NEOPLASMA 2

(KARSINOGENESIS)
Mata Kuliah :
Basic Mechanism of Disease
Prof. Dr. Syarifuddin Wahid, PhD, SpPA, DFM

Bagian Patologi Anatomi

Fak. Kedokteran Univ. Hasanuddin.

TEORI ASAL NEOPLASIA

tumor

Monoclonal
Origin

Polyclonal
Origin

Kecepatan Pertumbuhan
Karsinoma Lambung
Jml Sel
12
10
10

10cm
0,2cm

23
1-4th

30
14-21th

40 PD

1,5-8th

Doubling Time of Human Gastric

Carcinoma In Vivo (Kultur)
State of
Cancer
Early

No of Doubling Ref.
Cases
Time
15
2-3yrs Kawai,
Kohli
Metastases
3
0,6-2mo Fujita,
Kohli
Advanced
4
2-10mo Kohli

Pemberian awal (Initiator)

karsinogen kimia hidrokarbon

LAG TIME

polisiklik pada kulit mencit

Pemberian selanjutnya
(promoter) Croton oil

TERJADINYA KANKER

Pemberian
Croton oil
saja

Pemberian hidrokarbon polisiklik

dosis tinggi tanpa disusul promoter
(inisiator dapat berperan sebagai
promoter)

Kanker
kulit

Tidak timbul
kanker

Kanker
kulit

Serangan I
Virus Epstein
Barr (initiasi)

Infeksi malaria
(promoter)

Serangan II
Virus Epstein Barr

T
T
Limposit B

T
Proliferasi sel

Sel immortal

Translokasi 8;14,
Aktipnya onkogen
myc dan salah satu
jenis imunoglobulin

T
T

Burkitts lymphoma

Environmental agents
(Chemicals,radiation,
viruses)

Normal Cell
DNA repair

DNA damage

Failure of
DNA repair

Permanent DNA damage

Mutation in the genome of

Somatic cells

Activation of growthpromoting oncogenes

Tumor suppressor
genes

Unregulated cell proliferation

5
7

angiogenesis

Failure
apoptosis
Alteration in gene
Regulate apoptosis

Decreased apoptosis

Clonal Expansion
Additional mutation

Escape from immunity

Tumor Progression
MALIGNANT NEOPLASM

Invasion and
metastasis

Growth factor
Receptor
Growth factor

3
Signal 4

2
Onkogen/
Onkoprotein

DNA SYNTHESIS

SELF STIMULATION OF NEOPLASTIC CELL PROLIFERATION

MEDIATED BY ONCOPROTEINS.

Sel Normal Mutasi Sel Kanker

Mutasi : Nonlethal genetic (DNA)
damage.
Mutasi dicegah melalui mekanisme
DNA Repair dan Apoptosis.
Mutasi tetap terjadi
(k.l. 1 mutasi/1000 mitosis)

Sel Normal Mutasi Sel Kanker

Tumor : monoclonal origin
Perlu lebih dari satu mutasi untuk
menjadi sel kanker Karsinogenesis:
multistep process (level gen dan
penotipe).
Disebabkan oleh paparan
karsinogen kimia atau radiasi dan
infeksi virus.

SIFAT SEL KANKER

(Akibat mutasi bertahap )
Sediakan sendiri growth signal
Tidak sensitif terhadap growth
inhibitory signals
Menghindar dari apoptosis.
Replicative potensial tak
terbatas.
Diikuti oleh angiogenesis
Mampu invasi dan metastases.

Self-suffieciency in Growth Signal

Gen yang memicu pertumbuhan
otonom sel kanker : oncogene.
Oncogene berasal dari gen normal
(protooncogene) yang bermutasi.
Mutasi cukup pada satu allel gen
saja (bersifat dominan)
Produk oncogene: oncoproteins

Protooncogene mutasi oncogene

MYC Protooncogene MYC oncogene
MYC protein
DNA
cell cycle jalan
MYC prot stop
MYC prot terus
Pertumbuhan stop Pertumbuhan
terus
Normal
Neoplasma

Petumbuhan normal
Gen Virus
Produksi growth factor normal

Protoonkogen
Karcinogen
kimia,radiasi,
virus.

INTI
SEL
Onkogen seluler

Onkogen virus

Produksi growth factor abnormal

Kegagalan immune survailance

Pertumbuhan abnormal
NEOPLASIA

Insensitivity to growth
inhibitory signals.
Tumor Supressor Gene
protein
penghambat pertumbuhan (Cell Cycle
parkir di G0/cegah G1 S)
Mutasi Tumor Supressor Gene
pertumbuhan tak punya rem
neoplasma

Mutation of Tumor Supressor Gene

Mengenai kedua allel gen (minimal ada
dua mutasi): bersifar resessive
Mutasi I : Mengenai satu gen
lokus gen heterozygous (satu gen normal,
satu gen bermutasi).
Mutasi II : gen normal mutasi
homozygous (kedua gen bermutasi)
Neoplasma

RETINOBLASTOMA (RB) GENE

RB RB homozygous (Normal)
mutasi I
RB rb heterozygous(N& M)
mutasi II
homozygous/loss of
rb rb heterozygosity
(Retinoblastoma)

Adenomatous Polyposis Coli

(APC) Gene.
APC apc lahir dgn ribuan adenomatous polyps di kolon
Mutasi
apc apc adenoma (tumor jinak)
Mutasi
apc apc colonic cancers (t.ganas)

APC AND -CATHENIN

No Proliferation

Proliferation

Proliferation

TP53 Gene (dulu P53)

stress pada sel (anoksia, ekspressi
onkogen , dan DNA damage)
Gen TP53 terpicu
Stop cell cycle
perbaiki DNA
apoptosis
Mutasi/karsinogenesis dicegah

Evation of Apoptosis
DNA repair gagal sel dieksekusi mati
(apoptosis)
tidak terjadi mutasi.
Eksekusi sudah diputuskan oleh TP53
tetapi algojo tak mampu melakukan
tugasnya (evation).
Hukuman mati gagal sel dengan DNA
damage mitosis cikal bakal sel kanker.

Development of sustained
angiogensis
Prolifersi sel membentuk jaringan
tumor memerlukan makanan/O2
(memerlukan vaskularissi)
Hanya sel tumor yang dapat memicu
terbentuknya p.darah baru
(angiogenesis) dapat berkembang
dan metastases

Angiogenesis by Tumor Cells.

Tumor cells
other cells
Angiogenic fact. Antiangiogenic fact
Angiogenesis
Vascularization
Endothelial cells
Nutrients/O2
growth factors
proliferation of tumor cells

Angiogenesis by Tumor Cells.

Tumor cells

normal cells

Angiogenic fact. Antiangiogenic fact

Angiogenesis
Vascularization
Endothelial cells
Nutrients/O2
growth factors
proliferation of tumor cells

Ability to Invade and Metastases

Ekstracellular Matrix (ECM)
[collagens, glycoproteins & proteoglycans]

Interstitiel connective tissue (

basement membrans
(
)

Proses invasi sel tumor ke dalam

ECM
4 steps:
1. Sel tumor melepaskan diri dari sel
tumor didekatnya (loosening of
intracellular junctions).
2. Sel tumor tertanam dalam komponen
matriks (attachment).
3. ECM dirusak (degradation)
4. Sel tumor bermigrasi (migration)

INVASI dan METASTASES

Invasi : Sel Tumor tembus membrana basalis
masuk ke ECM.
Metastases : Sel Tumor selanjutnya
dari ECM menembus dinding
pembuluh limpe
kelenjar limpe,
atau menembus p.darah
organ
lain (hati, paru dan otak).

Genomic Instability Malignancy

DNA damage setiap saat bisa terjadi
(dampak lingkungan).
DNA damage
mutasi gen selama
DNA repair bekerja baik (Stabil).
DNA damage
mutasi gen jika
DNA repair gagal (Tidak Stabil)
DNA repair gagal jika terjadi mutasi
gen pengkode peotein DNA Repair.

Hereditary Nonpolyposis
ColonCarsinoma (HNPCC)
Missmatch repair genes
Inherited mutation

Permanent
DNA damage

Acquired mutation
Allowi

Mutation of TGF-B & BAX genes No apoptosis

HNPCC

Inherited Mutation of DNA

Repair Genes and Cancer Risk
Inherited Mutation
of DNA Repair Genes
DNA mismatch repair
Nucleotid excision
repair.
BRCA1 & BRCA2

Cancer Risk
HNPCC
Skin Cancer
Breast Ca.

Molecular Basis of Multistep

Carsinogenesis
Neoplasm is the result of multiple
mutations.
Epidemiological study: age
associated increased in cancers.
Every mutation is acrucial
stepsof carcinogenesis.

Loss of P53 gene on

Chromosome 17p

Mismatch repair abnormallities

APC mutation
DNA methylation
abnormalities

Hyperproliperative
epithelium

K-ras mutation DC LOH, LOH of

Other Genes on 18q

Adenoma of increasing size and

degree of dysplasia

P53 mutation
And/or LOH

Invasive carcinoma

GASTROINTESTINAL CANCER, 2004.

Tumor progression and

Heterogenity
Tumor initiation is monoclonal origin

tumor progression
(multisteps mutation)
heterogenity of tumor cells

Heterogenity of Tumor Cells

1. Nonantigenic : Evade from immune
respone (negative selection)
2. Invasive : invasion to basement membrane
3. Metastatic : invasion to blood and lymph
vessels (Intravasation).
4. growth factor requirement: More
lower requirement more survive (positive
selection)

transformation

progression

Proliferation
of genetically
Unstable cells

Tumor cells
variants
heterogeneity

Karyotypic Change in Tumors

Karyotype is a method to visualizising
DNA damage (abnormal DNA) in
chromosome level
Abnormal chromosome :
balanced translocation, deletions
and gene amplifications.

Balanced Translocation
Translocational axchange of gene positions
between two different chromosomes (Ch) :
1. Translocation Ch. 22 and 9
(Philadelphia Ch)
Chronic Myelogenous Leucemia.
2. Translocation Ch 8 abd 14
Burkitt lymphoma

Deletion
(a part of chromosome is loss)
1. Deletion of ch 13q14:
Retinoblastoma
2. Deletion of ch 17p, 5q, 18q:
Colorectal Cancers.
3. Deletion of ch. 3p:
Small Cell Lung Carcinoma

Gene Amplification
Karyotyping:
Homogenous-Staining Region (HSR)
Double Minutes
Amplification of N-MYC gene
pada Ch. 2p:
Neuroblastoma

CHEMICAL CARCINOGEN

CHEMICAL CARCINOGENS
Sangat bervariasi (natural atau sintetik)
Ada yang bekerja langsung (direct acting)
ada yang perlu di metabolisme dulu baru
aktip sebagai karsinogen (Indirect acting)
Direct acting carsinogen elektropilik
yang sangat reaktif bereaksi dengan atom
yang kaya elektron pada DNA, RNA, dan
protein seluler

CHEMICAL CARCINOGENS
Efek karsinogen sejumlah bahan
kimia diperhebat oleh bahan kimia lain
yang sebenarnya tidak memiliki efek
karsinogen (promoters).
Beberapa karsinogen kimia bekerja
bersama denga karsinogen lain (virus
atau radiasi).

Pemberian awal (Initiator)

karsinogen kimia hidrokarbon

LAG TIME

polisiklik pada kulit mencit

Pemberian selanjutnya
(promoter) Croton oil

TERJADINYA KANKER

Pemberian
Croton oil
saja

Pemberian hidrokarbon polisiklik

dosis tinggi tanpa disusul promoter
(inisiator dapat berperan sebagai
promoter)

Kanker
kulit

Tidak timbul
kanker

Kanker
kulit

Karsinogen kimia masuk tubuh

I
N
I
T
A
S
I

Aktipasi metabolik dalam tubuh

Intermediat elektropilik
Mengikat ke DNA sel
Kerusakan DNA
Perbaikan DNA Gagal
Apoptosis Gagal

P
R
O
M
O
S
I

Appoptosis berhasil

Kerusakan permanen DNA

(mutasi)
Proliferasi

Neolasma

Perbaikan DNA berhasil

Sel Mati

Sel Normal

Hepatosit Normal
Paparan karsinogen
DNA damage

DNA repair

(lesi biokimiawi)

Initiated hepatocyte
(Fiksasi lesi biokimiawi)

Promoter

Promoter

Nodul hiperplastik

Karsinoma Hepatoseluler

VIRAL CARCINOGEN

T GENES
ONCOGENIC
DNA VIRUS

INFECTED CELL

NUCLEAR DNA

CELL KILLING

CELL TRANSFORMATION

CELL DEATH

TRANFFORMED CELL

DNA virus

V-onc

Infection
V-onc

Host Cell
Transformation

Integration

C-onc
Integrated viral oncogene

V-onc

Host Cell

C-onc

Activated viral oncogene

NEOPLASTIC CELL

ONCOGENIC DNA VIRUS

RNA virus

V-prom

(RNA transcript)

Infection
V-prom

Host Cell
Transformation

Integration

C-onc
Integrated viral promoter gene
(RNA transcript
DNA transcript)

V-prom C-onc

Host Cell

Enzyme reverse
transcriptase

Activated cellular oncogene

NEOPLASTIC CELL

SLOW TRANSFORMING ONCOGENIC VIRUS RNA

RNA virus

ACUTE TRANSFORMING
ONCOGENIC RNA VIRUS

Infection

1st Host Cell

RNA virus
Transduction

C-onc

RNA Transcript

C-onc

Incorporated C-onc
into viral genome

C-onc
Integration

2nd Host Cell

Transformation

C-onc
Integrated cellular oncogene
(RNA transcript DNA transcript)

C-onc

2nd Host Cell

C-onc

Activated cellular oncogene

NEOPLASTIC CELL

Enzyme reverse
transcriptase

TUMOR IMMUNOLOGY

Sel Tumor