Cancer
No doubt the mere mention of “cancer” elicits fear and anxiety. Cancer is the growth of abnormal cells that tend to invade neighboring tissue and spread to distant body sites. It is a condition of uncontrolled cellular proliferation that knows no limits and serves no purpose for the host. According to the American Cancer Society, approximately 1.4 new cancer cases were predicted to be diagnosed in 2008.
The term cancer refers to more than 100 forms of the disease. Although each cancer has unique features, all cancers develop by following a few shared processes that in turn depend upon crucial genetic alterations. For a cell to become cancerous, these genetic alterations must spur cell growth, inactivate genes that normally slow growth, allow cells to keep dividing, thereby immortalizing them, and allow cells to live on with abnormalities that otherwise would cause them to undergo apoptosis. In addition, genetic alterations must occur that allow cancer cells to recruit normal cells to support and nourish them, and to develop strategies that prevent the immune system from destroying them. These processes that cancer cells share and that differ substantially from those of normal cells are the focus of this chapter and of the ongoing, worldwide research effort to prevent and cure cancer.
● Physiologic Concepts
CELLULAR REPRODUCTION
Although all cells reproduce during embryogenesis, only certain cells continue to do so after birth. Cells that continue to reproduce, such as liver, skin, and gastrointestinal (GI) cells, duplicate their DNA exactly before splitting into two new daughter cells. Cells reproduce by going through a process called the cell cycle, described fully in Chapter 2. Advancement through the cell cycle is tightly controlled and can be stopped or started depending on the conditions of the cell and the signals it receives, some of which are described below.
Cell cycling is controlled by the contributions of a variety of genes that respond to cues on cell crowding, tissue injury, and growth needs. In general, cells go through the cell cycle when stimulated to do so by hormones and growth factors secreted by distant cells, by locally produced growth factors, and by chemical cues released from neighboring cells, including cytokines produced by immune and inflammatory cells. These external cues act by binding to specific receptors on the plasma membrane of the target cell. Once bound, the receptor complex activates a second messenger system, which delivers the growth signal to the nucleus. When the signal reaches the nucleus, certain proteins there, called transcription factors, turn on or off specific genes that in turn produce proteins that control cell proliferation. Activated genes also produce proteins that feed back on each of the steps of signaling and messenger stimulation to amplify or minimize the effects of the initial stimulus.
The following discussion describes the external cues controlling cell growth and provides an example of an important second messenger system. Finally, the two broad categories of genes whose end products ultimately control the cell cycle are presented: the tumor suppressor genes and the proto-oncogenes.
Hormones and Growth Factors that Control Cellular Reproduction
Various hormones and growth factors may stimulate cells to increase or decrease their rate of reproduction. Table 3-1 includes selected growth hormones and their significance. Some of these substances inhibit growth of other cells while stimulating cell division and growth in target cells.
Chemicals that Control Cellular Reproduction
Various chemicals may stimulate cells to increase or decrease their rate of reproduction. These chemicals may be released by injured or infected neighboring cells or by immune and inflammatory cells drawn to an area after tissue
injury. Many cytokines, released by cells of the immune system, stimulate cellular proliferation and differentiation. Cells possess receptors on their plasma membranes for immune and inflammatory mediators. Binding by some of these substances causes cells to produce more receptors for other immune proteins, thereby amplifying the initial response.
injury. Many cytokines, released by cells of the immune system, stimulate cellular proliferation and differentiation. Cells possess receptors on their plasma membranes for immune and inflammatory mediators. Binding by some of these substances causes cells to produce more receptors for other immune proteins, thereby amplifying the initial response.
TABLE 3-1 Growth Factors and Associated Significance | ||||||||||||||||||||
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Physical Cues that Control Cellular Reproduction
Neighboring cells appear to communicate with each other about tissue crowding and tissue type by releasing locally active chemicals, and by passing ions and other small molecules through channels called gap junctions. Normal cells respond to physical and chemical cues released by a large number of similar cells by slowing or stopping their rate of reproduction. This allows cellular growth and proliferation to be controlled based on tissue space requirements. These methods of communication allow cells to recognize other cells of the same type (e.g., kidney cells recognize other kidney cells).
Cytoplasmic Second Messenger System Controlling Cellular Reproduction
The cytoplasmic signal cascade begins after a protein hormone, growth factor, or other chemical binds to a cell membrane receptor and turns on a specific second messenger system. Activated second messenger proteins relay the growth-controlling signal to the nuclear transcription proteins. An example of an important cytoplasmic messenger is the ras protein. The normal ras protein transmits stimulatory signals from bound growth factor receptors on a cell’s membrane to other proteins down the line that ultimately turn on cell cycling. Many cancer cells show a mutation in the gene that produces the ras protein, such that it is always produced, even when growth factor receptors are not stimulated. Mutation of the ras protein was discovered as the first human oncogene in bladder cancer cells. This mutation results in uncontrolled cellular proliferation even when growth factors are not present. Hyperactive ras proteins are found in approximately one-fourth of all human tumors.
Tumor Suppressor Genes
Several different genes, called tumor suppressor genes, control cell cycling by coding for proteins that inhibit cellular growth and reproduction. Tumor suppressor genes are vitally important in all normally functioning cells. As described later, although cancer results from many accumulated mutations, the first mutation that sets a cell on its way to becoming cancerous often occurs in one of the tumor suppressor genes. For cancer to occur, the tumor suppressor gene must be inactivated.
Tumor suppressor genes act by producing proteins that slow down or stop the second messenger brigade, including proteins that interfere with the functioning of the stimulatory ras protein. Tumor suppressor genes may also code for proteins that make up surface receptors that bind growth-inhibiting hormones or factors. Other tumor suppressor genes, when activated, stimulate a damaged cell to undergo apoptosis (programmed cell death). Finally, some tumor suppressor genes produce proteins that code for important brakes that
act directly on cells about to commit to going through the cell cycle; these genes include the Rb gene and the p53 gene.
act directly on cells about to commit to going through the cell cycle; these genes include the Rb gene and the p53 gene.
The Rb Gene
The Rb gene codes for the pRb protein, the master brake of the cell cycle. Without this protein, the cell cycle is constantly in the “on mode,” and cellular reproduction can occur nonstop. Mutations in this gene have been identified in a variety of human cancers including bone, bladder, pancreatic, small cell lung, and breast cancer, and the cancer after which the gene was named, retinoblastoma. Mutations in the Rb locus have been identified in up to 70% of individuals with osteosarcoma.
The p53 Gene
The p53 gene codes for the p53 protein, which normally monitors the health of the cell and the integrity of cellular DNA. The p53 protein can act as a powerful brake to halt cell division before it is too late if errors in DNA transcription are present or if cellular conditions are not favorable. The p53 protein can cause the cell either to pause in the cycle indefinitely until a DNA error is corrected, or to undergo apoptosis. By controlling cellular replication, the p53 gene ensures that a genetic error is not passed on and only healthy cells reproduce. Deletion or mutation of the gene occurs in approximately 75% of colorectal cancer cases. It has also been associated with breast cancer, small cell lung carcinoma, hepatocellular carcinoma, astrocytoma, and many other tumors. Mutations in the p53 gene are shown to occur in at least 50% of all types of tumors making it the most common genetic change in human cancer.
Other Tumor Suppressor Genes
Although Rb and p53 have been the most extensively studied tumor suppressor genes, Table 3-2 includes other genes and their associated pathologies when mutations occur.
Proto-oncogenes
Proto-oncogenes are genes found in all cells that, when activated, stimulate a cell to go through the cell cycle, resulting in cellular growth and proliferation. These genes may stimulate cell cycling at all levels, including (1) producing proteins that make up membrane receptors for growth-stimulating hormones and chemicals, (2) increasing the production of second messenger proteins, including the ras protein, that transfer growth signals to the nucleus, and (3) producing transcription factors that turn on vital genes to force cell growth forward (e.g., the family of myc genes).
The myc Genes
The myc genes are a family of proto-oncogenes that code for transcription factor proteins that drive cellular reproduction. In healthy cells, myc genes are
activated only in response to growth factors acting on the cell surface. In many types of cancer, however, the myc gene is turned on constantly, even in the absence of growth factors. Typically, low levels of proliferating lymphocytes stimulate the gene and mature lymphocytes stop the myc. Cellular proliferation can occur without control when this gene is damaged.
activated only in response to growth factors acting on the cell surface. In many types of cancer, however, the myc gene is turned on constantly, even in the absence of growth factors. Typically, low levels of proliferating lymphocytes stimulate the gene and mature lymphocytes stop the myc. Cellular proliferation can occur without control when this gene is damaged.
TABLE 3-2 Tumor Suppressor Genes and Associated Pathologies | ||||||||||||||||||||
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When normal proto-oncogenes become overactive and cause uncontrolled cell division, they are called oncogenes, or cancer-causing genes. Typically, after early embryonic life oncogenes are turned off or tightly controlled. Exposure to a carcinogen can damage the cell’s DNA and cause overstimulation of the oncogene resulting in development of cancer cells. Overstimulated oncogenes produce excess cyclins that interfere with suppressor genes and thus interrupt the balance between cell growth initiation and suppression. Approximately 70 oncogenes have been identified and it is noteworthy that these are not abnormal genes. They are part of a normal cell and only become problematic when exposed to a carcinogen.
CELLULAR DIFFERENTIATION
Differentiation is the process of development in which cells acquire specialized characteristics including structure and function. Normal cells differentiate during development and aggregate with similar differentiated cells. For example, some embryonic cells are destined to become cells of the retina, whereas others are destined to become cells of the skin or heart. The more highly differentiated
a cell, the less frequently it will go through the cell cycle to reproduce and divide. Neurons are highly specialized cells and do not retain the ability to reproduce after the nervous system is completely developed. Skin and mucosal cells continue to be proliferative. Cells that seldom or never go through the cell cycle are unlikely to become cancerous, whereas cells that go through the cell cycle frequently are more likely to become cancerous.
a cell, the less frequently it will go through the cell cycle to reproduce and divide. Neurons are highly specialized cells and do not retain the ability to reproduce after the nervous system is completely developed. Skin and mucosal cells continue to be proliferative. Cells that seldom or never go through the cell cycle are unlikely to become cancerous, whereas cells that go through the cell cycle frequently are more likely to become cancerous.
Differentiation is a sequential process and appears to occur from the selective suppression of certain genes in some cells, whereas in other cells those same genes are active. Differentiation of each cell and tissue appears to affect differentiation of neighboring cells and tissues. Cells release specific growth factors that initiate or guide differentiation of neighboring cells.
CELL RECOGNITION AND ADHESION TO LIKE CELLS
Normal cells adhere to others of the same type and group together. Although the mechanism by which cells recognize each other is not well understood, it appears to involve chemical cues secreted only by certain cells and bound by receptors present only on similar cells. Surface proteins present on one cell type that match up with proteins on similar cells, also appear to assist in similar cell recognition. These surface proteins are cell adhesion molecules that maintain contact between cells and the extracellular matrix. They provide signals that maintain cell survival and cell type differentiation. Cell-to-cell recognition is demonstrated by placing cells of many different types together in a Petri dish; after a certain period, the cells will have moved into clusters with only sametype cells in each cluster.
Other adhesion molecules exist between cells and the underlying tissue matrix. These connections anchor cells to one location. When normal cells become detached from each other or experience a loosening of their attachment to underlying tissue, they respond by initiating apoptosis, which prohibits cells from floating free of their tissue of origin.
THE CELL CLOCK
Normal human cells reproduce a predictable number of times, after which they stop and become senescent. This predictability implies that cells possess some counting system that tells them when to stop dividing. This system is important because if cells divided indefinitely we would have many more cells than is compatible with life. The mechanism by which cells tick off their own divisions involves a telomere-based counting system.
Telomeres, described in Chapter 2, are the end pieces of chromosomes that shorten with each division. When the telomere length becomes sufficiently short (indicating that it has divided a certain number of times) the cell stops dividing. Putting the brakes on cell division in response to telomere shortening
requires that the cell has functioning Rb and p53 proteins. Occasionally, a cell continues to divide after the telomere reaches its threshold length; usually these cells soon self-destruct as their chromosomes begin to chaotically fuse and randomly break.
requires that the cell has functioning Rb and p53 proteins. Occasionally, a cell continues to divide after the telomere reaches its threshold length; usually these cells soon self-destruct as their chromosomes begin to chaotically fuse and randomly break.
Cell crowding also results in neighboring cells releasing signals that inhibit the further replication of cells. This is called contact inhibition.
● Pathophysiologic Concepts
UNCONTROLLED CELLULAR REPRODUCTION
Cancer cells do not respond to the normal cues controlling cellular reproduction. Instead, they go through the cell cycle more often than normal, resulting in an overabundance of abnormal cells. Cancer cells spend little time in the gap stages of interphase and are frequently found in the M (mitosis) and S (DNA copying) stages. This information is vital when selecting treatment for different types of cancer.
Uncontrolled cellular reproduction occurs when cells become independent of normal growth control signals. This characteristic of cancer cells is called autonomy. Autonomy results when cells do not respond to the cues controlling contact inhibition—for example, growth inhibitors released by neighboring cells or inhibitory growth factors and hormones traveling in the circulation. Cancer cells may disregard these signals by not producing membrane receptors that bind the inhibitory growth signals or by not activating appropriate second messengers that transmit inhibitory information to the nucleus. Other cancer cells may overproduce membrane receptors that respond to growth stimulatory signals. Cancer cells may also produce their own growth factors that bind to their cell membranes, thereby promoting self-proliferation and allowing them to be independent of any outside control.
When placed in an in vitro experimental setting, cancer cells aggressively grow on top of each other and produce layers of disorderly cells, ignoring not only chemical signals but the tendency to respect neighboring borders. Autonomy is demonstrated in the tendency of cancer cells to detach from neighboring cells and spread to distant body sites. It has been suggested that the adhesion molecules that exist between cells of the same type and between normal cells and the extracellular matrix no longer exist for cancer cells. Cancer cell autonomy may result from the inactivation of tumor suppressor genes or the change from proto-oncogenes to oncogenes.
ANAPLASIA
A change in the structure of a cell with loss of differentiation is known as anaplasia. Cancer cells demonstrate various degrees of anaplasia. By undergoing
anaplasia, a cancer cell loses its ability to perform its previous functions and bears little resemblance to its tissue of origin. Highly anaplastic cells may appear embryonic and begin to express functions of a different cellular type. Some cancer cells may become ectopic sites of hormone production. For instance, antidiuretic hormone (ADH) or adrenocorticotrophic hormone (ACTH), hormones that are normally synthesized by cells of the hypothalamus and anterior pituitary, respectively, may be secreted by ectopic sites of hormone production. Lung cancers frequently become ectopic sites of hormone production such as ADH or parathyroid hormone (PTH).
anaplasia, a cancer cell loses its ability to perform its previous functions and bears little resemblance to its tissue of origin. Highly anaplastic cells may appear embryonic and begin to express functions of a different cellular type. Some cancer cells may become ectopic sites of hormone production. For instance, antidiuretic hormone (ADH) or adrenocorticotrophic hormone (ACTH), hormones that are normally synthesized by cells of the hypothalamus and anterior pituitary, respectively, may be secreted by ectopic sites of hormone production. Lung cancers frequently become ectopic sites of hormone production such as ADH or parathyroid hormone (PTH).
Because the immune system poorly responds to embryonic antigens, the presence of highly anaplastic cells may interfere with the host’s immune response to the tumor and usually indicates a particularly aggressive cancer.
LOSS OF THE CELL CLOCK
Many cancer cells secrete an enzyme, telomerase, that acts to replace the telomere ends of chromosomes that shorten with each cell division. This leads to a destruction of the cell counting system and immortality of the cell. Not only does telomere replacement allow a cancer cell to continue to divide, increasing its number, but it also gives the cancer cell time to accumulate more mutations, some of which may improve the cell’s ability to evade the immune system or produce newer, more potent growth-stimulatory factors.
NUCLEAR AND CYTOPLASMIC DERANGEMENT
Cancer cells often demonstrate multiple derangements of the nucleus, cytoplasmic organelles, and cytoskeleton. The nucleus is frequently enlarged and deformed, with obvious chromosomal breaks, deletions, additions, and translocations. The rate of mitosis is usually increased. In the cytoplasm, intracellular structures show disorganization and changes in size and shape. Changes in the microtubules that support the cell and are necessary for the control of virtually all intracellular functions are especially significant. The mitochondria become disorganized and misshapen.
TUMOR CELL MARKERS
Some cancer cells release tumor cell markers, which are specific substances secreted by a tumor into the blood, urine, or spinal fluid of an individual with a particular cancer. These markers are especially helpful in identifying the origin of a metastatic or poorly differentiated tumor. Tumor cell markers may be immunoglobulins, fetal proteins (oncofetal antigens), enzymes, hormones, genes, antigens, antibodies, or cystoskeletal and junctional proteins. Because fetal antigens often do not provoke an immune response, they may mask the tumor against the host’s immune system. Tumor cell markers may even include
fragments of DNA that are detectable, with increasingly sensitive measurement techniques, in the circulation when produced in excess by certain tumors.
fragments of DNA that are detectable, with increasingly sensitive measurement techniques, in the circulation when produced in excess by certain tumors.
Clinical Implications of Tumor Cell Markers
Tumor cell markers are clinically important because they offer a means of identifying those at high risk for cancer, identifying certain cancers, and monitoring cancer’s progression before, during, and after treatment. For instance, if a specific tumor cell marker is identified in a patient, it suggests that cancer may exist in the person, and further diagnostic evaluation is necessary. Furthermore, in patients with a known malignancy, if after radiation or chemotherapy the tumor cell marker is not detectable, it suggests that the cancer is in remission. If, however, the tumor cell marker fails to decrease during therapy or reappears in high concentration after therapy, the tumor is unlikely to be in remission.
Examples of Tumor Cell Markers
Table 3-3 includes examples of tumor cell markers and associated cancers.
Although the presence of a tumor cell marker may indicate the presence or recurrence of cancer, sole reliance on the presence or absence of a cell marker is not recommended. Interpretations must be made in the context of a thorough assessment. For example, PSA is detectable in all adult men; only an unexpected rise in PSA in a given individual, or an elevation above a certain age-dependent threshold, is suggestive of disease. Likewise, pregnant women have increased hCG, and CA-125 may be increased in women for reasons other than ovarian cancer. Failure to detect a tumor cell marker does not mean that an individual is cancer-free.
Although the presence of a tumor cell marker may indicate the presence or recurrence of cancer, sole reliance on the presence or absence of a cell marker is not recommended. Interpretations must be made in the context of a thorough assessment. For example, PSA is detectable in all adult men; only an unexpected rise in PSA in a given individual, or an elevation above a certain age-dependent threshold, is suggestive of disease. Likewise, pregnant women have increased hCG, and CA-125 may be increased in women for reasons other than ovarian cancer. Failure to detect a tumor cell marker does not mean that an individual is cancer-free.
TABLE 3-3 Tumor Cell Markers | ||||||||||||||||||||||||||||||
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TUMOR GROWTH RATE
Each tumor grows at a certain rate dependent on characteristics of both the host and the tumor itself. Important characteristics of the host that affect a tumor’s growth rate include the person’s age, sex, and overall health and nutritional status. The status of the host’s immune system is also important. An individual who is immunosuppressed may be unable to recognize a tumor as foreign, or may be unable to respond to a tumor that he or she recognizes. Certain hormonal states (e.g., pregnancy) may stimulate certain tumor growth rates, while stress may affect the host’s ability to restrict the development or growth of a tumor.
Important characteristics of a tumor that affect its growth rate include its location in the body and its blood supply. The degree of cellular anaplasia and the presence or absence of tumor growth factors are also important characteristics. Many tumors depend on circulating or self-produced growth factors to stimulate their growth. Therefore, the tumors that grow most rapidly often populate their surface membranes with receptors for these factors. In addition, some tumor cells secrete chemicals that make the local environment more favorable to their growth. An example is secretion of tumor angiogenesis factors, described below.
TUMOR ANGIOGENESIS FACTORS
Tumor angiogenesis factors are substances secreted by tumor cells that stimulate the development of new blood vessel formation. To survive, all cells require an adequate blood supply for the delivery of oxygen and nutrients and the removal of waste products. Once a group of cancer cells has grown to a certain size (approximately 1-2 mm in diameter), it will outgrow its original blood vessel supply and must stimulate the development of new blood vessels to grow further.
Measuring tumor angiogenesis factors in the blood or urine may allow for early diagnosis of some cancers. Even more exciting are new treatments for cancer that involve blocking the production of tumor angiogenesis factors. Experiments demonstrate that without angiogenesis, tumors soon shrink and
sometimes disappear. Interventions to block tumor angiogenesis factors in humans with cancer are a promising avenue of targeted drug therapy.
sometimes disappear. Interventions to block tumor angiogenesis factors in humans with cancer are a promising avenue of targeted drug therapy.
DESCRIPTIONS OF TUMOR GROWTH AND SPREAD
Growth and spread of a tumor is often described clinically; some of the different terms used are listed below. Tumor treatment often depends on the grade and stage of the cancer.
Grading: Tumors are classified as grade I, II, III, or IV based on cellular or histologic characteristics. The more poorly differentiated (highly anaplastic) the cells, the higher the grade (Box 3-1).
Staging: A clinical decision concerning the size of a tumor, the degree of local invasion it has produced, and the degree to which it has spread to distant sites in a given individual. The tumor classification system, also known as the TNM Classification System, developed by the American Joint Committee on Cancer (AJCC) is included in Box 3-2.
Ploidy defines the tumor chromosomes as normal or abnormal based on number and appearance. Normal ploidy (euploidy) has the typical 46 chromosomes. Cancer cells may gain or lose chromosomes and have an abnormal structure (aneuploidy). The degree of malignancy increases with the degree of aneuploidy.
Doubling time: An estimate of the mean amount of time required for the division of the tumor cells. Tumor cells that rapidly divide have a short doubling time.
BOX 3-1 Grading of Malignant Tumors
Gx Cannot be determined
G1 Well differentiated, low grade of malignance, slow growing
G2 Moderately differentiated
G3 Poorly differentiated, few normal cell characteristics
G4 Poorly differentiated, no normal cell characteristics, unable to determine tissue of origin
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