The Molecular Biology of Cancer

• What is cancer?

• What is molecular biology?

• What role does molecular biology play in cancer?

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

What is cancer?

• The number two killer in the U.S.

• Right behind heart disease.

US Mortality, 2006

• 1. Heart Diseases 631,636 26.0

• 2. Cancer 559,888 23.1

• 3. Cerebrovascular diseases 137,119 5.7

• 4. Chronic lower respiratory diseases 124,583 5.1

• 5. Accidents (unintentional injuries) 121,599 5.0

• 6. Diabetes mellitus 72,449 3.0

• 7. Alzheimer disease 72,432 3.0

• 8. Influenza & pneumonia 56,326 2.3

• 9. Nephritis* 45,344 1.9

• 10. Septicemia 34,234 1.4

Rank Cause of DeathNo. of deaths

% of all deaths

2009 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2009.

Men766,130

Women713,220

•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

Prostate 25%

Lung & bronchus 15%

Colon & rectum 10%

Urinary bladder 7%

Melanoma of skin 5%

Non-Hodgkin5% lymphoma

Kidney & renal pelvis 5%

Leukemia 3%

Oral cavity 3%

Pancreas 3%

All Other Sites 19%

What is cancer?

• Malfunction of the control systems that regulate cell growth and death

“Mother”Cell

“Daughter”Cells

growdivide

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.

What controls cell growth and death?

• Proteins!• Oncogenes produce proteins

(oncoproteins) that promote growth.• Tumor suppressors = proteins that

inhibit growth or promote cell death

“Mother”Cell

“Daughter”Cells

growdivide

Onc

Onc

die X

TS

TS

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.

Basic Gene Expression

proteins

genes

cell

genome

chromosomes

DNA

Genes containinstructions for makingproteins

Proteins act aloneor in complexes to perform many cellularfunctions

Basic Gene Expression

gene: ---TTCAAGTGG---

---AAGTTCACC---

mRNA: ---UUCAAGUGG---

protein: ---Phe Lys Trp---

Transcription

Translation

Mutation

gene: ---TTCAATTGG---

---AAGTTAACC---

mRNA: ---UUCAAUUGG---

protein: ---Phe Asn Trp---

Transcription

Translation

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.

Fig. 20.28

What damages DNA?

• Chemicals– 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!)

Fig. 20.29

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.

Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.

Druker, B. J. Blood 2008;112:4808-4817

Unique translocation in Chronic Myelogenous Leukemia (CML)

gleevec

Onc=

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.

Fig. 12.36

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.

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.

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].

Biological attributes (“hallmarks”) shared by most cancers

• Generate their own mitogenic signals.• Resist exogenous growth-inhibitory

signals.• Evade apoptosis (programmed cell

death).

ApoptosisA 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)

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).

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)

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).

Dr. Judah Folkman “Father of angiogenesis research”

1933 - 2008

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.

Control Issues: Cancer

Normal CellObeys strict rulesDivides only when told toDies rather than misbehavingStays close to home

Careful with chromosomes Careless with chromosomes

Cancer CellDisobeys rulesDivides at willBad behavior doesn’t killWanders through body

At least 5mutations

Cancer: Is there any good news?

Cancer Death Rates* Among Men, US,1930-2005

*Age-adjusted to the 2000 US standard population.Source: US Mortality Data 1960-2005, US Mortality Volumes 1930-1959,National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.

0

20

40

60

80

10019

30

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

2005

Lung & bronchus

Colon & rectum

Stomach

Rate Per 100,000

Prostate

Pancreas

LiverLeukemia

Cancer Death Rates* Among Women, US,1930-2005

*Age-adjusted to the 2000 US standard population.Source: US Mortality Data 1960-2005, US Mortality Volumes 1930-1959,National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.

0

20

40

60

80

10019

30

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

2005

Lung & bronchus

Colon & rectum

Uterus

Stomach

Breast

Ovary

Pancreas

Rate Per 100,000

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%

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.

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

Acknowledgment

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