Cancer will occur in about 1 of every 3 people currently living in North America (ACS, 2011; Canadian Cancer Society, 2010), although cancer risk differs for each person. More than 10 million Americans with a history of cancer are alive today, nearly 5 million of whom are considered cured (ACS, 2011).

Pathophysiology

Growth of cells and tissues is expected during infancy and childhood, and many human body cells continue to “grow” by mitosis (cell division) long after maturation is complete. Such cells are located in tissues in which constant damage or wear is likely and continued cell growth is needed to replace dead tissues. Cells of the skin, hair, mucous membranes, bone marrow, and linings of organs such as the lungs, stomach, intestines, bladder, and uterus, among others have the ability to divide throughout a person’s life span. The growth of these cells is well controlled, ensuring that only the right number of cells is always present in any tissue or organ.

Some tissues and organs stop growing by cell division after development is complete. For example, heart muscle cells no longer divide after fetal life; the number of heart muscle cells is fixed at birth. The size of the heart increases as the person grows because each cell gets larger, but the number of heart muscle cells does not increase. Growth that causes tissue to increase in size by enlarging each cell is hypertrophy. Growth that causes tissue to increase in size by increasing the number of cells is hyperplasia (Fig. 23-1).

FIG. 23-1 Tissue growth by hypertrophy and hyperplasia.

Any new or continued cell growth not needed for normal development or replacement of dead and damaged tissues is called neoplasia. This cell growth is always abnormal even if it causes no harm. Whether the new cells are benign or cancerous, neoplastic cells develop from normal cells (parent cells). Thus cancer cells were once normal cells but changed to no longer look, grow, or function normally. The strict processes controlling normal growth and function have been lost. To understand how cancer cells grow, it is helpful to first understand the regulation and function of normal cells.

Biology of Normal Cells

Many different normal cells work together to make the whole person function at an optimal level. For optimal function, each cell must perform in a predictable manner.

Specific morphology is the feature in which each normal cell type has a distinct and recognizable appearance, size, and shape, as shown in Fig. 23-2.

FIG. 23-2 Distinctive morphology of some normal cells.

A small nuclear-to-cytoplasmic ratio means that the nucleus of a normal cell does not take up much space inside the cell. As shown in Fig. 23-2, the size of the normal cell nucleus is small compared with the size of the rest of the cell, including the cytoplasm.

Differentiated function means that every normal cell has at least one special function it performs to contribute to whole-body function. For example, skin cells make keratin, liver cells make bile, cardiac muscle cells contract, nerve cells conduct impulses, and red blood cells make hemoglobin.

Tight adherence occurs because normal cells make proteins that protrude from the membranes, allowing cells to bind closely and tightly together. One such protein is fibronectin, which keeps most normal tissues bound tightly to each other. Exceptions are blood cells. Red blood cells and white blood cells produce no fibronectin and do not usually adhere together.

Nonmigratory means that normal cells do not wander throughout the body (except for blood cells). This occurs in normal cells because they are tightly bound together, which prevents cell wandering from one tissue into the next.

Orderly and well-regulated growth is a very important feature of normal cells. They divide (undergo mitosis) for only two reasons: (1) to develop normal tissue or (2) to replace lost or damaged normal tissue. Even when they are capable of mitosis, normal cells divide only when body conditions, including the need for more cells, adequate space, and sufficient nutrients and other resources, are just right. Cell division (mitosis), occurring in a well-recognized pattern, is described by the cell cycle. Fig. 23-3 shows the phases of the cell cycle. The amount of time needed for one cell to divide completely into two cells is the generation time. For normal cells, the generation time varies by tissue and organ type.

FIG. 23-3 The cell cycle.

Living cells not actively reproducing are in a reproductive resting state termed G₀. During the G₀ period, cells actively carry out their functions but do not divide. Normal cells spend most of their lives in the G₀ state rather than in a reproductive state.

Mitosis makes one cell divide into two cells. These two new cells are identical to each other and to the cell that began mitosis. The steps of entering and completing the cell cycle are tightly controlled. Much of this control is regulated by proteins produced by “suppressor genes.”

Whether a cell enters and completes the cell cycle to form two new cells depends on the presence and absence of specific proteins. Proteins that promote cells to enter and complete cell division are produced by oncogenes and are known as cyclins. When cyclins are activated, they allow a cell to leave G₀ and enter the cycle. These activated cyclins then drive the cell to progress through the different phases of the cell cycle and divide. Proteins produced by suppressor genes regulate the amount of cyclins present and ensure that cell division occurs only when it is needed. Thus normal cell division is a balance between the proteins that promote cell division (cyclins) and the proteins that limit cell division (suppressor gene products).

Fig. 23-4 shows the activities of the phases of the cell cycle (described below):

• G₁. In this phase, the cell is getting ready for division by taking on extra nutrients, making more energy, and growing extra membrane. The amount of cytoplasm also increases.

• S. Because making one cell into two cells requires twice as much of everything, including DNA, the cell must double its DNA content through DNA synthesis. This process occurs in S phase.

• G₂. In this phase, the cell makes important proteins that will be used in actual cell division and in normal physiologic function after cell division is complete.

• M. The single cell splits apart into two cells (actual mitosis) during M phase.

FIG. 23-4 Cellular events during mitotic cell division.

Contact inhibition is the stopping of further rounds of cell division when the dividing cell is completely surrounded and touched (contacted) by other cells. Of the normal cells that can divide, each cell divides only when some of its surface is not in direct contact with another cell. Once a normal cell is in direct contact on all surface areas with other cells, it no longer undergoes mitosis. Thus normal cell division is contact inhibited.

Apoptosis is programmed cell death. Not only do normal cells have to divide only when needed and perform their specific differentiated functions, some cells also have to die at the appropriate time to ensure optimum body function. Thus normal cells have a finite life span. With each round of cell division, the telomeric DNA at the ends of the cell’s chromosomes shortens (see Chapter 6). When this DNA is gone, the cell responds to signals for apoptosis. The purpose of apoptosis is to ensure that each organ has an adequate number of cells at their functional peak.

Normal chromosomes (euploidy) is a feature of most normal human cells. These cells have 23 pairs of chromosomes, the correct number for human beings.

Biology of Abnormal Cells

Body cells are exposed to a variety of conditions that can alter how the cells grow or function. When either cell growth or cell function is changed, the cells are considered abnormal. Table 23-1 compares features of normal, benign tumor, and cancer (malignant) cells.

TABLE 23-1 CHARACTERISTICS OF NORMAL AND ABNORMAL CELLS

Features of Benign Tumor Cells

Benign tumor cells are normal cells growing in the wrong place or at the wrong time. Examples include moles, uterine fibroid tumors, skin tags, endometriosis, and nasal polyps. Benign tumor cells have these characteristics:

• Specific morphology occurs with benign tumors. They look like the tissues they come from, retaining the specific morphology of parent cells.

• A small nuclear-to-cytoplasmic ratio is a feature of benign tumors just like completely normal cells.

• Specific differentiated functions continue to be performed by benign tumors. For example, in endometriosis, a type of benign tumor, the normal lining of the uterus (endometrium) grows in an abnormal place (e.g., on an ovary, on the peritoneum, or in the chest cavity). This displaced endometrium acts just like normal endometrium by changing each month under the influence of estrogen. When the hormone level drops and the normal endometrium sheds from the uterus, the displaced endometrium, wherever it is, also sheds.

• Tight adherence of benign tumor cells to each other occurs because they continue to make fibronectin. In addition, many benign tissues are “encapsulated,” or surrounded with fibrous connective tissue, helping to hold the benign tissue together.

• No migration or wandering of benign tissues occurs because they remain tightly bound and do not invade other body tissues.

• Orderly growth with normal growth patterns occurs in benign tumor cells even though their growth is not needed. Growth may continue beyond an appropriate time or occur in the wrong place, but the rate of growth is normal. The benign tumor grows by hyperplastic expansion. It does not invade.

• Normal chromosomes are usually found in benign tumor cells, although there are exceptions. Most of these cells have 23 pairs of chromosomes, the correct number for humans.

Features of Cancer Cells

Cancer (malignant) cells are abnormal, serve no useful function, and are harmful to normal body tissues. Cancers commonly have these features:

• Anaplasia is the cancer cells’ loss of the specific appearance of their parent cells. As a cancer cell becomes more malignant, it becomes smaller and rounded. This appearance change can make diagnosis of cancer type difficult, because many different types of cancer cells look alike.

• A large nuclear-cytoplasmic ratio occurs in cancer cells with the cancer cell nucleus being larger than that of a normal cell and the cancer cell being small. The nucleus occupies much of the space within the cancer cell, creating a large nuclear-to-cytoplasmic ratio.

• Specific functions are lost partially or completely in cancer cells. Cancer cells serve no useful purpose.

• Loose adherence is typical for cancer cells because they do not make fibronectin. As a result, cancer cells easily break off from the main tumor.

• Migration occurs because cancer cells do not bind tightly together and have many enzymes on their cell surfaces. These features allow the cells to slip through blood vessel walls and between tissues, spreading from the main tumor site to many other body sites. This ability to spread (metastasize) is unique to cancer cells and a major cause of death. Cancer cells expand by mitosis and invade other tissues, both close by and more remote from the original tumor. Invasion and persistent growth make untreated cancer deadly.

• Contact inhibition does not occur in cancer cells, even when all sides of these cells are in continuous contact with the surfaces of other cells. This persistence of cell division makes the disease difficult to control.

• Rapid or continuous cell division occurs in many types of cancer cells because they re-enter the cell cycle for mitosis almost continuously. In addition, some cancer cells have a short generation time (2 to 4 hours), but most cancer cells have a generation time similar to that of the parent cells. These cells also do not respond to signals for apoptosis. Most cancer cells have a lot of the enzyme telomerase, which maintains telomeric DNA. As a result, cancer cells do not respond to apoptotic signals and have an unlimited life span (are “immortal”).

• Abnormal chromosomes (aneuploidy) are common in cancer cells as they become more malignant. Chromosomes are lost, gained, or broken; thus cancer cells can have more than 23 pairs or fewer than 23 pairs. Cancer cells also may have broken and rearranged chromosomes.

Cancer Development

Carcinogenesis and oncogenesis are other names for cancer development. Table 23-2 lists key concepts about cancer development. The process of changing a normal cell into a cancer cell is called malignant transformation, occurring through the steps of initiation, promotion, progression, and metastasis.

TABLE 23-2 KEY CONCEPTS RELATED TO CANCER DEVELOPMENT

• Neoplastic cells originate from normal body cells.

• Transformation of a normal cell into a cancer cell involves mutation of the genes (DNA) of the normal cell.

• Oncogenes that are overexpressed can cause a cell to develop into a tumor.

• Only one cell has to undergo malignant transformation for cancer to begin.

• Benign tumors grow by expansion, whereas malignant tumors grow by invasion.

• Most tumors arise from cells that are capable of cell division.

• A key feature of cancer cells is the loss of apoptosis. These cells have an “infinite” life span.

• Primary prevention of cancer involves avoiding exposure to known causes of cancer.

• Secondary prevention of cancer involves screening for early detection.

• Tobacco use is a causative or permissive factor in 30% of all cancers.

• Tumors that metastasize from the primary site into another organ are still designated as tumors of the originating tissue.