Initiation refers to the damage to or mutation of DNA that occurs when the cell is exposed to an initiating substance or event (such as chemicals, a virus, or radiation) during DNA replication (transcription). Usually, enzymes detect errors in transcription and remove or repair them. Sometimes, however, an error is missed. If regulatory proteins recognize the error and block further division, then the error may be repaired or the cell may self-destruct, a process known as apoptosis. If these proteins miss the error, it becomes a permanent mutation that’s passed on to future generations of cells.

Promotion involves the mutated cell’s exposure to factors (promoters) that enhance its growth. This exposure may occur shortly after initiation or years later.

Promoters may be hormones such as estrogen, food additives such as nitrates, or drugs such as nicotine. They can affect the mutated cell by altering:

♦ the function of genes that control cell growth and replication

♦ cell response to growth stimulators or inhibitors

♦ intercellular communication.

Progression occurs as tumor cells acquire additional mutations, enabling the tumor to invade adjacent tissue, metastasize to distant sites, and become resistant to therapy. This step is irreversible.

Although cancers may be considered genetic in nature because they result from mutations in genes, only about 10% are inherited. When mutations occur in reproductive cells (germline), damage can be passed on to future generations. This results in a predisposition to develop the cancer.

The discovery of cancerrelated genes has enhanced the identification, guidance, and management of persons at high risk for common cancers associated with inheritance of cancer-predisposing, genetic mutations. Recent discoveries include:

♦ Breast and ovarian cancers—Women with a BRCA 1 or BRCA 2 gene alteration have a 36% to 85% lifetime risk of developing breast cancer and a 16% to 60% lifetime risk of developing ovarian cancer.

♦ Colon cancer—In a gene alteration, the helicase-like transcription factor gene (one of the genes that helps stabilize DNA and regulates protein production in the cell) is inactivated, which contributes to the transformation of normal colon cells into cancer cells.

♦ Melanoma—The p16 gene causes some melanomas that run in certain families.

Common characteristics of genetically predisposed cancer include:

♦ early onset of malignant disease

♦ increased incidence of bilateral cancer in paired organs (breasts, adrenal glands, kidneys, and eighth cranial nerve [acoustic neuroma])

♦ increased incidence of multiple primary cancers in nonpaired organs

♦ increased risk of development of a less differentiated tumor

♦ abnormal chromosome complement in tumor cells.

Viral proto-oncogenes typically contain DNA that’s identical to that of human oncogenes. In animal studies of viral ability to transform cells, some viruses that infect people have demonstrated the potential to cause cancer. For example, the Epstein-Barr virus, which causes infectious mononucleosis, has been linked to Burkitt’s lymphoma and nasopharyngeal carcinoma.

Research suggests that cancer cells develop continually, but the immune system recognizes these cells as foreign and destroys them. This defense mechanism, termed immunosurveillance, has two major components: cell-mediated immune response and humoral immune response. Together these two components interact to promote antibody production, cellular immunity, and immunologic memory. Researchers believe that an intact immune system is responsible for spontaneous regression of tumors. Thus, cancer development is a concern for patients who are immunodeficient or who must take an immunosuppressant.

Air pollution has been linked to the development of cancer, particularly lung cancer. Persons living near industries that release toxic chemicals have an increased risk of cancer. Many outdoor air pollutants—such as arsenic, benzene, hydrocarbons, polyvinyl chlorides, and other industrial emissions as well as vehicle exhaust —have been studied for their carcinogenic properties.

Indoor air pollution, such as from cigarette smoke and radon, also poses an increased risk of cancer. In fact, indoor air pollution is considered to be more carcinogenic than outdoor air pollution.

Cigarette smoking increases the risk of lung cancer more than tenfold over that of nonsmokers by late middle age. Tobacco smoke contains nitrosamines and polycyclic hydrocarbons, two carcinogens that are known to cause mutations. The risk of lung cancer from cigarette smoking correlates directly with the duration of smoking and the number of cigarettes smoked per day. Tobacco smoke is also associated with laryngeal cancer and is considered a contributing factor in cancer of the bladder, pancreas, kidney, and cervix. Research also shows that smoking cessation may decrease a person’s risk of lung cancer.

Although the risk associated with pipe and cigar smoking is similar to that of cigarette smoking, some evidence suggests that the effects are less severe. Smoke from cigars and pipes is more alkaline. This alkalinity decreases nicotine absorption in the lungs and is more irritating to the lungs, so the smoker doesn’t inhale as readily.

Inhalation of secondhand smoke, or passive smoking, by nonsmokers also increases the risk of lung and other cancers. Use of smokeless tobacco, in which the oral tissue directly absorbs nicotine and other carcinogens, is linked to an increase in oral cancers that seldom occur in persons who don’t use the product.

Alcohol consumption, especially in conjunction with cigarette smoking, is commonly associated with cirrhosis of the liver, a precursor to hepatocellular cancer. The risk of breast and colorectal cancers also increases with alcohol consumption. Possible mechanisms for breast cancer development include impaired removal of carcinogens by the liver, impaired immune response, and interference with cell membrane permeability of the breast tissue. Alcohol stimulates rectal cell proliferation in rats, an observation that may help explain the increased incidence of colorectal cancer in humans who regularly consume alcohol.

Heavy use of alcohol and cigarette smoking synergistically increase the incidence of cancers of the mouth, larynx, pharynx, and esophagus. Alcohol probably acts as a solvent for the carcinogenic substances found in smoke, enhancing their absorption.

Sexual practices have been linked to specific types of cancer. The age of first sexual intercourse and the number of sexual partners are positively correlated with a woman’s risk of cervical cancer. Furthermore, a woman who has had only one sexual partner is at higher risk if that partner has had multiple partners. The suspected underlying mechanism here involves virus transmission, most likely human papillomavirus (HPV). HPV types 6 and 11 are associated with genital warts. HPV is the most common cause of abnormal Papanicolaou smears, and cervical dysplasia is a direct precursor to squamous cell carcinoma of the cervix, both of which have been linked to HPV (especially types 16 and 18). (See Preventing cervical cancer.)

Because of exposure to specific substances, certain occupations increase the risk of cancer. People exposed to asbestos, such as insulation installers and miners, are at risk for a type of lung cancer called mesothelioma. Asbestos also may act as a promoter for other carcinogens. Workers involved in the production of dyes, rubber, paint, and beta-naphthylamine are at increased risk for bladder cancer.

Exposure to ultraviolet B (UVB) radiation can damage the skin and increase the risk of skin cancer development. UVB is known to cause damage to the DNA of skin cells. Specifically, it causes a genetic mutation in the P53 tumorsuppressor gene. Recent evidence shows that
exposure to ultraviolet A (UVA) radiation from sunlamps and tanning booths also contributes to skin cancer development. The damaging effects of UVA are thought to be indirect, occurring as a result of energy transferred through reactive oxygen intermediates (free radicals).

The amount of exposure to ultraviolet radiation also correlates with the type of cancer that develops. For example, cumulative exposure to ultraviolet radiation is associated with basal and squamous cell skin cancer, and severe episodes of burning and blistering at a young age are associated with melanoma. (See Preventing basal cell carcinoma.)

Ionizing radiation (such as X-rays) is associated with acute leukemia, thyroid, breast, lung, stomach, colon, and urinary tract cancers as well as multiple myeloma. Low doses can cause DNA mutations and chromosomal abnormalities, and large doses can inhibit cell division. This damage can directly affect carbohydrate, protein, lipid, and nucleic acids (macromolecules), or it can act on intracellular water to produce free radicals that damage the macromolecules.

Ionizing radiation can also enhance the effects of genetic abnormalities. For example, it increases the risk of cancer in people with a genetic abnormality that affects DNA repair mechanisms. Other compounding variables include the area and percentage of the body exposed, the person’s age, hormonal balance, prescribed drugs, and preexisting or concurrent conditions.

Hormones—specifically the sex steroid hormones estrogen, progesterone, and testosterone —have been implicated as promoters of breast, endometrial, ovarian, and prostate cancers.

Estrogen, which stimulates the proliferation of breast and endometrial cells, is considered a promoter for breast and endometrial cancers. Prolonged exposure to estrogen, as in women with early menarche and late menopause, increases the risk of breast cancer. Likewise,
long-term use of estrogen replacement therapy without progesterone supplementation for menopausal symptoms increases a woman’s risk of endometrial cancer. Progesterone may play a protective role, counteracting estrogen’s stimulatory effects.

The male sex hormones stimulate the growth of prostatic tissue. However, research fails to show an increased risk of prostate cancer in men who take exogenous androgens.

Numerous aspects of diet are linked to an increase in cancer, including:

♦ obesity (in women only, possibly related to production of estrogen by fatty tissue), which is linked to a suspected increased risk of endometrial cancer

♦ high consumption of dietary fat, which is linked to endometrial, breast, prostate, ovarian, and rectal cancers

♦ high consumption of smoked foods, salted fish or meats, and foods containing nitrites, which may be linked to gastric cancer

♦ naturally occurring carcinogens (such as hydrazines and aflatoxin) in foods, which are linked to liver cancer

♦ carcinogens produced by microorganisms stored in foods, which are linked to stomach cancer

♦ diet low in fiber (which slows transport through the gut), which is linked to colorectal cancer.

The American Cancer Society has developed specific nutritional guidelines for cancer prevention. (See American Cancer Society recommendations for cancer prevention.)

Typically, each of the billions of cells in the human body has an internal clock that tells the cell when it’s time to reproduce. Mitotic reproduction occurs in a sequence called the cell cycle. Normal cell division occurs in direct proportion to cells lost, thus providing a mechanism for controlling growth and differentiation. These controls are absent in cancer cells, and cell production exceeds cell loss. Consequently, cancer cells enter the cell cycle more frequently and at different rates. They’re most commonly found in the synthesis and mitosis phases of the cell cycle, and they spend very little time in the resting phase.

Normal cells reproduce at a rate controlled through the activity of specific control or regulator genes (called proto-oncogenes when they function normally). These genes produce proteins that act as on-and-off switches. There’s no generalized control gene; different cells respond to specific control genes. The P53 and c-myc genes are two examples of control genes: P53 is
a tumor-suppressor gene that can stop DNA replication if the cell’s DNA has been damaged; c-myc helps initiate DNA replication and if it senses an error in DNA replication, it can cause the cell to self-destruct.

Hormones, growth factors, and chemicals released by neighboring cells or by immune or in-flammatory cells can affect control gene activity. These substances bind to specific receptors on the cell membranes and send out signals causing the control genes to stimulate or suppress cell reproduction. Examples of hormones and growth factors that affect control genes include:

♦ erythropoietin, which stimulates red blood cell (RBC) proliferation

♦ epidermal growth factor, which stimulates epidermal cell proliferation

♦ insulin-like growth factor, which stimulates fat and connective tissue proliferation

♦ platelet-derived growth factor, which stimulates connective tissue cell proliferation.

Substances released by injured or infected nearby cells or by cells of the immune system also affect cellular reproduction. For example, interleukin, released by immune cells, stimulates cell proliferation and differentiation. Interferon, released from virus-infected and immune cells, may affect the cell’s rate of reproduction.

Additionally, cells that are close to one another appear to communicate with each other through gap junctions (channels through which ions and other small molecules pass). This communication provides information to the cell about the neighboring cell types and the amount of space available. The nearby cells send out physical and chemical signals that control the reproduction rate. For example, if the area is crowded, the nearby cells will signal the same type of cells to slow or cease reproduction, thus allowing the formation of only a single layer of cells. This feature is called densitydependent growth inhibition.

In cancer cells, the control genes fail to function normally. The control may be lost or the gene may become damaged. An imbalance of growth factors may occur, or the cells may fail to respond to the suppressive action of the growth factors. Any of these mechanisms may lead to uncontrolled cellular reproduction.

One striking characteristic of cancer cells is that they fail to recognize the signals emitted by nearby cells about available tissue space. Instead of forming only a single layer, cancer cells continue to accumulate in a disorderly array.

The loss of control over normal growth is termed autonomy. This independence is further evidenced by the ability of cancer cells to break off and travel to other sites.

Usually, cells become specialized during development. That is, the cells develop highly individualized characteristics that reflect their specific structure and functions in their corresponding tissue. For example, all blood cells are derived from a single stem cell that differentiates into RBCs, white blood cells (WBCs), platelets, monocytes, and lymphocytes. As the cells become more specialized, their reproduction and development slow down. Eventually, highly differentiated cells become unable to reproduce and some— skin cells, for example— are programmed to die and be replaced.

Cancer cells lose the ability to differentiate— that is, they enter a state, called anaplasia, in which they no longer appear or function like the original cell. (See Understanding anaplasia, page 18.)

Anaplasia occurs in varying degrees. The less the cells resemble the cell of origin, the more anaplastic they’re said to be. As the anaplastic cells continue to reproduce, they lose the typical characteristics of the original cell.

Some anaplastic cells begin functioning as another type of cell, possibly becoming a site for hormone production. For example, small-cell lung cancer cells often produce antidiuretic hormone, which is produced by the hypothalamus but stored in and secreted by the posterior pituitary gland.

When anaplasia occurs, cells of the same type in the same site exhibit many different shapes and sizes. Mitosis is abnormal and chromosome defects are common.

The abnormal and uncontrolled cell proliferation of cancer cells is associated with numerous changes within the cancer cell itself. These changes affect the cell membrane, cytoskeleton, and nucleus.

Typically, a long time passes between the initiating event and the appearance of cancer. During this time, the cancer cells continue to grow, develop, and replicate, each time undergoing successive changes and further mutations.

How fast a tumor grows depends on specific characteristics of the tumor and its host.

Between the initiating event and the emergence of a detectable tumor, some or all of the mutated cells may die. The survivors, if any, reproduce until the tumor reaches a diameter of 1 to 2 mm. New blood vessels form to support continued growth and proliferation. As the cells further mutate and divide more rapidly, they become more undifferentiated. The number of cancerous cells soon begins to exceed the number of normal cells. Eventually, the tumor mass extends, spreading into local tissues and invading the surrounding tissues. When the local tissue is blood or lymph, the tumor can gain access to the circulation. Once access is gained, tumor cells that detach or break off travel to distant sites in the body, where they can survive and form a new tumor in that secondary site. This process is called metastasis.