NEOPLASMA II

dr. Upik A. Miskad, PhD

Patologi Anatomi, FK Unhas
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.
 ORIGIN TEORI OF
NEOPLASM
tumor

MONOCLONAL POLYCLONAL
ORIGIN ORIGIN
.
Proliferation rate of Human
Gastric Cancer
Cell No
12
10 10cm
0,2cm
6
10

23 30 40 PD
1-4th 14-21th 1,5-8th
Incipient Early Late
Doubling Time of Human Gastric
Carcinoma In Vivo (culture)

State of No of Doubling Ref.

Cancer Cases Time
Early 15 2-3yrs Kawai,
Kohli
Metastases 3 0,6-2mo Fujita,
Kohli
Advanced 4 2-10mo Kohli
Multifactorial Effects
Environmental agents
Normal Cell DNA damage
(Chemicals,radiation,
viruses)
DNA repair No DNA repair

Permanent DNA damage

Mutation in the genome of

Somatic cells

Activation of growth- Tumor suppressor Alteration in gene

promoting oncogenes genes Regulate apoptosis

Unregulated cell proliferation Decreased apoptosis

NEOPLASM
 Growth factor

Receptor
Growth factor
3
Signal 4 2

Onkogen/
Onkoprotein
1

SELF STIMULATION OF NEOPLASTIC CELL PROLIFERATION

MEDIATED BY ONCOPROTEINS.
Normal Cell Mutation Cancer Cell

• Mutation : Nonlethal genetic (DNA)

damage.
• Prevention of mutation by 2 mekanisms
“DNA Repair” and “Apoptosis”.
• Mutation still happen
(about 1 mutation/1000 mitosis)
Normal Cell Mutation Cancer Cell

•Tumor : monoclonal origin

• It is needed more than one mutation to
develop cancer Carsinogenesis is a
multistep process (gen and phenotype
level).
• It is due to the exposure of carsinogens
(chemical agents, radiation and viral
infection).
 Perubahan pada sel kanker
1. Menghasilkan sendiri sinyal pertumbuhan
2. Insensitif terhadap sinyal penghambat
pertumbuhan
3. Menghindari apoptosis
4. Poternsi replikasi tanpa batas
5. Angiogenesis berkelanjutan
6. Kemampuan menginvasi dan metastasis
 Self-suffieciency in Growth Signal

• Gene stimulates normal production of growth signal

by normal cell is protooncogene (normal gene)
• Gene stimulates outonomous production of growth
signal by cencer cell is oncogene.
• Oncogene is mutation of protooncogene
• The mutation on only one allel is enough to make
uncontrol cell proliferation due to the production of
oncoprotein as a growth signal continuesly.
Protooncogene mutation oncogene
MYC Protooncogene MYC oncogene

MYC protein
DNA
cell cycle progression (cell proliferation)

MYC prot stop MYC prot continue

Proliferation stop Proliferation continue
Normal Neoplasm
 Normal growth
Viral Gene
Normal production of growth factor

Protooncogene
Carcinogen
Mutation
DNA
(chemical,
viral and
radiation) Cellular Oncogene Viral Oncogene

Abnormal production of growth factor

Devective immune survailance

Abnormal Growth

NEOPLASM
 Signal Transmision
• Terikatnya faktor pertumbuhan ke receptor
spesifik di membran sel
• Aktifasi receptor pertumbuhan secara
transien dan terbatas
• Pengaktifan protein transduksi signal
dalam sitosol
• Transmisi sinyal melalui perantara kedua
• Induksi dan aktivasi faktor regulatorik inti
sel untuk memicu transkripsi dna
Mutation of Tumor Supressor
Gene
• Affected both allel of gene (minimal 2
mutation): resessive
• 1st Mutation : Affected one allel
heterozygous (normal gene with
mutated gene).
• 2nd Mutation: Affected the rest normal
gene) Loss of heterozygousity
(Mutation of both allel of gene)
Neoplasm
RETINOBLASTOMA (RB) GENE
RB RB homozygous (Normal)
1st mutation
RB rb heterozygous(N& M)
2nd mutation
homozygous/ loss of
rb rb heterozygosity
(Retinoblastoma)
 APC AND β-CATHENIN

No Proliferation Proliferation Proliferation

 Adenomatous Polyposis Coli
(APC) Gene.
APC apc hundreds to thousands of
colorectal polyps
2nd Mutation
apc apc adenoma (benign tumor))
3rd Mutation
apc apc’ colonic cancers
 P53 (TP53) Gene
“stress of the cell”
(anoxia, oncogene expression, and
DNA damage)

Activation of P53
Stop cell cycle DNA repair
apoptosis

No mutation/carciogenesis
 Evation of Apoptosis
• Fail DNA repair cell execution
(apoptosis) no mutation.
• The Apoptosis process is not happen
(evation).
• Fail of cell execution Nonlethal genetic
(DNA) damage.
• Mitosis of cell with DNA damage permanent
DNA damage (mutation) carcinogenesis
Angiogenesis by Tumor Cells.
Tumor cells normal cells

Angiogenic fact. Antiangiogenic fact

Angiogenesis
Vascularization Endothelial cells
Nutrients/O2 growth factors
proliferation of tumor cells
 Development of sustained
angiogensis
High requirement of Tumor Tissue for
nutrition and O2
new vascularisation of tumor tissue

Tumor Cell with angiogenesis capability

show high growth rate.
Ability to Invade and Metastases
Ekstracellular Matrix (ECM)
[collagens, glycoproteins & proteoglycans]

Interstitiel connective tissue ( )

basement membrans
( )