Transcript Molecular Biology of Cancer

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-consumingflesh, 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
Rank Cause of Death
No. of
deaths
% of all
deaths
•
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
2009 Estimated US Cancer Cases*
Men
766,130
Women
713,220
Prostate
25%
•27% Breast
Lung & bronchus
15%
•14% Lung & bronchus
Colon & rectum
10%
•10% Colon & rectum
Urinary bladder
7%
• 6% Uterine corpus
Melanoma of skin
5%
Non-Hodgkin
lymphoma
5%
• 4% Non-Hodgkin
lymphoma
Kidney & renal pelvis
5%
• 4% Melanoma of skin
Leukemia
3%
• 4%
Oral cavity
3%
• 3% Kidney & renal pel
Pancreas
3%
• 3% Ovary
All Other Sites
19%
Thyroid
• 3% Pancreas
•22% All Other Sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2009.
What is cancer?
• Malfunction of the control systems that
regulate cell growth and death
grow
divide
“Mother”
Cell
“Daughter”
Cells
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
Onc
(oncoproteins) that promote growth.
• Tumor suppressors = proteins that
TS
inhibit growth or promote cell death
TS
die
grow
divide
“Mother”
Cell
Onc
“Daughter”
Cells
X
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
genome
cell
chromosomes
genes
DNA
proteins
Proteins act alone
or in complexes to
perform many cellular
functions
Genes contain
instructions
for making
proteins
Basic Gene Expression
gene:
---TTCAAGTGG---
---AAGTTCACC--Transcription
mRNA: ---UUCAAGUGG--Translation
protein: ---Phe Lys Trp---
Mutation
gene:
---TTCAATTGG---
---AAGTTAACC--Transcription
mRNA: ---UUCAAUUGG--Translation
protein: ---Phe Asn Trp---
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.
Unique translocation in Chronic
Myelogenous Leukemia (CML)
gleevec
=
Druker, B. J. Blood 2008;112:4808-4817
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
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).
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)
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
At least 5
mutations
Normal Cell
Cancer Cell
Obeys strict rules
Divides only when told to
Dies rather than misbehaving
Stays close to home
Disobeys rules
Divides at will
Bad behavior doesn’t kill
Wanders through body
Careful with chromosomes
Careless with chromosomes
Cancer: Is there any good news?
Cancer Death Rates* Among
Men, US,1930-2005
100
Rate Per 100,000
Lung & bronchus
80
60
Stomach
Prostate
40
Colon & rectum
20
Pancreas
*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.
2005
2000
1995
1990
1985
1980
1975
1970
1965
1960
Liver
1955
1950
1945
1940
1935
0
1930
Leukemia
Cancer Death Rates* Among
Women, US,1930-2005
100
Rate Per 100,000
80
60
Lung & bronchus
40
Uterus
Breast
Colon & rectum
Stomach
20
Ovary
*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.
2005
2000
1995
1990
1985
1980
1975
1970
1965
1960
1955
1950
1945
1940
1935
Pancreas
1930
0
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
2008
4300
4830
2400
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.