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31 Cards in this Set
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Case: Chronic myelogenous leukemia (CML), |
Mannie Weitzels: chronic myelogenous leukemia (CML), disease in which a single line of myeloid cells in the bone marrow proliferates abnormally, causing a large increase in the number of nonlymphoid white blood cells. His myeloid cells contain the abnormal Philadelphia chromosome, which increases their proliferation. He has recently complained of pain and tenderness in various areas of his skeleton, possibly stemming from the expanding mass of myeloid cells within his bone marrow. He also reports various hemorrhagic signs, including bruises (ecchymoses), bleeding gums, and the appearance of small red spots (petechiae caused by release of red cells into the skin). |
Determination of abnormal chromosome structures is done by karyotype analysis. Karyotypes created by arresting cells in mitotic metaphase, a stage at which the chromosomes are condensed and visible under the light microscope. Nuclei are isolated, placed on a microscope slide, and the chromosomes are stained. Pictures of the chromosomes through the microscope are obtained, and the homologous chromosomes are paired. Through this type of analysis, translocations between chromosomes can be determined, as can trisomies and monosomies. As seen in the figure, this karyotype indicates a translocation between chromosomes 9 and 22 (a piece of chromosome 22 is now attached to chromosome 9; note the arrows in the figure). This is known as the Philadelphia chromosome, and it gives rise to CML. Mannie Weitzels’s bone marrow cells contain the Philadelphia chromosome, typical of CML. The Philadelphia chromosome results from a reciprocal translocation between the long arms of chromosome 9 and 22. As a consequence, a fusion protein is produced that contains the N-terminal region of the Bcr protein from chromosome 22 and the C-terminal region of the Abl protein from chromosome 9. Abl is a proto-oncogene, and the resulting fusion protein (Bcr-Abl) has lost its regulatory region and is constitutively active, resulting in deregulated tyrosine kinase activity. When it is active, Abl stimulates the Ras pathway of signal transduction, leading to cell proliferation Mannie Weitzels. The treatment of a symptomatic patient with chronic myelogenous leukemia (CML) whose white blood cell count is in excess of 50,000 cells/mL is usually initiated with a tyrosine kinase inhibitor. If the patient is intolerant to the tyrosine kinase inhibitor, then busulfan, a DNA-alkylating agent, may be used. Other alkylating agents, such as cyclophosphamide, have also been used alone or in combination with busulfan. Purine and pyrimidine antagonists and hydroxyurea (an inhibitor of the enzyme ribonucleotide reductase, which converts ribonucleotides to deoxyribonucleotides for DNA synthesis) are sometimes effective in CML as well. In addition, past experience with both - and -interferon has shown promise in increasing survival in these patients if they are intolerant to the tyrosine kinase inhibitors. Interestingly, the interferons have been associated with the disappearance of the Philadelphia chromosome in dividing marrow cells of some patients treated in this way. |
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adenocarcinoma |
Nick O’Tyne was diagnosed with a poorly differentiated adenocarcinoma of the lungs (see Chapter 13). He underwent procedures to determine the location and severity of the tumor. As a result of these tests, he was considered a candidate for surgical resection of the primary tumor, aimed at cure. He survived the surgery and was recovering uneventfully until 6 months later, when he complained of an increasingly severe right temporal headache. A computerized tomography (CT) scan of his brain was performed. Results indicated that the cancer, which had originated in his lungs, had metastasized to his brain |
Malignant neoplasms (new growth, a tumor) of epithelial cell origin (including the intestinal lining, cells of the skin, and cells lining the airways of the lungs) are called carcinomas. If the cancer grows in a glandlike pattern, it is an adenocarcinoma. Thus, Nick O’Tyne and Colin Tuma have adenocarcinomas. Mel Anoma had a carcinoma arising from melanocytes, which is technically a melanocarcinoma but is usually referred to as a melanoma. Nick O’Tyne. Surgical resection of the primary lung cancer with an attempt at cure was justified in Nick O’Tyne who had a good prognosis with a T1N0M0 staging classification preoperatively. Without some evidence of spread to the central nervous system at that time, a preoperative CT scan of the brain would not have been justified. This conservative approach would require scanning of all of the potential sites for metastatic disease from a non–small-cell cancer of the lung in all patients who present in this way. In an era of runaway costs of health care delivery, such an approach could not be considered cost-effective. Unfortunately, Mr. O’Tyne developed a metastatic lesion in the right temporal cortex of his brain. Because metastases were almost certainly present in other organs, Mr. O’Tyne’s brain tumor was not treated surgically. In spite of palliative radiation therapy to the brain, Mr. O’Tyne succumbed to his disease just 9 months after its discovery, an unusually virulent course for this malignancy. On postmortem examination, it was found that his body was riddled with metastatic disease //Colin Tuma requires regular colonoscopies to check for new polyps in his intestinal tract. Because the development of a metastatic adenoma requires several years (because of the large numbers of mutations that must occur), frequent checks will enable new polyps to be identified and removed before malignant tumors develo |
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intestinal adenocarcinoma |
Colin Tuma has had an intestinal adenocarcinoma resected, but there were several metastatic nodules in his liver (see Chapters 12 and 13). He completed his second course of chemotherapy with 5-fluorouracil (5-FU) and had no serious side effects. He assured his physician at his most recent checkup that, this time, he intended to comply with any instructions his physicians gave him. He ruefully commented that he wished he had returned for regular examinations after his first colonoscopy. |
Burkitt lymphoma, a general name for several types of B-cell malignancies, results from a translocation between chromosomes 8 and 14. The translocation of genetic material moves the proto-oncogene transcription factor c-myc (normally found on chromosome 8) to chromosome 14. The translocated gene is now under the control of the promoter region for the immunoglobulin heavy-chain gene, which leads to inappropriate and overexpression of c-myc. The result may be uncontrolled cell proliferation and tumor development. All subtypes of Burkitt lymphoma contain this translocation. Epstein-Barr virus infection of B cells is also associated with certain types of Burkitt lymphom Patients with leukemia experience various hemorrhagic (bleeding) manifestations caused by a decreased number of platelets. Platelets are small cells that initiate clot formation at the site of endothelial injury. Because of the uncontrolled proliferation of white cells within the limited space of the marrow, the normal platelet precursor cells (the megakaryocytes) in the marrow are “squeezed” or crowded and fail to develop into mature platelets. Consequently, the number of mature platelets (thrombocytes) in the circulation falls, and a thrombocytopenia develops. Because there are fewer platelets to contribute to clot formation, bleeding problems are common. The first experiments to show that oncogenes were mutant forms of proto-oncogenes in human tumors involved cells cultured from a human bladder carcinoma. The DNA sequence of the ras oncogene cloned from these cells differed from the normal c-ras proto-oncogene. Similar mutations were subsequently found in the ras gene of lung and colon tumors. Colin Tuma’s malignant polyp had a mutation in the ras proto-oncogene. |
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mole |
Mel Anoma returned to his physician after observing a brownish black irregular mole on his forearm (see Chapter 13). His physician thought the mole looked suspiciously like a malignant melanoma and so performed an excision biopsy (surgical removal for cytologic analysis). |
Moles (nevi) are tumors of the skin. formed: melanocytes that have been transformed from highly dendritic single cells interspersed among other skin cells to round oval cells that grow in aggregates or “nests.” (Melanocytes produce the dark pigment melanin, which protects against sunlight by absorbing ultraviolet [UV] light.) Additional mutations may transform the mole into a malignant melanoma. addition to sunlight and a preexisting nevus, hereditary factors also play a role in the development of malignant melanoma. Ten percent of melanomas tend to run in families. Some of the suspected melanoma-associated genes include the tumor suppressor gene p16 (an inhibitor of cdk4) and CDK4. Mel Anoma was the single child of parents who had died of a car accident in their 50s, and thus a familial tendency could not be assessed The biopsy of Mel Anoma’s excised mole showed that it was not malignant. The most important clinical sign of a malignant melanoma is a change in color in a pigmented lesion. Unlike benign (nondysplastic) nevi, melanomas exhibit striking variations in pigmentation, appearing in shades of black, brown, red, dark blue, and gray. Additional clinical warning signs of a melanoma are enlargement of a preexisting mole, itching or pain in a preexisting mole, development of a new pigmented lesion during adult life, and irregularity of the borders of a pigmented lesion. Mel Anoma was advised to conduct a monthly self-examination, to have a clinical skin examination once or twice yearly, to avoid sunlight, and to use appropriate sunscreens. |
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I. CAUSES OF CANCER: group of diseases: cells no longer respond to normal restraints on growth. |
Normal cells in the body respond to signals, such as cell–cell contact (contact inhibition), that direct them to stop proliferating. Cancer cells do not require growth-stimulatory signals, and they are resistant to growthinhibitory signals. They are also resistant to apoptosis, the programmed cell death process whereby unwanted or irreparably damaged cells self-destruct. They have an infinite proliferative capacity and do not become senescent (i.e., they are immortalized). Furthermore, they can grow independent of structural support, such as the extracellular matrix (loss of anchorage dependence). The study of cells in culture was, and continues to be, a great impetus for the study of cancer. Tumor development in animals can take months, and it was difficult to do experiments with tumor growth in animals. Once cells could be removed from an animal and propagated in a tissue culture dish, the onset of transformation (the normal cell becoming a cancer cell) could be seen in days. Once cells were available to study, it was important to determine the criteria that distinguish transformed cells from normal cells in culture. 3 criteria were established. The first is the requirement for serum in the cell culture medium to stimulate cell growth. Serum is the liquid fraction of clotted blood and contains many factors that stimulate cell proliferation. Transformed cells have, in general, a reduced requirement for serum, approximately 10% that required for normal cells to grow. The second criterion is the ability to grow without attachment to a supporting matrix (anchorage dependence). Normal cells (such as fibroblasts or smooth muscle cells) require adherence to a substratum (in this case, the bottom of the plastic dish) and will not grow if suspended in a soft agar mixture. Transformed cells, however, have lost this anchorage dependence. The third and most stringent criterion used to demonstrate that cells are truly transformed is the ability of cells to form tumors when they are injected into mice that lack an immune system. Transformed cells will do so, whereas normal cells will not. Drs. Michael Bishop and Harold Varmus demonstrated that cancer is not caused by unusual and novel genes but rather by mutation within existing cellular genes, and that for every gene that causes cancer (an oncogene), there is a corresponding cellular gene called the proto-oncogene. Although this concept seems straightforward today, it was a significant finding when it was first announced and, in 1989, Drs. Bishop and Varmus were awarded the Nobel Prize in Medicine. A single cell that divides abnormally eventually forms a mass called a tumor. A tumor can be benign and harmless; the common wart is a benign tumor formed from a slowly expanding mass of cells. In contrast, a malignant neoplasm (malignant tumor) is a proliferation of rapidly growing cells that progressively infiltrate, invade, and destroy surrounding tissue. Tumors develop angiogenic potential, which is the capacity to form new blood vessels and capillaries. Thus, tumors can generate their own blood supply to bring in oxygen and nutrients. Cancer cells also can metastasize, separating from the growing mass of the tumor and traveling through the blood or lymph to unrelated organs where they establish new growths of cancer cells. The transformation of a normal cell to a cancer cell begins with damage to DNA (base changes or strand breaks) caused by chemical carcinogens, ultraviolet (UV) light, viruses, or replication errors (see Chapter 13). Mutations result from the damaged DNA if it is not repaired properly or if it is not repaired before replication occurs. A mutation that can lead to transformation also may be inherited. When a cell with one mutation proliferates, this clonal expansion (proliferation of cells arising from a single cell) results in a substantial population of cells containing this one mutation, from which one cell may acquire a second mutation relevant to control of cell growth or death. With each clonal expansion, the probability of another transforming mutation increases. Because mutations accumulate in genes that control proliferation, subsequent mutations occur even more rapidly until the cells acquire the multiple mutations (in the range of four to seven) necessary for full transformation. The transforming mutations occur in genes that regulate cellular proliferation and differentiation (proto-oncogenes), suppress growth (tumor suppressor genes), target irreparably damaged cells for apoptosis, or repair damaged DNA. The genes that regulate cellular growth are called proto-oncogenes, and their mutated forms are called oncogenes. The term oncogene is derived from the Greek word onkos, meaning bulk or tumor. A transforming mutation in a proto-oncogene increases the activity or amount of the gene product (a gain-of-function mutation). Tumor suppressor genes (normal growth suppressor genes) and repair enzymes protect against uncontrolled cell proliferation. A transforming mutation in these protective genes results in a loss of activity or a decreased amount of the gene product. In summary, cancer is caused by the accumulation of mutations in the genes involved in normal cellular growth and differentiation. These mutations give rise to cancer cells that are capable of unregulated, autonomous, and infinite proliferation. As these cancer cells proliferate, they impinge on normal cellular functions, leading to the symptoms exhibited by individuals with the tumors. |
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II. DAMAGE TO DNA LEADING TO MUTATIONS A. Chemical and Physical Alterations in DNA |
An alteration in the chemical structure of DNA, or of the sequence of bases in a gene, is an absolute requirement for the development of cancer. The function of DNA depends on the presence of various polar chemical groups in DNA bases, which are capable of forming hydrogen bonds between DNA strands or other chemical reactions. The oxygen and nitrogen atoms in DNA bases are targets for various electrophiles (electronseeking chemical groups). A typical sequence of events leading to a mutation is shown for dimethylnitrosamine in Figure 18.2. Chemical carcinogens (compounds that can cause transforming mutations) found in the environment and ingested in foods are generally stable lipophilic compounds that, like dimethylnitrosamine, must be activated by metabolism in the body to react with DNA (see also benz[o]pyrene, “Action of Mutagens,” Chapter 13, Section III.A, and Fig. 13.12). Many chemotherapeutic agents, which are designed to kill proliferating cells by interacting with DNA, may also act as carcinogens and cause new mutations and tumors while eradicating the old. Structural alterations in DNA also occur through radiation and through UV light, which causes the formation of pyrimidine dimers. More than 90% of skin cancers occur in sunlightexposed areas. UV rays derived from the sun induce an increased incidence of all skin cancers, including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma of the skin. The wavelength of UV light that is most associated with skin cancer is UVB (280 to 320 nm), which forms pyrimidine dimers in DNA. This type of DNA damage is repaired by nucleotide excision repair pathways that require products of at least 20 genes. With excessive exposure to the sun, the nucleotide excision repair pathway is overwhelmed, and some damage remains unrepaired. Each chemical carcinogen or reactant creates a characteristic modification in a DNA base. The DNA damage, if not repaired, introduces a mutation into the next generation when the cell proliferates. |
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II. DAMAGE TO DNA LEADING TO MUTATIONS B. Gain-of-Function Mutations in Proto-oncogenes |
Proto-oncogenes are converted to oncogenes by mutations in the DNA that cause a gain in function; that is, the protein can now function better in the absence of the normal activating events. Several mechanisms that lead to the conversion of protooncogenes to oncogenes are known. • Radiation and chemical carcinogens act (1) by causing a mutation in the regulatory region of a gene, increasing the rate of production of the proto-oncogene protein; or (2) by producing a mutation in the coding portion of the oncogene that results in the synthesis of a protein of slightly different amino acid composition capable of transforming the cell (Fig. 18.3A). • The entire proto-oncogene or a portion of it may be transposed or translocated, that is, moved from one position in the genome to another (see Fig. 18.3B). In its new location, the proto-oncogene may be under the control of a promoter that is regulated differently than the promoter that normally regulates this gene. This may allow the gene to be expressed in a tissue where it is not normally expressed or at higher-than-normal levels of expression. If only a portion of the proto-oncogene is translocated, it may be expressed as a truncated protein with altered properties, or it may fuse with another gene and produce a fusion protein containing portions of what are normally two separate proteins. The truncated or fusion protein may be hyperactive and cause inappropriate cell growth. • The proto-oncogene may be amplified (see Fig. 18.3C) so that multiple copies of the gene are produced in a single cell. If more genes are active, more protooncogene protein will be produced, increasing the growth rate of the cells. As examples, the oncogene N-myc (a cell proliferation transcription factor, related to c-myc) is amplified in some neuroblastomas, and amplification of the erb-b2 oncogene (a growth factor receptor) is associated with several breast carcinomas. • If an oncogenic virus infects a cell, its oncogene may integrate into the host cell genome, permitting production of the abnormal oncogene protein. The cell may be transformed and exhibit an abnormal pattern of growth. Rather than inserting an oncogene, a virus may simply insert a strong promoter into the host cell genome. This promoter may cause increased or untimely expression of a normal proto-oncogene. The important point to remember is that transformation results from abnormalities in the normal growth-regulatory program caused by gain-of-function mutations in proto-oncogenes. However, loss-of-function mutations also occur in the tumor suppressor genes, repair enzymes, or activators of apoptosis, and a combination of both types of mutations is usually required for full transformation to a cancer cell. |
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C. Mutations in Repair Enzymes |
Repair enzymes are the first line of defense preventing conversion of chemical damage in DNA to a mutation (see Chapter 13, Section III.B). DNA repair enzymes are tumor suppressor genes in the sense that errors repaired before replication do not become mutagenic. DNA damage is constantly occurring from exposure to sunlight, background radiation, toxins, and replication errors. If DNA repair enzymes are absent, mutations accumulate much more rapidly, and once a mutation develops in a growth-regulatory gene, a cancer may arise. As an example, inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to the development of breast cancer (see “Biochemical Comments”). The protein products of these genes play roles in DNA repair, recombination, and regulation of transcription. A second example, HNPCC (hereditary nonpolyposis colorectal cancer), was introduced in Chapter 13. It results from inherited mutations in enzymes involved in the DNA mismatch repair system. |
?The TNM system standardizes the classification of tumors. The T stands for the stage of tumor (the higher the number, the worse the prognosis), the N stands for the number of lymph nodes that are affected by the tumor (again, the higher the number, the worse the prognosis), and M stands for the presence of metastasis (0 for none, 1 for the presence of metastatic cells).??Mutations associated with malignant melanomas include ras (gain of function in growth signal transduction oncogene), p53 (loss of function of tumor suppressor gene), p16 (loss of function in Cdk inhibitor tumor suppressor gene), Cdk4 (gain of function in a cell cycle progression oncogene), and cadherin/-catenin regulation (loss of regulation that requires attachment). |
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III. ONCOGENES |
Proto-oncogenes control normal cell growth and division. Fx: encode proteins that are growth factors, growth factor receptors, signal transduction proteins, transcription factors, cell cycle regulators, and regulators of apoptosis (Table 18.1). (The name representing the gene of an oncogene is referred to in lowercase letters and italics [e.g., myc], but the name of the protein product is capitalized and italics are not used [e.g., Myc]). The mutations in oncogenes that give rise to transformation are usually gain-of-function mutations; either a more active protein is produced or an increased amount of the normal protein is synthesized. MicroRNAs (miRNAs) can also behave as oncogenes. If a miRNA is overexpressed (increased function), it can act as an oncogene if its target (which would exhibit reduced expression under these conditions) is a protein that is involved in inhibiting, or antagonizing, cell proliferation. |
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A. Oncogenes and Signal Transduction Cascades |
All of the proteins in growth factor signal transduction cascades are proto-oncogenes |
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1. GROWTH FACTORS AND GROWTH FACTOR RECEPTORS |
Proto-oncogenes: growth factors and growth factor receptors. Growth factors generally regulate growth by serving as ligands that bind to cellular receptors located on the plasma membrane (cell surface receptors) (see Chapter 11). Binding of ligands to these receptors stimulates a signal transduction pathway in the cell that activates the transcription of certain genes. If too much of a growth factor or a growth factor receptor is produced, the target cells may respond by proliferating inappropriately. Growth factor receptors may also become oncogenic through translocation or point mutations in domains that affect binding of the growth factor, dimerization, kinase activity, or some other aspect of their signal transmission. In such cases, the receptor transmits a proliferative signal even though the growth factor normally required to activate the receptor is absent. In other words, the receptor is stuck in the “on” position. |
The gene for the human epidermal growth factor receptor (HER2, c-erbB-2 ) is overexpressed in 10% to 20% of breast cancer cases. When this gene is overexpressed, the prognosis for recovery is poor because the patients display shorter disease-free intervals, increased risks for metastasis, and resistance to therapy. A drug has been developed that recognizes and blocks the receptor’s action (herceptin, a monoclonal antibody with specificity to the HER2 protein). Preliminary results are encouraging in that use of this drug, either alone or in combination with others, appears to control the growth of some tumors that overexpress the HER2 gene. However, not all tumors that overexpress HER2 are responsive to herceptin. Thus, it appears that a complete genotyping of breast cancer cells may be necessary (using the microarray techniques described in Chapter 17) to develop an effective therapy for each patient with the disease, leading to individualized therapy. |
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2. SIGNAL TRANSDUCTION PROTEINS |
Proto-oncogenes. Encode proteins involved in growth factor signal transduction cascades. EX: the monomeric G p rotein Ras. Binding of growth factor leads to the activation of Ras When Ras binds guanosine triphosphate (GTP), it is active, but Ras slowly inactivates itself by hydrolyzing its bound GTP to guanosine diphosphate (GDP) and inorganic phosphate (Pi). This controls the length of time that Ras is active. Ras is converted to an oncogenic form by point mutations that decrease the activity of the GTPase domain of Ras, thereby increasing the length of time it remains in the active form. Ras, when it is active, activates the serine–threonine kinase Raf (a mitogenactivated protein [MAP] kinase kinase kinase), which activates MEK (a MAP kinase kinase), which activates MAP kinase (Fig. 18.5). Activation of MAP kinase results in the phosphorylation of cytoplasmic and nuclear proteins, followed by increased transcription of the transcription factor proto-oncogenes myc and fos (see the following sections). Note that mutations in the genes for any of the proteins that regulate MAP kinase activity, as well as those proteins induced by MAP kinase activation = uncontrolled cell proliferation. |
(see Fig. 11.11). |
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3. TRANSCRIPTION FACTORS |
Transcription factors: products proto-oncogenes: Myc and Fos. MAP kinase directly activates the activator protein-1 (AP-1) transcription factor = phosphorylation AP-1 is a heterodimer formed by the protein products of the fos and jun families of proto-oncogenes. The targets of AP-1 activation are genes involved in cellular proliferation and progression through the cell cycle, as are the targets of the myc transcription factor. The synthesis of the transcription factor C-myc is tightly regulated in normal cells, and it is expressed only during the S phase of the cell cycle. In a large number of tumor types, this regulated expression is lost, and c-myc becomes inappropriately expressed or overexpressed throughout the cell cycle, driving cells continuously to proliferate. The net result of alterations in the expression of transcription factors is the increased production of the proteins that carry out the processes required for proliferation. |
(see Fig. 18.5). |
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B. Oncogenes and the Cell Cycle |
The growth of human cells, DNA replication and cell division in the cell cycle, is activated by growth factors, hormones, (and other messengers.) These activators work through cyclins and cyclin-dependent kinases (CDKs) that control progression from one phase of the cycle to another For quiescent cells to proliferate, they must leave G0 and enter the G1 phase of the cell cycle If the proper sequence of events occurs during G1, the cells enter the S phase and are committed to DNA replication and cell division. Similarly, during G2, cells make a commitment to mitotic division. CDKs are made constantly throughout the cell cycle but require binding of a specific cyclin to be active. Different cyclins made at different times in the cell cycle control each of the transitions (G1/S, S/G2, G2/M). The activity of the cyclin–CDK complex is further regulated through phosphorylation and through inhibitory proteins called cyclin-dependent kinase inhibitors (CKIs). CKIs slow cell cycle progression by binding and inhibiting the cyclin–CDK complexes. CDKs are also controlled through activating phosphorylation by cyclin-activating kinases (CAKs) and inhibitory hyperphosphorylation kinases.To illustrate the role of these proteins, consider some of the events that occur at the G1/S checkpoint (Fig. 18.8). Because the cell is committed to DNA replication and division once it enters the S phase, multiple regulatory proteins are involved in determining whether the cell is ready to pass this checkpoint. These regulatory proteins include cdk4 and cdk6 (which are constitutively produced throughout the cell cycle), cyclin D (whose synthesis is induced only after growth factor stimulation of a quiescent cell), the retinoblastoma gene product (Rb), and a class of transcription factors known collectively as E2 transcription factor (E2F). In quiescent cells, Rb is complexed with E2F, resulting in inhibition of these transcription factors. Upon growth factor stimulation, the cyclin Ds are induced (there are three types of cyclin D: D1, D2, and D3). They bind to cdk4 and cdk6, converting them to active protein kinases. One of the targets of cyclin/CDK phosphorylation is the Rb protein. Phosphorylation of Rb releases it from E2F, and E2F is then free to activate the transcription of genes required for entry into S. The Rb protein is a tumor suppressor gene (more discussions in the following sections). The proteins induced by E2F include cyclin E, cyclin A, cdc25A (an activating protein phosphatase), and proteins required to bind at origins of replication to initiate DNA synthesis. The synthesis of cyclin E allows it to complex with cdk2, forming another active cyclin complex that retains activity into S phase (see Fig. 18.6). One of the major functions of the cyclin E1–cdk2 complex is hyperphosphorylation of the Rb protein, thereby keeping Rb in its inactive state. Cyclin A also complexes with Cdk2, and it phosphorylates and inactivates the E2F family of transcription factors. This ensures that the signals are not present for extended periods of time. Thus, each phase of the cell cycle activates the next through cyclin synthesis. The cyclins are removed by regulated proteolysis. |
(Fig. 18.6). (see Chapter 13, Fig. 13.7). (Fig. 18.7) |
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IV. TUMOR SUPPRESSOR GENES |
Like the oncogenes, the tumor suppressor genes encode molecules involved in the regulation of cell proliferation. The normal function of tumor suppressor proteins is generally to inhibit proliferation in response to certain signals such as DNA damage. The signal is removed when the cell is fully equipped to proliferate; the effect of the elimination of tumor suppressor genes is to remove the brakes on cell growth. They affect cell cycle regulation, signal transduction, transcription, and cell adhesion. The products of tumor suppressor genes frequently modulate pathways that are activated by the products of proto-oncogenes. Tumor suppressor genes contribute to the development of cancer when both copies of the gene are inactivated. This is different from the case of proto-oncogene mutations because only one allele of a proto-oncogene needs to be converted to an oncogene to initiate transformation. As with the oncogenes, this is also applicable to miRNAs. If the expression of a particular miRNA is lost, the mRNA it regulates would be overexpressed, which could lead to enhanced cellular proliferation. Thus, miRNAs can be classified as either oncogenes (overexpression) or tumor suppressors (loss of function) depending on the gengenes that they regulate. |
Table 18.2 provides several examples. |
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A. Tumor Suppressor Genes that Regulate the Cell Cycle Directly cell cycle regulators tumor suppressors 1. THE RETINOBLASTOMA (rb) GENE |
fx: transition from G1 to S phase and regulates the activation of members of the E2F family of transcription factors . If an individual inherits a mutated copy of the rb allele, there is a 100% chance of that individual developing retinoblastoma, because of the high probability that the second allele of rb will gain a mutation This is considered familial retinoblastoma. Individuals who do not inherit mutations in rb but who develop retinoblastoma are said to have sporadic retinoblastoma and acquire two specific mutations, one in each rb allele of the retinoblastoma, during their lifetime. |
(see Fig. 18.8) (Fig. 18.9). |
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2. p53, THE GUARDIAN OF THE GENOME transcription factor that regulates the cell cycle and apoptosis, programmed cell death. |
Loss of both p53 alleles is found in more than 50% of human tumors. p53 acts as the “guardian of the genome” by halting replication in cells that have suffered DNA damage and targeting unrepaired cells to apoptosis. In response to DNA-damaging mutagens, ionizing radiation, or UV light, the level of p53 rises . p53, acting as a transcription factor, stimulates transcription of p21 (a member of the Cip/Kip family of CKIs), as shown in Figure 18.10, circle 2. The p21 gene product inhibits the cyclin–CDK complexes, which prevents the phosphorylation of Rb and release of E2F proteins. The cell is thus prevented from entering S phase. p53 also stimulates the transcription of a number of DNA repair enzymes (including GADD45, growth arrest and DNA damage). If the DNA is successfully repaired, p53 induces its own downregulation through the activation of the mdm2 gene. If the DNA repair was not successful, p53 activates several genes involved in apoptosis, including Bax (discussed subsequently) and insulinlike growth factor–binding protein 3 (IGF-BP3) (see Fig. 18.10, circle 4). The IGF-BP3 protein product binds the receptor for insulinlike growth factor, which presumably induces apoptosis by blocking the antiapoptotic signaling by growth factors, and the cell enters a growth factor deprivation mode. |
(Fig. 18.10, circle 1) (see Fig. 18.10, circle 3) Inheritance of a mutation in p53 = Li-Fraumeni syndrome, which is characterized by multiple types of tumors. Mutations in p53 are present in more than 50% of human tumors. These are secondary mutations within the cell, and if p53 is mutated, the overall rate of cellular mutation will increase because there is no p53 to check for DNA damage, to initiate the repair of the damaged DNA, or to initiate apoptosis if the damage is not repaired. Thus, damaged DNA is replicated, and the frequency of additional mutations within the same cell increases remarkably. |
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B. Tumor Suppressor Genes that Affect Receptors and Signal Transduction fx: encode receptors, components of the signaling transduction pathway, or transcription factors. 1. REGULATORS OF RAS |
The Ras family of proteins is involved in signal transduction for many hormones and growth factors (see previous discussion) and is therefore oncogenic. The activity of these pathways is interrupted by GAPs (GTPase-activating proteins; see Chapter 9, Section III.C.2), which vary among cell types. Neurofibromin, the product of the tumor suppressor gene NF-1, is a nervous system–specific GAP that regulates the activity of Ras in neuronal tissues (Fig. 18.11). The growth signal is transmitted so long as the Ras protein binds GTP. Binding of NF-1 to Ras activates the GTPase domain of Ras, which hydrolyzes GTP to GDP, thereby inactivating Ras. Without a functional neurofibromin molecule, Ras is perpetually active. |
An inherited mutation in NF-1 can lead to neurofibromatosis, a disease primarily of numerous benign, but painful, tumors of the nervous system. The movie Elephant Man was based on an individual who was believed to have this disease. Recent analysis of the patient’s remains, however, indicates that he may have suffered from the rare Proteus syndrome, not neurofibromatosis |
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2. PATCHED AND SMOOTHENED A good example of tumor suppressors and oncogenes working together is provided by the coreceptor genes patched and smoothened, which |
encode the receptor for the hedgehog class of signaling peptides. (The strange names of some of the tumor suppressor genes arose because they were first discovered in Drosophila [fruit fly], and the names of Drosophila mutations are often based on the appearance of a fly that expresses the mutation. Once the human homolog was found, it was given the same name as the Drosophila gene.) These coreceptors normally function to control growth during embryogenesis and illustrate the importance of maintaining a balance between oncogenes and tumor suppressor genes. The patched receptor protein inhibits smoothened, its coreceptor protein. Binding of a hedgehog ligand to patched releases the inhibition of smoothened, which then transmits an activating signal to the nucleus, stimulating new gene transcription (Fig. 18.12). Smoothened is a proto-oncogene, and patched is a tumor suppressor gene. If patched loses its function (definition of a tumor suppressor), then smoothened can signal the cell to proliferate, even in the absence of a hedgehog signal. Conversely, if smoothened undergoes a gain-of-function mutation (definition of an oncogene), it can signal in the absence of the hedgehog signal, even in the presence of patched. Inherited mutations in either smoothened or patched will lead to an increased incidence of basal cell carcinoma. |
An inherited mutation in NF-1 can lead to neurofibromatosis, a disease primarily of numerous benign, but painful, tumors of the nervous system. The movie Elephant Man was based on an individual who was believed to have this disease. Recent analysis of the patient’s remains, however, indicates that he may have suffered from the rare Proteus syndrome, not neurofibromatosis |
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C. Tumor Suppressor Genes that Affect Cell Adhesion |
1. Cadherin family of glycoproteins mediates: calcium-dependent cell–cell adhesion. Cadherins form intercellular complexes that bind cells together (Fig. 18.13A). They are anchored intracellularly by catenins, which bind to actin filaments. Loss of E-cadherin expression may contribute to the ability of cancer cells to detach and migrate in metastasis. Individuals who inherit a mutation in E-cadherin (this mutation is designated CDH1) are sharply predisposed to developing diffuse-type gastric cancer. The catenin proteins have two functions: In addition to anchoring cadherins to the cytoskeleton, they act as transcription factors (see Fig. 18.13B). -Catenin also binds to a complex that contains the regulatory protein APC (adenomatous polyposis coli), which activates it for degradation. When the appropriate signal inactivates APC, -catenin levels increase, and it travels to the nucleus where it activates myc and cyclin D1 transcription, leading to cell proliferation. APC is a tumor suppressor gene. If it is inactivated, it cannot bind -catenin and inhibit cell proliferation. Mutations in APC or proteins that interact with it are found in most sporadic human colon cancers. Inherited mutations in APC lead to the most common form of hereditary colon cancer, familial adenomatous polyposis (FAP). |
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V. CANCER AND APOPTOSIS |
In the body, superfluous or unwanted cells are destroyed by a pathway apoptosis, 'programmed cell death. Apoptosis is a regulated energy-dependent sequence of events by which a cell self-destructs. In this suicidal process, cell shrinks, chromatin condenses, and the nucleus fragments. The cell membrane forms blebs (outpouches), and the cell breaks up into membrane-enclosed apoptotic vesicles (apoptotic bodies) containing varying amounts of cytoplasm, organelles, and DNA fragments. Phosphatidylserine, a lipid on the inner leaflet of the cell membrane, is exposed on the external surface of these apoptotic vesicles. It is one of the phagocytic markers recognized by macrophages and other nearby phagocytic cells that engulf the apoptotic bodies. Apoptosis is a normal part of multiple processes in complex organisms: embryogenesis, the maintenance of proper cell number in tissues, the removal of infected or otherwise injured cells, the maintenance of the immune system, and aging. It can be initiated by injury, radiation, free radicals, or other toxins; withdrawal of growth factors or hormones; binding of proapoptotic cytokines; or interactions with cytotoxic T cells in the immune system. Apoptosis can protect organisms from the negative effects of mutations by destroying cells with irreparably damaged DNA before they proliferate. Just as an excess of a growth signal can produce an excess of unwanted cells, the failure of apoptosis to remove excess or damaged cells can contribute to the development of cancer. |
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A. Normal Pathways to Apoptosis three general phases:" an initiation phase, a signal integration phase, and an execution phase. |
initiated by external signals that work through death receptors, such as tumor necrosis factor (TNF), or deprivation of growth hormones . It can also be initiated by intracellular events that affect mitochondrial integrity (e.g., oxygen deprivation, radiation), and irreparably damaged DNA. In the signal integration phase, these proapoptotic signals are balanced against antiapoptotic cell survival signals by several pathways, including members of the Bcl-2 family of proteins. The execution phase is carried out by proteolytic enzymes called caspases. |
(Fig. 18.14) |
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1. CASPASES 'cysteine proteases' |
Cleave peptide bonds next to an aspartate residue. Present in the cell as: procaspases, zymogen-type enzyme precursors that are activated by proteolytic cleavage of the inhibitory portion of their polypeptide chain. The different caspases are generally divided into two groups according to their function: 1. initiator caspases, which specifically cleave other procaspases; 2. execution caspases, which cleave other cellular proteins involved in maintaining cellular integrity (see Fig. 18.14). The initiator caspases are activated through two major signaling pathways: the death receptor pathway and the mitochondrial integrity pathway. They activate the execution caspases, which cleave protein kinases involved in cell adhesion, lamins that form the inner lining of the nuclear envelope, actin and other proteins required for cell structure, and DNA repair enzymes. They also cleave an inhibitor protein of the endonuclease CAD (caspase-activated DNase), thereby activating CAD to initiate the degradation of cellular DNA. With destruction of the nuclear envelope, additional endonucleases (Ca2- and Mg2-dependent) also become activated. |
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2. THE DEATH RECEPTOR PATHWAY TO APOPTOSIS |
The death receptors are a subset of TNF-1 receptors, which includes Fas/CD95, TNF-receptor 1 (TNF-R1), and death receptor 3 (DR3). These receptors form a trimer that binds TNF-1 or another death ligand on its external domain and binds adaptor proteins to its intracellular domain (Fig. 18.15). The activated TNF– receptor complex forms the scaffold for binding two molecules of procaspase 8 (or procaspase 10), which autocatalytically cleave each other to form active caspase 8 (or caspase 10). Caspases 8 and 10 are initiator caspases that activate execution caspases 3, 6, and 7. Caspase 3 also cleaves a Bcl-2 protein, Bid, to a form that activates the mitochondrial integrity pathway to apoptosis. |
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3. THE MITOCHONDRIAL INTEGRITY PATHWAY TO APOPTOSIS Apoptosis is also induced by intracellular signals indicating that cell death should occur. |
Examples of these signals include growth factor withdrawal, cell injury, the release of certain steroids, and an inability to maintain low levels of intracellular calcium. All of these treatments or changes lead to release of cytochrome c from the mitochondria (Fig. 18.16). Cytochrome c is a necessary protein component of the mitochondrial electron-transport chain that is loosely bound to the outside of the inner mitochondrial membrane. Its release initiates apoptosis. In the cytosol, cytochrome c binds Apaf (proapoptotic protease-activating factor). The Apaf/cytochrome c complex binds caspase 9, an initiator caspase, to form an active complex called the apoptosome. The apoptosome, in turn, activates execution caspases (3, 6, and 7) by zymogen cleavage. |
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4. INTEGRATION OF PROAPOPTOTIC AND ANTIAPOPTOTIC SIGNALS BY THE BCL-2 FAMILY OF PROTEINS |
The Bcl-2 family members are decision makers that integrate prodeath and antideath signals to determine whether the cell should commit suicide. Both proapoptotic and antiapoptotic members of the Bcl-2 family exist (Table 18.3). Bcl-2 family members contain regions of homology, known as Bcl-2 homology (BH) domains. There are four such domains. The antiapoptotic factors contain all four domains (BH1–BH4). The channel-forming proapoptotic factors contain just three domains (BH1–BH3), whereas the proapoptotic BH3-only family members contain just one BH domain (BH3). The antiapoptotic Bcl-2–type proteins (including Bcl-2, Bcl-L, and Bcl-w) have at least two ways of antagonizing death signals. They insert into the outer mitochondrial membrane to antagonize channel-forming proapoptotic factors, thereby decreasing cytochrome c release. They may also bind cytoplasmic Apaf so that it cannot form the apoptosome complex (Fig. 18.17). These antiapoptotic Bcl-2 proteins are opposed by proapoptotic family members that fall into two categories: ion channel–forming members and BH3-only members. The prodeath ion channel–forming members, such as Bax, are very similarto the antiapoptotic family members, except that they do not contain the binding domain for Apaf. They have the other structural domains, however, and when they dimerize with proapoptotic BH3-only members in the outer mitochondrial membrane, they form an ion channel that promotes cytochrome c release rather than inhibiting it (see Fig. 18.17). The prodeath BH3-only proteins (e.g., Bim and Bid) contain only the structural domain that allows them to bind to other Bcl-2 family members (the BH3 domain) and not the domains for binding to the membrane, forming ion channels, or binding to Apaf. Their binding activates the p rodeath family members and inactivates the antiapoptotic members. When the cell receives a signal from a prodeath agonist, a BH3 protein like Bid is activated (see Fig. 18.17). The BH3 protein activates Bax (an ion channel–forming proapoptotic channel member), which stimulates release of cytochrome c. Normally, Bcl-2 acts as a death antagonist by binding Apaf and keeping it in an inactive state. However, at the same time that Bid is activating Bax, Bid also binds to Bcl-2, thereby disrupting the Bcl-2/Apaf complex and freeing Apaf to bind to released cytochrome c to form the apoptosome. |
When Bcl-2 is mutated, and oncogenic, it is usually overexpressed, for example, in follicular lymphoma and CML. Overexpression of Bcl-2 disrupts the normal regulation of proapoptotic and antiapoptotic factors and tips the balance to an antiapoptotic stand. This leads to an inability to destroy cells with damaged DNA, such that mutations can accumulate within the cell. Bcl-2 is also a multidrug-resistant transport protein and if it is overexpressed, it will block the induction of apoptosis by antitumor agents by rapidly removing them from the cell. Thus, strategies are being developed to reduce Bcl-2 levels in tumors that overexpress it before initiating drug or radiation treatment. |
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B. Cancer Cells Bypass Apoptosis |
Apoptosis should be triggered by several stimuli, such as 1. withdrawal of growth factors, 2.elevation of p53 in response to DNA damage, monitoring of DNA damage by repair enzymes, or release of TNF or other immune factors. However, mutations in oncogenes can create apoptosis-resistant cells. One of the ways this occurs is through activation of growth factor–dependent signaling pathways that inhibit apoptosis, such as the PDGF/Akt/BAD pathway. Nonphosphorylated BAD acts like Bid in promoting apoptosis (see Fig. 18.17). Binding of the platelet-derived growth factor to its receptor activates PI-3 kinase, which phosphorylates and activates the serine–threonine kinase Akt (protein kinase B, see Chapter 11, Section III.B.3). Activation of Akt results in the phosphorylation of the proapoptotic BH3-only protein BAD, which inactivates it. The PDGF/ Akt/BAD pathway illustrates the requirement of normal cells for growth factor stimulation to prevent cell death. One of the features of neoplastic transformation is the loss of growth factor dependence for survival. The MAP kinase pathway is also involved in regulating apoptosis and sends cell survival signals. MAP kinase kinase phosphorylates and activates another protein kinase known as RSK. Like Akt, RSK phosphorylates BAD and inhibits its activity. Thus, BAD acts as a site of convergence for the PI-3 kinase/Akt and MAP kinase pathways in signaling cell survival. Gain-of-function mutations in the genes that control these pathways, such as ras, create apoptosis-resistant cells. |
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C. MicroRNAs and Apoptosis |
Recent work has identified several miRNAs that regulate apoptotic factors. Bcl-2, for example, is regulated by at least 2 miRNAs, designated as miR-15 and miR-16. Expression of these miRNAs will control Bcl-2 (an antiapoptotic factor) levels in the cell. If, for any reason, the expression of these miRNAs is altered, Bcl-2 levels will also be altered, promoting either apoptosis (if Bcl-2 levels decrease) or cell proliferation (if Bcl-2 levels increase). Loss of both of these miRNAs is found in 68% of chronic lymphocytic leukemia (CLL) cells, most often caused by a deletion on chromosome 13q14. Loss of miR-15 and miR-16 expression would lead to an increase in Bcl-2 levels, favoring increased cell proliferation. Other miRNA species have been identified, which regulate factors involved in apoptosis. miR-21 regulates the expression of the programmed cell death 4 gene (PDCD4). PDCD4 is upregulated during apoptosis and functions to block translation. Loss of miR-21 activity would lead to cell death, as PDCD4 would be overexpressed. However, overexpression of miR-21 would be antiapoptotic, as PDCD4 expression would be ablated. The miR-17 cluster regulates the protein kinase B/akt pathway by regulating the levels of PTEN (the enzyme that converts PIP3 to PIP2), as well as the levels of the E2F family of transcription factors. An upregulation of miR-17, acting as an oncogene, would decrease PTEN levels such that cellular proliferation is favored over apoptosis because of the constant activation of the akt pathway. |
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VI. CANCER REQUIRES MULTIPLE MUTATIONS |
long time to develop in humans because multiple genetic alterations are required to transform normal cells into malignant cells A single change in one oncogene or tumor suppressor gene in an individual cell is not adequate for transformation. For example, if cells derived from biopsy specimens of normal cells are not already “immortalized,” that is, able to grow in culture indefinitely, addition of the ras oncogene to the cells is not sufficient for transformation. However, additional mutations in a combination of oncogenes, for example, ras and myc, can result in transformation (Fig. 18.18). Epidemiologists have estimated that four to seven mutations are required for normal cells to be transformed. Cells accumulate multiple mutations through clonal expansion. When DNA damage occurs in a normally proliferative cell, a population of cells with that mutation is produced. Expansion of the mutated population enormously increases the probability of a second mutation in a cell containing the first mutation. After one or more mutations in proto-oncogenes or tumor suppressor genes, a cell may proliferate more rapidly in the presence of growth stimuli and with further mutations grow autonomously, that is, independent of normal growth controls. Enhanced growth increases the probability of further mutations. Some families have a strong predisposition to cancer. Individuals in these families have inherited a mutation or deletion of one allele of a tumor suppressor gene, and as progeny of that cell proliferate, mutations can occur in the second allele, leading to a loss of control of cellular proliferation. These familial cancers include familial retinoblastoma, familial adenomatous polyps of the colon, and multiple endocrine neoplasia (MEN), one form of which involves tumors of the thyroid, parathyroid, and adrenal medulla (MEN type II). Studies of benign and malignant polyps of the colon show that these tumors have several different genetic abnormalities. The incidence of these mutations increases with the level of malignancy. In the early stages, normal cells of the intestinal epithelium proliferate, develop mutations in the APC gene, and develop polyps This change is associated with a mutation in the ras proto- oncogene that converts it to an active oncogene. Progression to the next stage is associated with a deletion or alteration of a tumor suppressor gene on chromosome 5. Subsequently, mutations occur in chromosome 18, inactivating a gene that may be involved in cell adhesion, and in chromosome 17, inactivating the p53 tumor suppressor gene. The cells become malignant, and further mutations result in growth that is more aggressive and metastatic. This sequence of mutations is not always followed precisely, but an accumulation of mutations in these genes is found in a large percentage of colon carcinomas. |
(see Fig. 18.1). Nick O’Tyne had been smoking for 40 years before he developed lung cancer. The fact that cancer takes so long to develop has made it difficult to prove that the carcinogens in cigarette smoke cause lung cancer. Studies in England and Wales show that cigarette consumption by men began to increase in the early 1900s. Followed by a 20-year lag, the incidence in lung cancer in men also began to rise. Women began smoking later, in the 1920s. Again, the incidence of lung cancer began to increase after a 20-year lag |
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VII. AT THE MOLECULAR LEVEL, CANCER IS MANY DIFFERENT DISEASES |
More than 20% of the deaths in the United States each year are caused by cancer, with tumors of the lung, the large intestine, and the breast being the most common (Fig. 18.19). Different cell types typically use different mechanisms through which they lose the ability to control their own growth. An examination of the genes involved in the development of cancer shows that a particular type of cancer can arise in multiple ways. For example, patched and smoothened are the receptor and coreceptor for the signaling peptide, sonic hedgehog. Either mutation of smoothened, an oncogene, or inactivation of patched, a tumor suppressor gene, can give rise to basal cell carcinoma. Similarly, transforming growth factor and its signal transduction proteins Smad4/DPC are part of the same growth-inhibiting pathway, and either may be absent in colon cancer. Thus, treatments that are successful for one patient with colon cancer may not be successful in a second patient with colon cancer because of the differences in the molecular basis of each individual’s disease (this now appears to be the case with breast cancer as well). Medical practice in the future will require identifying the molecular lesions involved in a particular disease and developing appropriate treatments accordingly. The use of proteomics and gene chip technology (see Chapter 17) to genotype tumor tissues, and to understand which proteins they express, will aid greatly in allowing patient-specific treatments to be developed. |
A treatment for CML based on rational drug design has been developed. The fusion protein Bcr-Abl is found only in transformed cells that express the Philadelphia chromosome and not in normal cells. Once the structure of Bcr-Abl was determined, the drug Gleevec was designed to specifically bind to and inhibit only the active site of the fusion protein and not the normal protein. Gleevec was successful in blocking Bcr-Abl function, thereby stopping cell proliferation, and in some cells inducing apoptosis, so the cells would die. Because normal cells do not express the hybrid protein, they were not affected by the drug. The problem with this treatment is that some patients suffered relapses, and when their Bcr-Abl proteins were studied, it was found that in some patients, the fusion protein had a single amino acid substitution near the active site that prevented Gleevec from binding to the protein. Other patients had an amplification of the Bcr-Abl gene product. Other tyrosine kinase inhibitors (such as dasatinib and nilotinib) can also be used in treating CML if a resistance to Gleevec is encountered |
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VIII. VIRUSES AND HUMAN CANCER |
Three RNA retroviruses are associated with the development of cancer in humans: HTLV-1, HIV, and hepatitis C. There are also DNA viruses associated with cancer, such as hepatitis B, Epstein-Barr virus (EBV), human papillomavirus (HPV), and herpesvirus (HHV-8). HTLV-1 causes adult T-cell leukemia. The HTLV-1 genome encodes a protein Tax, which is a transcriptional coactivator. The cellular proto-oncogenes c-sis and c-fos are activated by Tax, thereby altering the normal controls on cellular proliferation and leading to malignancy. Thus, tax is a viral oncogene without a counterpart in the host cell genome. Infection with HIV, the virus that causes AIDS, leads to the development of neoplastic disease through several mechanisms. HIV infection leads to immunosuppression and, consequently, loss of immune-mediated tumor surveillance. HIV-infected individuals are predisposed to non-Hodgkin lymphoma, which results from an overproduction of T-cell lymphocytes. The HIV genome encodes a protein, Tat, a transcription factor that activates transcription of the interleukin-6 (IL-6) and interleukin-10 (IL-10) genes in infected T cells. IL-6 and IL-10 are growth factors that promote proliferation of T cells, and thus their increased production may contribute to the development of non-Hodgkin lymphoma. Tat can also be released from infected cells and act as an angiogenic (blood vessel–forming) growth factor. This property is thought to contribute to the development of Kaposi sarcoma. DNA viruses also cause human cancer but by different mechanisms. Chronic hepatitis B infections will lead to hepatocellular carcinoma. A vaccine currently is available to prevent hepatitis B infections. EBV is associated with B- and T-cell lymphomas, Hodgkin disease, and other tumors. The EBV encodes a Bcl-2 protein that restricts apoptosis of the infected cell. HHV-8 has been a ssociated with Kaposi sarcoma. Certain strains of papillomavirus have been shown to be a major cause of cervical cancer, and a vaccine has been developed against the specific papillomavirus strains that often lead to cancer development |
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