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Mitosis & Cancer Lecture Notes Biol 100 – K.Marr Topics for the next few lectures Mitosis and Cancer: Cause of Cancer + Therapies Reading assignments in Essential Biology : Ch 8: Cellular Basis of Repro. & Inheritance pp. 128-129: Cancer Cells—growing out of control pp. 211-214: The Genetic Basis of Cancer This week’s lab activity Lab 5: Online Karyotyping and Mitosis. Optional further reading See the Biology 100 web site for links to the articles below and more! Varmus, H. & R.A. Weinberg "Genes and the Biology of Cancer" Scientific American Library 1993 "What You Need to Know About Cancer" Special Issue of Scientific American, September 1996 Cancer Statistics How many of us will develop cancer? One million new cases of cancer yearly in U.S. 10 million currently being treated for cancer 1. 2. 3. How much do you know about cancer.....? Questions we will try to answer 1. What is cancer? 2. How are cancerous cells different than normal cells? 3. How do you get cancer? i.e. What makes normal cells become cancer cells? US Mortality, 2002 Rank Cause of Death No. of deaths % of all deaths 1. Heart Diseases 696,947 28.5 2. Cancer 557,271 22.8 3. Cerebrovascular diseases 162,672 6.7 4. Chronic lower respiratory diseases 124,816 5.1 5. Accidents (Unintentional injuries) 106,742 4.4 6. Diabetes mellitus 73,249 3.0 7. Influenza and pneumonia 65,681 2.7 8. Alzheimer disease 58,866 2.4 Nephritis 10. Septicemia 40,974 1.7 33,865 1.4 Source: US Mortality Public Use Data Tape 2002, National Center for Health Statistics, Centers for Disease Control and Prevention, 2004. Lifetime Probability of Developing Cancer, By Site, Women, US, 1999-2001 Site Risk All sites Breast 1 in 3 1 in 7 Lung & bronchus 1 in 18 Colon & rectum 1 in 18 Uterine corpus 1 in 38 Non-Hodgkin lymphoma 1 in 56 Ovary 1 in 68 Melanoma 1 in 78 Pancreas 1 in 81 Urinary bladder 1 in 88 Uterine cervix 1 in 130 Source:DevCan: Probability of Developing or Dying of Cancer Software, Version 5.2 Statistical Research and Applications Branch, NCI, 2004. http://srab.cancer.gov/devcan Lifetime Probability of Developing Cancer, By Site, Men, US, 1999-2001 Site All sites Prostate Risk 1 in 2 1 in 6 Lung and bronchus 1 in 13 Colon and rectum 1 in 17 Urinary bladder 1 in 28 Non-Hodgkin lymphoma 1 in 46 Melanoma 1 in 53 Kidney 1 in 67 Leukemia 1 in 68 Oral Cavity 1 in 73 Stomach 1 in 81 Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 5.2 Statistical Research and Applications Branch, NCI, 2004. http://srab.cancer.gov/devcan 2005 Estimated US Cancer Deaths* Men 295,280 Women 275,000 27% Lung and bronchus 15% Breast 10% 10% Colon and rectum Pancreas 5% 6% Ovary Leukemia 4% 6% Pancreas Esophagus 4% 4% Leukemia Liver and intrahepatic bile duct 3% 3% Non-Hodgkin lymphoma Non-Hodgkin Lymphoma 3% 3% Uterine corpus 2% Multiple myeloma Urinary bladder 3% 2% Brain/ONS Kidney 3% All other sites 24% Lung and bronchus 31% Prostate 10% Colon and rectum ONS=Other nervous system. Source: American Cancer Society, 2005. 22% All other sites Gilda Radner’s Story Formerly of Sat. Night Live; was married to actor Gene Wilder Complained to physician of ..... Died of Ovarian Cancer in 1989 Fatigue, abdominal pain and bloating Symptoms progressively got worse General population: 1 in 70 chance of getting Ovarian Cancer. Not given ultra-sound or blood tests for Ovarian Cancer.....Why not? Did not mention: Aunt & Grandmother died of ovarian cancer Makes Gilda’s chances of ovarian cancer: 1 in 2 Cancer Case Study The cell cycle out of control An Unavoidable Loss of Control (Available at the Lecture Note section of the class website) Questions we’ll try to answer 1. 2. 3. 4. 5. 6. 7. How do body cells (somatic cells) divide? What is mitosis and what happens during cell division? What controls the timing and location of cell division? Why do some cells become cancerous? What can we do to stop, prevent, and recognize cancer? How are gametes (sex cells) produced? What is meiosis and what happens during the process? What is cancer? Cancer is a genetically dictated loss of cell cycle control Cancer cells cannot stop dividing 1. 2. form a large mass of immortal cells malignant tumor Cell cycle 3. Activities of a cell from one cell division to the next Cancerous cells arise in everyone…... 4. Why doesn’t everyone get cancer? The Cell Cycle Things that must happen before a cell divides: In the nucleus 1. _________________________________________________ Cell organelles 2. _________________________________________________ What must happen to the chromosomes during cell division? 3. __________________________________________________ The Cell Cycle Mitosis: division of the nucleus M-phase G2-phase Cytokinesis: division of cytoplasm G1-phase Cells divide Prep. for division: organelles duplicate Daughter cells Cell growth + normal cell activities Synthesis of DNA (chromosomes replicate) S-phase Interphase = G1, S, G2 The Events of Interphase Interphase—the phase between cell divisions Divided into 3 phases S ______________________________________ G2 ______________________________________ G1 ______________________________________ What happens in each phase? How long does G1 Last? G1 can vary greatly a. Can last indefinitely b. e.g. Liver & kidney cells Can live months to years w/o dividing e.g. Nerve & muscle cells Usually never divide (G0) Cell Division Cell Division consists of two parts 1. Mitosis Division of the nucleus to form 2 complete nuclei. 2. Cytokinesis Division of the cytoplasm to form two cells What needs to happen to the chromosomes prior to Mitosis? During mitosis? Sketch of a duplicated chromosome Each Chromatid has One DNA molecule 1. 2. How do sister chromatids compare genetically? What happens to sister chromatids during meiosis? Kinetochore Sister chromatids Centromere Spindle fibers The chromosome cycle Mitosis—sister chromatids separate One-chromatid chromosome Two-chromatid chromosome One-chromatid chromosome S-Phase: DNA Replication Interphase G1 G1 Human Life Cycle Mitosis 1. Produces somatic cells Daughter cells are genetically identical to parent cell 2. Sperm (23 C) Fertilization Fertilization Zygote (46 C) Meiosis Produces gametes A reductive division (46 C 23 C) Daughter cells are genetically different Egg (23 C) Mitosis Meiosis Adult Human (Somatic cells: 46 C) Meiosis Normal Karyotype of Human Chromosomes 1. 2. 3. 4. 5. How do you inherit chromosomes? How many pairs of chromosomes in this Karyotype? What are homologous chromosomes? What gender? Sex vs. autosomal chromosomes? Sex chromosomes determine a person’s gender 1. Humans have 46 chromosomes: Sex chromosomes 2. 3. 44 autosomal chromosomes 2 sex chromosomes Female: XX Male: XY Diploid number (2n) vs. haploid number (n) of chromosomes? Two sets of 3 chromosomes A pair of homologous chromosomes Haploid cell, n = _______ Diploid cell, 2n = ____ Haploid cell, n = ______ One set of non-homologous chromosomes One set of non-homologous chromosomes Mitosis: Division of the Nucleus View Animation of mitosis 1. 2. Go to link found at the ALE section of the class website See the following slides for diagrams of each step of mitosis Interphase to Prophase DNA is replicated in the nucleus Chromatin begins to coil—makes it more compact Prophase to Prometaphase Chromatin continues to coil, making it more compact. Chromosomes are now visible: consist of identical, paired sister chromatids. Nuclear envelope breaks down. Spindle fibers (microtubule proteins) attach to centromeres, resulting in movement of chromosomes. Metaphase to Anaphase Telophase and Cytokinesis Modeling Mitosis w/ Pipe Cleaners for a cell with 3 pairs of Chromosomes 3 pairs of chromosomes: 2n = 6 1. • • 2. 3. 4. 5. 6. Diploid Number ?? Haploid Number ?? What does one pipe cleaner represent? How do you represent a duplicated chromosome? What do the colors represent? What are Homologous chromosome? What do the different sizes represent? Modeling the Cell Cycle for a Cell containing 3 pairs of Chromosomes Go through entire process: S G2 M G1 Ask each other these questions as you model mitosis • • 1. 2. 3. 4. 5. How many molecules of DNA does one pipe cleaner represent?” What do two pipe cleaners twisted together represent?” What do the chromosomes look like from this organism just before the S phase? • How many chromosomes are present? What do the chromosomes look like from this organism just after the S phase? • How many chromosomes are present? What is happen in the cell during each phase of the cell cycle? Regulation of Cell Division What evidence in your own life do you have that cell division is regulated by your body? 1. 2. Left ear is about same size as right ear—Why? A cut your finger heals, but the skin doesn't just keep growing—Why? What normally controls cell division? Contact Inhibition Cells do not normally grow or divide when in contact w/ other Cells 1. E.g. Cultured cells in a petri dish divide until they form a layer one cell thick and then stop when make contact w/ other cells. Called contact inhibition of cell growth Cells may migrate in culture. 2. Stop moving when touch other cells due to contact inhibition of cell movement. Cancer Cells No Contact inhibition 1. continue growing and moving when they touch other cells. Pile up to form tumors Metastasize 2. Cancer cells migrate to other parts of the body—the cancer spreads Growth Factors 3. made of protein Chemical messages that control the cell cycle How do we know the cell cycle is under genetic control? 1. Normal cell growth 2. Basal cell carcinoma One daughter differentiates Only one daughter Cell divides Actively dividing cells (basal cells): controlled by growth factors Both daughter cells divide Growth control in a normal cell Signaling cell Growth factor Growth factor binds to receptor Receptor sends a signal to the nucleus target cell Nucleus target cell enters S-phase and then divides Growth Factors: Stimulate Cell Division Chemical messengers produced in one part of the body, but effect cells elsewhere Travel in the blood and other body fluids Bind to Membrane Receptors, like a key fitting into a lock. 1. 2. 3. 4. 5. Stimulates a cell to divide Each receptor binds to a different growth factor. Different cell types are stimulated by different growth factors. Several ways to get faulty growth control in a cancer cell 2. 1. Cell might produce its own growth factor Mutant receptor might turn on even without binding growth factor 3. Signal cascade might occur even without trigger from receptor In each case: cancer cell enters S phase and divides inappropriately, causing a tumor Cancer: It’s all in the Genes Proto-oncogenes 1. Normal genes that code for growth factors Active in actively dividing tissues (e.g. skin) Sometimes mutate into...... • • • Oncogenes: 2. genes that cause cancer produce too much growth factor • • Over stimulate mitosis Oncogenes are rarely inherited.....Why? Tumor Suppressor Genes Tumor Suppressor Genes 1. • Code for Proteins that turn off mitosis e.g. p53 gene p53 Gene 2. • • 3. Codes for a protein that stops the cell cycle after G1 Half of all cancers involve p53 One mutant Tumor Suppressor Gene does not cause cancer....Why? p53: A Tumor Suppresser Gene 1. How many p53 genes did you inherit? Why? 2. How many p53 genes need to mutate before a cell becomes cancerous? Why? BRCA 1 Breast Cancer Susceptibility Gene 1. BRCA 1 is a Tumor Suppresser gene 2. If a women inherits BRCA 1 she has a a. b. c. d. 80 to 90% chance of developing breast cancer 40 to 50% chance of ovarian cancer. Why aren’t the percentages 100%? Why are the percentages much lower for the average woman? The Role of the Environment in Causing Cancer 1. Certain Viruses, toxins, or Radiation may lead to a p53 mutation 2. A 2nd p53 mutation may lead to one of the following cancers Cancer of the.... Bladder, blood, brain, breast, colon, esophagus, liver, lung, spleen, thyroid, etc. Summary of the Characteristics of Cancer Cells Immortal Metastasize: Spread into other tissues Not subject to contact inhibition Have lost the genetic ability to stop dividing— mutations to... 1. 2. 3. 4. • • Tumor Suppressor Genes (e.g. p53, BRCA1) Growth factor Genes Cancer is heritable: Cancer cells give rise to cancer cells Are Dedifferentiated 5. 6. • less specialized than the cell it came from) Therapeutic Strategies: Attack Actively Dividing Cells Since cancer is uncontrolled cell division, all treatments involve the cell cycle. Phase-specific chemotherapies Prevent cells from entering S-phase 2. Block the S-phase 3. Block the M-phase (mitosis) 1. Phase-specific Chemotherapies Prevent cells from entering the S-phase 1. Block Growth factor receptors on cell membrane with antibody (e.g. Herceptin) Block the S phase 2. Methotrexate and other chemotherapeutic drugs block DNA synthesis Block or stop mitosis 3. Taxol interferes with the movement of the chromosomes along spindle fibers Cells Affected by Chemotherapy 1. May affect all rapidly dividing cells 2. Which cells divide rapidly? a. Hair follicle cells b. Skin cells c. Cells lining digestive tract d. Blood stem cells • Divide to produce??? So.... What would be the side effects? Side Effects of Chemotherapy 1. Lose hair 2. Wounds don’t heal well 3. Destroy lining of digestive tract • nausea and severe bacterial infection 4. Decrease Blood cell Production • RBC’s Anemia • WBC’s decreased ability to fight infections and kill cancer cells How to Lower your Cancer Risks Eat plenty of fiber 1. • 2. 3. 4. 5. 6. 7. 8. Fiber speeds passage through digestive tract decrease risk of colon cancer Do not smoke Drink alcohol in moderation or not at all Exercise regularly Do not become overweight fat cells produce estrogen, a growth factor increases risk of breast cancer Limit dietary fat animal contains growth hormones Limit sun exposure or use sunscreen (SPF 30) Learn to recognize the warning signs of cancer Common Warning Signs of Cancer: C.A.U.T.I.O.N. C - change in bowel or bladder habits A - a sore that does not heal U - unusual bleeding or discharge T - thickening or lump in the breast or any part the body I - indigestion or difficulty swallowing O - obvious change in a wart or mole N - nagging cough or hoarseness of Preconceptions Revisited Evaluate your responses to these questions 1. What is cancer? 2. How are cancerous cells different than normal cells? 3. How do you get cancer? i.e. What makes normal cells become cancer cells? Mitosis and Meiosis Practice Problems 1. 2. 3. 4. 5. 6. 7. The phase of mitosis in which sister chromatids are separated is called A. prophase. B. metaphase. C. anaphase. D. telophase. The phase of mitosis in which chromosomes condense is called A. prophase. B. metaphase. C. anaphase. D. telophase. The phase of meiosis in which the nuclear membrane is dismantled is called A. prophase I. B. anaphase I. C. prophase II. D. metaphase II. The phase of meiosis in which sister chromatids are separated is called A. metaphase I. B. anaphase I. C. anaphase II. D. metaphase I Most of the problems with chromosome numbers in cells are a result of A. alcohol. B. U.V. light C. non-disjunction. D. mitosis List four differences between mitosis and meiosis. Cite two ways that allow for genetic variation in an organism from meiosis. Mitosis Practice Problems 1. 2. Identify the stage of mitosis for cell #1 below. Identify the stage of mitosis for cell #2 below. 3. 4. Identify the stage of mitosis for cell #3 below. Identify the stage of mitosis for cell #4 below. Mitosis Practice Problems 1. Identify the stage of mitosis for cell #4 below. 2. A diploid cell is one that a. has two homologues of each chromosome. b. is designated by the symbol 2n. c. has chromosomes found in pairs. d. All of the above Mitosis and Meiosis Practice Problems 1. 2. 3. 4. 5. During anaphase of mitosis in humans or other diploid organisms, how many chromatids does each chromosome have as they move toward the poles? During anaphase I of meiosis, how many chromatids does each chromosome have as they move toward the poles? During anaphase II of meiosis, how many chromatids does each chromosome have as they move toward the poles?. A student is simulating meiosis 1 with chromosomes that are red long and yellow long; red short and yellow short. Why would you not expect to find both red long and yellow long in one resulting daughter cell? If there are 13 pairs of homologous chromosomes in a pre-sperm cell, how many chromosomes are there in a sperm? How many chromatids? Mitosis and Meiosis Practice Problems Mitosis and Meiosis Practice Problems Mitosis and Meiosis Practice Problems Control of Cell Cycle and Cancer Practice Problems What role do each of the following play in controlling the cell cycle and in cancer? 1. 2. 3. 4. 5. 6. Proto-oncogenes Oncogenes Tumor Suppressor genes Growth factors p53 gene BRCA 1 gene