1. But I’m Too Young! A Case Study of Ovarian Cancerby
Nancy A. Rice, Department of Biology, Western Kentucky University, and
Bruno Borsari, Biology Department, Winona State University

2. Abby is Sick: Review of the Story So Far…
Abby has been having abdominal pain.
She has gone to see Dr. Allen.
An ultrasound has indicated a mass on her right ovary.
She is preparing to have the mass and ovary removed surgically.

3. Group Discussion If you were Abby, what questions would you have?
Should Abby be worried about cancer? The doctor said it was a cyst!

4. CQ1: Do you know someone personally that has had cancer?
A: Yes
B: No

5. Overall Cancer Incidence and Mortality Trends in U.S.

6. A snapshot of ovarian cancer
From: A Snapshot of Ovarian Cancer, National Cancer Institute, updated 2007.

7. CQ2: Abby wondered: what is the difference between cancer and tumor
CQ2: Abby wondered: what is the difference between cancer and tumor? What do you think?
A: The two terms can be used interchangeably as they are synonymous.
B: Cancer is a disease that eventually disrupts body functions whereas a tumor is a mass of cells with no apparent function in the body.
C: Cancer is a disease which affects men whereas a tumor may affect both men and women.
E: Cancer is a disease of the digestive tract whereas a tumor may develop anywhere in the body. B

8. What is Cancer? Simplest definition Tumor
From the American Cancer Society
“ cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death.”
Tumor
Two types:
Benign (non-cancerous) – this is not cancer!
Does not spread; it can eventually become malignant in some cases.
Malignant (cancerous) – this is cancer!
Has the potential to spread to other parts of body.

9. Role of Cell Division in Cancer
Top = normal cell division
Bottom = unregulated cell division and tumor formation
Malignant
If tumor invades surrounding tissue (cancerous)
Benign
If tumor has no effect on surrounding tissue
(non-cancerous)
Metastatic
If individual cells break away and start a new tumor elsewhere
(cancerous)
Image from the National Cancer Institute

10. CQ3: Normal CA-125 levels are indicated by values of 35 U/ml or less
CQ3: Normal CA-125 levels are indicated by values of 35 U/ml or less. Abby’s CA-125 levels taken at two different times are indicated below. Is Abby likely to have a cyst or cancer?
Cyst
Cancer
CA-125 is a marker that measures inflammation; there is no specific blood test for ovarian cancer like there is for prostate cancer – if there WAS a blood test for ovarian cancer, we could potentially save over 15,000 lives/year and diagnose cancer at stage 1 or stage 2 instead of 3 o4 4 when cure rates are much lower.

11. Preparing for Surgery
Before the surgery, Dr. Allen came in to talk to Abby about her test results.
“I am really sorry, but your CA125 level is high and it looks like your ovary actually does not have a cyst, but instead has a tumor. It is best now to go ahead and remove both of your ovaries.”
Dr. Allen explained she had consulted with a pathologist to verify the diagnosis. She pulled out a brochure titled Ovarian Cancer and opened it to show Abby three photographs. One showed normal ovarian tissue; the other two showed benign and malignant ovarian tissue.

12. Normal ovarian epithelium
Ovary cystoadenoma (benign)
Ovarian adenocarcinoma (malignant)

13. The genetics of ovarian cancer
Abby had already learned a lot about ovarian cancer so she followed Dr. Allen’s explanation.
“I’m only 20 years old. How did I get ovarian cancer? Isn’t this a disease of older women?
“Typically ovarian cancer does affect older women. However, you may have a genetic predisposition for it. Cancer cells have mutations in specific genes that regulate cell division. When they are mutated, cell division becomes uncontrollable,” the doctor explained.
“I learned about those genes on the Internet! Is it true that some ovarian cancers are associated with mutated copies of genes called BRCA1 or BRCA2?” asked Abby.
“Yes,” said Dr. Allen. “You likely were born with one a mutated copy of these genes already. A mutation of the second copy could have occurred more recently, triggering the development of your tumor.”

14. CQ4: Why does cancer primarily affect older people rather than young people?
A: Because the immune system of older people is not as effective in distinguishing normal cells from cancer cells.
B: Because older people have been exposed to more carcinogens.
C: Because cancer develops after multiple mutations have occurred which takes years to happen.
D: None of the above. C

15. Cancer is a genetic disease
Cancer arises from the accumulation of genetic changes (mutations).
Most cancers have a minimum of 6-9 different genes mutated.
Not a hereditary disease – we do not pass on cancer to offspring.
We can inherit dispositions (susceptibility) to cancer.
Many genes that are mutated in cancer are involved in regulating the cell cycle.

16. Review: The cell cycle has four phases and controls cell division
Two gap or growth phases (G1 and G2)
S phase - DNA synthesis
M phase - Mitosis
Interphase

17. Checkpoint control system
3 major checkpoints: G1
Can DNA synthesis begin? G2
Has DNA synthesis been completed correctly?
Commitment to mitosis M
Are all chromosomes attached to spindle?
Can sister chromatids separate correctly?

18. Cell Cycle Checkpoints
Three checkpoints in cell cycle
G1-S transition
G2-M transition
Exit M phase transition
Checkpoints are where the cell assesses whether conditions are favorable for cell division.
When the environment is not favorable (for example, when the cell’s DNA is damaged), a protein called p53 can stop the cell cycle and cause the cell to die.
When the proteins that regulate the cell cycle are mutated or absent, cells can divide uncontrollably, leading to cancer.

19. Major Checkpoints – G1 G1 checkpoint (Most important!) G2 checkpoint
Controlled by cell size, growth factors, environment
“Go”  completes whole cell cycle
“Stop”  cell enters nondividing state (G0 Phase)
G2 checkpoint
Controlled by DNA replication completion, DNA mutations, cell size
M-spindle (Metaphase) checkpoint
Check spindle fiber (microtubule) attachment to chromosomes at kinetochores (anchor sites)

20. G0 phase G0 phase non-dividing, differentiated state
many human cells in G0 phase
liver cells
in G0, but can be “called back” to cell cycle by external cues
nerve & muscle cells
highly specialized
stopped in G0 & can never divide

21. Cell Cycle Control System
Checkpoint = control point where stop/go signals regulate the cell cycle

22. “Go-ahead” signals
Protein molecules that promote cell growth & division
internal signals
“promoting factors”
external signals
“growth factors”
Where is the P attached?
We still don’t fully understanding the regulation of the cell cycle. We only have “snapshots” of what happens in specific cases.

23. External Regulatory Factors

24. External Regulatory Factors
Growth Factor: proteins released by other cells to stimulate cell division
Density-Dependent Inhibition: crowded cells normally stop dividing; cell-surface protein binds to adjoining cell to inhibit growth
Anchorage Dependence: cells must be attached to another cell or ECM to divide

25. Internal Regulatory Molecules
MPF = maturation-promoting factor
specific cyclin-Cdk complex which allows cells to pass G2 and go to M phase

26. Cancer & Cell Growth
Cancer is essentially a failure of cell division control
unrestrained, uncontrolled cell growth
What control is lost?
gene p53 plays a key role in G1 restriction point
p53 protein halts cell division if it detects damaged DNA
options:
stimulates repair enzymes to fix DNA
forces cell into G0 resting stage
keeps cell in G1 arrest
causes apoptosis of damaged cell
ALL cancers have to shut down p53 activity
p53 is the Cell Cycle Enforcer

27. p53 — master regulator gene
NORMAL p53
p53 allows cells
with repaired
DNA to divide.
p53
protein
DNA repair enzyme
p53
protein
Step 1
Step 2
Step 3
DNA damage is caused
by heat, radiation, or
chemicals.
Cell division stops, and p53 triggers enzymes to repair damaged region.
p53 triggers the destruction of cells damaged beyond repair.
ABNORMAL p53
abnormal
p53 protein
cancer
cell
Step 1
Step 2
DNA damage is
caused by heat,
radiation, or
chemicals.
The p53 protein fails to stop
cell division and repair DNA.
Cell divides without repair to
damaged DNA.
Step 3
Damaged cells continue to divide.
If other damage accumulates, the
cell can turn cancerous.

28. CQ5: What would you expect cells to be like if they did not have properly functioning p53?
A: The absence of p53 inside cells would cause them to divide more rapidly.
B: The absence of p53 could cause cells to replicate with damaged DNA that could ultimately lead to cancer.
C: The absence of p53 could cause cells to skip mitosis (M phase) and stay in S phase of the cell cycle.
D: The absence of p53 would have no effect on the cells. B

29. Development of Cancer
Cancer develops only after a cell experiences ~6 key mutations (“hits”)
unlimited growth
turn on growth promoter genes
ignore checkpoints
turn off tumor suppressor genes (p53)
escape apoptosis
turn off suicide genes
immortality = unlimited divisions
turn on chromosome maintenance genes
promotes blood vessel growth
turn on blood vessel growth genes
overcome anchor & density dependence
turn off touch-sensor gene
It’s like an out of control car!

30. What causes these “hits”?
Mutations in cells can be triggered by
UV radiation
chemical exposure
radiation exposure
heat
cigarette smoke
pollution
age
genetics

31. Cancer Prevention
Anyone can get cancer but there are ways to minimize risk:
Don’t smoke, legal or illegal (includes hookahs, chew, 2nd-hand smoke)
Use sun protection
Exercise and keep weight at ideal level
Eat 5-7 servings of fruit and veggies a day
Use screening/preventative measures-breast/testicle/mole checks
Practice abstinence or use condoms
Vaccines (eg. HPV)

32. Tumor suppressors and oncogenes
Mutations in oncogenes and tumor suppressor genes can lead to cancer.
(Animation #5)

33. CQ6: The BRCA1 and BRAC2 genes that may be mutated in Abby’s cells would be considered?
A: An oncogene
B: A tumor suppressor gene

34. From Benign to Malignant
Cancer cells divide too quickly and can leave the original site and enter the blood, lymph, or tissues.
Most cells divide a set number (60-70) of times, then they stop dividing.
This usually limits benign tumors to small sizes.
Cancer cells can divide indefinitely.

35. Tumors Mass of abnormal cells Benign tumor Malignant tumors
abnormal cells remain at original site as a lump
p53 has halted cell divisions
most do not cause serious problems & can be removed by surgery
Malignant tumors
cells leave original site
lose attachment to nearby cells
carried by blood & lymph system to other tissues
start more tumors = metastasis
impair functions of organs throughout body

36. CQ7: How do cancer cells travel through the human body?
A: Cancer travels through the body by way of sexual intercourse between a healthy person and one affected by the disease.
B: The circulatory system only is responsible for relocating cancer cells.
C: The lymphatic system collects fluids from capillaries and with it cancer cells, which are then delivered by the circulatory system.
D: They are moved around on neurons throughout the body. C

38. The vessels of the circulatory and lymphatic systems provide a pipeline for cancer cells to move to other locations in the body through a process called metastasis.

39. Abby’s treatment options
Dr. Allen came to see Abby after her surgery.
“Everything went really well. Now we need to think about preventing this from ever coming back. Typically we use a combination of various types of therapy, which includes radiation and chemotherapy.”
Radiation - Uses high-energy rays to kill cancer cells. A large machine directs radiation at the body.
Chemotherapy - Uses anticancer drugs to kill cancer cells.

40. Traditional treatments for cancers
Treatments target rapidly dividing cells
high-energy radiation
kills rapidly dividing cells
chemotherapy
stop DNA replication
stop mitosis & cytokinesis
stop blood vessel growth

41. Typical Ovarian Cancer Treatments
One common chemotherapy for ovarian cancer is Taxol, which was first isolated from Yew bark in 1962 by the National Cancer Institutes (NCI).
Taxol blocks a cell's ability to break down the mitotic spindle during mitosis. With the spindle still in place, the cell can't divide into daughter cells and therefore the cancer can’t grow.
Taxus Brevifolia

42. Cancer Detection and Treatment
C hange in bowel or bladder habits
A sore that does not heal
U nusual bleeding or discharge
T thickening or lump
I ndigestion or difficulty swallowing
O bvious change in wart or mole
N agging cough or hoarseness C U T I O N A
Earlier detection and treatment of cancer greatly increase the odds of survival.
Therefore, knowing the warning signs of cancer is important to health.

43. CQ8: Can surgery successfully cure a cancer that has metastasized?
No, all body cells are dividing uncontrollably
Yes, it could remove all cells with defective cell-cycle regulation
No, cancer cells are no longer localized in one spot
Yes, if the tumor is benign

44. Abby’s ovarian cancer has been in remission for 10 years
Abby’s ovarian cancer has been in remission for 10 years. She graduated from college with a BA in Anthropology. Three years later she married, and today she is living happily with her husband Charles and their four-year-old adopted daughter.