Transcript Biology of Cancer

The Biology and
Genetic Base of Cancer
Imad Fadl-Elmula
Al Neelain University
Cancer ........an old........ new problem
The oldest known cases (Osteosarcomas) have
been verified in Egyptian mummies that died 4000
Karkinos
Uroepithelial cancer
E Rarely occur before the age of 40 years
One
in three
persons develops cancer at
new cases
E 54,000
12,500
deaths
E
Three
times
more frequently
in 
thanone
in in
E
some time during
their lives,
and
four dies from his disease
4th most common cancer in 
E 7th most common cancer in 
E In areas where Schistosoma haematobium is endemic
E The most common cancer (25%) in

In Sudan?
National Cancer registry (1968)
Steps on the wrong direction
The only available data
The radiation and isotopes Center Khartoum and Madani
My personal advice
‫ست‬
‫الودع‬
‫حاالت السرطان‬
!!‫فى السودان‬
‫طالب دراسات عليا‬
Geographical distribution of cancer cases seen
at the Radiation and Isotope centre at
9%
Khartoum
2%
31%
12%
Gazira
Northern
Western
Kordofan
7%
Darfor
26%
13%
Southern
Commonest cancer for Sudanese Males
1997-2000
C.M. Leukemia
Lymphosarcoma
5% 4%
4%
24%
6%
7%
Oesophagus
Testis
Hypopharynx
Bladder
10%
17%
10%
13%
Bone
H.D
Thyroid gland
Rectum
Commonest cancer for Sudanese females 1997-2000
Breast
4%
Cervix
2%
3% 3% 3%
30%
10%
C.M. Leukemia
Oesophagus
Ovary
Lymphosarcoma
Bone
12%
14%
19%
Thyroid gland
Hypopharynx
Bladder
What is Cancer Genetics?
 Molecular pathology.
 Tumor biology.
 Molecular genetics.
 Cytogenetics.
 Epidemiology.
 Others.
Tumor Growth
By the time a tumor is
detected, it already
contains about a
billion cells.
Does a tumor
originate from a single
abnormal cell?
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What is Cancer?
Aging process!
Uncontrolled cell division
Loss of Normal Growth Control
The whole scenario
Mutation
Mutation
Disturbed apoptosis weeding
☻Immortal cells!
☻Deranged growth control
☻Continuous cell proliferation
☻Deranged growth control
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What is Cancer?
The somatic mutation theory of cancer
Theodor Boveri (1862-1915)
Acquired genetic changes are
the main causes of malignant
transformation of target cells
Nowell & Hungerford, 1960
G-bands
R-bands
C-bands
Q-bands
Caspersson et al., 1970
Rowley, 1973
Summary
Carcinogens
Diet
Biological
Chemicals
z
Heredity
Physical
N
Cancer & Ethnicity
• Anglo men – higher rates of bladder cancer.
• Hispanics – lowest rates of lung cancer but
women have highest rates of cervix cancer.
• Blacks – highest rates of prostate cancer.
• Japanese – highest rates of stomach cancer.
• Chinese- Americans lowest rates of liver cancer.
• Northern Europeans – high rates of breast cancer.
Polymorphisms
• Polymorphism in CYP1A1 found in 10% of
Caucasians associated with increased
inducibility produces heightened activation of
carcinogens in tobacco smoke.
• CYP genes also play a role in the metabolism of
estrogens making them relevant to breast cancer.
• N-acetyltransferases (NATs) play a role in
detyoxifying aromatic amines in tobacco smoke.
Individuals with 2 mutant NAT2 alleles exhibit
“slow acetylator phenotype”with reduced
detoxification of aromatic amines and an
association with bladder cancer.
7
Style of live and cancer
6
5
4
Stomach
Liver
Colon
Prostate
3
2
1
0
Japan
Japanese
imigrants to
California
Sons of
Japanese
Imigrants
California whites
Large number of dividing cells
Large variable shaped nuclei
Small cytoplasmic volume
relative to nuclei
Variation in cell size and shape
Loss of normal specialized cell
features
Disorganized arrangment of cells
Poorly defined tumor boundary
Cancer cell
characteristics
Histology
Natural
history
of cancer
The
development
of Carcinomas
Invasive Cancer
In situ Cancer
Mutation
Hyperplasia
Dysplasia
Biology of Cancer!
Genetic
Initiation
(Oncogenes/ tr suppressor genes)
Epigenetic
Promotion
(clonal expansion)
Mitogenesis
Progression
Immune surveillance
Angiogenesis
Ist Hit
Normal Cell
Mild Dysplasia
Severe Dysplasia
Cancer
Genetic alterations
100
inflammation
GSTP
expression
Gene defects
Proliferation
Oxidative stress
0
30 year
Normal
80 year
PIA
?
Well differentiated Moderately differentiated
PIN
?
Poorly differentiated
PCA
Undifferentiated
Multistep Carcinogenesis in Prostate Cancer
Multistep Carcinogenesis of Prostate Cancer
Hit 1
Ist oncogene
activated
Hit 2
Ist TSG
deleted
(e.g c-Erb) (e.g RB gene)
Normal
Prostate cells
Hit 3
Hit 4
Hit 5
2nd oncogene
activated
2nd TSG
deleted
Loss of
Invasion
suppressor
gene
(e.g p53)
E-cadherin)
(e.g c-myc)
PIN (prostatic Microscopic latent
Locally invasive
CA prostate
intraepithelial
CA prostate
neoplasia)
Metastatic
CA prostate
The Big Picture
Multihit ± Synergism
"MUTATOR"
ACTIVATED ONCOGENE 1
ACTIVATED ONCOGENE 2
INACTIVATED TSG
CANCER
Activation of Oncogenes by Chromosomal Translocations
CRC
80%
70%
70%
Sporadic
Family history
HNPCC
FAP
Rare syndromes
60%
50%
40%
30%
19%
20%
10%
4%
0%
CRC
1%
1%
Cancer Cells Contain Multiple Mutations
Normal Epithelium
loss of APC
Abnormal Proliferation
Early Adenoma
Late Adenoma
activation of RAS
loss of DPC4
loss of p53
Carcinoma
The Good,
the Bad, and the Ugly

Tumor suppressor genes prevent
transformation of cells [good]

Oncogenes cause transformation [Bad]

Loss of genomic integrity [Ugly]
 Inactivation of tumor suppressor genes.
 Activation of oncogenes.
Genetic changes contribute to carcinogenesis
Point
mutation
Chromosome
translocation
Oncogenes
Normal
cell
Tumor
cell
Tumor suppressor genes
DNA repair genes
Point
mutation
Deletion (LOH),
partial or whole
chromosome loss
DNA tumor
virus
Alterations of Specific Cellular
Functions in Cancer
DNA Repair
Tumor Suppressor Genes
Oncogenes
Inactivation
Activation
Differentiation
Apoptosis/Proliferation
CANCER
Gene group
Example
Chromosomal location
Oncogenes
MYC, ABL
8q24,
Tumor suppressor genes
TP53, RB1
17p13, 13q14
DNA repair genes
MSH2, PMS2
2p21, 3p21
Apoptosis regulating genes
BCL2
18q21
Cell cycle regulator genes
CDKN2A,
MDM2
9p21, 12q14
Genes involved in tumorigenesis
Familial Cancer Syndromes Retinoblastoma
Knudson’s “Two Hit” Hypothesis
Normal
Hereditary Retinoblastoma
Germaine
mutation
Occasional mutation
of one allele - no tumor
Retinoblastoma
Sporadic Retinoblastoma
Somatic
mutation
Rare
second
mutation
Retinoblastoma
Mutation
Chromosome
Definition
Germinal and/or acquired,
stable alteration in DNA
sequence or amount
causing
harmful, beneficial, or
neutral effects.
Gene
DNA Molecule
Chemical bases
Mutation …Bad ….Good
It is good, it is bad also!!
• Mutation in the long term it is essential to our
existence.
• Without mutation there Could be no change and
without change life cannot evolve.
Ex. Adaptive mutation
Definition of mutation
A change in DNA
1.
2.
3.
4.
Arrangement.
Context.
Dosage.
Sequence.
Size of mutation
• Point mutation.
• Submicroscopic mutation.
• Microscopically visible
mutation.
• Loss of a whole chromosome.
Types of mutations
Somatic or germinal?
Type of Mutations
 Familiar.
 Sporadic.
Born with mutation 2nd event
Normal
1st event
2nd event
Apoptosis
Death Receptor-ligand interactions
Apaf-1
Cytochrome C
Regulated by
cytokines and
hormones
Mitochondria
Cell Injury
Initiator Caspases
Execution Caspases
DNA
Fragmentation
Nucleus
Keeping apoptosis under control.
Activation mechanism
autoactivated protease cascade
Negative regulator
ced-9 and bcl-2 family proteins
Telomeres and
Chromosomal Anomalies
Invasive
carcinoma
Tumor angiogenesis
Tumorgrowth
Hypoxia
Growth factors
Vessels sprouting
Tumor growth
Monoclonality
PrimaryTumor Shed of tumor
Intraluminal Intraluminal
Development of
Intraluminalseeding
Primary tumor
cells Shedding of Seeding Intraluminal
seeding
cancer cells
seedingMultifocal Tumors
Normal
epithelium
Development of
multifocal tumors
Polyclonality
Tumor 1
Carcinogenic effect
Development of
multifocal tumors
Carcinogenic effect
Tumor 2
2
Polychronotopicity
Field disease
Normal epithelium
Field cancerization
Tumor 3
Tumor3
Multifocal tumors
Take home massage
Cancer arises from damage to DNA.
The damage to DNA is acquired.
The damage typically occurs in multiple
steps.
The damage affects protooncogenes and/or
tumor suppressor genes.