a certain rate that is suitable for the function of those cells. For example, neurons or muscle cells almost never divide after reaching adulthood, whereas the epithelial cells lining the interior of the intestines or under the skin divide at a fast rate continuously throughout our lives. The rate of division of a cell is mainly controlled by extra-cellular cues, i.e. a normal cell doesn’t grow or divide unless it receives growth and proliferation signals from neighboring cells.
There is a safe rate at which a cell must divide – just as a car needs to be driven at a safe speed. The requirement of cells for external stimuli in order to grow and divide is like the car’s need for someone to step on the gas pedal in order to accelerate. Normal cells cannot grow without control as neighboring cells produce growth signals when they are necessary and stop producing them in a regulated manner. A good example of the control of cell proliferation rate is seen in the wound healing process. When there is a cut in the skin, the cells adjacent to the wound are stimulated to divide rapidly by signals given from the injured cells; they divide and close the wound as soon as possible. However, when there are no wounds, there is no signal to divide and the skin cells only divide at a very slow rate, just enough to replace dying cells; this is a much slower process than wound healing. Cancer cells, on the other hand, are known to produce their own growth signals and proliferate abnormally fast and in an uncontrolled manner.(6) Therefore, the environmental control of cell division is an important barrier against cancer formation.
Cancer cells cannot divide uncontrollably unless they are independent of the external stimuli to divide. However, cancer cells can produce their own growth and proliferation signals, so they are free from external constraints. But even then, all is not yet lost. This situation of uncontrolled and rapid cellular proliferation is like a car in which the accelerator has become jammed– the car accelerates continuously and an accident is impending. In this situation the way to prevent too much speed is to step on the brake of the car. Similarly, in a cell, there are a set of genes called tumor-suppressor genes, which are responsible for stopping cell division upon excessive growth stimuli.(7) These genes act like brakes in cell division and prevent further progression into a malignant state. In many cancers,(8) it has been shown that these genes have been inactivated. If the brakes of the car are functional, you can safely bring your car to a stop and fix the problem that caused the accelerator to jam. Similarly, if a cell starts to divide too rapidly, it can stop dividing and repair the damage that caused the uncontrolled growth. Therefore, tumor suppressor genes represent a third line of defense.
If all the previous safety valves fail, there is one more defense to cancer. A situation in which a cell with harmful mutations promotes its own proliferation and cannot abort the division process is similar to one where the accelerator of the car is jammed and the brakes don’t work. In this case, in order to prevent greater damage, one can choose to hit a wall or a tree to stop the car– this will total the car, but will prevent further damage to others. Similarly, if a cell begins to grow uncontrollably and can’t slow down its rate of division, a process called apoptosis, or programmed cell death is initiated. In apoptosis, the cellular DNA and cellular compartments, like lysozomes, Endoplasmic Reticulum, and Golgi are degraded, and the cell shrinks in size. In the end, the cell dies and is absorbed by neighboring normal tissue. Therefore, the programmed death of an aberrantly behaving cell is another way that the body is protected from cancer. As expected, in cancer cells defects in this last line of defense are observed as well.(9)
These four mechanisms, i.e. DNA repair, external/ internal cell division suppression, and programmed cell death, are only the ones that we are aware of at this time. In addition to these, there are multiple levels of other redundant safety checks. All these safety features work without our knowledge or will. Findings from cancer research show that the design of cells was carried out so intelligently that even the carcinogenic environment which we produce today was accounted for within the genes of the very first human being.
1. Cancer Statistics 2006. 2006, American Cancer Society.
2. Vogelstein, B. and K.W. Kinzler, “The multistep nature of cancer.” Trends Genet, 1993. 9(4): p. 138-41.
3. Wogan, G.N., et al., “Environmental and chemical carcinogenesis.” Semin Cancer Biol, 2004. 14(6): p. 473-86.
4. Dixon, K. and E. Kopras, “Genetic alterations and DNA repair in human carcinogenesis.” Semin Cancer Biol, 2004. 14(6): p. 441-8.
5. Jiricny, J., “The multifaceted mismatch-repair system.” Nat Rev Mol Cell Biol, 2006. 7(5): p. 335-46.
6. Brattain, M.G., et al., “Growth factor balance and tumor progression.” Curr Opin Oncol, 1994. 6(1): p. 77-81.
7. Hanahan, D. and R.A. Weinberg, “The hallmarks of cancer.” Cell, 2000. 100(1): p. 57-70.
8. Coleman, W.B. and G.J. Tsongalis, “Molecular mechanisms of human carcinogenesis.” Exs, 2006(96): p. 321-49.
9. Dlamini, Z., Z. Mbita, and T. Ledwaba, “Can targeting apoptosis resolve the cancer saga?” Future Oncol, 2005. 1(3): p. 339-49.