CARCINOGENESIS

BAGIAN PATHOLOGI ANATOMI

FAKULTAS KEDOKTERAN

UNIVERSITAS MUHAMMADIYAH
YOGYAKARTA

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Chemical Carcinogenesis
Experimental model:

Normal Cells

INITIATION

PROMOTION
Cancer Cells

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Initiation-promotion scheme

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INITIATION
Initiator alone is not sufficient for tumor
formation (Group 1)
Initiation results from exposure of cells
to an appropriate dose of initiator
(carcinogenic agents)
Initiation irreversible mutation (DNA
damage) memory months later
+promoter tumor (Group 2&3)

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PROMOTER
Non-tumorigenic by itself
Induce tumors in initiated cells (Group
5)
When promoter is applied before
initiator, no
tumor developed (Group 4)
When the time between multiple
application is
extended the effect of promoter is
reversible
tumors failed to develop (Group 6)
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Major Chemical Carcinogen

Direct-acting Carcinogens
Alkylating Agents
Acylating agents
Procarcinogen that Require Metabolic
activation
Polycyclic & Heterocyclic Aromatic Hydrocarbons
Aromatic Amines, Amides, Azo Dyes
Natural Plant and Microbial Products
Others

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Initiation of Carcinogenesis
1. Direct acting compound do not require
chemical transformation for their
carcinogenicity
2. Indirect acting compound / procarcinogen,
require metabolic conversion in vivo to
produce ultimat carcinogen
Property in common:
= They are highly reactive electrophiles that
can react with nucleophilic sites in the cell
electrophilic reaction sub-lethal damage to
DNA
= Molecular fingerprint
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Carcinogen tumor types

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(fingerprinting)

Events in Chemical
Carcinogenesis

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Promotion of Carcinogenesis
Promoters: phorbol esters, hormone, phenols,
drugs
Not mutagenic how do they contribute to
tumorigenesis study of TPA
TPA: - phorbol esters
- powerful activator for protein kinase C, an
enzyme that phophrylates several
substrates
involved in signal transduction pathways

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Initiation
&
Promotion

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Initiation & promotion

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Radiation Carcinogenesis
Transform all kind of cells in vitro and induce
neoplasms in vivo, in human & experimental animal
UV light skin cancer
Ionizing radiation of medical, occupational, and
bomb of origins produce a variety of malignant
neoplasms
The effect of UV light is somewhat differ from those
of ionizing radiation

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UV
UV effects on cells inhibition of cell division,
inactivation of enzymes, induction of mutation,
and killing the cells
UV type:
- UVA (320 400 nm): non-mutagenic
- UVB (280 320 nm): mutagen, not filtered by
ozone
- UVC (200 280 nm): mutagen, filtered by ozone
Type of cancer results are skin cancers: SCC, BCC,
melanoma
UVB also causes mutation in oncogenes (ras) and
tumor suppressor genes (p53)
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The carcinogenicity of UVB is attributed to its

formation of pyrimidine dimers in DNA
This DNA damage is repaired by NER (nucleotide
excision repair)
1. Recognition of the DNA lesion
2. Incision of the damage strand on both sites of the
lesion
3. Removal of the damage nucleotide
4. Synthesis of a nucleotide patch
5. Synthesis of its ligation

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NER (nucleotide excision

repair)
This process needs at least the product of 20 genes
Postulation: excessive sun exposure capacity of
NER pathway in overwhelmed some DNA
damage remains unrepaired large transcription
errors cancer
Xeroderma pigmentosum (photosensitivity, 200-fold
risk of ckin cancer) has several mutated genes
involved in NER

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Ionizing Radiation
Electromagnetic radiation
- X-rays and gamma rays
Particulate radiation
- particles, particles, proton, neutron

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Hierarchy of Vulnerability
1.
2.
3.
4.

Leukemia
Thyroid
Breast, lung, salivary gland (intermediate)
Skin, bone, gastrointestinal tract (relatively resistant)

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CARCINOGENESIS:
The Molecular basis of Cancer
Nonlethal genetic damage lies at the heart of
carcinogenesis
3 classes of normal regulatory genes: growth
promoting protooncogenes, antioncogenes (growth
inhibiting suppressor genes), apoptotic genes
(regulate programmed cell death) the principal
targets of genetic damage.
DNA repair genes, affect cell proliferation or survival
indi-rectly by influencing the ability of the organism
to repair nonlethal damage of other genes.
Carcinogenesis is a multistep process at both the
genetic and phenotypic level
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Perubahan fenotipik
Sifat pertumbuhan
- lepas dari kontrol
- kegagalan maturasi
- transplantable
- immortal
Perubahan morfologik
Kariotipik
Antigenik
Deviasi metabolik
Membran sel

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AKTIVASI ONKOGENA
Mechanism by which protooncogenes are
transformed into oncogenes
Changes in the structure of the gene abnormal
gene product (oncoprotein)
- Point mutations
- Insertion and deletion
Changes of regulation: gene expression
enhanced / inappropriate production of the
structurally normal growth-promoting protein
- Chromosomal translocations
- Gene amplification

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Point Mutation
ras oncogene the besat example
A very large number of human tumors carry ras
point-mutations
Mutation affect a domain critical to the GAPinduced hydrolysis of GTP mutant ras proteins
have a reduced ability to hydrolyze GTP
Frequency:
- 90%: pancreatic adenocarcinoma
- 50%: colon and thyroid cancer
- 30%: lung adenocarcinoma & myelid leukemia
- 0%: most ovarial and breast tumors

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Model for Action of ras gene

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Chromosom
al
translocatio
ns
Burkitts lymphoma
Chronic Myelogenous
Leukemia

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Gene Amplification
Amplification of N-myc
gene in neuroblastoma:
double minutes / HSR
(Homogenous-staining
region)

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CLASSIFICATION

A. The cell type origin (typing)

1. Adeno gland cell
Fibro
fibroblast
Osteo
osteoblast
Myo
muscle cell
Lymphoma lymphoid cell
Leukemia blod cell

folicular adenoma

leiomyoma

2. Carcinoma
Sarcoma

mesenchymal
Blastoma
Lymphoma
Leukemia

epithelial
blast (cell)
lymphoid
blood cell

sarcoma

blastoma

B. Clinical and histological

behaviour
1. Adenoma - adenocarcinoma
Fibroma - fibrosarsoma
Osteoma - osteosarcoma
Myoma
- myosarcoma
etc.

osteosarcoma

leiomyosarcoma

2. Malignant tumor
cell type origin can be recognized
by

a. Specific cell product

Mucine : adenocarcinoma
Keratine : squamous cell
carcinoma
Melanine : melanoma
Reticulin/kolagen :
fibrosarcoma

pearl formation

melanoma

b. Specific cell structure

Tonofibril : squamous cell carcinoma
Myofibril : myosarcoma

c. Specific histological structure

Tubular
: adenocarcinoma
Transitional epithel : transitional
carcinoma
Glomeruli like
: nephroblastoma

transitional

glomeruli like

d. Grade of differentiation
1. Well differerentiated
2. Moderate differentiated
3. Poorly differentiated
4. Undifferentiated/anaplastic

C. Organ or tissue origin

W.D. squamous carcinoma
bronkhus
P.D. squamous cell carcinoma
cervik
W.D. adenocarcinoma
endometrium
etc

D. The volume comparation

between parenchym and stroma
1. Medullary carcinoma
parenchym > stroma soft
consistency
2. Simplex carcinoma
parenchym = stroma : similar
volume
3. Scirrhous carinoma
parenchym < stroma hard
consistency

E. Macroscopic aspect
1. Benign epithelial tumor
a. Papilloma
b. Polyp
c. Cyst
2. Carcinoma
a. Papillomatous
b. Ulcerated
c. Diffuse infiltrated lin itis
plastica

MIXED TUMOR
mixed of 2 or more tumor cell
type
- Adenofibroma
- Carcinosarcoma
- Mesenchyma - eutop

fibroadenoma

HAMARTOMA
local misformation tissue with limited growth
1. Hemangioma : a. Capillare
b. Cavernosus
c. Simplex
2. Nevus pigmentosus
melanoblast in the skin / corium
a. Intradermal
b. Epidermal
c. Junctional
d. Compound
e. Verrucous / papillomatous

TUMOR OF EMBRYONAL TISSUE

REST
Chorda dorsalis : chordoma
Sach of Rathke : craniopharyngioma
Enamel organ : amelloblastoma/adamantinoma

adamantinoma

EMBRYONAL TUMOR
congenital tumor
1. Neuroblastoma
- Sympathicoblastoma
- Medulloblastoma
- Retinoblastoma
Syndrome Pepper : neuroblastoma of
suprarenal gland metastasis in
the abdominal lymphnode and
liver
and
Syndrome van Hutchinson : basis skull
metastasis
2. Nephroblastoma

TERATOMA
tumor of heterotopic tissue element more than one
dermoblast
Teratogenesis
1. Pluripotent cells embryonal stage separated and
isolated unsuccesful twin
2. Primordial germ cells parthenogenesis - unsuccesful
growth
Location : basis cranii - sacrum
3. Anaplasia theory/dediffrentiation
Location : everywhere in the body

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Teratoma is different with fetus in fetu/parasitic twin

Fetus in fetu is Siamic twin

Classification
1. Well differentiated dermoid cyst benign
2. Poorly differentiated malignant especially in testicle

teratoma

Tumor with special

nomenclature
A. Gonade tumor
1. Seminoma : malignant germ cell tumor
Location : testicle
ovary : dysgerminoma
2. Granulosa cell theca cell tumor = ovarial stromal
tumor
Graulosa cell tumor
Thecoma
Most of them benign

seminoma

Granulosa cell
tumor

B. Placenta tumor
1. Mola hydatidosa
Benign, trophoblastic tumor
Mole hydatid grape fruit form
No fetus
Edematous stroma without blood capilaary
Surrounded by cytotrophoblast & syncitiotropholbast

2. Choriocarcinoma
Malignant, trophoblastic tumor without stroma
Post abortion
Post mole
Post normal gestation
Bleeding necrotic hematogen metastatic

mola hydatidosa

choriocarcinoma

C. NERVE SYSTEM TUMOR

1. Central nerve system

Glia cells glioma
Astrocyt astrocytoma
local malignant, uncapsulated
surgical excition : difficult
Medulloblast medulloblastoma

2. Peripheral nerve system

Schwann cells schwanoma
neurilemmoma
neurofibroma

astrocytoma

perifer nerve tumor

3. Mesothel of arachnoid
- meningioma benign
- nest of mesothel in fibrous stroma
- malignant mesothelioma

D. TUMOR OF THE SEROUS

MEMBRANE
Mesothel pleura and peritoneum
- mesothelioma
- benign variant local tumor
- malignant variant infiltrative mass
tumor in pleura and
peritoneum

E. Hemopoetic and lymphoid tissue

R.E.S. : malignant reticulosis
1. Leukemia
2. Hematosarcoma
1. Leukemia : hemopoetic cells tumor
a. Spontaneous multiple location
bone marrow, spleen, lymph node, liver
b. Diffuse in the tissue at the end phase :
circumscribed mass
c. Leukemic cells often in the peripheral blood

2. Hematosarcoma
invasiveness of hemopoetic cells, but
a. often local circumscribed growth in lymph node,
spleen, skin and bowel lymphoid
tissue disseminated fastly to
hemopoetic tissue
b. very often circumscribed tumor
c. rare in the peripheral blood small amount

1. LEUKEMIA
cells origin : myelocyt, lymphoid,
erythroblast, megakaryocyt,
monocyt, plasma cells
most frequent : lymphatic and
myeloid
two variants : acute and chronic
a. Acute lymphatic leukemi
Lymphoblast lymphoblastic leukemia
Incidence : especially in children
b. Chronic lymphatic leukemi
The infiltrative cells : mature lymphocyt
Incidence : especially in the old age

c. Acute myeloid
The infiltrative cells : myeloblast & promyelocyt
Incidence : all ages
d. Chronic myeloid
The infiltrative cells : myelocyt
Incidence : all ages
Abnormal in small chromosome : Philadelphia/ Ph1
chromosome

2. HEMATOSARCOMA
The most popular :
a. Non Hodgkin lymphoma : B cells
T cells
1. Small cells
2. Intermediate
3. Large cells
4. Anaplastic large cell lymphoma (ALCL)

b. Hodgkin lymphoma
- Pleomorphisme
- Sternberg-Reed cells
c. 1. Multiple myeloma morbus Kahler
2. Plasmacytoma
Plasmablast pro plasmacyt

BIOLOGY OF TUMOR GROWTH

The tumor cells tend to replicate rather than
to differentiate due to genetic alterations
(oncogene activation, anti-oncogene
suppression, etc)
Most tumors are of monoclonal origin
Increasing in the proportion of stem cells
undergoing replication, and a corresponding
decrease in the proportion progressing to full
end-stage maturation
3 factors influencing are: growth fraction,
angiogenesis, and doubling time
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Angiogenesis

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Schematic representation of tumor

growth: growth fraction

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Tumor Progression and

Heterogeneity

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Invasion Sequence of Basement

Membrane by Tumor Cells

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The

METASTATIC
CASCADE

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T(tumor)N(nodule)M(metastasis)

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PERBEDAAN ANTARA TUMOR JINAK DAN TUMOR GANAS

Karakteristik
Diferensiasi/

Tumor jinak

Tumor ganas

Diferensiasi baik, struktur sama Difernsiasi tidak ada, dengan

dengan struktur jaringan asal
anaplasia; struktur sering atipi

anaplasi
Kecepatan
pertumbuhan

Biasanya progresif - lambat;

bisa menjadi stasioner atau
regresi; tidak ada gambaran
nitosis patologik

Bervariasi dari lambat sampai

cepat, sering banyak mitosis
patologik

Invasi lokal

Biasanya kohesif dan

ekspansif; batas tegas;
sentrifugal

Invasif lokal, infiltratif ke

jaringan sekitar.

Metastasis

Tidak ada

Sering terjadi; makin besar dan

makin jelek diferensiasinya
makin sering terjadi metastasis

Simpai

Bersimpai

Tidak bersimpai

Reaksi radang

Jarang terjadi

Sering terjadi

Kematian

Hampir tidak pernah terjadi

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Hampir selalu terjadi

TUMOR IMMUNITY
Normal cell
Genetic alteration
Neoplastic transformation
Expression of surface antigens
Non-self antigen
Induce tumor surveillance

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TUMOR IMMUNITY
Questions:

1.

What is the nature of tumor antigens

2. What host effector systems may
recognize tumor cells
3. Is antitumour immunity effective
against spontaneous neoplasms
4. Can immune reactions against tumors
be exploited for immunotherapy

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Tumor antigen
Tumor antigenicity is usually assessed by:

The ability of an animal to resist a live tumor implant after

previous immunization with live or killed tumor cells
The ability of tumor free host animals to resist challenge
when infused with sensitized T cells from a tumorimmunized syngeneic donor
The demonstration in vitro of tumor cells destruction by
cytotoxic CD8+ T cells derived from a tumor-immunized
animal

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Tumor antigen
Two broad categories:

TSAs (Tumor Spesific Antigens)

TAAs (Tumor Associated Antigens)

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Tumor antigens
TSAs (Tumor Specific Antigens)
Present only on tumor cells not on any
normal cells
Derived from peptides that are uniquely
present within tumor cells and presented
on the cell surface by class I MHC
molecules evoke a cytotoxic cell
response
TAAs (Tumor Associated Antigens)
Present on tumor cells as well as on some
normal cells

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Tumor antigen
TSA (Tumor Spesific Antigen)
A. Tissue-specific shared
antigen
B. Antigen resulting from
mutation
C. Viral antigen
TAA (Tissue Associated Antigen)
D. Tissue specific antigen
E. Overexpressed antigen
F. Oncofetal antigen
G. Differentiation antigen

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Tumor Specific Antigens

A.Tissue-specific shared antigen

- Encoded by genes that are silent in virtually all normal adult tissues
- but expressed in a number of tumors of various histologic types
- Testis (no HLA): the only normal organ in which MAGE protein are
present cannot be expressed on their cell surface

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Tumor Specific Antigens

B. Antigen resulting from

mutation
Mutated proto-oncogene and tumor
suppressor gene
P53, K-ras, CDK4, bcr-c-abl

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Tumor Specific
Antigens

C. Viral antigens
Antigens derived from
oncogenic viruses
E7 protein of HPV-16

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Tissue Associated Antigen

D. Tissue specific antigen

Shared by tumor cells and their normal
untransformed counterparts
Melanocytes and melanoma cells both express
tyrosinase
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Tissue Associated Antigens

E. Overexpressed antigen
C-erbB2 (neu): overexpressed in 30% of breast
and ovarian cancer

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Tissue Associated Antigens

F. Oncofetal antigens
Normally expressed in embryonic
tissue
AFP: Alpha Fetoprotein
CEA: Carcinoembryonic antigen

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Tissue Associated antigens

G. Differentiation antigen

Peculiar to the differentiation state at

which cancer cells are arrested
CD10 (CALLA antigen expressed by
early B cell, B-cell lymphoma and
leukemia)
PSA (Prostate Specific Antigen)
-hCG

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Antitumor Effector Mechanisms

ADCC

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Cellular effectors that mediate

immunity
Cytotoxic T lymphocytes
Protective role against virus-associated tumors
EBV, HPV (possessing MHC class 1)
Natural killer cells (NK cells)
Lymphocytes capable of destroying tumor cells
without prior sensitization (after activation with
IL-2), including many that appear nonimmunogenic for T cells
Macrophages
ADCC

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IMMUNOSURVEILLANCE
Facts:
Increased occurrence of tumors
In immunodeficient host

Immunosurveillance
(it is not perfect)

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Mechanisms to escape from

Tumor Immunosurveillance
1.
2.
3.
4.

5.

Selective outgrowth of antigen-negative

variants
Loss or reduced expression of histocompatibility antigens
Lack of co-stimulation
Immunosuppression
- oncogenic agent : ionizing radiation, chemicals
- tumor product : TGF-
- immune response induced by tumor cells activation
of suppressor T cells
Apoptosis of cytotoxic T cells
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CANCER SUPPRESSOR GENES

Misnomer
Physiologic function: regulate cell growth
apply brakes to cell proliferation
Discovered by studying rare disease such
as retinoblastoma
Knudson two-hit hypothysis of
oncogenesis

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Sub-cellular location of protein product

of tumor suppressor genes
2 broad categories regarding the functions:
Molecules that regulate nuclear transcription
and cell cycle
Cell surface: TGF-receptor, E-cadherin
Under plasma mebrane: NF-1
Cytoskeleton: NF-2
Cytosol: APC
Molecules that regulate signal tranduction
Nucleus: Rb, p53, WT-1, p16(INK4a), BRCA-1,
BRCA-2

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CANCER SUPPRESSOR GENES

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The central role of the pRB in

regulating the cell cycle

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Selected tumor-suppressor gene involved

in human neoplasm
TGF- receptor

Function: Growth inhibition

Tumors associated with somatic mutation:
Carcinoma of colon
Tumors associated with inherited mutation:
Unknown

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Selected tumor-suppressor gene involved

in human neoplasm
E-cadherin

Function:
Cell adhesion
Tumors associated with somatic mutation:
Ca. gaster & breast
Tumors associated with inherited mutation:
Familial gastric cancer

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Selected tumor-suppressor gene

involved in human neoplasm
NF-1

Function:
Inhibition of ras signal
transduction
Tumors associated with somatic mutation:
Schwannoma
Tumors associated with inherited mutation:
Neurofibromatosis type 1 and
sarcomas

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Selected tumor-suppressor gene involved

in human neoplasm
NF-2
Function:
Unknown
Tumors associated with somatic mutation:
Schwannoma and meningioma
Tumors associated with inherited mutation:
Neurofibromatosis type 2,
acoustic schwannoma & meningioma

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Selected tumor-suppressor gene involved

in human neoplasm
APC
Function:
Inhibition of signal transduction
Tumors associated with somatic mutation:
Ca. of stomach, colon, pancreas;
melanoma
Tumors associated with inherited mutation:
Familial Adenomatous Polyposis coli;
colon cancer

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Selected tumor-suppressor gene

involved in human neoplasm
Rb

Function:
Regulation of cell cycle
Tumors associated with somatic mutation:
Retinoblastoma, osteosarcoma,
Ca breast, colon, lung
Tumors associated with inherited mutation:
Retinoblastoma, osteosarcoma

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Selected tumor-suppressor gene

involved in human neoplasm
p53
Function:
Regulation of cell cycle & apoptosis in
response
to DNA damage
Tumors associated with somatic mutation:
Ca. gaster & breast
Tumors associated with inherited mutation:
Li-Fraumeni syndrome
Multiple carcinoma and sarcoma

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Selected tumor-suppressor gene

involved in human neoplasm
WT-1

Function:
Nuclear transcription
Tumors associated with somatic mutation:
Wilms tumor
Tumors associated with inherited mutation:
Wilms tumor

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Selected tumor-suppressor gene involved

in human neoplasm
p16(INK-4a)

Function:
Regulation of cell cycle by
inhibiting CDK
Tumors associated with somatic mutation:
Pancreatic, esophageal cancer
Tumors associated with inherited mutation:
Melanoma

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Selected tumor-suppressor gene involved in

human neoplasm
BRCA-1

Function:
DNA repair
Tumors associated with somatic mutation:
Unknown
Tumors associated with inherited mutation:
Ca of female breast and ovary

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Selected tumor-suppressor gene involved

in human neoplasm
BRCA-2

Function:
DNA repair
Tumors associated with somatic mutation:
Unknown
Tumors associated with inherited mutation:
Ca of male and female breast

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The role of p53 in maintaining the

integrity of the genome

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Apoptosis

(programmed cell death)

Internally programmed and coordinated death / loss
of single cells spread among healthy cells,
in a form of cell death designed to eliminate
unwanted cells,
through the serial event activities,
by a set of responsible gene product.

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Genes that Regulate Apoptosis

bcl-2 family:
Antagonists
bcl-2 and bcl-xL
Agonists
bax, bcl-xS, bad, bid

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Regulation of cell death

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Biological Mechanism
1. Signaling pathways apoptosis
initiation
2. Control dan integration balance
between negative regulatory molecule
(inhibit) dan positive (stimulate)
3. Common-execution phase actual
death program accomplished largly by
caspase family protease
4. Removal of death cells by phagocytosis

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APOPTOSIS

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APOPTOSIS

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Mitochondrial events and the effects of

bcl-2 in apoptosis

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The role of apoptosis

1. Growth an development
- Embriogenesis: implantation, organogenesis,
differentiation, involution
2. Homeostatic mechanism to maintain cell population
in tissue
- hormone dependent involution
- proliferative cells population: intestinal crypt epihtel
3. Defense mechanism
- neutrophils death during an acute inflammatory response
- cell death induced by cytotoxic T cells: in cellular immune
rejection
4. When cells are damaged by disease or noxious agent
- virus infection: hepatitis Councilman bodies
- low doses injurious stimuli: heat, radiation, anti-cancer
drugs, hypoxia
5. Aging process

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MORPHOLOGY
Cell shrinkage
Chromatin condensation
Formation of cytoplasmic blebs and
apoptotic bodies
Phagocytosis of apoptotic cells by
adjacent healthy cells (parenchymal
cells or macrophages)
Intact plasma membrane during
apoptosis

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MORFOLOGI ultrastructural change sequences

NECROSIS & APOPTOSIS

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APOPTOSIS: gambaran ultrastruktur

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Apoptosis pada kulit dengan

reaksi imun

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Biochemical features
Protein Cleavage
Specific: protein hydrolysis involving the
activation of several members of cystein
protease (caspase)
Protein cross-linking
Transglutaminase activation: apoptotic bodies
DNA breakdown
DNA pecah breakdown 50 300 kbp
Internucleosomal breakdown by endonuclease
(Ca++ & Mg++ dependent) endonucleosom
(120 200 kbp) DNA ladders
Phagocytic recognition
Apoptotic cells ekspress phosphatidylserine
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Electrophoresis of the
DNA extractedi from
cell culture
underwent apoptosis
A. CONTROL
B. APOPTOSIS
C. NECROSIS

DNA ladders

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Specific example of apoptosis

Signalling by receptors from Tumor
Necrosis Factor (TNFR) family
- Apoptosis dimediasi oleh Fas-Fas ligand
(FasL / CD95L)
Apoptosis induced by TNF
- CTL stimulated Apoptosis
- Apoptosis after growth factor
deprivation
- DNA damage-induced Apoptosis

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Model: Fas-mediated signal,

caspase activation, and death
signal induction

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Model: TNF receptor mediated signal and apoptosis

induction : apoptosis vs survival induced
byTNF

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KESIMPULAN
Apoptosis is an important physiological process in the
body which can be triggered by pathologic etiology as
well
Apoptosis has an important role in the pathogenesis
of several diseases as the consequenses of
dysregulation
Apoptosis has an important role in therapy, especially
in chemotherapyand radiotherapy of neoplasm
Apoptosis is more important in biomedical research

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