1. The Molecular Biology of Cancer
What is cancer?
What is molecular biology?
What role does molecular biology play in cancer?

2. What is cancer?
A cancer cell is: “…a savage cell that somehow corrupts the forces that normally protect the body, invades the well-ordered society of cells surrounding it, colonizes distant areas, and, in a finale to its cannibalistic orgy of flesh-consuming-flesh, commits suicide by destroying its host.”
Pat McGrady, The Savage Cell

3. What is cancer? The number two killer in the U.S.
Right behind heart disease.

4. US Mortality, 2006 1. Heart Diseases 631,636 26.0
No. of deaths
% of all deaths
Rank
Cause of Death
1. Heart Diseases 631,
2. Cancer ,
3. Cerebrovascular diseases 137,
4. Chronic lower respiratory diseases 124,
5. Accidents (unintentional injuries) 121,
6. Diabetes mellitus 72,
7. Alzheimer disease 72,
8. Influenza & pneumonia 56,
9. Nephritis* 45,
10. Septicemia 34,
Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. In 2006, there were 559,888 cancer deaths in the US.
*Includes nephrotic syndrome and nephrosis.
Source: US Mortality Data 2006, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009.

5. 2009 Estimated US Cancer Cases*
Men 766,130
Women 713,220
Prostate 25%
Lung & bronchus 15%
Colon & rectum 10%
Urinary bladder 7%
Melanoma of skin 5%
Non-Hodgkin 5% lymphoma
Kidney & renal pelvis 5%
Leukemia 3%
Oral cavity 3%
Pancreas 3%
All Other Sites 19%
27% Breast
14% Lung & bronchus
10% Colon & rectum
6% Uterine corpus
4% Non-Hodgkin lymphoma
4% Melanoma of skin
4% Thyroid
3% Kidney & renal pelvis
3% Ovary
3% Pancreas
22% All Other Sites
Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that about 1.5 million new cases of cancer will be diagnosed in Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers in both men and in women.
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2009.

6. What is cancer?
Malfunction of the control systems that regulate cell growth and death
“Mother”
Cell
“Daughter”
Cells
grow
divide

7. Cell Proliferation & death in the Adult
Human body (~150 lbs) consists of about 1 x 1014 cells (100 trillion).
Each day we lose and replace a number of cells that corresponds to ~2.5 lbs.
Certain cells in the mucosal lining of the intestine are replaced 4,400 times during our life. This represents ~25 miles of intestine.
Epidermal cells are replaced about 1,000 times and connective tissues are replaced about 400 times.
Bone marrow weighs on average 3.2 lbs. Its turnover time is two weeks. During our lifetime, we produce 3 tons of bone marrow.

8. What controls cell growth and death?
Proteins!
Oncogenes produce proteins (oncoproteins) that promote growth.
Tumor suppressors = proteins that inhibit growth or promote cell death
Onc TS X
die
grow
divide
“Mother”
Cell
“Daughter”
Cells

9. What is molecular biology?
The study of the production of proteins, using the instructions written in genes.
In other words, genes are blueprints for making proteins.
We say a gene “codes for” a protein, or “encodes” a protein, because the instructions are written in code: the genetic code.

10. Basic Gene Expression genome cell chromosomes genes DNA proteins
Genes contain
instructions
for making
Proteins act alone
or in complexes to
perform many cellular
functions
The U.S. Department of Energy Human Genome Project Information Web site illustrates the size of the human genome by estimating that it would take "about 9.5 years to read out loud (without stopping) the more than three billion pairs of bases in one person's genome sequence". [Source: Human Genome Projects Information].
Another example of the immensity of the human genome is given by the Centre for Integrated Genomics:
"If our strands of DNA were stretched out in a line, the 46 chromosomes making up the human genome would extend more than six feet [close to two metres]. If the ... length of the 100 trillion cells could be stretched out, it would be ... over 113 billion miles [182 billion kilometres]. That is enough material to reach to the sun and back 610 times." [Source: Centre for Integrated Genomics]

11. Basic Gene Expression gene: ---TTCAAGTGG--- ---AAGTTCACC---
mRNA: ---UUCAAGUGG---
protein: ---Phe Lys Trp---
Transcription
Translation

12. Mutation gene: ---TTCAATTGG--- ---AAGTTAACC--- mRNA: ---UUCAAUUGG---
protein: ---Phe Asn Trp---
Transcription
Translation

13. How do mutations arise?
DNA replication machinery makes mistakes (G-C becomes T-A).
DNA becomes damaged. (DNA in each cell receives >104 lesions every day.)
This damage forces mistakes during DNA replication, which converts the damage to mutations.

14. Fig

15. What damages DNA? Chemicals Radiation
Environmental agents (cigarette tar)
Cellular agents (oxygen is toxic!)
Radiation
UV (Strong sunlight induces about 100,000 lesions per exposed skin cell per hour.)
Ionizing radiation (e.g., x-rays) causes chromosome breaks (very toxic!)

16. Fig

17. Why do mutations matter?
Mutations can activate oncogenes.
For example, a translocation fuses the bcr and abl genes, activating the abl oncogene. Chronic myelogenous leukemia (CML) results.

18. Unique translocation in Chronic Myelogenous Leukemia (CML)
gleevec
Onc =
Druker, B. J. Blood 2008;112:
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.

19. Why is bcr-abl an oncogene?
The abl gene codes for a membrane receptor with protein tyrosine kinase activity (Abl).
A protein tyrosine kinase puts phosphate groups on the amino acid tyrosine in proteins.
The Abl protein is at the beginning of a signal transduction pathway that leads to activation of genes that promote cell division.

20. Fig

21. Why is bcr-abl an oncogene?
The abl gene codes for a membrane receptor with protein tyrosine kinase activity (Abl).
A protein tyrosine kinase puts phosphate groups on the amino acid tyrosine in proteins.
The Abl protein is at the beginning of a signal transduction pathway that leads to activation of genes that promote cell division.
Bcr-Abl constantly sends the growth signal.
Thus, the pathway loses control; cells divide without control; cancer gets started.

22. Why do mutations matter?
Mutations can activate oncogenes.
E.g., a translocation fuses the bcr and abl genes, activating the abl oncogene. Chronic myelogenous leukemia (CML) results.
Mutations can inactivate tumor suppressor genes.
E.g., inactivation of the p53 gene leads to many cancers, including breast cancer
Congenital p53 mutation = Li-Fraumeni syndrome.

23. Most mutations that cause cancer are not inherited.
Cancer incidence changes over time.
Migration and altered environment or lifestyle can alter cancer incidence.
Identical twins typically do not develop the same cancers.
World Health Organization and American Cancer Society estimate 60-90% of all cancer cases are due to environmental factors [chemicals, diet, exercise, sun exposure, tobacco use].

24. Biological attributes (“hallmarks”) shared by most cancers
Generate their own mitogenic signals.
Resist exogenous growth-inhibitory signals.
Evade apoptosis (programmed cell death).

25. Apoptosis
A cell fate that plays a key role in embryonic development (e.g. cells between digits, loss of tadpole tail), but also in the maintenance of adult tissues… “From 50 to 70 billion cells die each day due to apoptosis in the average human adult. In a year, this amounts to the proliferation and subsequent destruction of a mass of cells equal to an individual's body weight” (see "Cell Proliferation, Differentiation, and Apoptosis" by Michael Andreeff ''et al.'' in ''Cancer Medicine'', 5th Edition)

26. Biological attributes “hallmarks” shared by most cancers
Generate their own mitogenic signals.
Resist exogenous growth-inhibitory signals.
Evade apoptosis (programmed cell death).
Acquire genomic instability.
Mutation rate increases.
Cells become aneuploid (non-standard number of chromosomes).

27. Protect the Chromosomes
The corrupted genomes of most human epithelial cancers are, like the Yucatan crater formed by the meteor that wiped out the dinosaurs, unambiguous relics of some catastrophic calamity within the tumor cell, a salient reminder of the genomic abyss that opens when the mechanisms that maintain chromosomal integrity fail or are overridden.
Laura Soucek and Gerard Evan (2002)

28. Biological attributes “hallmarks” shared by most cancers
Generate their own mitogenic signals.
Resist exogenous growth-inhibitory signals.
Evade apoptosis.
Acquire genomic instability.
Proliferate without limits (i.e. undergo immortalization).
Acquire vasculature (i.e. undergo angiogenesis).
Typical cells in the body grow only for a certain number of generations and then die. One crucial feature that distinguishes a cancer cell from a normal somatic cell is its ability to divide indefinitely. The basis for the cellular mortality of normal cells is that your chromosomes are constantly shortening with every cell division. Without the activity of a special enzyme, telomerase, the chromosome ends will shorten to the point where the cell can no longer survive.

29. “Father of angiogenesis research”
A dividing cell can only expand up to a certain size before it needs to recruit new blood vessels to feed the cells. No living cell in your body is more than about the thickness of your fingernail away from a blood vessel.
Without new blood vessels, cells proliferating out of control will eventually starve to death as they proliferate beyond the range of a normal blood supply.
Because of Dr. Folkman's vision, more than 10 new cancer drugs are currently on the market, and more than 1.2 million patients worldwide are now receiving anti-angiogenic therapy.
Dr. Judah Folkman
“Father of angiogenesis research”

30. Biological attributes “hallmarks” shared by most cancers
Generate their own mitogenic signals.
Resist exogenous inhibitory signals.
Evade apoptosis.
Acquire genomic instability.
Proliferate without limits.
Acquire vasculature.
Invade and metastasize (in more advanced cancers).
Evade elimination by immune system.

31. Control Issues: Cancer
Normal Cell
Obeys strict rules
Divides only when told to
Dies rather than misbehaving
Stays close to home
Careful with chromosomes
Careless with chromosomes
Cancer Cell
Disobeys rules
Divides at will
Bad behavior doesn’t kill
Wanders through body
At least 5
mutations
Sid Vicious English punk rock musician, the bass guitar player of the Sex Pistols, late 70s.

32. Cancer: Is there any good news?

33. Cancer Death Rates* Among Men, US,1930-2005
Rate Per 100,000
Lung & bronchus
Stomach
Prostate
Colon & rectum
Most of the increase in cancer death rates for men prior to 1990 was attributable to lung cancer. However, since 1990, the age-adjusted lung cancer death rate in men has been decreasing; this decrease has been estimated to account for about 40% of the overall decrease in cancer death rates in men. Stomach cancer mortality has decreased considerably since Death rates for prostate and colorectal cancers have also been declining.
Pancreas
Leukemia
Liver
*Age-adjusted to the 2000 US standard population.
Source: US Mortality Data , US Mortality Volumes ,
National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.

34. Cancer Death Rates* Among Women, US,1930-2005
Rate Per 100,000
Lung & bronchus
Uterus
Breast
Lung cancer is currently the most common cause of cancer death in women, with the death rate more than twice what it was 30 years ago. In comparison, breast cancer death rates changed little between 1930 and 1990, but decreased 27% between 1990 to The death rates for stomach and uterine cancers have decreased steadily since 1930; colorectal cancer death rates have been decreasing for more than 50 years.
Colon & rectum
Stomach
Ovary
Pancreas
*Age-adjusted to the 2000 US standard population.
Source: US Mortality Data , US Mortality Volumes ,
National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.

35. Cancer death rate dropped nearly 20 percent in 15 yr.
American Cancer Society estimates 650,000 lives spared from cancer 1990 to 2005
Cancer death rate for men dropped 19.2%
Decreased lung, prostate and colon cancer deaths
Cancer death rate for women dropped 11.4%
Decreased breast and colorectal cancer deaths
The 5-year survival rate for breast cancer is approaching 90%

36. Gleevec Trade name for Imatinib mesylate. Developed by Novartis.
Approved by FDA in 2001.
Targets the active site of the Bcr-Abl protein kinase and inhibits the enzyme.

37. Success of Gleevec CML New Cases Deaths 1997 4300 2400 2008 4830 450
The annual mortality rate has been reduced from 15-20% to 2%
Estimated median survival rate is expected to exceed 20 years based on current data

41. Acknowledgment
I am grateful to Dr. Kristi Neufeld, who prepared some of these slides for her presentation at last year’s Mini College.