15 cancer - Objectives 1 To identify some cellular and...

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Unformatted text preview: Objectives 1. To identify some cellular and molecular events that may lead to cancer development 2. To realize how the malfunctions of some signal transduction pathways in cell cycle and apoptosis may affect proper cell growth and division 3. To understand how the interactions between different oncogenes and tumor suppressor genes may cause cell transformation and cancer development 1 Death Rate for Leading Causes in HK, 1961-2006 (No. of Registered Deaths per 100,000 Population) 1961 72.0 72.0 2001 169.6 2002 172.9 2003 171.0 2004 173.8 Cause of Death 1. Malignant neoplasms (Cancers) 2. Diseases of heart 2005 180.7 2006 176.4 58.9 70.0 73.7 78.9 86.5 86.1 81.9 3. Pneumonia 84.1 45.1 47.4 57.6 54.2 63.0 61.3 4. Cerebrovascular diseases 44.2 46.6 47.7 51.4 50.4 50.4 48.2 5. External causes of morbidity and mortality 34.7 27.5 30.7 30.4 33.1 31.6 28.6 All other causes 297.5 137.0 136.5 151.8 152.3 156.0 149.3 All causes 591.5 496.0 508.8 541.1 550.2 567.8 545.6 Source: Department of Health, HKSAR 2 Tumor (Neoplasm) • A group of cells which are not under control and coordination with the needs of the organism as a whole: A. Benign tumor • Encapsulated local mass of cells (do not spread) (do B. Malignant tumor (Cancer) • Spread to neighboring tissues (invasion); spread to distant organs via lymphatic or vascular circulation (metastasis) Lethal secondary tumors (metastases) are established elsewhere 3 Normal cells • Remain as a single layer of cells Cancer cells • The capacity for growth and division is not drastically different; they continue to grow, piling on top of one another to form clumps 4 Phenotype of a Cancer Cell • There are a large number of differences (both (both structural and biochemical) between normal and cancer cells vs. there are also many vs. differences from one type of cancer cell to another Impossible to describe the properties of a “typical” cancer cell: • 1. Often have highly aberrant chromosome complements (aneuploidy) 5 Karyoptype of a Cancer Cell with Spectral Visualization Technique • Normal cells The two members of a pair should be identical Each chromosome should be a single continuous color • Cancer cells Extra and missing chromosomes Chromosomes of more than one color (large number of translocations have occurred in (large previous cell generations vs. a cell with normal cell cycle checkpoints and apoptotic pathways would never have attained this chromosome complement) 6 2. Cytoskeleton is often reduced and/or disorganized 3. Numerous changes have been observed at the cell surface, including the appearance (or (or increase) and disappearance (or (or decrease) of particular components: • Some possess new cell surface proteins (tumor-associated antigens) • They are less adhesive both to other cells and to non-cellular substrates (easier to leave a tumor (easier mass and migrate to other sites) Normal cells Normal Cancer cells 7 Cell number Time in culture (days) Time 4. Less dependent on growth factors (e.g., EGF) (e.g., • Cell cycle does not depend on signals transmitted from growth-factor receptors located at the surface • Lose of anchorage dependence (can grow even in suspension) 5. Immortal and indefinite division (because of the presence of (because telomerase) 8 The Six Hallmarks of Cancer Cells (Hanahan and Weinberg, 2000) 1. Self-sufficiency in growth signals or response 2. Insensitivity to growth inhibitory signals 3. Evasion of programmed cell death (apoptosis) 4. Limitless replicative potential 5. Sustained angiogenesis (stimulation of blood vessel growth) 6. Tissue invasion and metastasis 9 Different Stages of Carcinogenesis (1) (1) Genetically altered cell (2) Hyperplasia (3) Dysplasia 10 Different Stages of Carcinogenesis (2) (4) (4) (4) Benign tumor (5) Malignant tumor Colon adenoma Adenocarcinoma 11 12 • Cancers are classified according to the tissue and cell type from which they arise: 1. Carcinomas (from epithelial cells) Account for 90% of human cancers (most of the cell (most proliferation in the body occurs in epithelia; epithelial tissues are most frequently exposed to the various forms of physical and chemical damage) 2. Sarcomas (from connective tissue or muscle cells) 3. Leukemias (from hemopoetic cells) • Adenoma (benign epithelial tumor with a glandular (benign organization) vs. adenocarcinoma; chondroma (benign tumor of cartilage) vs. chondrosarcoma chondrosarcoma 13 How Cancer Arises? • Oncogene / Tumor Suppressor Gene Theory: - Oncogenes encode proteins that promote the loss of growth control and the conversion of a cell to a malignant state (cell’s accelerators) (cell - Tumor suppressor genes encode proteins that restrain cell growth and prevent cells from becoming malignant (cell’s brakes) (cell 14 Absence or Inactivation of Tumor Suppressor Genes • Tumor suppressor genes as brakes on cell proliferation • In 1990, p53 gene was recognized as tumor p53 suppressor gene Persons with Li-Fraumeni syndrome inherit one normal and one abnormal (or deleted) allele of p53; (or p53 highly susceptible to cancers that result from random mutations in the normal allele (e.g., breast (e.g., and brain cancers, and leukemia) 15 • “Guardian of the genome” • 50 percent of all human cancers with point mutations or deletions in both alleles (> 1000 (> different p53 mutations have been identified !) - Proper functioning of the protein is very sensitive to even slight changes in amino acid sequence - Poorer survival rate of the patients than those containing the wild-type gene 16 • An important anti-tumor weapon: • Increase in p53 level is due to a decrease in the protein’s degradation: (Mouse Double Minutes 2) (Mouse (Ataxia Telangiectasia Mutant) - Mdm2 binds to p53 and escorts it out of the nucleus into the cytosol Degradation Degradation where it is ubiquintinated and destroyed - ATM is normally activated following DNA damage (p53 is one (p53 of the proteins to phosphorylate) - The phosphorylated p53 molecule is no longer able to interact with Mdm2 - Existing p53 molecules are thus stabilized in the nucleus (activate (activate the expression of p21 and Noxa/Puma genes) 17 Noxa / Puma Actions of Different Mutagens on p53 Gene p53 • Aflatoxin B (produced by certain mold on nuts and grains) causes a characteristic G → T substitution in base pair of codon 249 • Deamination from cytosine residues by endogenous metabolism produces a distinctive C → T substitution in codon 248 18 • The six most frequently mutated residues of p53 have been identified (arginine 175, (arginine glycine 245, R248, R249, R273, and R282) - Occur at or near the protein-DNA interface 19 Anticancer drugs p53 gene gene status in the cells • The compounds had a dramatic effect on arresting growth and inducing apoptosis in normal cells • The p53-/- cells continued to proliferate in the presence of these compounds p53 (they become drug-resistant) (they 20 21 • Tumor viruses carry genes whose products interfere with the cell’s normal growth-regulating activities - e.g., Human papilloma virus HPV (present in about 90% of cervical cancers): E7 vs. pRb; E6 binds to the p53 protein and targets it for destruction 22 Development and OverExpression of Oncogenes • Genetic defects of normal cellular genes that control cell growth: proto-oncogenes proto → oncogenes - As accelerator to speed up cell division - Trigger the development of cancer 23 Ras-MAPK Pathway in Normal Cell Proliferation 24 25 Cyclins, CDKs, CDIs Cell Cycle 26 1. Growth Factors • • A cell acquires an oncogene that produces its own growth factor e.g., Oncogene sis carried by simian sis sarcoma virus (codes for an altered (codes form of a polypeptide subunit of the growth factor PDGF) Cell produces its own supply of active PDGF Altered growth factor receptor with permanently activated tyrosine kinase e.g., Oncogene erb-B in chicken red erb blood cancer cells An altered version of the receptor for EGF → tyrosine kinase remains active even without EGF binding - 2. Receptors • • • 27 3. Plasma Membrane G Proteins • • Permanent activation of plasma membrane G protein e.g., Oncogene ras (normal c-ras) ras Abnormal Ras proteins that retain bound GTP instead of hydrolyzing it to GDP Ras protein in a permanently activated state Mutant forms are permanently locked in an active configuration e.g., Oncogene raf (normal c-raf) raf Abnormal Raf proteins are permanently active Continually stimulate the rest of the protein kinase cascade 28 - 4. Protein Kinases • • - 5. Transcription Factors • Nuclear transcription factors turn on the expression of genes required for cell proliferation Overexpression of oncogenes, e.g., myc, fos and jun, cause myc fos jun hyper-proliferation of cell • 6. Cdk-Cyclins • e.g., Human breast cancers Cdk oncogene Cdk4 Cdk4 Cyclin oncogene CYCD1 CYCD1 Overproduction of Cdk-cyclin complexes stimulate progression through the cell cycle, even in the absence of growth factors 29 7. Bcl-2 • • An exceptional oncogene that cannot be fitted into the above six basic categories When the DNA damages in a cell are so great that cannot be repaired, the cell will suicide by apoptosis Overproduction of Bcl-2 blocks apoptosis (prolonging the survival of genetically damaged (prolonging cells and may lead to cancer development) - 30 31 What Causes Cancer? • Cancer is a genetic disease because it can be traced to alterations within specific genes (but in most cases, it is not an (but inherited disease) • Agents that can alter the genome are potentially carcinogenic (cancer-causing; e.g., tumor viruses, ionizing radiation, and chemicals) 32 33 Types of Carcinogen in Tobacco Products 34 Cytochrome P450 oxygenases (P450s) Glutathione-S-transferases (GSTs) Glutathione(GSTs) UDP glucuronosyltransferases (UGTs) UGTs) 35 a. Alters the properties of the gene product b. Alters a nearby regulatory sequence; excessive quantity of the gene product is produced c. Chromosome rearrangement; alters the expression of the gene or the nature of the gene product 36 (produces a tyrosine kinase) (produces • A chimeric protein having N-terminal fragment of Bcr fused to the C-terminal portion of Abl - Abl becomes hyperactive (stimulates inappropriate (stimulates proliferation and inhibits apoptosis in hemopoietic precursor cells that contain it) • Philadelphia (Ph) chromosome (named after the city where it was (named discovered) - Accounts for 95% of chronic myeloid leukemia CML 37 How We Can Tackle Cancer with Our Current Knowledge of Cancer Biology • Once we understand precisely what genetic lesions have occurred in a cancer, we can begin to design effective rational methods to treat it The chimeric Bcr-Abl protein is an obvious target for therapeutic attack Synthetic drug molecule STI-571 (currently known as Gleevec) (currently blocks Bcr-Abl Produced by Novartis • - Gleevec at the ATP-binding ATPpocket of BcrBcrAbl Bcr-Abl Bcr- - 38 • • - In a study, Gleevec was given to 54 patients with early CML All but one of them had their white blood cell counts returned to normal (apparent (apparent eradication of the blood cells carrying the Ph chromosome) Not so good for patients who had already progressed through further mutations to the acute CML Showed a response at first and then relapsed (the cancer cells were able to evolve a (the resistance to the Gleevec) 39 ...
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