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You are watching: A disease characterized by the unrestrained growth of abnormal cells on or in tissues of the body

Cooper GM. The Cell: A molecule Approach. Second edition. Sunderland (MA): Sinauer Associates; 2000.

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The basic abnormality bring about the advance of cancer is the continual unregulated proliferation of cancer cells. Fairly than responding as necessary to the signal that control normal cell behavior, cancer cell grow and also divide in an uncontrolled manner, invading common tissues and organs and also eventually dispersing throughout the body. The generalised loss the growth manage exhibited by cancer cell is the net result of built up abnormalities in multiple cabinet regulatory systems and also is reflect in several facets of cell habits that identify cancer cells from their normal counterparts.

Types the Cancer

Cancer can an outcome from abnormal proliferation of any type of of the various kinds of cell in the body, so over there are more than a hundred distinct varieties of cancer, which deserve to vary substantially in their actions and an answer to treatment. The many important issue in cancer pathology is the distinction between benign and also malignant tumors (Figure 15.1). A tumor is any abnormal proliferation the cells, which might be one of two people benign or malignant. A bright tumor, such together a common skin wart, continues to be confined come its initial location, neither invading neighboring normal tissue nor spreading to far-off body sites. A malignant tumor, however, is capable of both invading neighboring normal tissue and also spreading throughout the body via the circulatory or lymphatic equipment (metastasis). Only malignant tumors are effectively referred to together cancers, and it is their capacity to invade and metastasize that renders cancer therefore dangerous. Whereas bright tumors can usually be gotten rid of surgically, the spread out of malignant tumors to remote body sites commonly makes lock resistant to such localized treatment.


Figure 15.1

A malignant tumor that the uterus. Micrographs of typical uterus (A) and a section of a uterine sarcoma (B). Keep in mind that the cancer cells (darkly stained) have actually invaded the neighboring normal tissue. (Cecil Fox/Molecular Histology, Inc.)

Both benign and malignant tumors room classified follow to the form of cabinet from which they arise. Many cancers autumn into among three main groups: carcinomas, sarcomas, and also leukemias or lymphomas. Carcinomas, which include about 90% of human being cancers, room malignancies the epithelial cells. Sarcomas, which are rare in humans, are solid tumors of connective tissues, such together muscle, bone, cartilage, and also fibrous tissue. Leukemias and also lymphomas, i m sorry account for about 8% of person malignancies, arise indigenous the blood-forming cells and from cell of the immune system, respectively. Tumors are further classified according to organization of origin (e.g., lung or breast carcinomas) and also the type of cell involved. For example, fibrosarcomas arise native fibroblasts, and erythroid leukemias from precursors of erythrocytes (red blood cells).

Although there are countless kinds of cancer, just a couple of occur generally (Table 15.1). Much more than a million situations of cancer space diagnosed every year in the united States, and an ext than 500,000 Americans dice of cancer every year. Cancers of 10 different body web page account for more than 75% of this complete cancer incidence. The 4 most common cancers, accounting for an ext than fifty percent of all cancer cases, room those that the breast, prostate, lung, and colon/rectum. Lung cancer, by far the many lethal, is responsible for practically 30% of every cancer deaths.


The development of Cancer

One the the an essential features the cancer is tumor clonality, the development of tumors from single cells that start to proliferate abnormally. The single-cell origin of plenty of tumors has actually been prove by analysis of X chromosome inactivation (Figure 15.2). As discussed in chapter 8, one member the the X chromosome pair is inactivated by being converted come heterochromatin in female cells. X inactivation wake up randomly during embryonic development, for this reason one X chromosome is inactivated in part cells, when the various other X chromosome is inactivated in various other cells. Thus, if a mrs is heterozygous for an X chromosome gene, different alleles will certainly be express in different cells. Regular tissues are composed of mixtures of cells with various inactive X chromosomes, therefore expression of both alleles is detect in typical tissues of heterozygous females. In contrast, tumor tissues typically express only one allele that a heterozygous X chromosome gene. The implicitly is that all of the cell constituting together a tumor were derived from a solitary cell the origin, in i m sorry the sample of X inactivation to be fixed before the tumor started to develop.


Figure 15.2

Tumor clonality. Common tissue is a mosaic of cell in which different X chromosomes (X1 and also X2) have actually been inactivated. Tumors develop from a single initially altered cell, so each tumor cell displays the same pattern that X inactivation (X1 inactive, X (more...)

The clonal origin of tumors go not, however, suggest that the original progenitor cabinet that provides rise to a tumor has initially acquired every one of the attributes of a cancer cell. Top top the contrary, the development of cancer is a multistep process in which cells gradually end up being malignant v a progressive series of alterations. One point out of the multistep advance of cancer is that many cancers build late in life. The incidence of colon cancer, for example, increases an ext than tenfold between the periods of 30 and also 50, and also another tenfold in between 50 and 70 (Figure 15.3). Together a dramatic boost of cancer incidence through age says that most cancers develop as a repercussion of multiple abnormalities, i beg your pardon accumulate over periods of numerous years.


Figure 15.3

Increased price of colon cancer v age. Yearly death rates from colon cancer in the unified States. (Data from J. Cairns, 1978. Cancer: Science and also Society, brand-new York: W. H. Freeman.)

At the cellular level, the breakthrough of cancer is regarded as a multistep procedure involving mutation and selection for cells v progressively boosting capacity because that proliferation, survival, invasion, and metastasis (Figure 15.4). The first step in the process, tumor initiation, is assumed to it is in the result of a genetic alteration leading come abnormal proliferation the a solitary cell. Cabinet proliferation then leads to the outgrowth that a population of clonally derived tumor cells. Tumor progression continues as added mutations take place within cells of the tumor population. Several of these mutations confer a selective benefit to the cell, such as more rapid growth, and the descendants of a cell bearing together a mutation will certainly consequently come to be dominant in ~ the tumor population. The process is referred to as clonal selection, due to the fact that a new clone of tumor cells has progressed on the communication of that is increased growth rate or various other properties (such as survival, invasion, or metastasis) that confer a selective advantage. Clonal selection continues transparent tumor development, for this reason tumors continuously become much more rapid-growing and also increasingly malignant.

Figure 15.4

Stages that tumor development. The development of cancer initiates as soon as a single mutated cell begins to proliferate abnormally. Extr mutations adhered to by selection for an ext rapidly farming cells in ~ the populace then result in progression of (more...)

Studies the colon carcinomas have detailed a clear example of tumor progression during the development of a common human malignancy (Figure 15.5). The earliest phase in tumor advance is enhanced proliferation of colon epithelial cells. One of the cell within this proliferative cell populace is then assumed to give rise come a little benign neoplasm (an adenoma or polyp). Further rounds that clonal selection lead to the growth of adenomas of raising size and proliferative potential. Malignant carcinomas then arise from the bright adenomas, indicated by invasion of the tumor cells through the basal lamina into underlying connective tissue. The cancer cells then proceed to proliferate and also spread v the connective tissues of the colon wall. Eventually the cancer cells permeate the wall of the colon and also invade other abdominal muscle organs, such as the bladder or small intestine. In addition, the cancer cells invade blood and lymphatic vessels, allowing them come metastasize transparent the body.

Figure 15.5

Development that colon carcinomas. A single initially changed cell gives rise to a proliferative cell population, which progresses first to light adenomas of raising size and also then come malignant carcinoma. The cancer cells invade the underlying connective (more...)

Causes that Cancer

Substances that cause cancer, called carcinogens, have actually been established both by researches in experimental animals and by epidemiological analysis of cancer frequencies in human populations (e.g., the high incidence that lung cancer amongst cigarette smokers). Due to the fact that the breakthrough of malignancy is a complex multistep process, plenty of factors may influence the likelihood that cancer will develop, and it is overly simplistic to speak of solitary causes of many cancers. Nonetheless, many agents, consisting of radiation, chemicals, and also viruses, have actually been uncovered to induce cancer in both experimental animals and also humans.

Radiation and many chemistry carcinogens (Figure 15.6) action by damaging DNA and inducing mutations. These carcinogens are normally referred to together initiating agents, because the induction that mutations in crucial target gene is believed to be the initial event leading to cancer development. Few of the initiating agents that contribute to human being cancers encompass solar ultraviolet radiation (the significant cause that skin cancer), carcinogenic chemicals in tobacco smoke, and aflatoxin (a potent liver carcinogen produced by part molds the contaminate improperly stored provides of peanuts and other grains). The carcinogens in tobacco acting (including benzo(a)pyrene, dimethylnitrosamine, and also nickel compounds) space the major identified causes of human being cancer. Smoking cigarettes is the undisputed reason of 80 come 90% that lung cancers, and being implicated in cancers of the oral cavity, pharynx, larynx, esophagus, and also other sites. In total, the is estimated that cigarette smoking is responsible for practically one-third of every cancer deaths—an exceptional toll for a single carcinogenic agent.

Other carcinogens add to cancer advance by stimulating cabinet proliferation, quite than through inducing mutations. Such compounds are referred to as tumor promoters, due to the fact that the enhanced cell department they induce is compelled for the outgrowth that a proliferative cell population during early stages of tumor development. The phorbol esters that stimulate cabinet proliferation by activating protein kinase C (see figure 13.26) are classic examples. Their activity was identified by research studies of chemical induction the skin tumors in mice (Figure 15.7). Tumorigenesis in this system have the right to be initiated by a solitary treatment through a mutagenic carcinogen. Tumors execute not develop, however, unless the mice room subsequently treated v a tumor promoter (usually a phorbol ester) to wake up proliferation the the mutated cells.

Figure 15.7

Induction of tumors in computer mouse skin. Tumors are initiated by mutations induced by a carcinogen. Development of a tumor then requires treatment v a tumor promoter to wake up proliferation of the mutated cells.

Hormones, specifically estrogens, are important as tumor promoters in the breakthrough of some human cancers. The proliferation of cells of the uterine endometrium, because that example, is stimulated by estrogen, and exposure come excess estrogen considerably increases the likelihood that a woman will build endometrial cancer. The danger of endometrial cancer is as such substantially increased by long-term postmenopausal estrogen replacement treatment with high doses of estrogen alone. Fortunately, this threat is decreased by management of progesterone to counteract the stimulatory effect of estrogen ~ above endometrial cell proliferation. However, permanent therapy through combinations the estrogen and progesterone may result in an increased risk of chest cancer.

In enhancement to chemicals and radiation, some viruses induce cancer both in experimental animals and also in humans. The usual human cancers brought about by viruses encompass liver cancer and also cervical carcinoma, which with each other account for 10 to 20% of global cancer incidence. These viruses are crucial not just as causes of person cancer; as discussed later in this chapter, studies of tumor viruses have played a an essential role in elucidating the molecular events responsible for the advance of cancers induced by both viral and nonviral carcinogens.

Properties the Cancer Cells

The uncontrolled growth of cancer cells outcomes from collected abnormalities affecting numerous of the cell regulatory mechanisms that have been disputed in coming before chapters. This partnership is reflected in several aspects of cell actions that differentiate cancer cell from their normal counterparts. Cancer cells commonly display abnormalities in the instrument that manage normal cabinet proliferation, differentiation, and survival. Bring away together, these characteristic properties of cancer cells provide a summary of malignancy at the to move level.

The untreated proliferation the cancer cells in vivo is mimicked through their behavior in cell culture. A primary distinction between cancer cells and normal cells in society is that normal cells display screen density-dependent inhibition of cell proliferation (Figure 15.8). Typical cells proliferate until they with a finite cell density, i beg your pardon is determined in component by the access of development factors included to the culture medium (usually in the form of serum). They then cease proliferating and become quiescent, arrested in the G0 phase of the cabinet cycle (see figure 14.6). The proliferation of many cancer cells, however, is not sensitive to density-dependent inhibition. Rather than responding to the signal that reason normal cell to stop proliferation and enter G0, tumor cells generally continue growing come high cabinet densities in culture, mimicking their uncontrolled proliferation in vivo.

Figure 15.8

Density-dependent inhibition. Regular cells proliferate in society until they with a finite cabinet density, at which suggest they become quiescent. Tumor cells, however, proceed to proliferate independent of cabinet density.

A associated difference in between normal cells and also cancer cell is that numerous cancer cell have diminished requirements because that extracellular expansion factors. As debated in thing 13, the proliferation of most cells is controlled, at the very least in part, by polypeptide expansion factors. For some cell types, particularly fibroblasts, the availability of serum growth determinants is the major determinant of your proliferative volume in culture. The development factor requirements of this cells are very closely related come the phenomenon that density-dependent inhibition, because the density at which common fibroblasts become quiescent is proportional to the concentration the serum growth factors in the society medium.

The expansion factor requirements of numerous tumor cells are reduced compared to their common counterparts, contributing to the unregulated proliferation the tumor cells both in vitro and also in vivo. In some cases, cancer cells produce growth determinants that wake up their own proliferation (Figure 15.9). Such abnormal production of a development factor through a responsive cell leads to constant autostimulation the cell department (autocrine development stimulation), and the cancer cells are as such less dependency on growth determinants from other, physiologically typical sources. In various other cases, the lessened growth aspect dependence of cancer cells outcomes from abnormalities in intracellular signaling systems, such together unregulated task of growth factor receptors or other proteins (e.g., Ras protein or protein kinases) the were discussed in thing 13 as aspects of signal transduction pathways bring about cell proliferation.

Figure 15.9

Autocrine growth stimulation. A cell produces a expansion factor to which it likewise responds, resulting in continuous stimulation of cell proliferation.

Cancer cells are likewise less stringently regulation than normal cells by cell-cell and also cell-matrix interactions. Most cancer cell are much less adhesive than regular cells, frequently as a result of lessened expression the cell surface adhesion molecules. For example, lose of E-cadherin, the principal adhesion molecule the epithelial cells, is necessary in the advance of carcinomas (epithelial cancers). As a an outcome of reduced expression of cabinet adhesion molecules, cancer cells are comparatively unrestrained by interactions with various other cells and tissue components, contributing to the capability of malignant cell to invade and also metastasize. The lessened adhesiveness that cancer cells also results in morphological and also cytoskeletal alterations: plenty of tumor cells are rounder than normal, in component because lock are less firmly attached to one of two people the extracellular matrix or surrounding cells.

A striking difference in the cell-cell interactions shown by regular cells and also those of cancer cells is shown by the phenomenon of contact inhibition (Figure 15.10). Normal fibroblasts migrate across the surface of a society dish till they make call with a surrounding cell. Further cell hike is climate inhibited, and also normal cells adhere to every other, developing an orderly selection of cell on the society dish surface. Tumor cells, in contrast, continue moving after contact with their neighbors, migrating over adjacent cells, and growing in disordered, multilayered patterns. Not only the activity but additionally the proliferation of many normal cell is inhibited by cell-cell contact, and also cancer cells are characteristically insensitive to such contact inhibition of growth.

Figure 15.10

Contact inhibition. Irradiate micrographs (left) and scanning electron micrographs (right) of regular fibroblasts and tumor cells. The hike of normal fibroblasts is inhibited by cabinet contact, for this reason they form an orderly side-by-side selection on the surface ar of (more...)

Two additional properties of cancer cells affect their interaction with other tissue components, thereby playing crucial roles in invasion and also metastasis. First, malignant cells normally secrete proteases that digest extracellular procession components, allowing the cancer cells to invade nearby normal tissues. Cheap of collagenase, for example, appears to be vital determinant that the ability of carcinomas to digest and also penetrate with basal laminae to invade underlying connective organization (see figure 15.5). Second, cancer cell secrete growth components that encourage the formation of brand-new blood ship (angiogenesis). Angiogenesis is required to support the growth of a tumor past the dimension of about a million cells, in ~ which point brand-new blood ship are compelled to supply oxygen and nutrients come the proliferating tumor cells. Such blood vessels are created in response to expansion factors, secreted through the tumor cells, that stimulate proliferation that endothelial cell in the wall surfaces of capillaries in surrounding tissue, resulting in the outgrowth of new capillaries right into the tumor. The formation of such new blood ship is necessary not only in sustaining tumor growth, but additionally in metastasis. The proactively growing brand-new capillaries developed in response to angiogenic stimulation are conveniently penetrated by the tumor cells, giving a ready opportunity for cancer cells to go into the circulatory system and begin the metastatic process.

Another general characteristic of most cancer cells is the they failure to identify normally. Such defective differentiation is carefully coupled to abnormal proliferation, since, as debated in thing 14, most completely differentiated cell either cease cell division or divide only rarely. Quite than transferring out their common differentiation program, cancer cells room usually clogged at very early stage the differentiation, continuous with their continued energetic proliferation.

The leukemias provide a particularly good example that the relationship between defective differentiation and malignancy. Every one of the different types of blood cell are obtained from a typical stem cell in the bone marrow (see number 14.44). Descendants of this cells then come to be committed to particular differentiation pathways. Part cells, because that example, identify to form erythrocytes whereas others differentiate to form lymphocytes, granulocytes, or macrophages. Cells of every of these species undergo several rounds of division as lock differentiate, yet once lock become completely differentiated, cell division ceases. Leukemic cells, in contrast, fail to undergo terminal differentiation (Figure 15.11). Instead, they become arrested at at an early stage stages that maturation at which they maintain their volume for proliferation and also continue to reproduce.

Figure 15.11

Defective differentiation and leukemia. Different varieties of blood cells construct from a multipotential (pluripotent) stem cell in the bone marrow. The precursors of distinguished cells undergo number of rounds the cell department as they mature, however cell division (more...)

As disputed in chapter 13, programmed cell death, or apoptosis, is one integral component of the differentiation regimen of countless cell types, consisting of blood cells. Many cancer cells fail to experience apoptosis, and therefore exhibit boosted life spans contrasted to their normal counterparts. This failure of cancer cells to experience programmed cell death contributes dramatically to tumor development. Because that example, the survive of numerous normal cells is dependence on signal from growth components or native the extracellular procession that prevent apoptosis. In contrast, tumor cell are often able to survive in the absence of growth components required by their typical counterparts. Together a fail of tumor cell to undergo apoptosis once deprived the normal eco-friendly signals may be essential not just in major tumor development but also in the survival and growth of metastatic cells in abnormal tissue sites. Regular cells likewise undergo apoptosis complying with DNA damage, while numerous cancer cells fail to perform so. In this case, the fail to undergo apoptosis contributes come the resistance of cancer cell to irradiation and many chemotherapeutic drugs, which plot by damaging DNA. Abnormal cabinet survival, and cell proliferation, for this reason plays a significant role in the unrelenting growth of cancer cell in an animal.

Transformation of cell in Culture

The study of tumor induction by radiation, chemicals, or viruses requires speculative systems in which the effects of a carcinogenic agent can be reproducibly observed and quantitated. Back the task of carcinogens have the right to be assayed in undamaged animals, together experiments are complicated to quantitate and also control. The advance of in vitro assays come detect the conversion of normal cells come tumor cells in culture, a procedure called cell transformation, as such represented a major advance in cancer research. Together assays are designed come detect reinvented cells, which display the in vitro expansion properties of tumor cells, complying with exposure the a society of common cells come a carcinogenic agent. Their applications has enabled experimental evaluation of cell revolution to with a level the sophistication that might not have been attained by studies in whole animals alone.

The an initial and many widely used assay of cell transformation is the emphasis assay, i beg your pardon was arisen by Howard Temin and Harry Rubin in 1958. The emphasis assay is based on the capacity to recognize a group of transformed cells as a morphologically distinctive “focus” against a lift of regular cells on the surface ar of a culture dish (Figure 15.12). The focus assay takes advantage of three properties of revolutionized cells: changed morphology, ns of call inhibition, and also loss of density-dependent inhibition that growth. The an outcome is the development of a swarm of morphologically changed transformed cells that overgrow the lift of typical cells in the culture. Such foci of changed cells have the right to usually be detected and quantified within a mainly or two after exposure to a carcinogenic agent. In general, cells changed in vitro are able to type tumors complying with inoculation right into susceptible animals, supporting in vitro revolution as a precious indicator that the development of cancer cells.

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Figure 15.12

The focus assay. A focus of chicken embryo fibroblasts induced by Rous sarcoma virus. (From H. M. Temin and also H. Rubin, 1958. Virology 6: 669.)

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