Mitosis & Cancer Lecture Notes Biol 100 – K.Marr

1. Mitosis & Cancer Lecture NotesBiol 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.

2. 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

3. 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 • How much do you know about cancer.....?

4. 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?

5. US Mortality, 2002 No. of deaths % of all deaths Rank Cause of Death • 1. Heart Diseases 696,947 28.5 • 2. Cancer557,271 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 40,974 1.7 • 10. Septicemia 33,865 1.4 Source: US Mortality Public Use Data Tape 2002, National Center for Health Statistics, Centers for Disease Control and Prevention, 2004.

6. Lifetime Probability of Developing Cancer, By Site, Women, US, 1999-2001 Site Risk All sites 1 in 3 Breast 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

7. Lifetime Probability of Developing Cancer, By Site, Men, US, 1999-2001 Site Risk All sites 1 in 2 Prostate 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

8. 2005 Estimated US Cancer Deaths* Men295,280 Women275,000 Lung and bronchus 31% Prostate 10% Colon and rectum 10% Pancreas 5% Leukemia 4% Esophagus 4% Liver and intrahepatic 3%bile duct Non-Hodgkin 3% Lymphoma Urinary bladder 3% Kidney 3% All other sites 24% 27% Lung and bronchus 15% Breast 10% Colon and rectum 6% Ovary 6% Pancreas 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Multiple myeloma 2% Brain/ONS 22% All other sites ONS=Other nervous system. Source: American Cancer Society, 2005.

9. Gilda Radner’s StoryFormerly of Sat. Night Live; was married to actor Gene Wilder • Complained to physician of ..... • Fatigue, abdominal pain and bloating • Symptoms progressively got worse • Died of Ovarian Cancer in 1989 • 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

10. Cancer Case StudyThe cell cycle out of control An Unavoidable Loss of Control (Available at the Lecture Note section of the class website)

11. Questions we’ll try to answer • 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?

12. What is cancer? • Cancer is a genetically dictated loss of cell cycle control • Cancer cells cannot stop dividing • form a large mass of immortal cells  malignant tumor • Cell cycle • Activities of a cell from one cell division to the next • Cancerous cells arise in everyone…... • Why doesn’t everyone get cancer?

13. 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. __________________________________________________

14. Cytokinesis: division of cytoplasm The Cell Cycle Mitosis: division of the nucleus M-phase Daughter cells G2-phase G1-phase Cells divide Prep. for division: organelles duplicate Cell growth + normal cell activities Synthesis of DNA (chromosomes replicate) Interphase = G1, S, G2 S-phase

15. The Events of Interphase Interphase—the phase between cell divisions • Divided into 3 phases S ______________________________________ G2 ______________________________________ G1 ______________________________________ • What happens in each phase?

16. How long does G1 Last? G1 can vary greatly • Can last indefinitely • e.g. Liver & kidney cells • Can live months to years w/o dividing • e.g. Nerve & muscle cells • Usually never divide (G0)

17. 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?

18. Sketch of a duplicated chromosome Each Chromatid has One DNA molecule Sister chromatids How do sister chromatids compare genetically? What happens to sister chromatids during meiosis? Kinetochore Centromere Spindle fibers

19. The chromosome cycle Mitosis—sister chromatids separate G1 One-chromatid chromosome Two-chromatid chromosome G1 One-chromatid chromosome S-Phase: DNA Replication Interphase

20. Mitosis Produces somatic cells Daughter cells are genetically identical to parent cell Meiosis Produces gametes A reductive division (46 C  23 C) Daughter cells are genetically different Fertilization Human Life Cycle Sperm (23 C) Egg (23 C) Fertilization Zygote(46 C) Mitosis Meiosis Meiosis Adult Human (Somatic cells: 46 C)

21. Normal Karyotype of Human Chromosomes • How do you inherit chromosomes? • How many pairs of chromosomes in this Karyotype? • What are homologous chromosomes? • What gender? • Sexvs. autosomal chromosomes?

22. Sex chromosomes determine a person’s gender • Humans have 46 chromosomes: • 44 autosomal chromosomes • 2 sex chromosomes • Sex chromosomes • Female: XX • Male: XY • Diploid number(2n)vs.haploid number (n) of chromosomes?

23. Two sets of 3 chromosomes A pair of homologous chromosomes Diploid cell, 2n = ____ Haploid cell, n = _______ Haploid cell, n = ______ One set of non-homologous chromosomes One set of non-homologous chromosomes

24. Mitosis: Division of the Nucleus • View Animation of mitosis • Go to link found at the ALE section of the class website • See the following slides for diagrams of each step of mitosis

25. Interphase to Prophase DNA is replicated in the nucleus Chromatin begins to coil—makes it more compact

26. 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.

27. Metaphase to Anaphase

28. Telophase and Cytokinesis

29. Modeling Mitosis w/ Pipe Cleaners for a cell with 3 pairs of Chromosomes • 3 pairs of chromosomes: 2n = 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?

30. 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 • 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?

31. Regulation of Cell Division • What evidence in your own life do you have that cell division is regulatedby your body? • 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?

32. Contact Inhibition • Cells do not normally grow or divide when in contact w/ other Cells • 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 inhibitionof cell growth • Cells may migrate in culture. • Stop moving when touch other cells due to contact inhibition of cell movement.

33. Cancer Cells • No Contact inhibition • continue growing and moving when they touch other cells. • Pile up to form tumors • Metastasize • Cancer cells migrate to other parts of the body—the cancer spreads • Growth Factors • made of protein • Chemical messages that control the cell cycle • How do we know the cell cycle is under genetic control?

34. 1. Normal cell growth 2. Basal cell carcinoma One daughter differentiates Only one daughter Cell divides Both daughter cells divide Actively dividing cells (basal cells): controlled by growth factors

35. Growth control in a normal cell Signaling cell Growth factor Growth factor binds to receptor Receptor sends a signal to the nucleus target cell enters S-phase and then divides target cell Nucleus

36. 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. • Stimulates a cell to divide • Each receptor binds to a different growth factor. • Different cell types are stimulated by different growth factors.

37. Several ways to get faulty growth control in a cancer cell 2. Mutant receptor might turn on even without binding growth factor 1.Cell might produce its own 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

38. Cancer: It’s all in the Genes • Proto-oncogenes • Normal genes that code for growth factors • Active in actively dividing tissues (e.g. skin) • Sometimes mutate into...... • Oncogenes: • genes that cause cancer • produce too much growth factor • Over stimulate mitosis • Oncogenes are rarely inherited.....Why?

39. Tumor Suppressor Genes • Tumor Suppressor Genes • Code for Proteins that turn off mitosis e.g. p53 gene • p53 Gene • Codes for a protein that stops the cell cycle after G1 • Half of all cancers involve p53 • One mutant Tumor Suppressor Gene does notcause cancer....Why?

40. p53: A Tumor Suppresser Gene • How many p53 genes did you inherit? Why? • How many p53 genes need to mutate before a cell becomes cancerous? Why?

41. BRCA 1 Breast Cancer Susceptibility Gene • BRCA 1 is a Tumor Suppresser gene • If a women inherits BRCA 1 she has a • 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?

42. The Role of the Environment in Causing Cancer • Certain Viruses, toxins, or Radiation may lead to a p53 mutation • 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.

43. 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... • Tumor Suppressor Genes (e.g. p53, BRCA1) • Growth factor Genes • Cancer is heritable: Cancer cells give rise to cancer cells • Are Dedifferentiated • less specialized than the cell it came from)

44. 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 • Block the S-phase • Block the M-phase (mitosis)

45. Phase-specific Chemotherapies • Prevent cells from entering the S-phase • Block Growth factor receptors on cell membrane with antibody (e.g. Herceptin) • Block the S phase • Methotrexate and other chemotherapeutic drugs block DNA synthesis • Block or stop mitosis • Taxol interferes with the movement of the chromosomes along spindle fibers

46. Cells Affected by Chemotherapy • May affect all rapidly dividing cells • Which cells divide rapidly? • Hair follicle cells • Skin cells • Cells lining digestive tract • Blood stem cells • Divide to produce??? So.... What would be the side effects?

47. Side Effects of Chemotherapy • Lose hair • Wounds don’t heal well • Destroy lining of digestive tract • nausea and severe bacterial infection • Decrease Blood cell Production • RBC’s Anemia • WBC’s  decreased ability to fight infections and kill cancer cells

48. How to Lower your Cancer Risks • Eat plenty of fiber • 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

49. 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 of the body I - indigestion or difficulty swallowing O - obvious change in a wart or mole N - nagging cough or hoarseness

50. 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?