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Why is cancer so common?

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Title: Why is cancer so common? Why is cancer so difficult to cure? Why is some cancer curable? Author: John Masters Last modified by: Rosemary Clark – PowerPoint PPT presentation

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Title: Why is cancer so common?


1
Cellular and Molecular Basis of Cancer Overview
  • Why is cancer so common?
  • Why is cancer so difficult to cure?

2
  • 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?
3
Cancer is a disease of eukaryotic cells
MEMBRANE
CYTOPLASM
NUCLEUS
DNA
4
Cancer starts in a single cell
  • 200 different cell types
  • 1013-14 cells/human

Large number of cells
5
Cancer is a genetic disease
  • DNA vulnerable during cell division
  • 23 pairs of chromosomes
  • 4 bases (A-TC-G)
  • 3x109 base pairs/cell
  • (6000 million bases)

6
Cell division
  • 6000 million bases
  • One hour

7
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

8
Environmental Causes
  • DNA damaging agents
  • Smoking
  • Diet
  • Environmental Carcinogens
  • May account for up to 50 of cancer incidence

9
Cancer incidence increases with age
2000 6 million 2020 20 million deaths
10
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?
11
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

12
Cancer takes a long time to develop
Aniline dye workers
13
DNA repair protects
  • Base excision repair
  • Nucleotide excision repair
  • Mismatch repair
  • Recombinational repair

14
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
15
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)

16
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

17
Summary Why is cancer not more common?
  • Takes a long time to develop
  • DNA repair protects
  • Stem cells are rare?
  • Immunity protects

18
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
19
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20
Cancer or Normal Cell?
MEMBRANE
CYTOPLASM
NUCLEUS
DNA
21
100
Narrow therapeutic window
Cell Survival
Normal cells
Cancer cells
1
1
2
3
0
4
Increasing Dose (mg.h/ml)
22
Cancer is detected late
7.5 x 108 cells/g 0.1g 7mm diameter
23
Fractional Cell Kill Hypothesis Double the dose,
double the log cell kill
24
Fractional Cell Kill Hypothesis
Dose killing 99.99 cells Cells treated Cells
Surviving 1012 108 108 104 104 100
25
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
26
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)

27
Bladder cancer T staging
28
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

29
Many genes can cause cancer
  • 300 genes associated with cancer development
  • Oncogenes (accelerator)
  • Tumour suppressor genes (brake)

30
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

31
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32
P53 has many functions
  • Transcription factor
  • DNA damage recognition protein
  • Arrest cell growth
  • Trigger apoptosis
  • Different treatment may be needed depending which
    function altered

33
Each cancer is unique
  • 5-10 genetic alterations needed for each cancer
  • Each cancer contains thousands of changes in gene
    expression

34
Cancer is genetically unstable
  • Higher mutation rate than normal cells
  • Evolves new variants constantly
  • Resistant variants selected

35
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
36
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

37
Why does everyone with cancer not die of it?
38
5 year survival with distant spread
  • Prostate 30
  • Breast 20
  • Melanoma 16
  • Cervix 9
  • Colorectal 7
  • Bladder 6
  • Lung 2

More men die with than of prostate cancer
39
Surgery or radiotherapy can cure cancer that is
local and has not spread beyond the primary site
40
Metastatic testis cancer
Cured in over 85 of patients
  • Cisplatin
  • Bleomycin
  • Etoposide

41
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)

42
Principles of Cancer
  • Disease of (stem) cells
  • Starts in a single cell (clonal)
  • Genetic disease
  • Requires changes in many genes
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