It is estimated that there are approximately 100 trillion cells in the human body. They fulfill their duties harmoniously with all the systems, organs, and tissues manifesting innumerable signs of wonder and wisdom. If a disruption occurs to the working of cells or the coordination among cells, the process leading to cancer starts to develop in the body’s tissue.

The recent increase in cancer occurrences has led researchers to look into its development. The phrase “cellular anarchy” is sometimes used to refer to cancer’s development. Indeed, when we examine the mechanism of cancer development, we see that cells engage in irregular – anarchic – activities in addition to regular ones.

Abnormalities emerge in cancerous cells during cell division and differentiation (when they transform into specialized cells according to different tissues). Cancer cells divide uncontrollably. Under normal circumstances, numerous genes are active in cell division. In cancerous cells, however, failures occur in the mechanisms that control division. Moreover, due to differentiation flaws in cancerous cells, undifferentiated cells, which fail to acquire features that enable them to function in a tissue or organ, form groups of cells that constrain and damage other cells because of the space they occupy.

Checkpoints in cell division and tumor suppressing genes

How is cell division controlled in a normal cell?

Our cells go through numerous stages as they divide. The beginning of each stage is called a “checkpoint” because it is where errors in cell divisions are checked. At each checkpoint (called G1, S and G2) are proteins with certain duties. One of these proteins, P53, suppresses development of cancer. In other words, P53’s job is to prevent failures during cell division, hence blocking the path to cancer’s development in the cell. Whether there is a flaw in the DNA it is checked over and over again at each checkpoint. If no error is identified, the next stage proceeds. In this way, it is ensured that there is not any genetic error in the cells formed as a result of division. If there is an error, cell division is stopped. First an attempt is made to correct this genetic error. If it can be corrected, cell division is resumed. If the error is too big to be corrected, then the cell is scheduled to die; this is called apoptosis. It is worth remembering at this point that proteins that are too minute to be observed even by microscopes are tasked to perform these stupendous mechanisms. It is remarkable that they were designed to work so effectively.

Because these systems are disrupted during the development of cancer, genetically flawed cells form and multiply. Proteins produced with the genetic codes of the flawed cells are also flawed, and these flawed proteins cause a failure of the mechanisms that constrain cell division. Unconstrained cells have an abnormal capacity for division and they divide continuously, which is why cancerous cells have a greater ability to divide than normal cells.

Proto-oncogenes and oncogenes

It is essential that the parts of our body that grow, develop, or get damaged be repaired. In such cases, our cells synthesize certain “signal” molecules which are responsible for carrying to the nucleus the information that our cells should divide. As a result of the incoming information, some DNA regions called proto-oncogenes are stimulated and cell division gets underway. Proto-oncogenes are genes responsible for checking the start of cell division. When the human body encounters various cancer-making elements, damages occur in proto-oncogenes, which transform into oncogenes, or genes with the potential to cause cancer. Oncogenes lead a cell to develop cancer because cell division does not stop where it should and continues endlessly in the absence of healthy proto-oncogenes. Underlying abnormal tissue growth and spread to other organs is the fact that the control over cell division is lost.

Genetic treatment of cancer

It became apparent that age-old treatment methods proved wrong once it was discovered that the biological foundations of cancer stemmed from genetic disruptions. Despite its increase in the last century, cancer has in fact been seen throughout the history of mankind; even ancient Egyptian papyri talked about it. Because there was not a definite treatment for cancer, radical treatments were used, such as burning or cauterizing the tumor. In the first half of the twentieth century, only surgical methods were implemented in cancer treatments. Desired results could not be obtained by surgical procedures, which ended up with the excision of entire organs.

Research studies were launched in the second half of the twentieth century into whether it was possible to treat cancer using drugs. These studies revealed that cancer stemmed from genetic flaws (like the ones in oncogenes and tumor suppressing genes), which led to questions about types of treatment. Treatments of flaws at the genetic level are based on genes themselves. These treatments use such methods as stopping genes that work abnormally, eliminating the products of these genes, and killing cancer cells by making use of their genetic mechanisms.

New incidents of cancer are likely to continue to develop, for people are exposed to factors that cause disruptions of the makeup of genes. To prevent cancer, it is critically important that one should have a conscious, natural, and balanced lifestyle. People should be well-informed about the effects of smoking, genetically modified food, radiation, stress, and chemicals, so that they can lessen exposure to such risk factors. Moreover, more frequent implementation of screening tests will make early diagnosis easier. More effective methods with fewer adverse effects should also be developed for higher success rates in cancer treatment. Genetic treatment of cancer is a relatively new field but an increasing number of studies focus on it. These studies aim to kill only cancerous cells and spare healthy ones. It can be expected that research into this field will produce promising outcomes in coming years.

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 cancer-critical 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.

Notes

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.