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Cancer and the Cell Cycle. Chapter 11. Central Points (1). Cancer involves uncontrolled cell division Mutations in certain types of genes may lead to cancer Cancer is a disease of the cell cycle Breast cancer is a common type of cancer. Central Points (2).
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Cancer and the Cell Cycle Chapter 11
Central Points (1) • Cancer involves uncontrolled cell division • Mutations in certain types of genes may lead to cancer • Cancer is a disease of the cell cycle • Breast cancer is a common type of cancer
Central Points (2) • Chromosomal changes often a cause of cancer • Environmental causes of cancer are being studied • Lawsuits have addressed smoking as a cause of cancer
11.1 What Is Cancer? • Complex disease, affects many different cells and tissues • Characterized by uncontrolled cell division • Malignant cells spread, or metastasize, to other sites within the body • Unchecked growth may result in death
Cancer Deaths • Reduced deaths from infectious disease, increases in life span in U.S. • Cancer a major cause of illness and death • Risk age-related, living longer, increased risk of cancer • Pedigrees suggest some cancer has genetic component
Cancer Is a Genetic Disorder • Mutation: change in genetic makeupand cause cells to become cancerous • Carcinogens and certain behaviors increase rate of mutations and cancer risk • Not all tumors are cancerous, benign tumors,increase in size, but do not metastasize
Characteristics of Cancer • Tumors begin with a single cell that reproduces by mitosis • Cells in tumors divide continuously • Metastasis: Process in whichcells are invasive and move to other sites in the body
11.2 How Is Genetics Involved? • Two classes of genes: Oncogenes and tumor suppressor genes • Proto-oncogenes: control cell division • Tumor suppressor genes turn off cell division • Mutated alleles, oncogenes, and tumor suppressor genes cause cells to divide uncontrollably
Cancer-Causing Mutations • Exposure to environmental agents, virus, or lifestyle changes may cause a mutation • Certain virus infections can transform the cell • Human papillomavirus (HPV): Viral proteins interact with cell proteins, cause cervical cancer • Mistakes in DNA replication also cause mutations
11.3 Cell Cycle • Interphase: time between divisions • G1, S, and G2 • Mitosis: division of the chromosomes • Cytokinesis: division of the cytoplasm • Checkpoints in the cell cycle regulate cell division
G2/M checkpoint 4 Cell division 3 DNA repair 1 Mitosis G2 Cell grows, doubles in size G1 S Chromosome duplication 2 G1/S checkpoint Stepped Art p. 181
Interphase • G1 • Begins immediately after division • New organelles formed • End of G1, cell has doubled in size • S phase • Duplicate copy of each chromosome • G2 phase • Cell prepares to begin mitosis
Stages of Mitosis: Prophase • Replicated chromosomes condense and become visible • 46 chromosomes composed of two sister chromatids • Nuclear membrane breaks down • Spindle fibers form
Stages of Mitosis: Metaphase • Chromosomes, with spindle fibers attached, move to middle of cell
Stages of Mitosis: Anaphase • Centromeres divide • Converts each sister chromatid to a chromosome • Chromosomes migrate to opposite ends of cell • Complete set of 46 chromosomes at each end of cell
Stages of Mitosis: Telophase • Final stage of mitosis • Chromosomes unwind • Spindle fibers break down • Nuclear membrane re-forms
Cytokinesis: Last Stage of Cell Cycle • Cell membrane constricts and divides cell into two daughter cells with 46 chromosomes
Regulation of Cell Cycle • G1/S checkpoint • G2/M checkpoint • Tumor suppressor genes and proto-oncogenes control these checkpoints • Tumor suppressor genes turn off or decrease rate of cell division • Proto-oncogenes turn on or increase rate
Signal Transduction • In normal cells, signals from outside cell can • Activate tumor suppressor genes (turning off cell division) or • Activate proto-oncogenes (turning on cell division) • Signals can be proteins, hormones, or nerve signals • May include steroids, pollutants, and other molecules
Process of Signal Transduction • Signal binds to a receptor in plasma membrane • Binding sets off series of interactions inside cell • Signal molecule may remain outside cell • Binding of signal changes shape of receptor and allows it to transmit signal to other proteins • May alter gene expression
Signal molecule Signal–receptor binding Cellular response Protein molecules Changes in gene expression Outside cell Receptor Plasma membrane Cytoplasm Nucleus Stepped Art p. 183
Signal Transduction and Cancer • Cancer related to loss of cell cycle control • Often involves change in signal transduction pathway • Or change in cell cycle control machinery
Proto-Oncogene RAS (1) • Produces RAS protein that: • Attaches to inside of plasma membrane • Is part of a pathway that turns on cell division • Is signaled by growth factors from outside the cell • Changes shape and switches on when activated • Transfers signal to another protein in pathway • Changes shape again after signal transmitted, switches off (inactive)
Proto-Oncogene RAS (2) • RAS mutations in many types of cancer, including colon, lung, pancreatic, and stomach cancer • Mutant RAS stuck “on” and produces uncontrolled cell division
11.4 Breast Cancer • Most common form of cancer in U.S. woman • > 40,000 die, 178,000 new cases per year • Environmental factors involved • Mutations in BRCA1andBRCA2predispose women to breast cancer and ovarian cancer
BRCA1 (1) • In 1970s, Mary-Claire King and colleagues analyzed the pedigrees of 1,500 families • ~15% families, multiple cases of breast cancer • Tested the blood of 100s of families to locate a genetic marker for breast cancer • Testing difficult, most breast cancers occur at random
BRCA1 (2) • In 1980s, used DNA markers and polymerase chain reaction (PCR) for screening • In 1990, after testing 100s of markers, found link • D17S74 marker, chromosome 17 • Dominantly inherited, carry one mutant copy gene, develop breast cancer if other copy mutates • 82%: Second mutation = breast cancer • 44%: Second mutation = ovarian cancer
BRCA2 • Discovered in 1995, chromosome 13 • When mutated, causes breast cancer susceptibility • Rare in general population, < 1% • Some populations much higher • Ashkenazi Jews’ combined frequency of BRCA1 and BRCA2 is 2.5%
Breast Cancer in Men (1) • Frequently diagnosed in later stages, often more difficult to treat • In U.S., ~1% of breast cancers in males • Parts of Africa, rates significantly higher • Egypt: 6% of all cases • Zambia: 15% of all cases
Breast Cancer in Men (2) • Ashkenazi Jews and black males have higher rates of breast cancer • Risk factors • Age • Family history of breast cancer • Occupational exposure to heat, gasoline, or estrogen-containing creams in soap and perfume industry
11.5 Other Genetic Causes of Cancer • Changes in number and structure of chromosomes are common feature of cancer cells • Down syndrome individuals: 18–20X more likely to develop leukemia • Connection not yet been discovered
Translocations and Cancer • Philadelphia chromosome, between chromosomes 9 and 22, commonin: • Chronic myelogenous leukemia (CML) • Others, including acute myeloblastic leukemia • Burkitt’s lymphoma and multiple myeloma, associated with other translocations • Suggests chromosomal changes related to the development of the cancer
11.6 Environment and Cancer • Solid relationship exists between environmental factors and cancer • Cancer cluster: Large number of cases in restricted area • Epidemiologists examine environment for link • Cancer cluster in Woburn, Massachusetts, environmental trigger, industrial solvents
Environmental Factors and Populations • Determine types of cancer populations may develop • Many forms of cancer related to: • Physical surroundings • Personal behavior • Or both • At least 50% of all cancer can be attributed to some type of environmental factor
Smoking • Number one factor in cancer, either direct (smoker) or indirect (secondhand smoke) • Related to cancers of oral cavity, larynx, esophagus, and lungs • Accounts for 30% of all cancer deaths • Most have very low survival rate (e.g. 13% lung cancer sufferers survive beyond 5 yrs • Snuff or chewing tobacco users 50X more likely to develop cancer of the mouth
Skin Cancer (1) • ~1 million new cases in U.S. per year • Almost all cases related to UV light exposure from sun or tanning lamps • Increasing, may be due to outdoor recreation or moving to regions with more sun exposure • Lightly pigmented people higher risk, genetic characteristics can affect the susceptibility
Skin Cancer (2) • Ozone depletion also contributes to increased UV exposure and risk • > 80% of lifetime skin damage occurs by age 18 • In spite of risk, some choose suntans and only 25% of Americans consistently use sunscreen