REPLIKASI SEL KANKER

TIM KEMOTERAPI
Instalasi Patologi Anatomik
Rumah Sakit Kanker “Dharmai
 Terminology
INTERNIS. Gynaecologist
Paediatrician Surgical oncologist
Endokrinology
Neurologist Psychiatrist
Oncologist Haematologist

Dll.....  GERIATRY ? ? Pathologist

 Terminologi
Definisi : ?????
Replikasi ??? Oncogenes

??? Proliferasi ?? Tumorigenesis

Hiperplasia ??? carcinogenesis

???
Tumor supressor gene Hipertrofi
 Tujuan Instruksional

Patofisiologi sel kanker 

 PROLIFERASI SEL

• Mekanisme siklus sel normal

• Disregulasi proliferasi
 The Most Common Malignancy in Male and Female
Dharmais National Cancer Hospital, Jakarta-Indonesia in 1997-1999

Ca. Pharynx 16.43%

Ca. Oral Cavity 2.40 %
Nodule Lymphoma 6.93 % 3.79 % Ca. Pharynx
2.62 % Ca. Thyroid Gland
3.12% Nodule Lymphoma

Ca. Bronchus and Lung 22.56 % 4.46 % Ca. Bronchus and Lung
27.05 % Ca. Breast
Ca. Hepar 4.97 %

Ca. Colorectal 7.55 %

3.96 % Ca. Colorectal

Ca. Prostate Gland 2.84 % 2.62 % Ca. Corpus Uteri

7.25 % Ca. Ovary
27.55 % Ca. Cervix Uteri

Leukemia 5.42 % 2.51 % Leukemia

Ca. Skin 2.58 %

Soft Tissue Sarcoma 3.02 %

Sub Division Cancer Registry

Research and Development Department
Dharmais National Cancer Hospital, Jakarta, Indonesia
Data unpublished
 The Most Common Mortality in Male and Female
Dharmais National Cancer Hospital, Jakarta-Indonesia in 1997-1999

Ca. Pharynx 11.66%

Ca. Oral Cavity 2.04 %
3.23 % Ca. Pharynx
Nodule Lymphoma 5.83 % 1.84 % Ca. Oral Cavity

Ca. Bronchus and Lung 29.74 % 2.07 % Ca. Thyroid Gland

3.00 % Nodule Lymphoma
8.53 % Ca. Bronchus and Lung
Ca. Hepar 7.87 % 27.42 % Ca. Breast
Ca. Pancreas 3.79 %
Ca. Stomach 3.21 %
Ca. Colorectal 8.45 % 4.38 % Ca. Colorectal

Ca. Prostate Gland 2.33 % 9.68 % Ca. Ovary

18.20 % Ca. Cervix Uteri

Leukemia 6.41 % 4.38 % Leukemia

Sub Division Cancer Registry

Research and Development Department
Dharmais National Cancer Hospital, Jakarta, Indonesia
Data unpublished
 Pendahuluan
Definisi
Sel : Suatu struktur dan fungsi pada hewan, tumbuhan
dan manusia yang merupakan satuan hidup yang
paling kecil yang sanggup hidup mandiri.

Sejarah
Robert Hooke 1665 – Jaringan gabus – rongga –
rongga kosong.
Virchow 1885 – Semua sel berkembang dari sel
yang telah ada.
 Genome
 Genome – complete set of hereditary information for
any organism

 Chromosome – a discrete unit of genome carrying many

genes

 Consists of long duplex DNA molecule and proteins

Chromosomes Organization
 Genes
 Gene – segment of DNA that codes for a polypeptide
chain

 Includes Exons and Introns

 Transcriptome – the complete set of genes expressed

under particular conditions
Gene Structure

Molecular Basis
Of Diseases
Environment
And genes
Growth regulation
e.g.Rb causing
Retinoblastoma etc
Changes in structural
Proteins
1.e.g. collagen, Deletions
Or point mutation that
Produce reduced amount
Of normal collagen or
Normal amounts of mutant
Collagen. Causing
Osteogenesis imperfecta
2.e.g cell membrane Fibrillin
Missense mutations causing
Marfan syndrome
Or deletion of dystrophin gene
Causing Duchene muscular
Dystrophy
Changes an Enzyme
e.g. Phenylalanine hydroxylase
Splice site mutation leading to reduced amount
Causing phenylketonuria
Changes an Enzyme inhibitor
e.g. 1-Antitrypsin
Missense mutation that impair secretion from liver
To serum causing Emphysema and Liver disease
Changes a receptor
e.g. Low density lipoprotein receptor
Deletion or point mutation that reduce synthesis,
Or transport to the cell surface or binding to low
density lipoprotein
Causing Familial hypercholesterolemia
Change a transport or carrier protein
1.e.g. Haemoglobin
Mutations in splice sites (commonest) leading to
Reduced -globin.causing -Thalassemia in
-Thalassemia the -globin gene is usually deleted
2.e.g. Cystic fibrosis transmembrane conductance
Regulator. Deletions or point mutation causing
Cystic fibrosis.
Changes in Hemostasis
e.g. Factor VIII deletions, insertions, nonsense
Mutation reduce synthesis or abnormal factor VIII
Causing Hemophilia A.
 Molecular Pathology?

o Pathology: is the study of diseases.

o Molecular biology: the study of molecules in
biological systems that are responsible for normal
biological traits or behaviors i.e.: DNA replication,
transcription and translation in normal cells.
o Molecular pathology: an evolving field that
examines and identifies the molecules involved in
specific diseases.
– Integrates knowledge and techniques applied in
molecular biology to pathology.
 Sel – Jaringan – Organ –System

Fisik/ Raga/ Tubuh

Ada 12 System 1. Jantung dan Pembuluh Darah
2. Sal Nafas Atas & Bawah/Paru
3. Pencernaan Atas &Bawah
4. Ginjal, Saluran Kemih
5. Genitalia Pria & Wanita/System
Reproduksi
6. Syaraf Pusat & Syaraf Tepi
7. Panca Indera
8. Jaringan lunak dan Tulang
9. Darah & Retikuloendotel/Immunitas
10. Kulit dan Adneksa
11. Endokrin/hormon(Gondok, Hypofise)
12. Hati dan Empedu
 Relevance of Molecular Pathology
• Screening : of both familial and non familial disorders
– Genotyping
– Gene expression
– Protein markers
– Metabolites
• Diagnosis:
– Looking at the disease from the small molecules point of view
– Elucidates the causes of the disease
– Provides a more comprehensive understanding of a disease, it’s
natural history, complexity and progression.

• Prognosis:
– Associates specific molecules or a set of molecules with the probable
outcome of a disease.

• Treatment
– Pharmacogenomic approach
Struktur sel normal - tumor
Struktur sel normal
 Proliferasi sel
Pertumbuhan jaringan, penambahan ukuran dan jumlah Sel.

Bayi 3 – 4x.1015
Dewasa balance 1012
Kematian sel  degenerasi
Penambahan sel  pertumbuhan

Siklus sel
Cell cycle clock  siklin/cdk
Checkpoint  faktor ekstra selular, intraselular
Protoonkogenes >< Tumor supressor genes
 CELL CYCLE

Daugther cell

Mitosis Gateway

Growth
Factors

S
CELL CYCLE
DNA replication

Cell cycle
inhibitors

Control Point
 Mekanisme siklus sel normal
siklus sel normal
Teratur dan terkontrol  2 sel anak identik
Phase G0 : Anti mitogenig signal.
Phase G1 (Gap 1) : Tidak reproduktif
Phase G2(Synhesa) : DNA duplikasi/ Replikasi
Phase G2( Gap 2) : Persiapan mitosis-DNA 2X
normal.
Phase M (mitosis ) : Pembelahan diri.

WSGI :8 jam – 100 hari (usus – hepatosit)

1 fertilized egg
50x1012

1016 cell divisions/lifetime

Proliferation Differentiation Death

 Cellular equilibrium
Proliferation Differentiation Death

Transit
Renewing
Proliferating

Exiting
Mekanisme siklus sel normal
Mekanisme siklus sel normal
 Cancer: disruption of
cellular equilibrium

Proliferation Differentiation Death

 Oncogenes

Cell cycle

Apoptosis Tumor Suppressor

Angiogenesis Inv. and Mets

Hanahan and Weinberg, Cell 100: 57, 2000

 Cellular Basis of Cancer
• Cancer is a collection of diseases
characterized by abnormal and
uncontrolled growth

• Cancer arises from a loss of normal

growth control

• In normal tissues, the rates of new

cell growth and old cell death are
kept in balance

• In cancer, this balance is disrupted

• This disruption can result from

1) uncontrolled cell growth or
2) loss of a cell's ability to undergo
apoptosis
CARCINOGENESIS
 Screening for cervical cancer
Average Age (years):

Screening here Screening here has

encounters the maximum
Dysplasia swamp cost-effectiveness
~8% of cancers ~92% of cancers

NCCP 2nd Edition WHO 2002

 Pap smear
• Standard screening
test for cervical Ca &
precancerous lesions
for years

• Decreased incidence
& mortality rate of
cancers after
implementation
 Satisfactory Pap smear
• Adequate cell number
:8,000-12,000 (reference images of known
cellularity)

• Thin-layer dispersion
• Endocervical cells (EC)/
transformation zone (TZ)
component : 10
• Proper fixation & staining
• Proper data &
identification
Stem cells as the target of carcinogens
Post mitotic
Stem cell
Differentiated Normal
senescent
differentiated
cell
Benign
tumor
Grade 2
malignancy
Grade 3 or 4
malignancy
 Malignant versus Benign Tumors
•Benign tumors
generally do
not spread by
invasion or
metastasis
•Malignant
tumors are
capable of
spreading by
invasion and
metastasis
 Definisi

• Neoplasia  new growth/neoplasm.

• Tumor  Swelling  Inflammation “non-neoplastic”.
• Neoplasm  Swelling.
• Tumor (non-neoplastic) ~ Neoplasm.

• Oncology ( Greek “oncos” = tumor) is the study of

tumors or neoplasms.
• Cancer (?/Latin = crab “cancer”) : Malignant
tumors.
proses terjadinya kanker : Carcinogenesis
Mekanisme karsinogenesis dapat merupakan defek pada berbagai
tingkat pengaturan siklus proliferasi sel.
 What causes Cancer?
• Cancer is caused by
alterations or mutations
in the genetic code
• Can be induced in
somatic cells by:
– Carcinogenic
chemicals
– Radiation
– Some viruses
• Heredity - 5%
A generic signalling
pathway
GENES PLAYING ROLE IN CANCER
DEVELOPMENT

• Oncogenes
• Tumor suppressor genes
• DNA repair genes
. Genes responsible for
carcinogens metabolism
 ONCOGENES

• Oncogenes are mutated forms of

cellular proto-oncogenes.

• Proto-oncogenes code for cellular

proteins which regulate normal cell
growth and differentiation.
Five types of proteins encoded by proto-oncogenes
participate in control of cell growth:

Class I: Growth Factors

Class II: Receptors for Growth Factors and Hormones

Class III: Intracellular Signal Transducers

Class IV: Nuclear Transcription Factors

Class V: Cell-Cycle Control Proteins

 Functions of Cellular Proto-Oncogenes

1. Secreted Growth Factors

2. Growth Factor Receptors

4. Nuclear
Proteins:
Transcription
3. Cytoplasmic Factors
Signal Transduction
Proteins
5. Cell Growth
Genes
 Tumor suppressor genes

• Normal function - inhibit cell proliferation

• Absence/inactivation of inhibitor --> cancer
• Both gene copies must be defective
 TUMOR SUPPRESSOR GENES
Disorders in which gene is affected

Gene (locus) Function Familial Sporadic

DCC (18q) cell surface unknown colorectal

interactions cancer

WT1 (11p) transcription Wilm’s tumor lung cancer

Rb1 (13q) transcription retinoblastoma small-cell lung

carcinoma

p53 (17p) transcription Li-Fraumeni breast, colon,

syndrome & lung cancer

BRCA1(17q) transcriptional breast cancer breast/ovarian

tumors
BRCA2 (13q) regulator/DNA repair
 p53
• Phosphyorylated p53 activates transcription of p21 gene
• p21 Cdk inhibitor (binds Cdk-cyclin complex --> inhibits kinase
activity)
• Cell cycle arrested to allow
DNA to be repaired
• If damage cannot be repaired
--> cell death (apoptosis)

• Disruption/deletion of p53 gene

• Inactivation of p53 protein
--> uncorrected DNA damage
--> uncontrolled cell proliferation --> cancer
IMPORTANCE OF DNA REPAIR
 Tumor Progression
Cellular
Multiple mutations lead to colon cancer
Genetic changes --> tumor changes
Summary of 30 years of research (1971-2001)

Hanahan & Weinberg 2000

 HERCEPTIN

Bilimsel Araştırmaların
STI-571
ERCEPTİN Kanserle Savaşa Katkısı
 Thousands of Targets

?
? ? ?
?
?

? ?
HERCEPTIN
?
? ?

STI-571

? ?
?

? ?
?

?
 MOLECULAR BIOLOGY & INFORMATICS

Bioinformatics

~3.000.000.000 bp
DNA

~30.000 genes
~300.000 protein
~3.000.000 interaction
1 human cell
 Mekanisme kontrol
• Faktor ekstraseluler
1. Faktor pertumbuhan (GF)
2. Reseptor faktor pertumbuhan (GFR)
3. Sitokin ( Interleukin, interferon, CSF)
4. JAK (STAT dari Tirosin. DNA intranukleus)

• Faktor intraseluler
1. Kompleks siklin/cdks
2. Proto onkogenes (Kontrol positif proliferasi sel)
3. Tumor supressor genes (TSGs) (kontrol negatif
proliferasi sel).
 Kelainan siklus sel - kanker
Disregulasi kontrol terhadap siklus sel , dapat terjadi :
Peningkatan G0 – G1  GF
Peningkatan GFR
Pemendekan waktu siklus sel (Tc)
Penurunan apoptosis

Lokasi kelainan
Proto onkogen (c-sis peningkatan GF, Her 2/neu, c-fin 
peningkatan GFR, c-rcs,c-ras,c-rafprotein proliferasi 
proses autokrin.
TSGs, virus onkogen (HVP,EBV) pRb, P53.
Disregulasi proliferasi sel
1. Jantung dan Pembuluh Darah
2. Sal Nafas Atas & Bawah/Paru Carcinogenesis
3. Pencernaan Atas &Bawah
4. Ginjal, Saluran Kemih
5. Genitalia Pria &
Wanita/System Reproduksi
6. Syaraf Pusat & Syaraf Tepi
7. Panca Indera
8. Jaringan lunak dan Tulang
9. Darah &
Retikuloendotel/Immunitas
10. Kulit dan Adneksa
11. Endokrin/hormon(Gondok,
Hypofise)
12. Hati dan Empedu
Disregulasi proliferasi Massa tumor-
Jinak/Maligna
 Berbagai parameter proliferasi
• Statik
• Dinamik

Metode pemeriksaan aktifitas

Bahan pelabel (Pelabel DNA/PI) Jlh DNA  SPF
Monoklonal Ab : GFR  Ki 67
Tymidine
Pembacaan Immunohistokimia
Flow cytometer
Immunohistochemistry Cerb-B2/Her 2 neu
Growth Factors and Receptors
 Histopathology of GIST: Biological Markers
Used in Diagnosis of GIST
• GISTs positive for
– CD117 (c-Kit receptor tyrosine
kinase)
• Positive in >95%
– CD34
(mesenchymal/haematopoietic
precursor cell marker)
• Positive in 60% to 70%
– Vimentin and smooth muscle
actin
• Positive in 15% to 60%
• GISTs do not express
CD117 (c-Kit)–positive
– Desmin and S-100
staining GIST
Microscopic Appearance of GIST
and Normal Small Intestine
H+E Stain CD117 IHC Stain

GIST

Normal
Small
Intestine

CDM Fletcher, MD
 Kesimpulan
1. Disregulasi pada siklus sel selalu menjadi
bagian mekanisme karsinogenesis.
2. Mekanisme kontrol  kompleks 
2 anak sel identik
GF
Proto onkogen
TSGs
Apoptosis
Siklus siklin/cdk kompleks
3. Mekanisme karsinogenesis dapat merupakan
defek pada berbagai tingkat pengaturan
siklus proliferasi sel.
4. Pemeriksaan aktifitas proliferasi dapat
dilakukan
5. Aktifitas proliferasi  respons terapi.
WHO 1982, “Do not put years but life into years “

Usia panjang tidaklah ada artinya bila tidak

berguna dan bahagia dan mandiri sejauh mungkin
dengan mempunyai kualitas hidup yang baik