Molecular basic of cancer

Sofia Mubarika
Faculty of Medicine GMU
Yogyakarta, 28 December 2005

What is cancer?

How is cancer developed?

What is the cause of cancer?
What is the molecular basis of cancer?
can it be prevented? How
Can we analyse the gene abnormalities?
How?

Cancer Cells
Mutated

cells
Do not respond to cell cycle control
signals
Do

not repair DNA damage in interphase

Grow

continuously
Transplantable
Can

inject into an animal and it will continue

to grow

Cancer Cells (cont.)

Different
Some

appearance

are more round

Heritable
Offspring

of CA cells are also cancerous

Dedifferentiated
Less

from.

Loss
Do

specialized than the cells they arose

of contact inhibition
not stop dividing when crowd other cells

Cancer Cells (cont.)

Invasive
Secrete

tissue

chemical to cut paths through healthy

Angiogenesis
Stimulate

blood vessels to grow and feed CA

Metastasize
Travel

by bloodstream or lymphatic system to

start new tumors

Characteristics of Cancer Cells

Cancer

cells undergo unregulated growth

Cancer cells become immortal (active growth
when they should be quiescent)
Cancer cells have increased nutrient uptake
Cancer cells in tissue culture become
anchorage independent.
The cell cycle in cancer cells becomes active
Growth

signaling pathways activated (oncogenes

RNA tumor viruses)
Pathways to prevent cell proliferation are disrupted
(tumor suppressors DNA tumor viruses

What Causes Cancer?

Cancer

is a genetic
disorder at the cellular
level
Genes for the cell cycle
are altered

Carcinogen
Cancer

causing agent
Alters DNA
Examples
Cigarette

smoke

Radiation
Chemicals
Drugs

Biological mechanisms
Genetic

change

pre-existing
induced

Cell

proliferation
Events
loss

of control of cell division

benign

loss

tumour

of positional control

invasion

and metastasis

Proto-oncogene
Gene

that stimulates
rapid cell division
Embryonic

growth
Wound repair

Proto-oncogene

Occupation
many

links between occupation and

cancer risks
chemicals
radiation
UV

light
infection

Exposure to Carcinogen

DNA breaks

apart

Oncogene
Separated

DNA
recombines
incorrectly to form
an oncogene
Onco = cancer
Oncogene = cancer
causing gene
Oncogene

Cancer Cell
Oncogene

causes
cell to produce large
amounts of various
proteins.
Transforms

cell into
a cancer cell

Viruses Generate Oncogenes

Viral

DNA combines
with the DNA of a
Cell
A virus can insert an
oncogene into a
cells DNA or
change a protooncogene into an
oncogene

Recognised cancer risk factors

% of cancer risk
0

10

20

30

40

50

60

70

diet
tobacco
inf ection
sexual/reproductive
occupation
geophysical
alcohol
pollution
food additives

occupa
tio
n
se
xua
l/re
pro
ductive
in
fectio
n

industrial products
medical procedures

to
ba
cco

die
t

80

Aspects of diet related to cancer

Category
Essential nutrients
Major energy sources
Additives
agricultural chemicals
microbial contaminants
inorganic contaminants
chemicals formed in
cooking or processing
natural toxins
other natural compounds

example
fatty acids, vitamins
fat, carbohydrate
preservatives
pesticides
aflatoxin
cadmium PCBs
heterocyclic amines
hydrazines
cholesterol

Inherited susceptibility
genetic
environmental
retinoblastoma:
40%

are of the inherited

form
3.3 per million per year
autosomal dominant
colon

cancer

polyposis

coli
HNPCC: 4% of colorectal
cancers

Breast Ca

2 to 3 fold risk in close

relatives
BRCA1: about 50% of all
familial breast cancer 57% of all breast cancer
also ovarian cancer
BRCA2

Biochemical reactions which are

operating in Epigenetics
1- DNA methylation and demethylation
2- Histone acetylation and deacetylation.
3- Histone methylation and demethylation
4- Phosphorylation and dephosphorylation
of histones and non-histone proteins

Tumor Suppressor Genes

Prevent

cells from dividing too rapidly

Produce proteins that bind to
transcription factors
Prevents

Mutated

mitosis

tumor suppressor gene allows

mitosis to proceed unchecked

p53
Tumor

suppressor

gene
Binds with DNA (dark
blue)
Stops cell cycle to
enable cell to
Repair

damaged DNA

or
Cause cell to go into
apoptosis (cell death)

Carcinogens Mutate p53

Cancer Types

Chemicals
Viruses
Radiation

Mutate

p53 Gene

Bladder
Blood
Brain
Breast
Colon
Esophagus
Liver
Lung
Spleen
Thyroid

How Is the mechanism?

DOGMA
CENTRAL

DNA

RNA

Protein

Mathematical Biosciences Institute (Ohio State Univ), 2 October 2003

Cancer is
a multistep
process

Genes and Cancer

Oncogenes
Causes

Tumor

cells to divide too rapidly

suppressor gene mutation

Mutation

removes normal suppression

of cell division

DNA repair

gene mutation

Faulty DNA repair

to accumulate

gene allows mutations

Fig.19.13

Mutations : in stimulation of growth-stimulating pathways

or deficiencies in growth-inhibiting pathways increased
cell division.

Fig.19.14

How much information is in

our genome?
6

billion bases = 6 Gigabyte

30.000 - 50.000 genes
a lot of junk-DNA contains no code bus
has a different function

Gene Therapy ???

Gene

therapy is the correction of defective

genes for disease
A: Addition of a functional gene copy
B: Replacement of defective gene with a
functional copy of the gene
C: Repair of defective gene
D: Shut off defective gene

Biology target therapy.??

VEGF makes the tumour

vessels abnormal
Normal vessel
Maturation factors

Tumour vessel
Growth factors (VEGF)
Integrins

No growth factors
Tight

Support cells

Leaky

Fewer
support
cells

Jain RK. Semin Oncol 2002;29(Suppl. 16):39; Carmeliet P. Nat Med

2003;9:65360
2

VEGF overexpression correlates

with poor cancer prognosis
Cancer

Tumours
(%)

Breast1

260

95

Relapse-free survival, overall

survival

Non-small cell lung2

223

47

Tumour size, vascular density

Colorectal3

100

37

Overall prognosis

Oesophageal4

117

31

Overall survival

Ovarian5

70

97

Overall survival

Renal6

229

100

Tumour size and stage, survival

Chronic myeloid
leukaemia7

184

100

Survival

Prognostic value

Jacobsen J, et al. BJU Int 2004;93:297302; 2Maeda K, et al. Int J Mol Med 2000;5:3738 3OByrne KJ, et al.
5
Br J Cancer 2000;82:142732; 4Gasparini G, et al. J Natl Cancer Inst 1997;89:13947; Shih CH, et al. Clin
Cancer Res 2000;6:11618; 6Verstovsek S, et al. Blood 2002;99:22657; 7Yamamoto S, et al. Br J Cancer

RhuMAb VEGF

TM

(bevacizumab/Avastin )

Recombinant humanised
monoclonal anti-VEGF antibody
developed from murine anti-VEGF
mAb A4.6.11
93% human, 7% murine
has similar affinity to VEGF
as murine antibody
does not induce immune
response in humans
binds to primate VEGF and
rabbit VEGF but not to rat or
mouse VEGF
binds to all isoforms of VEGF
1

Presta LG, et al. Cancer Res 1997;57:45939

Anti-VEGF antibody normalises

the tumour vasculature
Anti-VEGF

Reduces
interstitial fluid pressure
vessel density
Increases
drug delivery
Jain R. Nature Med 2001;7:9879; Willett CG, et al. Nat Med 2004;10:1457; Tong
R, et al, Cancer Res 2004;64:37316