Dr, EMIR T PASARIBU SpB(K) Onk

Dr. SUYATNO SpB(K) Onk

Dr. Deri Edianto SpOG(K) Onk
FK-USU/ RS.HAM

PERSPECTI
VE
Cancer is not modern disease
Hippocrates ( 400 bc): Cancer

as imbalance between black

humor (spleen) and three bodily
humor (blood,plegm, bile)

Sir Percival Pott (1775):

one of the first scientific inquiries
in to the cause of the cancer
observed chimney soot
as carcinogen for cancer of
the scrotal.

Virchow, 19 th century,
pathologist
every cell is born from another cell

Cancer as a cellular disease,

where was loss of normal
control of the cell
prolifration

Fisher:
Breast cancer is
systemic
disease as its
inception

Mormons in Utah
Many type of cancer depend on

relatedness that is, on the sharing

of genes
Cancer, as a genetic disease

Basic molecules of
life
All life depends on three critical molecules:
1.DNAs
Hold information on how cell works

2.RNAs

Act to transfer short pieces of information to

different parts of cell

Provide templates to synthesize into protein

3.Proteins

Form enzymes that send signals to other cells

and regulate gene activity

Form bodys major components (e.g. hair,
skin, etc.)

DOGMA CENTRAL

DNA

RNA

Protein

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

Central Dogma of Molecular

Biology
DNA

Transcription

Translation

RNA

A gene is expressed in 3 steps:

Protein

1) Transcription: RNA synthesis

2) Splicing: removal of intron sequence from RNA
3) Translation: Protein synthesis

Genetic alteration may arise direct

or indirect from:
1.Inherited gen mutations
2.Chemical or radiation induced DNA
damage and genetic instability
3.Incorporation of virus into the cell
4.Random error during DNA
synthesis

Cause of cancer?
Multiple genetic abnormalities
Internal factors : defect
genetic/inherited
External factors :
X RAYS
Viral infections
Carcinogenic compounds : food,
working area, lifestyle

Cancer:
General
Etiology
and
Pathoge
nesis

KARSINOGENESIS
Merupakan proses perubahan menjadi

kanker
Melalui tahapan multi step karsinogenesis
1.TAHAP INISIASI
2.TAHAP PROMOSI
3.TAHAP PROGRESI (Transformasi maligna)
Inisiasi dan Promosi akibat akumulasi
mutasi DNA reversibel eg. displasia
PROGRESI irreversibel

INTERAKSI INISIATOR DAN

PROMOTOR

Proto-Oncogene

1.Mutation

2. Abnormal
Activity

Oncogene

3.Gene Translocation 4. Amplification

Abnormal
Activity

How does a Proto-oncogene

become an Oncogene?

Functions of oncogene
1. Growth Factor (ex: Epithelium

growth factor EGF , and platelet

derived growth factor PDGF)
2. Growth Factor Receptor (Ex:
PDGFR)
3. Signal transudation (example; Ras,
Raf, & MEK)
4. Transcription Factor (example; Jun,
Fos, Elk-1 & myc)

Oncogenes

Oncogene causes cancer by affecting:

1. Cell Proliferation: (ex: Ras, Raf, EGF)
2. Cell differentiation (ex: PML/RAR that

inhibits the differentiation of

promyelocyte to granulocyte which
will maintain the cell in its active
proliferate state)
3. Cell Survival (ex: PIK-3/AKT will
activate BCL-2
inhibit
Apoptosis & maintain cell survival.

Tumour Suppressor
Genes

Tumour Suppressor genes: are genes

that act to inhibit cell proliferation and
tumour development.

If Tumor Suppresor Gene was

Mutated

OR

Inactivated

It will lead to cell transformation

Function of Tumour Suppressor

gene
1.

Antagonize the action of oncogene. (ex.PTEN

which converts PIPIII to PIPII because PIPIII will
activate Pl-3/AKT which will activate BCL-2 that
will inhibit apoptosis and induce cell
transformation)

PIPII

PTEN
PI-3

PIPIII
AKT

BCL-2

Inhibit apoptosis & induce

cell transformation

Function of Tumour
Suppressor gene
2.

Transcription factors
Repressor transcription factors: exa,
WT1 is a repressor that appears to
suppress transcription factor ( Insulin
like growth factor) which will contribute
in the development of tumour
Activator transcription factors:
exa,SMAD family that are activated by
TGF-, leading to inhibition of cell
proliferation

Function of Tumour
Suppressor gene
3. Regulate cell cycle :
Rb gene: that inhibits the cell cycle in
the G1 phase
decrease cell
proliferation
INK-4 gene: that produces P16
that inhibits cdk4/cyclin D action ( to
phosphorylate Rb gene to inactivate
its action)
P53: that produces P21 that has the
same action of P16 in inhibiting the
action of cdk4/cyclin D

Function of Tumour
Suppressor gene
4.

Induce apoptosis:
P53 release will
increase
Bax
form holes in the
mitochondria
release cytochrom c
activate apoptosis

 number of
cancer cells

Tumor Growth

10 12

10

diagnostic
threshold
(1cm)

time
undetectable
cancer

detectable
cancer
limit of
clinical
detection

host
death

Gompertzian Growth
Growth rates are exponential at early stages of

development and slower at later stages of

development.

- Biological growth follows this characteristic curve.

24

The Future of
Oncology
Prevention
Early detection
Treatment

Biomarkers and
Prevention?
Folate and vit B12 decreased breast Ca
risk (Canc Epid Biomarkers Prev
2006;15(3):443-448)
Genetic variation of Nucleotide excission
repair (NER) and cancer risk ( Canc Epid
Biomarkers Prev 2006;15:536-542)
Lipid profile :Monosaturates lipid elevated
and low ratio w6/w3 fatty acid decreased
breast ca risk ( Canc Epid Biomarkers Prev
2006;15:416-421)

Cancer
Detection
Cancer detection :
Clinical detection by

mammogram, coloscopy etc

Molecular detection
Serotype
Restriction fragment length
polymorphism (RFLP)
PCR
Western Blot

CANCER TREATMENT
SURGERY
RADIATION THERAPY
CHEMOTHERAPY
HORMONAL THERAPY
TARGETED THERAPY

Cancer Treatment
Chemotherapy:
Deals with DNA damage, & has affinity to
all proliferating cells not specifying if it
was a cancer cell or not.
Inhibiting Angiogenesis
Inhibit blood flow/supply to the tumour
cells
Decrease franesylation of Ras
Decrease activation of Ras, because Ras
mutation causes most cancers.
Monoclonal Antibody

Molecular target in cancer

therapy
Anti tyrosine kinase: Gleevec, Iressa
Anti VEGF
EGFR inhibitor etc

Need to enhance translational research into early

IRT-MTA (Interdiscilinary Research Teams) for
Molecular Target assesment

Antiestrogens

Estrogen
biosynthesis
Nucleus
Estrogen
biosynthesis

AIs
Tumor cell
AIs = aromatase inhibitors.

Inhibition of
cell
proliferation

Development of
Technical Operation of
Breast Cancer

Ancient
NSP+TRAM

CRM/MRM

BCT

Key
Oncogenesis:words
Pathogenesis of neoplasm (b/m)
Carcinogenesis: Pathogenesis of cancer (m)
Carcinogen - agent causing cancer.
Oncogen - agent causing neoplasm.
Mutagen - agent causing mutation.
Tumour Suppressor genes: are genes that act
to inhibit cell proliferation and tumour
development.

1.
2.

3.
4.

Tannock IF. Introduction to Cancer

Biology. In : The Basic Science of
Oncology, Mc Graw-Hill Inc, Boston, 2005.
Devita VT, Hellman S, Rosenberg SA.
Penyunting. Cancer Principlels & practice
of Oncology. Edisi ke-8. Philadelphia.
Lippincott William & Wilkins. 2008.
Sofia MH. Mutagenesis dan Transformasi,
Basic Science of Oncology, Ilmu Onkologi
Dasar. POI.BP FKUI, Jakarta 2010
Cornain S. Perangai Biologik Sel Kanker
dan Onkogenesis, Basic Science of
Oncology, Ilmu Onkologi Dasar, POI,BP
FKUI,Jakarta 2010

TERIMA
KASIH