Malignancy and metastasis

ANATOMY OR SYSTEM AFFECTED: All

DEFINITION: Malignancy: the uncontrolled growth of tumor cells that invade and compress surrounding tissues and break through the skin or barriers within the body; metastasis: the tendency of malignant cells to break loose from their tumor of origin to travel to other locations within the body

CAUSES: Genetic factors, carcinogens, retroviruses

SYMPTOMS: Vary; can include loss or impairment of normal bodily functions, interrupted nerve function, internal or external bleeding and infection, pain, swelling, fatigue, weakness, weight loss

DURATION: Often chronic with recurrent episodes

TREATMENTS: Surgery, radiation, chemotherapy

Causes and Symptoms

Cancer cells are characterized by two primary features. One of these is uncontrolled cell division, in which cells enter an unregulated, rapid growth phase by losing the controls that normally limit division rates to the amount required for normal growth and maintenance of body tissues. The second feature is metastasis, in which cells lose the connections that normally hold them in place in body tissues, break loose, and spread from their original sites to lodge and grow in other body locations. Tumor cells with these characteristics are described as malignant.

The detrimental effects of solid malignant tumors are caused by the interference of rapidly growing masses of cancer cells with the activities of normal tissues and organs or by the loss of vital functions due to the conversion of cells with essential functions to nonfunctional forms. Some malignant tumors of glandular tissue upset bodily functions by producing and secreting excessive quantities of hormones.

As solid malignant tumors grow, they compress surrounding normal tissues, destroying normal structures by cutting off blood supplies and interrupting nerve function. They may also break through barriers that separate major body regions, such as internal membranes and or the gut wall. They may also break through the skin. Such breakthroughs cause internal or external bleeding and infection, and they destroy the organization and separation of body regions necessary for normal function. Both compression and breakthroughs can cause pain that, in advanced cases, may become extreme.

Malignant tumors of blood tissues involve cell lines that normally divide to supply the body’s requirements for red and white blood cells. Cancer in these cell lines crowds the bloodstream with immature, nonfunctional cells that are unable to accomplish required activities, such as the delivery of oxygen to tissues or the activation of the immune response.

When the total mass of actively growing and dividing malignant cells becomes large, their demands for may deprive normal cells, tissues, and organs of needed supplies, leading to generally impaired functions, fatigue, weakness, and weight loss.

Not all unregulated tissue growths are malignant. Some tumors, such as common skin warts, are benign—they do not usually interfere with normal body functions. They grow relatively slowly and do not metastasize. Often, benign tumors are surrounded by a closed capsule of that prevents or retards expansion and breakup. Some initially benign tumors may change to malignant forms, however, including even common skin warts.

Individual cells of a malignant tumor exhibit differences from normal cells in activity, biochemistry, physiology, and structure. First and foremost is the characteristic of uncontrolled division. Cancer cells typically move through the division cycle much more rapidly than normal cells. This rapid division is accompanied by biochemical changes characteristic of dividing cells, such as high metabolic rates; increases in the rate of transport of substances across the plasma membrane; increases in protein phosphorylation; raised cytoplasmic concentrations of sodium, potassium, and calcium ions; and an elevated pH. Often chromosomal abnormalities are present, including extra or missing chromosomes, exchanges of segments between chromosomes, and breakage.

Cancer cells also typically fail to develop all the characteristics and structures of fully mature cells of their type. They may lose mature characteristics if these were attained before conversion to the malignant state. Frequently, loss of mature characteristics involves disorganization or disappearance of the cytoskeleton. Alterations are also noted in the structure and density of surface carbohydrate groups. Cancer cells lose tight attachments to their neighbors or to supportive extracellular materials such as collagen; some cancer cells secrete enzymes that break cell connections and destroy elements of the extracellular material, aiding their movement into and through surrounding tissues. If removed from the body and placed in test-tube cultures, most cancer cells have the capacity to divide indefinitely. In contrast, most normal body cells placed in a culture medium eventually stop dividing.

The conversion of normal cells to malignant types usually involves multiple causes inducing a series of changes that occur in stages over a considerable length of time. This characteristic is known as the multistep progression of cancer. In most cases, the complete sequence of steps leading from an initiating alteration to full is unknown.

The initial event in a multistep progression usually involves the alteration of a gene from a normal to an aberrant form known as an oncogene. The gene involved is typically one that regulates cell growth and division or takes part in biochemical sequences with this effect. The alteration may involve the substitution or loss of DNA sequences, the movement of the gene to a new location in the chromosomes, or the movement of another gene or its controlling elements to the vicinity of the gene. In some cases, the alteration involves a gene that in normal form suppresses cell division in cells in which it is active. Loss or alteration of function of such genes, known as tumor suppressor genes, can directly or indirectly increase growth and division rates.

An initiating genetic alteration may be induced by a long list of factors, including exposure to radiation or certain chemicals, the insertion of viral DNA into the chromosomes, or the generation of random mutations during the duplication of genetic material. In a few cancers, the initiating event involves the insertion of an into the DNA by an infecting virus that carries the oncogene as a part of its genetic makeup.

In some cases, about 5 percent in humans, an initiating oncogene or faulty tumor suppressor gene is inherited, producing a strong predisposition to the development of malignancy. Among these strongly predisposed cancers are familial retinoblastoma, familial adenomatous of the colon, and multiple endocrine neoplasia, in which tumors develop in the thyroid, adrenal medulla, and parathyroid glands. In addition to the strongly predisposed cancers, some, including breast cancer, ovarian cancer, and colon cancers other than familial adenomatous polyps, show some degree of disposition in family lines, meaning that members of these families show a greater tendency to develop the cancer than individuals in other families.

Subsequent steps from the initiating change to the fully malignant state usually include the conversion of additional genes to oncogenic form or the loss of function of tumor suppressor genes. Also important during intermediate stages are further alterations to the initial and succeeding oncogenes that increase their activation. The initial conversion of a normal gene to oncogenic form by its movement to a new location in the may be compounded at successive steps, for example, by sequence changes or the multiplication of the oncogene into extra copies. The subsequent steps in progression to the malignant state are driven by many of the sources of change responsible for the initiating step. Because genetic alterations often occur during the duplication and division of the genetic material, an increase in the cell division rate by the initiating change may increase the chance that further alterations leading to full malignancy will occur.

A change advancing the progression toward full malignancy may take place soon after a previous change or only after a long delay. Moreover, further changes may not occur, leaving the progression at an intermediate stage, without the development of full malignancy, for the lifetime of the individual. The avoidance of environmental factors that induce genetic alterations, including overexposure to radiation sources such as sunlight, x-rays, and radon gas and chemicals such as those in cigarette smoke, increases the chance that progression toward malignancy will remain incomplete.

The last stage in progression to full malignancy is often metastasis. After the loss of normal adhesions to neighboring cells or to elements of the extracellular matrix, the separation and movement of cancer cells from a primary tumor to secondary locations may occur through the development of active or through breakage into elements of the circulatory system.

Relatively few of the cells that break loose from a tumor survive the rigors of passage through the body. Most are destroyed by various factors, including deformation by passage through narrow and destruction by blood turbulence around the heart and vessel junctions. Furthermore, tumor cells often develop changes in their surface groups that permit detection and elimination by the as they move through the body. Unfortunately, the rigors of travel through the body may act as a sort of natural selection for the cells that are most malignant—that is, those most able to resist destruction—which can then grow uncontrollably and spread further by metastasis.

Many natural and artificial agents trigger the initial step in the progression to the malignant state or push cells through intermediate stages. Most of these agents, collectively called carcinogens, are chemicals or forms of radiation capable of inducing chemical changes in DNA. Some, however, may initiate or further this progression by modifying ribonucleic acids (RNAs) or proteins, or they may act by increasing the rate of DNA and cell division.

Treatment and Therapy

Cancer is treated most frequently by one or a combination of three primary techniques: surgical removal of tumors, radiation therapy, and chemotherapy. Surgical removal is most effective if the growth has remained localized so that the entire tumor can be detected and removed. Often, surgery is combined with radiation or in an attempt to eliminate malignant cells that have broken loose from a primary tumor and lodged in other parts of the body. Surgical removal followed by chemotherapy is presently the most effective treatment for most forms of cancer, especially if the tumor is detected and removed before extensive has taken place. Most responsive to surgical treatments have been skin cancers, many of which are easily detected and remain localized and accessible.

Radiation therapy may be directed toward the destruction of a tumor in a specific body location. Alternatively, it may be used in whole-body exposure to kill cancer cells that have metastasized and lodged in many body regions. In either case, the method takes advantage of the destructive effects of radiation on DNA, particularly during periods when the DNA is under duplication. Because cancer cells undergo replication at higher rates than most other body cells, the technique is more selective for tumors than for normal tissues. The selection is only partial, however, so that body cells that divide rapidly, such as those of the blood, follicles, and intestinal lining, are also affected. As a consequence, often has side effects ranging from unpleasant to serious, including hair loss, and vomiting, anemia, and suppression of the immune system. Because radiation is mutagenic, radiation therapy carries the additional disadvantage of being carcinogenic; the treatment, while effective in the destruction or inhibition of a malignant growth, may also initiate new cancers or push cells through intermediate stages in progression toward malignancy.

When possible, radiation is directed only toward the body regions containing a tumor in order to minimize the destruction of normal tissues. This may be accomplished by focusing a radiation source on the tumor or by shielding body regions outside the tumor with a radiation barrier such as a lead sheet.

Chemotherapy involves the use of chemicals that retard cell division or kill tumor cells more readily than normal body cells. Most of the chemicals used in chemotherapy have been discovered by routine of substances for their effects on cancer cells in cultures and test animals. Several hundred thousand chemicals were tested in the screening effort that produced the thirty or so chemotherapeutic agents available for cancer treatment.

Many of the chemicals most effective in cancer chemotherapy alter the chemical structure of DNA, produce breaks in DNA molecules, slow or stop DNA duplication, or interfere with the natural systems repairing chemical lesions in DNA. These effects inhibit cell division or interfere with cell functions sufficiently to kill the cancer cells. Because DNA is most susceptible to chemical alteration during duplication and cancer cells duplicate their DNA and divide more rapidly than most normal tissue cells, the effects of these chemicals are most pronounced in malignant types. Normal cells, however, are also affected to some extent, particularly those in tissues that divide more rapidly. As a result, chemotherapeutic chemicals can produce essentially the same detrimental side effects as radiation therapy. The side effects of chemotherapy are serious enough to be fatal in 2 to 5 percent of persons treated. Because they alter DNA, many chemotherapeutic agents are carcinogens and carry the additional risk, as with radiation, of inducing the formation of new cancers.

Not all chemicals used in chemotherapy alter DNA. Some act by interfering with cell division or other cell processes rather than directly modifying DNA. Two chemotherapeutic agents often used in cancer treatment, vinblastine and taxol, for example, slow or stop cell division through their ability to interfere with the spindle structure that divides chromosomes. The drugs can slow or stop tumor growth as well as the division of normal cells.

Tumors frequently develop resistance to some of the chemicals used in chemotherapy, so that the treatment gradually becomes less effective. Development of resistance is often associated with random duplication of DNA segments, commonly noted in tumor cells. In some, the random duplication happens to include genes that provide resistance to the chemicals employed in chemotherapy. The genes providing resistance usually encode enzymes that break down the applied chemical or its metabolic derivatives or transport proteins of the plasma capable of rapidly excreting the chemical from the cell. One gene in particular, the multidrug resistance gene (MDR), is frequently found to be duplicated or highly activated in resistant cells. This gene, which is normally active in cells of the liver, kidney, adrenal glands, and parts of the digestive system, encodes a transport pump that can expel a large number of substances from cells, including many of those used in chemotherapy. Overactivity of the MDR pump can effectively keep chemotherapy drugs below toxic levels in cancer cells. Cells developing resistance are more likely to survive chemotherapy and give rise to malignant cell lines with resistance. The chemotherapeutic agents involved may thus have the unfortunate effect of selecting cells with resistance, thereby ensuring that they will become the dominant types in the tumor.

Success rates with chemotherapy vary from negligible to about 80 percent, depending on the cancer type. For most, success rates do not range above 50 to 60 percent. Some cancer types, including lung, breast, ovarian, and colorectal tumors, respond poorly or not at all to chemotherapy. The overall cure rate for surgery, radiation, and chemotherapy combined, as judged by no of the cancer for a period of five years, is between 50 and 60 percent.

It is hoped that full success in the treatment of cancer will come from the continued study of the genes controlling cell division and the regulatory mechanisms that modify the activity of these genes in the cell cycle. An understanding of the molecular activities of these genes and their modifying controls may bring with it a molecular means to reach specifically into cancer cells and halt their growth and metastasis.

Perspective and Prospects

Indications that malignancy and metastasis might have a basis in altered gene activity began to appear in the nineteenth century. In 1820, a British physician, Sir William Norris, noted that melanoma, a cancer involving pigmented skin cells, was especially prevalent in one family under study. More than forty kinds of cancer, including common types such as breast cancer and colon cancer, have since been noticed to occur more frequently in some families than in others. Another indication that cancer has a basis in altered gene activity was the fact that the chromosomes of many tumor cells show abnormalities, such as extra chromosomes, broken chromosomes, or rearrangements of one kind or another. These abnormalities suggested that cancer might be induced by altered genes with activities related to cell division.

These indications were put on a firm basis by research with tumors caused by viruses infecting animal cells, most notably those caused by a group of viruses called retroviruses. Many retroviral infections cause little or no damage to their hosts, but some are associated with induction of cancer. (Another type of pathogenic retrovirus is responsible for acquired immunodeficiency syndrome, or AIDS.) The cancer-inducing types of were found to carry genes capable of transforming normal cells into malignant ones. The transforming genes were at first thought to be purely viral in origin, but DNA sequencing and other molecular approaches revealed that the viral oncogenes had normal counterparts among the genes directly or indirectly regulating cell division in cells of the infected host. Among the most productive of the investigators using this approach were J. Michael Bishop and Harold E. Varmus, who received the 1989 Nobel Prize in Physiology or Medicine for their research establishing the relationship between retroviral oncogenes and their normal cellular counterparts.

The discovery of altered host genes in cancer-inducing retroviruses prompted a search for similar genes in nonviral cancers. Much of this work was accomplished by transfection experiments, in which the DNA of cancer cells is extracted and introduced into cultured mouse cells. Frequently, the mouse cells are transformed into types that grow much more rapidly than normal cells. The human oncogene responsible for the transformation is then identified in the altered cells. Many of the oncogenes identified by transfection turned out to be among those already carried by retroviruses, confirming by a different route that these genes are capable of contributing to the transformation of cells into a cancerous state. The transfection experiments also identified some additional oncogenes not previously found in retroviruses.

In spite of impressive advances in treatment, cancer remains among the most dreaded of human diseases. Recognized as a major threat to health since the earliest days of recorded history, cancer still counts as one of the most frequent causes of human fatality. In technically advanced countries, it accounts for about 15 to 20 percent of deaths each year. Smoking, the most frequent single cause of cancer, is estimated to be responsible for about one-third of these deaths. According to the US Centers for Disease Control and Prevention (CDC), cancer was the second-leading cause of death in the United States in 2023. Heart disease was first, but cancer killed 609,820 people in 2024, according to the CDC.

Bibliography

Alberts, Bruce, et al. Molecular Biology of the Cell. 5th ed. New York: Garland, 2008.

"An Update on Cancer Deaths in the United States." Centers for Disease Control and Prevention, 28 June 2023, www.cdc.gov/cancer/dcpc/research/update-on-cancer-deaths/index.htm. Accessed 2 Apr. 2024.

“Cancer.” MedlinePlus, May 2, 2013.

Eyre, Harmon J., Dianne Partie Lange, and Lois B. Morris. Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery. 2d ed. Atlanta: American Cancer Society, 2002.

Ko, Andrew, Malin Dollinger, and Ernest H. Rosenbaum. Everyone’s Guide to Cancer Therapy. 5th ed. Kansas City, Mo.: Andrews McMeel, 2008.

Lackie, J. M., ed. The Dictionary of Cell and Molecular Biology. 4th ed. Boston: Academic Press, 2007.

Lodish, Harvey, et al. Molecular Cell Biology. 7th ed. New York: W. H. Freeman, 2012.

“Metastatic Cancer Fact Sheet.” National Cancer Institute, March 28, 2013.

Vipler, Benjamin. "What’s Lymphoma?” — Risks Posed by Immediate Release of Test Results to Patients." The New England Journal of Medicine, vol. 390, 16 Mar. 2024, pp. 1064-1066, www.nejm.org/doi/full/10.1056/NEJMp2312953. Accessed 3 Apr. 2024.

Weinberg, Robert. “Finding the Anti-Oncogene.” Scientific American 259 (September, 1988): 44-51.

Wolfe, Stephen L. Molecular and Cellular Biology. Belmont, Calif.: Wadsworth, 1993.