What is cancer?

Causes and Symptoms

Cancer is a disease of abnormal cellular growth. Growth is a feature of all living things, but it must be precisely regulated for development to occur properly. All growing cells pass through a strictly regulated series of events called the cell cycle, where most cellular structures are duplicated. At the end of the cycle, one cell is separated into two “daughter cells,” each receiving one copy of the duplicated structures. The most important structures to be duplicated are the genes, which govern all cellular activities.

Human life begins as a fertilized egg which divides again and again; the adult human body is composed of a trillion cells, each with a specific job to perform. At adulthood, most cells stop duplicating. Some cells, however, must continue dividing to replace worn-out cells in places like the blood, skin, and intestine. Such growth is accurately controlled so excess cells are not produced. Sometimes, however, a mutation arises in one or more genes, resulting in needless cell duplication and ultimately loss of growth control: a malignant transformation. This is the start of cancer.

At first, these cells resemble their neighbors. For example, newly altered blood cells look like normal blood cells, and in most respects are. However, cancer cells differ in a number of ways from “normal” cells. First, cancer cells grow uncontrollably. They may or may not grow faster than normal cells, but cancer cells do not cease growth. If placed in a laboratory cell culture dish, cancer cells will pile upon one another in a manner analogous to the formation of a tumor. By contrast, normal cells grow in a single layer (monolayer) and stop replicating when they reach the edges of their dish when cellular signals instruct them to halt. Second, cancer cells often grow independently of hormones and growth factors, like insulin, required by other cells. They become “growth factor independent.” Third, cancer cells are immortal. Normal cells are able to replicate themselves a regulated number of times, usually approximately fifty divisions, while cancer cells have no such limit. For example, HeLa cells, originally obtained from a woman with cervical cancer in the mid-1950s, have been cultured in laboratories ever since. Fourth, cancer cells in later stages change shape and size compared to normal cells. They may look very different. Oncologists (cancer specialists) use this information to identify cancer types and make prognoses.

The first event triggering cancer is initiation, precipitated by a mutation in one of the genes controlling some feature of the cell cycle. There are several hundred such genes regulating different aspects of the cell cycle and cellular growth. These genes have mundane jobs governing the life of the cell until they become damaged. When there is a mutation in a controlling gene, it functions improperly. It does not govern the cell cycle correctly, and the cell cycle proceeds when it should be halted. Such cancer-causing genes are called oncogenes.

After initiation, additional mutations and defects begin to accumulate, and the defective cells become increasingly abnormal. Tumor-suppressor genes, normally functioning to keep cell division from becoming disorganized, are the site of these second-stage mutations. Those cells whose division and growth genes have mutated (oncogenes) and whose division and growth inhibitor genes (tumor-suppressor genes) have also mutated will become cancer cells. Typically, a further change, “promotion,” must take place before cancer cells begin growing freely. Promotion allows cells to escape the monitoring activity of the body. For example, various hormones instruct cells how to behave; a change of the promotion type may allow a cell to ignore such instructions. Both initiation and promotion occur randomly. Many initiated cells fail to grow into tumors. It is only those few cells that happen to acquire both defects that cause a problem. Fortunately, few cells have both their oncogenes turned “on” and their tumor suppressor genes turned “off.”

At this point in the process, the new cancer cell is dividing and producing larger numbers. These cells grow into a mass called a tumor—except in blood and lymph tissues, where cancer cells circulate individually. Nevertheless, these cells look normal at this early stage and are relatively easy to control with surgery. The excess cells may not cause much harm. Warts, for example, result from underlying skin cells exhibiting abnormal growth control. Such harmless tumors are called benign.

Unfortunately, as cells continue to replicate uncontrollably, more mutations develop. The most harmful changes result in complete loss of growth control. Cancer cells spread, resulting in damage to other parts of the body. For example, cancer cells may acquire the ability to digest their way through nearby tissues, a process called invasion. Eventually, the functioning of organs containing such cells becomes impaired. Other cancer cells may break loose from the tumor and travel to other parts of the body in the circulatory or lymphatic systems. This process is called metastasis. In advanced stages, a cancer patient may actually have dozens or hundreds of tumors, all of which developed from a single tumor cell. Cells that can invade or metastasize are called malignant. It becomes increasingly difficult to eradicate cancer cells as they become more malignant. Because each event leading to tumor development is rare, it may take years for the several acquired mistakes to aggregate in a single cell, resulting in a malignant tumor.

Cancer-causing mutations occur when outside forces cause oncogenes and tumor suppressor genes to function abnormally. For example, genes may be chemically damaged by a number of highly active and dangerous chemicals known as carcinogens. Additionally, several kinds of radiation can damage genes: ultraviolet radiation, gamma radiation, nuclear radiation, and possibly electromagnetic field radiation. Finally, several kinds of viruses, including certain strains of the human papillomavirus (HPV) or human herpesviruses, can cause oncogenes to function improperly. In most cancers, however, the origin of the disease is unknown and may result simply from a genetic mistake that takes place during gene duplication.

Treatment and Therapy

The most common cancer treatments fall into three categories: surgery, chemotherapy, and radiotherapy. The oldest treatment, going back several hundred years, is the surgical removal of tumors. If performed at an early stage, before metastasis, this method can be highly successful. Even so, surgery is much easier and less dangerous for some cancers (like that of the skin) than others (like that of the brain, which can be difficult to reach and remove). Surgery is not an option for blood and lymph cancers that are widely distributed.

The second most common type of cancer treatment for tumors is radiation therapy or radiotherapy. The radiation of choice is X-rays, which can penetrate the body to reach a tumor in very high dosages using modern equipment. X-rays can be focused on a specific small area or be administered over the whole body in the case of metastasized cancer. Therapeutic radiation damages genes to such an extent that they become physically fragmented and nonfunctional, ending the life of the target cell.

Radiotherapy has major drawbacks. The most serious problem is that normal cells in the path of the radiation will also be killed. Bone marrow , the source of blood cells, is destroyed with whole-body cancer treatments. This problem can be overcome after radiotherapy by transplanting new bone marrow into the patient, so that a treated patient can begin to manufacture new blood cells. Ironically, radiation designed to kill cancer cells can also cause malignant mutations in normal cells. Recent innovations in radiotherapy include instrumentation such as the gamma knife, a method to direct radiation precisely into the center of a tumor. In this manner, damage to surrounding cells may be minimized.

If a patient has metastasized tumor cells, radiation and surgery are not the treatments of choice. Neither of these therapies acts systemically. The most common systemic treatment used that can reach everywhere in the body is chemotherapy. Patients are treated with chemicals that prevent cells from duplicating or slow the process. Such drugs reach all parts of the body much more effectively than surgery when cancer has reached a later stage of distribution.

Different kinds of chemicals work in different ways to achieve this result. These chemicals can be divided into four major categories. First are chemicals that react directly with the substances required for cells to survive and function. Many such agents directly attack a cell’s genes, preventing them from passing along information required for a cancer cell to stay alive; these are known as alkylating agents. Second are antimetabolites, which prevent the chemical reactions that allow cells to produce the energy needed to live. The third category consists of steroid hormones. Cancer cells in some tissues respond to these hormones, which can therefore be used to regulate growth. Thus estrogens, the female steroid hormones, are often used for treatment of breast cancer, while the male steroids , androgens, may influence prostate cancer. Fourth are miscellaneous drugs that affect cancer cells in various ways. For example, drugs called vinca alkaloids (one type of the category known as antimicrotubule agents) stop the mechanical process of cell division and prevent growth. A derivative of the insecticide DDT (dichloro-diphenyl-tricholorethane) prevents unwanted steroid-hormone production and has been useful for treating tumors of the adrenal gland Other drug types include topoisomerase inhibitors and cytotoxic antibiotics.

The newest class of anticancer drugs is known as taxanes, another type of antimicrotubule agent. Taxol, isolated from the bark of the yew tree, is the best known of these drugs. Taxanes are active, poisonous constituents that can induce tumor cell death. This class of drug promotes the polymerization of the tubulin protein, which is needed to move chromosomes during cell division. By stabilizing the tubulin in the cancer cells, the equilibrium in the cell is disrupted, leading ultimately to cell death. The drugs paclitaxel and docetaxel are used frequently in ovarian and breast cancer and often in conjunction with one another.

The most common and difficult problem with the chemotherapeutic approach to cancer management is that normal cells are also affected by the same drugs that halt the growth of cancer cells. This reaction causes many difficulties for patients. Probably the most serious problems are with the immune system. Growth of the white blood cells that make antibodies is necessary to fight an infectious disease. Chemotherapy often depresses the immune system so it functions inefficiently; therefore patients in chemotherapy are more vulnerable to bacterial and viral illnesses. Red blood cells do not carry oxygen optimally during chemotherapy, making patients breathless and “sickly.” Skin often becomes pale and unhealthy looking. The digestive tract cells stop dividing, causing weight loss and digestive problems. Finally, a less serious irritant for such patients is hair loss, since hair follicles are also prevented from growing.

Accordingly, cancer surgery is inefficient, radiation therapy may cause as many problems as it solves, and chemotherapy, despite its anticancer efficiency, is toxic and can make the patient very ill. The problems for a cancer sufferer seem to have only just begun with their diagnosis since many of the cures seem, in the short term, as potentially harmful as the disease. Chemotherapy has developed such an unwholesome reputation that some patients refuse treatment, preferring death to the “indignities” of chemotherapy’s effects. Oncologists are presently experimenting with a whole series of promising new treatments that may be less harmful to patients while being more efficacious.

Antisense therapy is one method in the new arsenal of treatments emerging from advances in biotechnology. Oncogenes, like other genes, are read (transcribed) by the machinery of the cell so that cellular messages called messenger ribonucleic acid (mRNA) are made. The mRNA is then itself read (translated) by the ribosomes of the cell to make proteins. Proteins are the major component of every enzyme and structural part of a cell. The problem with oncogenes is that they have been turned on and cannot be turned off, so the cancer cells continue growing. One type of antisense cancer therapy works by injection into the cancer cells of a “backward” (complementary) copy of the mRNA molecule made from the active oncogene. This “backward” copy interferes with the oncogene’s “forward” mRNA message, causing it not to be made into an oncogenic protein. Consequently, this treatment stops the cancer cells from growing, because the cells are no longer encouraged to grow by the oncogenic protein. The advantages of this treatment are that it is very specific to cancer cells and has few side effects. The major disadvantages are that the physician must know precisely what oncogene is causing the disease in order to design the antisense treatment and that the treatment must be individualized in most cases, making a single “magic bullet” cure for all unavailable. University of Illinois oncologist Herbert Engelhard reports that this method has been successfully used to keep glial tumor cells (gliomas) of the brain from growing.

A related cancer treatment scheme is gene replacement therapy. In this method, an additional gene is introduced into the tumor cell with a laboratory-designed virus. This gene moves into the nucleus of the cell, becomes expressed as mRNA, and is translated into a protein. This protein is usually engineered to replace a missing or nonfunctioning gene. For example, the introduced factor may restore a missing tumor suppressor protein to the cancer cells, inducing them to become “normal” again.

A third biotechnologic approach to cancer treatment is gene-directed enzyme prodrug (“suicide gene”) therapy. In this method, the cancer cells are treated with viral DNA containing a special suicide gene. When an inactive antibiotic drug is later given to the cancer patient, the drug is converted into a toxic form by the gene. This kills only the tumor cells making the enzyme. Other cells without the suicide gene are unaffected. The chief advantages of this treatment are high cancer-cell specificity, few side effects, and effectiveness with a wide variety of tumor types.

Yet another approach, oncolytic virus therapy, holds a great deal of promise. Genetically engineered viruses are made “safe” by deleting essential genes but are left with the ability to replicate. They are also given the ability to target and bind only cancer cells. Cancer cells are treated with these viruses. Viral replication occurs within the cells. Many viruses are made within the cancer cell; it bursts open (lyses) and dies. More viruses are then released that have the ability to infect and destroy adjacent cancer cells. The herpes simplex virus 1 (HSV1) has become a popular virus for oncolytic therapy. The “wild” HSV1 is usually quite virulent and induces illness in humans, but researchers have produced a genetically modified virus with low binding capacity to normal cells but high affinity for tumor cells.

Another new therapeutic method is photodynamic therapy (PDT). Cancer cells are treated with certain photosensitive dyes. In the presence of light, the dyes react to make molecular oxygen radicals. These radicals are poisonous and specifically kill any cancer cells treated with the dye. Immunotherapy treatments, which use various aspects of the immune system to attack cancer cells, are also the subject of widespread research

Finally, a series of new types of anticancer drug treatments are being developed that do not simply kill cancer cells but prevent them from proliferating and growing. These new drugs are called cytostatic therapies and have a variety of functions. Some inhibit the formation of new blood vessels (angiogenesis) essential to tumor tissue growth. Other drugs inhibit the proteases used by certain tumors to dissolve the proteins that hold the normal tissues together. Without these proteases, tumor cells could not invade tissues, gain access to blood vessels, and colonize distant sites. Still other treatments inhibit growth by interfering with the signals that tell cancer cells to keep proliferating.

Perspective and Prospects

In the mid-1990s, evidence of a potential new basis for cancer emerged. The hypothesis suggested that overproduction of the enzyme telomerase, which synthesizes the telomeres at the ends of chromosomes, may cause uncontrolled growth in cells.

In normal human cells, the telomeres, long DNA repeats of TTAGGG, are slowly shortened and erode away as the cells age. The lengthening enzyme telomerase is not active in normal cells, so the ends of the chromosomes shorten more and more over a lifetime; in fact, these chromosomal changes have been postulated as one possible cause of cellular aging. When the telomeres become short enough, cell senescence is induced as the cells stop dividing. Tumor cells have active telomerase and do not lose their chromosomal ends. One source of immortality in cancer cells may be their long telomeres.

It is not clear whether lengthening of telomeres is an oncogenic event causing cells to become cancerous or whether these events are simply crucial in tumor formation. The importance of the telomerase activity in inducing cancer is quite controversial. Mice who have had telomerase genes turned off permanently show no ill effects and age normally. Although researchers have shown that oncogenes become operative if the telomerase is active in cell culture, it is unclear what role telomerase plays in actual biological systems. Researchers have suggested that perhaps the loss of that enzyme activity could be a protective mechanism against cancer. However, that is unlikely, since a phenomenon that usually occurs at the end of an organism’s lifetime, and after reproduction, such as cancer, would not be evolutionarily selected against.

Telomerase offers another possible avenue of treatment for cancer as a therapeutic agent. It may turn out that treatments that shut off the telomerase activity in cancer cells will slow or stop their growth. Pharmacological treatments may induce cancer cells to become normal cells once again. Once the mechanism of telomerase activity is understood, medical treatments may even induce cancer cells to destabilize and die.

Earlier detection and treatment have significantly improved the prognosis for people diagnosed with cancer. Nevertheless, there are millions of cancer cases diagnosed each year, many of them fatal. In 2012, there were an estimated 14 million cancer cases worldwide, and 8 million deaths from cancer. Improved diagnosis and treatment have resulted in decreased mortality from the most common forms of cancer (lung, breast, prostate, and colorectal). However, distribution and mortality of such cancers among ethnic or racial lines continues to show significant differences.

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