Cellular and Molecular Basis of Cancer
Overview
Why is cancer so common?
Why is cancer so difficult to cure?
Cancer is a common disease
1
in 3 of us get cancer
1
in 4 of us die of cancer
7 million deaths per year worldwide
Why is cancer so common?
Cancer is a disease of eukaryotic cells
MEMBRANE
CYTOPLASM
NUCLEUS
DNA
Cancer starts in a single cell
200 different cell types
1013-14 cells/human
Large number of cells
Cancer is a genetic disease
DNA vulnerable during cell division
23 pairs of chromosomes
4 bases (A-T;C-G)
3x109 base pairs/cell
(6000 million bases)
Cell division
6000 million bases
One hour
Large number of cell divisions
1010 new colon epithelial cells every day
3x1011 new blood cells every day
1016 cell divisions/lifetime
Each cell division – on average one error
Environmental Causes
DNA damaging agents
Smoking
Diet
Environmental Carcinogens
May account for up to 50% of cancer incidence
Cancer incidence increases with age
2000: 6 million; 2020: 20 million deaths
Why is cancer so common?
Large number of cells
Large number of cell divisions
Environmental pollution
Aging population
So why is cancer not more common?
Cancer requires alterations in many genes
Cancer is clonal
Most genetic changes occur by
chance
5-10 genes need to be altered
Takes a long time for 5-10 genetic
changes to accumulate in one cell
Cancer takes a long time to develop
Aniline dye workers
DNA repair protects
Base excision repair
Nucleotide excision repair
Mismatch repair
Recombinational repair
DNA repair reduces risk of cancer
Thousand of freckles and
multiple cancers on face
of child with xeroderma
pigmentosum
XP: 1000x higher risk of skin cancer
Cancer may be a stem cell disease
Most cells have a limited lifespan
(a few weeks or months)
Stem cells are long-lived
(potentially immortal)
Stem cells are very rare
(perhaps less than 0.1% of cells)
Immunity and cancer
40% of immunosuppressed renal
transplant patients develop cancer in 20
years (compared to 6% of controls)
Immune system kills cancer-inducing
infections and can kill developing cancer
cells
Summary – Why is cancer not
more common?
Takes a long time to develop
DNA repair protects
Stem cells are rare?
Immunity protects
Normal (stem) cell
Genetic changes
Cancer stem cell
More genetic changes
Local invasion
More genetic changes
Spread (metastasis via lymph/blood/nerves)
The progression of cancer
Cancer is a common disease
1
in 3 of us get cancer
1
in 4 of us die of cancer
Why is cancer difficult to cure?
Cancer or Normal Cell?
MEMBRANE
CYTOPLASM
NUCLEUS
DNA
100
% Cell Survival
Narrow therapeutic window
Cancer cells
1
0
1
2
Normal cells
3
4
Increasing Dose (mg.h/ml)
40
1012
30
109
20
Cell number
Population Doublings
Cancer is detected late
10
Limit of detectability: 7 mm
106
103
1
7.5 x 108 cells/g
0.1g = 7mm diameter
1g
1mg
1g
1kg
Fractional Cell Kill Hypothesis
Double the dose, double the log cell kill
106
105
Cell Number
104
103
102
101
1
0
0
1
2
3
4
mg.h/ml
5
6
7
Fractional Cell Kill Hypothesis
Dose killing 99.99% cells
Cells treated
Cells Surviving
1012
108
108
104
104
100
Small cancers are easier to cure
L1210 mouse leukemia
Cells innoculated ip
200mg/kg cyclophosphamide day 1
Cell Number Mice surviving
106
0/10
105
5/9
104
10/10
Skipper HE, 1968
TNM staging
T (primary tumour)
T1 and T2 – clinically localised
T3 and T4 – locally advanced
N (lymph node)
N0 (absent) or N1 (present)
M (metastasis)
M0 (absent) or M1 (present)
Bladder cancer T staging
Why is cancer difficult to cure?
Cellular basis
Cancer cells similar to normal cells
Cancer is detected late
Large ca needs higher dose
Large ca more likely metastatic
Molecular basis
Many genes can cause cancer
300+ genes associated with cancer development
Oncogenes (accelerator)
Tumour suppressor genes (brake)
Each gene can be altered many ways
Mutation
Amplification
Chromosomal loss
Translocation
Methylation
Compare with cystic fibrosis
70% patients have same mutation in one gene
P53 has many functions
Transcription factor
DNA damage recognition protein
Arrest cell growth
Trigger apoptosis
Different treatment may be needed
depending which function altered
Each cancer is unique
5-10 genetic alterations needed
for each cancer
Each cancer contains thousands
of changes in gene expression
Cancer is genetically unstable
Higher mutation rate than normal cells
Evolves new variants constantly
Resistant variants selected
Normal (stem) cell
Genetic changes
Cancer stem cell
More genetic changes
Local invasion
More genetic changes
Spread (metastasis via lymph/blood/nerves)
More genetic changes
Resistant cancer cells
Why is it difficult to cure cancer?
Cellular
basis
Molecular basis
Many cancer genes
Each gene can be genetically altered many ways
Each gene has many functions
Each cancer has many changes and is unique
Genetic instability
Why does everyone with
cancer not die of it?
5 year survival with distant spread
Prostate
Breast
Melanoma
Cervix
Colorectal
Bladder
Lung
30%
20%
16%
9%
7%
6%
2%
More men die with than of prostate cancer
Surgery or radiotherapy can cure
cancer that is local and has not
spread beyond the primary site
Metastatic testis cancer
Cured in over 85% of patients
Cisplatin
Bleomycin
Etoposide
When does cancer not kill?
When the patient dies of something else
before the cancer kills them
When the cancer is localised and can be
eradicated with surgery or radiotherapy
When the cancer is cured with drugs
(adjuvant or definitive therapy)
Principles of Cancer
Disease of (stem) cells
Starts in a single cell (clonal)
Genetic disease
Requires changes in many genes
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