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Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.

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Molecular Cell Biology. 4th edition.

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Section 24.1Tumor Cells and the Onset of Cancer

Although much research into the molecular basis of cancer utilizes cells growing in culture, we need first to consider tumors as they occur in experimental animals and in humans. In this way we can see the gross properties of the disease — the properties that ultimately must be explained by analysis of genes and cells.

Metastatic Tumor Cells Are Invasive and Can Spread

Tumors arise with great frequency, especially in older animals and humans, but most pose little risk to their host because they are localized and of small size. We call such tumors benign; an example is warts. It is usually apparent when a tumor is benign because it contains cells that closely resemble, and may function like, normal cells. The surface interaction molecules that hold tissues together keep benign tumor cells, like normal cells, localized to appropriate tissues. Benign liver tumors stay in the liver, and benign intestinal tumors stay in the intestine. A fibrous capsule usually delineates the extent of a benign tumor and makes it an easy target for a surgeon (Figure 24-1). Benign tumors become serious medical problems only if their sheer bulk interferes with normal functions or if they secrete excess amounts of biologically active substances like hormones.

Figure 24-1. Sections of two types of benign tumors.

Figure 24-1

Sections of two types of benign tumors. (a) A tumor derived from cells that secrete neuroendocrine hormones. It is organized like a little gland in the midst of normal tissue. (b) A rectal epithelial tumor seen here as invaginations into the normal smooth (more...)

In contrast, the cells composing a malignant tumor, or cancer, express some proteins characteristic of the cell type from which it arose, and a high fraction of the cells grow and divide more rapidly than normal. Some malignant tumors remain localized and encapsulated, at least for a time; an example is carcinoma in situ in the ovary or breast. Most, however, do not remain in their original site; instead, they invade surrounding tissues, get into the body’s circulatory system, and set up areas of proliferation away from the site of their original appearance. The spread of tumor cells and establishment of secondary areas of growth is called metastasis; most malignant cells eventually acquire the ability to metastasize. Thus the major characteristics that differentiate metastatic (or malignant) tumors from benign ones are their invasiveness and spread.

Cancer cells can be distinguished from normal cells by microscopic examination. They are usually less well differentiated than normal cells or benign tumor cells. Liver cancers, for instance, express some of but not all the proteins characteristic of normal liver cells and may ultimately evolve to a state in which they lack most liver-specific functions. In a specific tissue, malignant cells usually exhibit the characteristics of rapidly growing cells, that is, a high nucleus-to-cytoplasm ratio, prominent nucleoli, many mitoses, and relatively little specialized structure. The presence of invading cells in an otherwise normal tissue section is the most diagnostic indication of a malignancy (Figure 24-2).

Figure 24-2. Gross and microscopic views of a tumor invading normal liver tissue.

Figure 24-2

Gross and microscopic views of a tumor invading normal liver tissue. (a) The gross morphology of a human liver in which a metastatic lung tumor is growing. The white protrusions on the surface of the liver are the tumor masses. (b) A light micrograph (more...)

Malignant cells usually retain enough resemblance to the normal cell type from which they arose, as judged by morphology and by expression of cell-specific genes, that it is possible to classify them by their relationship to normal tissue. Normal animal cells are often classified according to their embryonic tissue of origin, and the naming of tumors has followed suit. Cancers occur in most types of cells; compared with the 300 or so different types of cells in the human body, we can recognize 200 different types of human cancers. Malignant tumors are classified as carcinomas if they derive from endoderm or ectoderm and sarcomas if they derive from mesoderm. The leukemias, a class of sarcomas, grow as individual cells in the blood, whereas most other tumors are solid masses. (The name leukemia is derived from the Latin for “white blood”: the massive proliferation of leukemic cells can cause a patient’s blood to appear milky.)

Alterations in Cell-to-Cell Interactions Are Associated with Malignancy

The restriction of a normal cell type to a given organ or tissue is maintained by cell-to-cell recognition and by physical barriers. Primary among the physical barriers that keep tissues separated is the basal lamina (also called the basement membrane), which underlies layers of epithelial cells as well as surrounds the endothelial cells of blood vessels (see Figures 15-23 and 22-21). Basal laminae define the surfaces of external and internal epithelia and the structure of blood vessels.

Metastatic cells break their contacts with other cells in their tissue of origin and overcome the constraints on cell movement provided by basal laminae and other barriers. As a result, metastatic cells can enter the circulation and establish themselves in another site distant from their original location. In the process of metastasizing, they may invade adjoining tissue before spreading to distant sites through the circulation. Both these events require breach of a basal lamina.

Tumor cells often produce elevated levels of cell-surface receptors specific for the proteins and polysaccharides composing basal laminae (e.g., collagens, proteoglycans, and glycosaminoglycans) and secrete enzymes that digest these proteins. Many tumor cells also secrete a protease called plasminogen activator, which cleaves a peptide bond in the serum protein plasminogen, converting it to the active protease plasmin. Secretion of a small amount of plasminogen activator causes a large increase in protease concentration by catalytically activating the abundant plasminogen in normal serum. This increased protease activity promotes metastasis by helping tumor cells digest and penetrate the basal lamina. The normally invasive extraembryonic cells of the fetus secrete plasminogen activator when they are implanting in the uterine wall, a compelling analogy to invasion by tumor cells. As the basal lamina disintegrates, some tumor cells will enter the blood, but fewer than 1 in 10,000 cells that escape the primary tumor survive to colonize another tissue and form a secondary, metastatic tumor (see Figure 24-2). Such a cell first must adhere to an endothelial cell lining a capillary and migrate across or through it into the underlying tissue. To set up a metastasis, a tumor cell must be able to multiply without a mass of surrounding identical cells and to adhere to new types of cells. The wide range of altered behaviors that underlie malignancy may have their basis in new or variant surface proteins made by malignant cells.

Tumor Growth Requires Formation of New Blood Vessels

Tumors, whether primary or secondary, require recruitment of new blood vessels in order to grow to a large mass. In the absence of a blood supply, a tumor can grow into a mass of about 106 cells, roughly a sphere 2 mm in diameter. At this point, division of cells on the outside of the tumor mass is balanced by death of those in the center due to an inadequate supply of nutrients. Such tumors, unless they secrete hormones, cause few problems. However, most tumors induce the formation of new blood vessels that invade the tumor and nourish it, a process called angiogenesis. Although this complex process is not understood in detail, it can be described as several discrete steps: degradation of the basal lamina that surrounds a nearby capillary, migration of endothelial cells lining the capillary into the tumor, division of these endothelial cells, and formation of a new basement membrane around the newly elongated capillary.

Many tumors produce growth factors that stimulate angiogenesis; other tumors somehow induce surrounding normal cells to synthesize and secrete such factors. Basic fibroblast growth factor (bFGF), transforming growth factor α (TGFα), and vascular endothelial growth factor (VEGF), which are secreted by many tumors, all have angiogenic properties. New blood vessels nourish the growing tumor, allowing it to increase in size and thus increase the probability that additional harmful mutations will occur. The presence of an adjacent blood vessel also facilitates the process of metastasis.

One of the most mysterious aspects of angiogenesis is that a primary tumor will often secrete a substance that inhibits angiogenesis around secondary metastases. In this case, surgical removal of the primary tumor may stimulate growth of its metastatic secondary tumors. Several natural proteins that inhibit angiogenesis (e.g., angiogenin and endostatin) or antagonists of the VEGF receptor have excited much interest as therapeutic agents since they might be useful against many kinds of tumors. While new blood vessels are constantly forming during embryonic development, few form normally in adults; thus a specific inhibitor of angiogenesis might have few adverse side effects.

DNA from Tumor Cells Can Transform Normal Cultured Cells

The morphology and growth properties of tumor cells clearly differ from those of their normal counterparts. That mutations cause these differences was conclusively established by transfection experiments with a line of cultured mouse fibroblasts called 3T3 cells. These cells normally grow only when attached to the plastic surface of a culture dish and are maintained at a low cell density. Because 3T3 cells stop growing when they contact other cells, they eventually form a monolayer of well-ordered cells that have stopped proliferating and are in the G0 phase of the cell cycle (Figure 24-3a). Although such quiescent cells in a saturated culture have stopped growing, they remain viable for a long time and can resume growth if they are released from contact inhibition and provided with growth factors present in serum. As is true for other cultured fibroblasts, the exact cell type that gives rise to 3T3 cells is uncertain, but they can differentiate into a range of mesodermally derived cell types, especially fat cells and endothelial cells (those that line blood vessels).

Figure 24-3. Scanning electron micrographs of normal and transformed 3T3 cells.

Figure 24-3

Scanning electron micrographs of normal and transformed 3T3 cells. (a) Normal 3T3 cells are elongated and are aligned and closely packed in an orderly fashion. (b) 3T3 cells transformed by the v-src oncogene encoded by Rous sarcoma virus. The cells are (more...)

When DNA from a human bladder carcinoma, mouse sarcoma, or other tumor is added to a culture of 3T3 cells, about one cell in a million incorporates a particular segment of bladder carcinoma DNA that causes a distinctive phenotype. The progeny of the affected cell are more rounded and less adherent to one another and to the dish than are the normal surrounding cells, forming a three-dimensional cluster of cells (a focus) that can be recognized under the microscope (Figure 24-3b). Such cells, which continue to grow when the normal cells have become quiescent, have undergone transformation and are said to be transformed. Transformed cells have many properties similar to those of the cells composing malignant tumors, including changes in cell morphology, ability to grow unattached to a basal lamina or other extracellular matrix, reduced requirement for growth factors, secretion of plasminogen activator, and loss of actin microfilaments.

Figure 24-4 outlines the procedure for transforming 3T3 cells with DNA from a human bladder carcinoma and cloning the specific DNA segment that causes transformation. Subsequent studies showed that the cloned segment included a mutant version of the cellular ras gene, designated rasD. Normal Ras protein, which participates in many intracellular signal transduction pathways activated by growth factors, cycles between an inactive, “off” state with bound GDP and an active, “on” state with bound GTP (see Figure 20-22). Because the mutated RasD protein hydrolyzes bound GTP very slowly, it accumulates in the active state, sending a growth-promoting signal to the nucleus even in the absence of the hormones normally required to activate the Ras – MAP kinase pathway (see Figure 20-28).

Figure 24-4. The identification and molecular cloning of the rasD oncogene.

Figure 24-4

The identification and molecular cloning of the rasD oncogene. Addition of DNA from a human bladder carcinoma to a culture of mouse 3T3 cells causes about one cell in a million to divide abnormally and form a focus, or clone of transformed cells. To clone (more...)

Expression of the RasD protein, however, is not sufficient to cause transformation of normal cells in a primary culture of human, rat, or mouse fibroblasts. Unlike cells in a primary culture, however, cultured 3T3 cells have undergone a loss-of-function mutation in the p16 gene; as discussed later, the p16 gene encodes a cyclin-kinase inhibitor that restricts progression through the cell cycle. Such cells can grow indefinitely if periodically diluted and supplied with nutrients. Transformation of these cells requires both loss of p16 and expression of a constitutively active Ras protein; for this reason, transfection with the rasD gene can transform 3T3 cells but not normal cultured primary fibroblast cells.

A mutant ras gene is found in most human colon, bladder, and other cancers, but not in normal human DNA; thus it must arise as the result of a somatic mutation in one of the tumor progenitor cells. Any gene, such as rasD or v-src, that encodes a protein capable of transforming cells in culture or inducing cancer in animals is referred to as an oncogene. The normal cellular gene from which it arises is called a proto-oncogene.

Development of a Cancer Requires Several Mutations

Conversion of a normal body cell into a malignant one is now known to require multiple mutations. Three different types of experimental approaches all converged on this important conclusion: epidemiology of human cancers, analyses of DNA in cells at several stages in the development of cancers in humans and mice, and overexpression of oncogenes in cultured cells and transgenic animals.

Epidemiology

Each individual cancer is a clone that arises from a single cell. Assuming that the rate of mutation is roughly constant during a lifetime, then the incidence of most types of cancer would be independent of age if only one mutation were required to convert a normal cell into a malignant one. In fact, however, the incidence of most types of human cancers increases markedly and exponentially with age (Figure 24-5). Although many explanations of this phenomenon have been considered, the incidence data are most consistent with the notion that multiple mutations are required for a cancer to form.

Figure 24-5. The incidence of several human cancers increases markedly with age.

Figure 24-5

The incidence of several human cancers increases markedly with age. Note that the logarithm of annual incidence is plotted versus the logarithm of age. [From B. Vogelstein and K. Kinzler, 1993, Trends Genet. 9:101.]

According to this “multi-hit” model, cancers arise by a process of clonal selection not unlike the selection of individual animals in a large population. A mutation in one cell would give it a slight growth advantage. One of the progeny cells would then undergo a second mutation that would allow its descendants to grow more uncontrollably and form a small benign tumor; a third mutation in a cell within this tumor would allow it to outgrow the others, and its progeny would form a mass of cells, each of which would have these three mutations. An additional mutation in one of these cells would allow its progeny to escape into the blood and establish daughter colonies at other sites, the hallmark of metastatic cancer. Since decades are required for these multiple mutations to occur, the exponential increase in cancer incidence with age is predicted by the multi-hit model of cancer induction.

Somatic Mutations in Human Tumors

Surgeons can produce fairly pure samples of many human cancers, but generally the cells that give rise to these tumors cannot be identified and analyzed. An exception is colon cancer, which evolves through distinct, well-characterized morphological stages (Figure 24-6). Because these intermediate stages — polyps, benign adenomas, and carcinomas — can be isolated by a surgeon, mutations that occur in each of the morphological stages can be identified. These studies have identified a series of mutations that commonly arise in a welldefined order, providing strong support for the multi-hit model. Invariably the first step in colon carcinogenesis involves loss of a functional APC gene; however, not every colon cancer acquires all the later mutations or acquires them in the same order.

Figure 24-6. The development and metastasis of human colorectal cancer and its genetic basis.

Figure 24-6

The development and metastasis of human colorectal cancer and its genetic basis. A mutation in the APC tumor-suppressor gene in a single epithelial cell causes the cell to divide, although surrounding cells do not, forming a mass of localized benign tumor (more...)

Polyps are precancerous growths on the inside of the colon wall. Most of the cells in a polyp contain the same one or two mutations in the APC gene that result in its loss or inactivation; thus they are clones of cells in which the original mutations occurred. APC is one of many tumor-suppressor genes, most of which encode proteins that inhibit the progression of certain types of cells through the cell cycle. APC does so by inhibiting the ability of the Wnt protein to activate expression of the myc gene. The absence of functional APC protein thus leads to inappropriate activation of Myc, a transcription factor that induces expression of many genes required for the transition from the G1 to the S phase of the cell cycle. Both alleles of the APC gene must carry an inactivating mutation for polyps to form, because cells with one wild-type APC gene express enough APC protein to function normally. Persons over 50 years of age are now advised to have a periodic colonoscopy, a procedure for scanning the wall of the colon. Any polyps that are present can be removed easily. Since polyps often evolve (or “progress”) into a benign and then a metastatic tumor, the identification and removal of polyps often prevents development of colon cancer.

If one of the cells in a polyp undergoes another mutation, this time an activating mutation in the ras gene, its progeny divide in an even more uncontrolled fashion, forming a larger adenoma (see Figure 24-6). Mutational loss of another tumor-suppressor gene, designated DCC, followed by inactivation of the p53 gene, results in a malignant carcinoma. DNA from different human colon carcinomas generally contains mutations in all these genes — APC, p53, K-ras, and DCC — establishing that multiple mutations in the same cell are needed for the cancer to form. Some of these mutations appear to confer growth advantages at an early stage of tumor development, whereas other mutations promote the later stages, including degradation of the basal lamina, which is required for the malignant phenotype.

Inherited Mutations That Increase Cancer Risk

Most colon cancer patients have two normal APC alleles in their germ-line DNA, indicating that two somatic mutations, one in each APC allele, must have occurred in a single colon epithelial cell. However, in individuals who inherit a germ-line mutation in one APC allele, somatic loss or mutation of only the one remaining functional APC allele, rather than two, is required for a polyp to form. Thousands of precancerous polyps develop in these individuals; since there is a very high probability that one or more of these polyps will progress to malignancy, such individuals have a greatly increased risk for developing colon cancer before the age of 50.

As we detail below, individuals with inherited mutations in other tumor-suppressor genes have a hereditary predisposition for certain cancers. Such individuals inherit a germ-line mutation in one allele of the gene; somatic mutation of the second allele facilitates tumor progression. Although such cancers, which constitute about 10 percent of human cancers, are referred to as inherited, the inherited, germ-line mutation alone is not sufficient to cause tumor development. The inherited forms of many cancers are clinically similar to the noninherited form but occur earlier in life and often are marked by formation of multiple primary tumors, rather than a single one.

Overexpression of Oncogenes

Overexpression of Myc protein is associated with many types of cancers, a not unexpected finding, since this transcription factor stimulates expression of many genes required for cell-cycle progression. But overexpression of Myc in transgenic mice is insufficient to induce tumor formation; other oncogenic mutations also must occur. This “cooperativity” of oncogenic mutations has been shown most dramatically in transgenic mice carrying both the myc gene and the mutant rasD gene driven by a mammary cell – specific promoter/enhancer from a retrovirus (Figure 24-7). By itself, a myc transgene causes tumors only after 100 days, and then in only a few mice; clearly only a minute fraction of the mammary cells that overexpress the Myc protein become malignant. Expression of the mutant RasD protein alone causes tumors earlier but still slowly and with about 50 percent efficiency over 150 days. When the myc and rasD transgenics are crossed, however, such that all mammary cells express both Myc and RasD, tumors arise much more rapidly and all animals succumb to cancer. Such experiments emphasize the synergistic effects of multiple oncogenes. They also suggest that the long latency of tumor formation, even in the double-transgenic mice, is due to the need to acquire additional somatic mutations.

Figure 24-7. Kinetics of tumor appearance in female transgenic mice carrying transgenes driven by the mouse mammary tumor virus (MMTV) breast-specific promoter.

Figure 24-7

Kinetics of tumor appearance in female transgenic mice carrying transgenes driven by the mouse mammary tumor virus (MMTV) breast-specific promoter. Shown are results for mice carrying either myc or rasD transgenes as well as for the progeny of a cross (more...)

Similar cooperative effects can be seen in cultured cells. When normal cells are placed in medium with low amounts of growth factors such as platelet-derived growth factor (PDGF) or epidermal growth factor (EGF), they become blocked in the G0 or G1 stage of the cell cycle but remain viable. Recombinant cells that overexpress Myc also arrest their growth under these conditions, but soon undergo apoptosis, or programmed cell death (Chapter 23). Apparently the cell “senses” it is receiving an inappropriate “growth” signal from Myc in the absence of other “growth signals” from surface receptors and commits suicide. However, overexpression of Bcl-2, a protein that inhibits apoptosis, rescues these Myc-overexpressing cells from death. As a consequence, a cell that overexpresses both the Myc and Bcl-2 proteins can proliferate in the absence of normal growth factors. Consistent with these cell culture studies, overexpression of both Myc and Bcl-2 proteins is frequently found in human leukemias and lymphomas.

Cancers Originate in Proliferating Cells

In order for oncogenic mutations to induce cancer, they must occur in dividing cells so that the mutations are passed on to many progeny cells. When such mutations occur in nondividing cells (e.g., neurons and muscle cells), they generally do not induce cancer, which is why tumors of muscle and nerve cells are rare in adults. Nonetheless, cancer occurs in many tissues composed of nondividing differentiated cells such as erythrocytes and most white blood cells, absorptive cells that line the small intestine, and keratinized cells that form the skin. Although such differentiated cells cannot divide, they are continually replaced by differentiation of stem cells. This process is the key to understanding how cancers arise in these tissues.

Stem cells are capable of regenerating a particular tissue for the life of an organism. They are considered self-renewing in that some of their daughters become stem cells. Unipotent stem cells give rise to only a single differentiated cell type, whereas pluripotent stem cells can differentiate into several cell types that perform specialized functions (see Figure 14-7). The hematopoietic system provides a well-studied example of pluripotent stem cells. For example, hematopoietic stem cells can be purified from bone marrow with a fluorescent activated cell sorter (see Figure 5-21). This sorting depends on the presence of certain cell-surface proteins that distinguish hematopoietic stem and progenitor cells from other cell types and the absence on stem cells of other cell-surface proteins that are characteristic of differentiated hematopoietic cells. Each of the surface proteins binds a different monoclonal antibody, tagged with a different fluorescent dye, and thus FACS can separate those cells with particular combinations of cell surface proteins. When purified stem cells are injected into a mouse whose stem cells have been destroyed by whole-body gamma irradiation, the injected cells give rise to all the various types of blood cells. A similar approach is used to treat leukemia and breast cancer in humans: bone marrow or purified stem cells are injected into patients first subjected to lethal doses of radiation or cytotoxic drugs in order to kill the tumor cells as well as normal stem cells.

Detailed studies have elucidated the hematopoietic pathway shown in Figure 24-8. Under appropriate conditions, stem cells in the bone marrow divide to form two types of cells: another stem cell and a lineage-committed progenitor cell. The latter cells sometimes are referred to as burstforming units (BFUs) and colony-forming units (CFUs) because after dividing several more times, each forms a clone (i.e., a colony) of differentiated cells. Numerous extracellular factors, called cytokines, are essential for formation of lineage-committed progenitors and the subsequent proliferation and differentiation of these cells. Many of these cytokines are secreted by stromal cells in the bone marrow or are on the surface of these cells. Some, like SCF, IL-3, or GM-CSF, support the proliferation and differentiation of progenitors for many blood cell types. Others, like Epo, exert their principal action on progenitors of a single lineage. In the absence of an essential cytokine, a progenitor cell undergoes apoptosis. Thus hematopoietic progenitor cells can undergo one of two fates: they can die, or they can give rise to a clone of a specific type of differentiated blood cell. Once formed in the bone marrow, differentiated blood cells enter the circulation.

Figure 24-8. Formation of differentiated blood cells from hematopoietic stem cells in the bone marrow.

Figure 24-8

Formation of differentiated blood cells from hematopoietic stem cells in the bone marrow. Pluripotent stem cells (dark red) may either self-renew or give rise to myeloid and lymphoid stem cells (light red). Although these stem cells retain the capacity (more...)

Stem cells exist in other tissues, such as intestine, liver, skin, bone, and muscle; they give rise to all or many of the cell types in these tissues, replacing aged cells, by pathways analogous to hematopoiesis in bone marrow. Because stem cells divide continuously over the life of an organism, generating additional stem cells, oncogenic mutations in their DNA can accumulate, eventually transforming them into cancer cells. Cells that have acquired these mutations have an abnormal proliferative capacity but generally cannot undergo normal processes of differentiation. Many oncogenic mutations, such as ones that prevent apoptosis or generate an inappropriate growth-promoting signal, also can occur in more differentiated but still replicating progenitor cells. Such mutations in hematopoietic progenitor cells can lead to various types of leukemia. Likewise, colon cancer arises from mutations in proliferating cells that continually are generated to replace worn-out epithelial cells lining the colon.

In humans, the kinetics of the appearance of tumors suggests that many different mutational events conspire together to cause cancer. Our longevity relative to that of mice, for instance, implies that the human species has evolved multiple ways to counter the tendency of cells to accumulate mutations, so that human cells have protections that rodent cells either lack or have in a less efficient form. Like the continual battle that we carry out with the infectious agents that surround us, we also are continually battling the tendency of cells to become transformed into cancer cells.

SUMMARY

  •  Cancer is a fundamental aberration in cellular behavior, touching on many aspects of molecular cell biology. Most cell types of the body can give rise to malignant tumor (cancer) cells.
  •  Cancer cells can multiply in the absence of growth-promoting factors required for proliferation of normal cells and are resistant to signals that normally program cell death (apoptosis).
  •  Cancer cells also invade surrounding tissues, often breaking through the basal laminas that define the boundaries of tissues and spreading through the body to establish secondary areas of growth, a process called metastasis. Metastatic tumors often secrete proteases, which degrade the surrounding extracellular matrix.
  •  Both primary and secondary tumors require angiogenesis, the recruitment of new blood vessels, in order to grow to a large mass.
  •  Certain cultured cells transfected with tumor-cell DNA undergo transformation (see Figure 24-4). Such transformed cells share many properties with tumor cells.
  •  The requirement for multiple mutations in cancer induction is consistent with the observed increase in the incidence of human cancers with advancing age. Most such mutations are somatic and are not carried in the germ-line DNA.
  •  Colon cancer develops through distinct morphological stages that commonly are associated with mutations in specific tumor-suppressor genes and oncogenes (see Figure 24-6).
  •  Cancer cells, which are closer in their properties to stem cells than to more mature differentiated cell types, usually arise from stem cells and other proliferating cells.
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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2000, W. H. Freeman and Company.
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