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Cancer and the Cell Cycle

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

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  1. Cancer and the Cell Cycle Chapter 11

  2. 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

  3. 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

  4. 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

  5. Cancer Cells

  6. Animation: How Cells Reproduce (cancer cells)

  7. 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

  8. Breast Cancer Pedigree

  9. 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

  10. 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. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. Stages of Mitosis

  17. Stages of Mitosis: Prophase • Replicated chromosomes condense and become visible • 46 chromosomes composed of two sister chromatids • Nuclear membrane breaks down • Spindle fibers form

  18. Prophase

  19. Stages of Mitosis: Metaphase • Chromosomes, with spindle fibers attached, move to middle of cell

  20. 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

  21. Anaphase

  22. Stages of Mitosis: Telophase • Final stage of mitosis • Chromosomes unwind • Spindle fibers break down • Nuclear membrane re-forms

  23. Cytokinesis: Last Stage of Cell Cycle • Cell membrane constricts and divides cell into two daughter cells with 46 chromosomes

  24. Identical Daughter Cells

  25. 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

  26. 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

  27. 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

  28. Signal molecule Signal–receptor binding Cellular response Protein molecules Changes in gene expression Outside cell Receptor Plasma membrane Cytoplasm Nucleus Stepped Art p. 183

  29. 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

  30. 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)

  31. 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

  32. Animation: How Cells Reproduce (cell cycle)

  33. 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

  34. 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

  35. 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

  36. BRCA1

  37. 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%

  38. BRCA2

  39. 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

  40. 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

  41. 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

  42. 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

  43. Cancer Genes on other Chromosomes

  44. 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

  45. 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

  46. 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

  47. Lungs of Non-Smoker and Smoker

  48. 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

  49. 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

  50. Melanoma

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