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

1. How many of us will develop cancer?2. One million new cases of cancer yearly in

U.S.3. 10 million currently being treated for

cancer 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

Source: US Mortality Public Use Data Tape 2002, National Center for Health Statistics, Centers for Disease Control and Prevention, 2004.

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

9. Nephritis 40,974 1.7

10. Septicemia 33,865 1.4

Rank Cause of DeathNo. of deaths

% of all deaths

Lifetime Probability of Developing Cancer, By Site, Women, US, 1999-2001

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

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

Lifetime Probability of Developing Cancer, By Site, Men, US, 1999-2001

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

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

2005 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2005.

Men295,280

Women275,000

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

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%

Gilda Radner’s Story Formerly 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

Cancer Case StudyThe 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. How do body cells (somatic cells) divide?2. What is mitosis and what happens during

cell division?3. What controls the timing and location of

cell division?4. Why do some cells become cancerous? 5. What can we do to stop, prevent, and

recognize cancer?6. How are gametes (sex cells) produced?7. What is meiosis and what happens during

the process?

What is cancer?

1. Cancer is a genetically dictated loss of cell cycle control

2. Cancer cells cannot stop dividing form a large mass of immortal cells

malignant tumor

3. Cell cycle Activities of a cell from one cell division to

the next

4. Cancerous cells arise in everyone…... Why doesn’t everyone get cancer?

The Cell Cycle Things that must happen before a cell

divides:In the nucleus

1. _________________________________________________

Cell organelles2. _________________________________________________

What must happen to the chromosomes during cell division?3. __________________________________________________

Mitosis: division ofthe nucleus

Cytokinesis:division of cytoplasm

Daughtercells

M-phase

Interphase = G1, S, G2S-phase

G2-phase G1-phase

Prep.for division: organelles duplicate

Cell growth + normal cell

activities

Synthesis of DNA(chromosomes replicate)

Cells divide

The Cell Cycle

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

e.g. Liver & kidney cells

b. 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. CytokinesisDivision of the cytoplasm to form two cells

What needs to happen to the chromosomes prior to Mitosis?

During mitosis?

Each Chromatid has One DNA molecule

Kinetochore

Spindle fibers

Centromere

Sister chromatids

1. How do sister chromatids compare genetically?

2. What happens to sister chromatids during meiosis?

Sketch of a duplicated chromosome

The chromosome cycle

Two-chromatidchromosome

Interphase

S-Phase: DNA Replication

G1

One-chromatidchromosome

One-chromatidchromosome

Mitosis—sister chromatids separate

G1

Human Life Cycle

1. Mitosis Produces somatic

cells Daughter cells are

genetically identical to parent cell

2. Meiosis Produces gametes A reductive

division (46 C 23 C)

Daughter cells are genetically different

Fertilization

Zygote (46 C)

MitosisMeiosisMeiosis

Sperm (23 C) Egg (23 C)

Adult Human (Somatic cells: 46

C)

Fertilization

Normal Karyotype of Human Chromosomes1. How do you

inherit chromosomes?

2. How many pairs of chromosomes in this Karyotype?

3. What are homologous chromosomes?

4. What gender?5. Sex vs. autosomal

chromosomes?

Sex chromosomes determine a person’s gender1. Humans have

46 chromosomes:

44 autosomal chromosomes

2 sex chromosomes

2. Sex chromosomes

Female: XX Male: XY

3. Diploid number (2n) vs. haploid number (n) of chromosomes?

Two sets of 3chromosomes

A pair ofhomologouschromosomes

Diploid cell, 2n = ____

One set ofnon-homologouschromosomes

One set of non-homologouschromosomes

Haploid cell, n = ______Haploid cell, n = _______

Mitosis: Division of the Nucleus

1. View Animation of mitosis Go to link found at the ALE section of the class

website

2. 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

1. 3 pairs of chromosomes: 2n = 6• Diploid Number ??• Haploid Number ??

2. What does one pipe cleaner represent?3. How do you represent a duplicated

chromosome?4. What do the colors represent?5. What are Homologous chromosome?6. 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. How many molecules of DNA does one pipe cleaner represent?”2. What do two pipe cleaners twisted together represent?”3. What do the chromosomes look like from this organism just before

the S phase? • How many chromosomes are present?

4. What do the chromosomes look like from this organism just after the S phase?

• How many chromosomes are present?5. What is happen in the cell during each phase of the cell cycle?

Regulation of Cell Division

1. 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?

2. What normally controls cell division?

Contact Inhibition

1. 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 inhibition of cell growth

2. Cells may migrate in culture. Stop moving when touch other cells due to

contact inhibition of cell movement.

Cancer Cells

1. No Contact inhibition continue growing and moving when they touch

other cells. Pile up to form tumors

2. Metastasize Cancer cells migrate to other parts of the body—

the cancer spreads

3. Growth Factors 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

Both daughtercells divideActively dividing cells

(basal cells): controlled by growth factors

Onedaughterdifferentiates

Only one daughterCell divides

Growth control in a normal cell

Signaling cell Growth factor

Growth factor binds to receptor

Receptor sends a signalto the nucleus

target cell entersS-phase and then

dividestarget cell

Nucleus

Growth Factors: Stimulate Cell Division

1. Chemical messengers produced in one part of the body, but effect cells elsewhere

2. Travel in the blood and other body fluids3. Bind to Membrane Receptors, like a key

fitting into a lock. Stimulates a cell to divide

4. Each receptor binds to a different growth factor.

5. Different cell types are stimulated by different growth factors.

Several ways to get faulty growth control in a cancer cell

2. Mutant receptor might turn on even without

binding growth factor

In each case: cancer cellenters S phase anddivides inappropriately,causing a tumor

1. Cell might produce its own growth factor

3. Signal cascade might occur even without

trigger from receptor

Cancer: It’s all in the Genes

1. Proto-oncogenes • Normal genes that code for growth factors• Active in actively dividing tissues (e.g.

skin)• Sometimes mutate into......

2. Oncogenes: • genes that cause cancer• produce too much growth factor

Over stimulate mitosis

Oncogenes are rarely inherited.....Why?

Tumor Suppressor Genes

1. Tumor Suppressor Genes• Code for Proteins that turn off mitosis

e.g. p53 gene

2. p53 Gene• Codes for a protein that stops the cell

cycle after G1• Half of all cancers involve p53

3. 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 gene2. If a women inherits BRCA 1 she has a

a. 80 to 90% chance of developing breast cancerb. 40 to 50% chance of ovarian cancer.c. Why aren’t the percentages 100%?d. 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

1. Immortal 2. Metastasize: Spread into other tissues3. Not subject to contact inhibition4. Have lost the genetic ability to stop

dividing—mutations to...• Tumor Suppressor Genes (e.g. p53, BRCA1)• Growth factor Genes

5. Cancer is heritable: Cancer cells give rise to cancer cells

6. Are Dedifferentiated • 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 chemotherapies1. Prevent cells from entering S-phase2. Block the S-phase3. Block the M-phase (mitosis)

Phase-specific Chemotherapies

1. Prevent cells from entering the S-phase Block Growth factor receptors on cell

membrane with antibody (e.g. Herceptin)

2. Block the S phase Methotrexate and other chemotherapeutic

drugs block DNA synthesis

3. Block or stop mitosis Taxol interferes with the movement of the

chromosomes along spindle fibers

Cells Affected by Chemotherapy1. May affect all rapidly dividing cells2. Which cells divide rapidly?

a. Hair follicle cellsb. Skin cellsc. Cells lining digestive tract d. Blood stem cells

• Divide to produce???

So.... What would be the side effects?

Side Effects of Chemotherapy

1. Lose hair2. Wounds don’t heal well3. 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

1. Eat plenty of fiber• Fiber speeds passage through digestive tract decrease risk

of colon cancer

2. Do not smoke3. Drink alcohol in moderation or not at all4. Exercise regularly5. Do not become overweight fat cells produce

estrogen, a growth factor increases risk of breast cancer

6. Limit dietary fat animal contains growth hormones

7. Limit sun exposure or use sunscreen (SPF 30)8. 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 of the body

I - indigestion or difficulty swallowing

O - obvious change in a wart or mole

N - nagging cough or hoarseness

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. The phase of mitosis in which sister chromatids are separated is called

A. prophase. B. metaphase.C. anaphase. D. telophase.

2. The phase of mitosis in which chromosomes condense is calledA. prophase. B. metaphase.C. anaphase. D. telophase.

3. The phase of meiosis in which the nuclear membrane is dismantled is calledA. prophase I. B. anaphase I.C. prophase II. D. metaphase II.

4. The phase of meiosis in which sister chromatids are separated is calledA. metaphase I. B. anaphase I.C. anaphase II. D. metaphase I

5. Most of the problems with chromosome numbers in cells are a result of A. alcohol. B. U.V. lightC. non-disjunction. D. mitosis

6. List four differences between mitosis and meiosis.7. Cite two ways that allow for genetic variation in an organism from meiosis.

Mitosis Practice Problems 1. Identify the stage of mitosis

for cell #1 below. 2. Identify the stage of mitosis

for cell #2 below.

3. Identify the stage of mitosis for cell #3 below.

4. 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 thata. 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. During anaphase of mitosis in humans or other diploid organisms, how many

chromatids does each chromosome have as they move toward the poles?

2. During anaphase I of meiosis, how many chromatids does each chromosome have as they move toward the poles?

3. During anaphase II of meiosis, how many chromatids does each chromosome have as they move toward the poles?.

4. 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?

5. 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. Proto-oncogenes

2. Oncogenes

3. Tumor Suppressor genes

4. Growth factors

5. p53 gene

6. BRCA 1 gene