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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 molecular Approach. Second edition. Sunderland (MA): Sinauer Associates; 2000.

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The basic abnormality causing the advance of cancer is the continuous unregulated proliferation the cancer cells. Fairly than responding appropriately to the signals that regulate normal cabinet behavior, cancer cell grow and divide in an untreated manner, invading normal tissues and also organs and also eventually spreading throughout the body. The generalised loss the growth regulate exhibited by cancer cell is the net result of collected abnormalities in multiple cell regulatory systems and is reflect in several aspects of cell actions that identify cancer cells from their common counterparts.

Types the Cancer

Cancer can result from abnormal proliferation of any of the various kinds of cells in the body, so there are much more than a hundreds distinct species of cancer, which have the right to vary considerably in their actions and response to treatment. The most important issue in cancer pathology is the difference between benign and malignant tumors (Figure 15.1). A tumor is any type of abnormal proliferation that cells, which might be either benign or malignant. A light tumor, such as a typical skin wart, continues to be confined come its initial location, neither invading neighboring normal organization nor dispersing to far-off body sites. A malignant tumor, however, is qualified of both invading neighboring normal tissue and spreading throughout the body via the circulatory or lymphatic systems (metastasis). Only malignant tumors are appropriately referred to as cancers, and also it is their ability to invade and metastasize that provides cancer therefore dangerous. Whereas bright tumors can usually be eliminated surgically, the spread of malignant tumors to remote body sites generally makes them resistant to such localized treatment.


Figure 15.1

A malignant tumor of the uterus. Micrographs of typical uterus (A) and a ar of a uterine sarcoma (B). Note that the cancer cells (darkly stained) have invaded the bordering normal tissue. (Cecil Fox/Molecular Histology, Inc.)

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

Although over there are plenty of kinds of cancer, just a few occur commonly (Table 15.1). Much more than a million situations of cancer room diagnosed every year in the joined States, and more than 500,000 Americans die of cancer every year. Cancers the 10 different body web page account for much more than 75% of this complete cancer incidence. The four most usual cancers, accounting for more than half of every cancer cases, are those that the breast, prostate, lung, and colon/rectum. Lung cancer, by far the most lethal, is responsible for nearly 30% of all cancer deaths.


The advance of Cancer

One that the an essential features that 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 evaluation of X chromosome inactivation (Figure 15.2). As discussed in thing 8, one member of the X chromosome pair is inactivated by being converted to heterochromatin in mrs cells. X inactivation occurs randomly during embryonic development, so one X chromosome is inactivated in some cells, when the other X chromosome is inactivated in various other cells. Thus, if a female is heterozygous for an X chromosome gene, different alleles will be express in various cells. Regular tissues space composed of mixtures of cells with various inactive X chromosomes, therefore expression the both alleles is detected in normal tissues that heterozygous females. In contrast, tumor tissues generally express only one allele of a heterozygous X chromosome gene. The implicitly is that all of the cell constituting together a tumor were derived from a single cell that origin, in which the sample of X inactivation to be fixed prior to the tumor started to develop.


Figure 15.2

Tumor clonality. Common tissue is a mosaic of cells in which various X chromosomes (X1 and also X2) have been inactivated. Tumors develop from a single initially transformed cell, so each tumor cell screens the very same pattern of X inactivation (X1 inactive, X (more...)

The clonal origin of tumors walk not, however, imply that the initial progenitor cabinet that gives rise come a tumor has initially acquired every one of the qualities of a cancer cell. Top top the contrary, the breakthrough of cancer is a multistep process in which cells gradually become malignant through a progressive series of alterations. One point out of the multistep breakthrough of cancer is that many cancers develop late in life. The incidence that colon cancer, for example, increases an ext than tenfold in between the ages of 30 and also 50, and also another tenfold between 50 and also 70 (Figure 15.3). Such a dramatic rise of cancer incidence with age argues that many cancers construct as a repercussion of lot of abnormalities, which accumulate over periods of many years.


Figure 15.3

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

At the cellular level, the advancement of cancer is viewed as a multistep procedure involving mutation and an option for cells through progressively enhancing capacity for proliferation, survival, invasion, and metastasis (Figure 15.4). The very first step in the process, tumor initiation, is thought to it is in the an outcome of a genetic change leading to abnormal proliferation the a single cell. Cell proliferation then leads come the outgrowth that a populace of clonally derived tumor cells. Tumor progression continues as additional mutations happen within cells of the tumor population. Several of these mutations confer a selective benefit to the cell, together as an ext rapid growth, and also the descendants of a cell bearing together a mutation will consequently end up being dominant within the tumor population. The process is dubbed clonal selection, due to the fact that a new clone of tumor cell has advanced on the communication of that increased growth rate or other properties (such together survival, invasion, or metastasis) that confer a selective advantage. Clonal selection continues throughout tumor development, so tumors consistently become much more rapid-growing and also increasingly malignant.

Figure 15.4

Stages of tumor development. The advancement of cancer initiates once a solitary mutated cell starts to proliferate abnormally. Additional mutations followed by choice for more rapidly cultivation cells in ~ the populace then result in progression of (more...)

Studies the colon carcinomas have noted a clear instance of tumor progression throughout the advance of a typical human malignancy (Figure 15.5). The earliest phase in tumor advancement is enhanced proliferation the colon epithelial cells. Among the cells within this proliferative cell populace is then believed to provide rise to a tiny benign neoplasm (an adenoma or polyp). More rounds of clonal an option lead come the growth of adenomas of enhancing size and proliferative potential. Malignant carcinomas then arise native the bright adenomas, suggested by invasion of the tumor cells through the basal lamina into underlying connective tissue. The cancer cells then proceed to proliferate and spread with the connective tissues of the colon wall. Ultimately the cancer cells penetrate the wall of the colon and also invade other abdominal muscle organs, such together the bladder or tiny intestine. In addition, the cancer cells invade blood and lymphatic vessels, enabling them to metastasize throughout the body.

Figure 15.5

Development of colon carcinomas. A single initially transformed cell provides rise to a proliferative cabinet population, i m sorry progresses an initial to bright adenomas of enhancing size and then come malignant carcinoma. The cancer cells attack the underlying connective (more...)

Causes that Cancer

Substances that cause cancer, dubbed carcinogens, have been established both by research studies in experimental animals and also by epidemiological analysis of cancer frequencies in human populations (e.g., the high incidence that lung cancer among cigarette smokers). Because the advance of malignancy is a complicated multistep process, plenty of factors may impact the likelihood that cancer will certainly develop, and it is overly simplistic come speak of solitary causes of most cancers. Nonetheless, plenty of agents, including radiation, chemicals, and also viruses, have actually been discovered to induce cancer in both experimental animals and also humans.

Radiation and many chemical carcinogens (Figure 15.6) act by damaging DNA and also inducing mutations. These carcinogens are normally referred to together initiating agents, due to the fact that the induction that mutations in crucial target genes is believed to be the initial occasion leading to cancer development. Some of the initiating agents that contribute to human being cancers encompass solar ultraviolet radiation (the major cause the skin cancer), carcinogenic chemicals in tobacco smoke, and aflatoxin (a potent liver carcinogen produced by part molds that contaminate improperly stored supplies of peanuts and other grains). The carcinogens in tobacco acting (including benzo(a)pyrene, dimethylnitrosamine, and also nickel compounds) are the major identified reasons of human being cancer. Cigarette smoking is the undisputed reason of 80 come 90% of lung cancers, as well as being implicated in cancers that the dental cavity, pharynx, larynx, esophagus, and other sites. In total, it is estimated that smoking cigarettes is responsible for practically one-third of all cancer deaths—an exceptional toll for a solitary carcinogenic agent.

Other carcinogens add to cancer advance by stimulating cell proliferation, fairly than through inducing mutations. Together compounds are described as tumor promoters, because the raised cell division they induce is required for the outgrowth the a proliferative cell population during at an early stage stages that tumor development. The phorbol esters the stimulate cabinet proliferation through activating protein kinase C (see figure 13.26) are standard examples. Their task was defined by research studies of chemistry induction the skin tumors in mice (Figure 15.7). Tumorigenesis in this system deserve to be initiated by a solitary treatment through a mutagenic carcinogen. Tumors execute not develop, however, unless the mice space subsequently treated v a tumor promoter (usually a phorbol ester) to wake up proliferation the the mutated cells.

Figure 15.7

Induction that tumors in mouse skin. Tumors are initiated by mutations induced by a carcinogen. Advance of a tumor then needs treatment through a tumor promoter to stimulate proliferation the the mutated cells.

Hormones, particularly estrogens, are essential as tumor promoters in the breakthrough of some person cancers. The proliferation of cell of the uterine endometrium, for example, is engendered by estrogen, and also exposure come excess estrogen substantially increases the likelihood the a mrs will construct endometrial cancer. The risk of endometrial cancer is because of this substantially raised by irreversible postmenopausal estrogen replacement therapy with high doses of estrogen alone. Fortunately, this danger is minimized by management of progesterone to against the stimulatory effect of estrogen top top endometrial cell proliferation. However, permanent therapy v combinations that estrogen and progesterone may result in an enhanced risk of breast cancer.

In addition to chemicals and radiation, some viruses induce cancer both in speculative animals and also in humans. The usual human cancers led to by viruses incorporate liver cancer and also cervical carcinoma, which with each other account because that 10 to 20% of global cancer incidence. These viruses are essential not just as causes of human cancer; as debated later in this chapter, studies of tumor viruses have actually played a key role in elucidating the molecular events responsible because that the development of cancers induced by both viral and also nonviral carcinogens.

Properties that Cancer Cells

The uncontrolled growth of cancer cells results from accumulated abnormalities affecting numerous of the cell regulatory mechanisms that have been discussed in preceding chapters. This relationship is reflected in several aspects of cell actions that distinguish cancer cells from their typical counterparts. Cancer cells typically display abnormalities in the mechanisms that manage normal cell proliferation, differentiation, and survival. Taken together, this characteristic properties of cancer cells carry out a description of malignancy at the to move level.

The untreated proliferation of cancer cell in vivo is mimicked through their habits in cabinet culture. A primary distinction between cancer cells and normal cell in society is that normal cells screen density-dependent inhibition of cell proliferation (Figure 15.8). Regular cells proliferate till they reach a finite cabinet density, i m sorry is identified in part by the accessibility of expansion factors included to the culture medium (usually in the kind of serum). They then cease proliferating and become quiescent, arrested in the G0 phase of the cell cycle (see figure 14.6). The proliferation of many cancer cells, however, is not sensitive come density-dependent inhibition. Rather than responding come the signal that reason normal cell to cease proliferation and enter G0, tumor cell generally proceed growing come high cell densities in culture, mimicking their untreated proliferation in vivo.

Figure 15.8

Density-dependent inhibition. Regular cells proliferate in culture until they reach a finite cabinet density, in ~ which allude they come to be quiescent. Tumor cells, however, continue to proliferate independent of cell density.

A connected difference in between normal cells and also cancer cell is that countless cancer cells have lessened requirements because that extracellular expansion factors. As questioned in thing 13, the proliferation of many cells is controlled, at least in part, by polypeptide development factors. For some cell types, particularly fibroblasts, the accessibility of serum growth determinants is the major determinant of your proliferative volume in culture. The development factor needs of this cells are closely related to the phenomenon the density-dependent inhibition, because the density at which regular fibroblasts become quiescent is proportional come the concentration that serum growth factors in the culture medium.

The expansion factor demands of many tumor cells are reduced compared to their typical counterparts, contributing to the unregulated proliferation of tumor cells both in vitro and in vivo. In some cases, cancer cells develop growth determinants that stimulate their very own proliferation (Figure 15.9). Together abnormal production of a development factor by a responsive cabinet leads to consistent autostimulation of cell department (autocrine development stimulation), and the cancer cells are thus less dependence on growth determinants from other, physiologically typical sources. In other cases, the diminished growth element dependence of cancer cells outcomes from abnormalities in intracellular signaling systems, such as unregulated activity of development factor receptor or other proteins (e.g., Ras protein or protein kinases) the were debated in thing 13 as aspects of signal transduction pathways causing cell proliferation.

Figure 15.9

Autocrine expansion stimulation. A cabinet produces a expansion factor come which it also responds, resulting in constant stimulation of cabinet proliferation.

Cancer cells are likewise less stringently regulation than common cells through cell-cell and also cell-matrix interactions. Most cancer cell are much less adhesive than typical cells, often as a an outcome of lessened expression of cell surface adhesion molecules. Because that example, ns of E-cadherin, the principal adhesion molecule that epithelial cells, is necessary in the breakthrough of carcinomas (epithelial cancers). As a result of reduced expression of cell adhesion molecules, cancer cells space comparatively unrestrained by interaction with various other cells and also tissue components, contributing come the ability of malignant cells to invade and metastasize. The decreased adhesiveness that cancer cells also results in morphological and cytoskeletal alterations: countless tumor cells space rounder than normal, in part because lock are much less firmly attached to either the extracellular procession or neighboring cells.

A striking difference in the cell-cell interactions presented by common cells and also those that cancer cell is depicted by the phenomenon of contact inhibition (Figure 15.10). Regular fibroblasts migrate across the surface ar of a society dish till they make call with a neighboring cell. Further cell migration is then inhibited, and normal cell adhere to each other, developing an orderly array of cell on the culture dish surface. Tumor cells, in contrast, continue moving after call with their neighbors, migrating over nearby cells, and growing in disordered, multilayered patterns. Not only the activity but also the proliferation of numerous normal cells is inhibited by cell-cell contact, and also cancer cells are characteristically insensitive come such contact inhibition of growth.

Figure 15.10

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

Two added properties that cancer cells affect their interactions with various other tissue components, thereby playing important roles in invasion and metastasis. First, malignant cells generally secrete proteases that digest extracellular matrix components, enabling the cancer cell to invade nearby normal tissues. Cheap of collagenase, because that example, appears to be crucial determinant of the capability of carcinomas to digest and also penetrate v basal laminae to attack underlying connective organization (see number 15.5). Second, cancer cells secrete growth factors that encourage the development of brand-new blood ship (angiogenesis). Angiogenesis is essential to support the expansion of a tumor past the dimension of around a million cells, at which point brand-new blood ship are forced to supply oxygen and also nutrients to the proliferating tumor cells. Together blood ship are developed in solution to development factors, secreted by the tumor cells, that stimulate proliferation the endothelial cell in the walls of capillaries in surrounding tissue, leading to the outgrowth of new capillaries into the tumor. The development of such brand-new blood vessels is important not only in supporting tumor growth, but additionally in metastasis. The actively growing brand-new capillaries developed in solution to angiogenic stimulation are quickly penetrated by the tumor cells, giving a ready opportunity for cancer cell to enter the circulatory system and begin the metastatic process.

Another basic characteristic of most cancer cells is the they fail to differentiate normally. Together defective differentiation is carefully coupled come abnormal proliferation, since, as debated in chapter 14, most completely differentiated cell either stop cell division or divide just rarely. Quite than transferring out their common differentiation program, cancer cells are usually blocked at an early stage that differentiation, continuous with their continued active proliferation.

The leukemias administer a particularly an excellent example of the relationship in between defective differentiation and malignancy. Every one of the different species of blood cell are derived from a usual stem cabinet in the bone marrow (see figure 14.44). Progeny of these cells then become committed to details differentiation pathways. Part cells, for example, identify to form erythrocytes conversely, others differentiate to kind lymphocytes, granulocytes, or macrophages. Cell of every of these types undergo numerous rounds of division as lock differentiate, but once castle become fully differentiated, cell division ceases. Leukemic cells, in contrast, fail to experience terminal differentiation (Figure 15.11). Instead, they end up being arrested at early on stages that maturation in ~ which they maintain their capacity for proliferation and also continue come reproduce.

Figure 15.11

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

As disputed in thing 13, programmed cell death, or apoptosis, is one integral part of the differentiation program of countless cell types, including blood cells. Many cancer cells fail to experience apoptosis, and therefore exhibit increased life spans contrasted to their common counterparts. This failure of cancer cell to undergo programmed cell death contributes dramatically to tumor development. For example, the survival of many normal cell is dependence on signal from growth components or native the extracellular procession that prevent apoptosis. In contrast, tumor cells are frequently able to endure in the lack of growth determinants required by their typical counterparts. Such a failure of tumor cells to undergo apoptosis once deprived the normal eco-friendly signals might be necessary not only in main tumor breakthrough but also in the survival and also growth that metastatic cells in abnormal tissue sites. Common cells also undergo apoptosis adhering to DNA damage, while numerous cancer cell fail to execute so. In this case, the fail to experience apoptosis contributes come the resistance that cancer cells to irradiation and many chemotherapeutic drugs, which action by damaging DNA. Abnormal cabinet survival, and cell proliferation, for this reason plays a major role in the unrelenting growth of cancer cell in one animal.

Transformation of cell in Culture

The study of tumor induction by radiation, chemicals, or viruses requires experimental systems in which the results of a carcinogenic agent can be reproducibly observed and quantitated. Although the activity of carcinogens deserve to be assayed in intact animals, such experiments are an overwhelming to quantitate and also control. The breakthrough of in vitro assays come detect the switch of typical cells come tumor cells in culture, a process called cell transformation, as such represented a significant advance in cancer research. Such assays room designed to detect reinvented cells, which display screen the in vitro growth properties the tumor cells, adhering to exposure that a culture of regular cells to a carcinogenic agent. Their application has permitted experimental evaluation of cell change to reach a level that sophistication that can not have actually been attained by research studies in whole animals alone.

The an initial and most widely used assay the cell revolution is the emphasis assay, i m sorry was emerged by Howard Temin and also Harry Rubin in 1958. The focus assay is based upon the capacity to identify a group of transformed cells as a morphologically distinct “focus” versus a background of typical cells on the surface ar of a society dish (Figure 15.12). The emphasis assay takes benefit of 3 properties of revolutionized cells: changed morphology, loss of call inhibition, and loss that density-dependent inhibition that growth. The an outcome is the development of a swarm of morphologically transformed transformed cells the overgrow the background of typical cells in the culture. Together foci of changed cells deserve to usually it is in detected and quantified in ~ a main or 2 after exposure come a carcinogenic agent. In general, cells reinvented in vitro space able to form tumors following inoculation right into susceptible animals, sustaining in vitro change as a valid indicator of the development of cancer cells.

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Figure 15.12

The emphasis assay. A emphasis 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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