Beruflich Dokumente
Kultur Dokumente
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Initiation-promotion scheme
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Inisiation & promotion
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Tumor Progression and Heterogeneity
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HALLMARK
OF CANCER
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What is the cause of cancer ?
External factors Internal factors
DNA viruses
Epstein-Barr Burkitts lymphoma
Nasopharyngeal cancer
Hepatitis B Liver cancer
Papilloma virus Benign warts
Cervical cancer
RNA viruses
Human immunodeficiency virus (HIV-1) Kaposis sarcoma
Human T-cell leukemia virus Type I (HTLV-1) Adult T-cell leukemia
HTLV-2
HTLV-5 Hairy cell leukemia
Cutaneous T-cell leukemia
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Effect of EBV gene product
Product Factor mechanism of induction biological effect
LMP1 MMP-9 induces transcription invasiveness, motility
LMP1 COX-2 induces transcription angiogenesis
LMP-1 VEGF induces transcription angiogenesis
LMP-1 FGF-2 induces transcription angiogenesis
LMP-1 HIF-1a induces transcription angiogenesis
LMP-1 MUC-1 induces transcription metastasis
LMP-1 MMP-1 induces transcription collagenase, metastasis
LMP-1 IL-8 induces transcription angiogenesis
BZLF-1 MMP-9 induces transcription degradation of ECM
EBNA-3C Nm23-H1 interacts with tumor supressor
protein, NM23-H1 metastasis
LMP-2A mTOR increases protein translation
ERK growth related genes & down motility, metastasis
reg. epith diff
Effect of HPV Protein E6 & E7 on
the Cell Cycle
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Nutritionally Linked Cancers
Carcinogen Promoter
Site Inhibitors
From From Mechanism
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Acute Lymphocytic Abnormality
Leukemia (ALL)
t(1;11)(p32;q23) t(10;14)(q24;q11)
t(1;19)(q23;p13) t(11;19)(q23;p13)
t(4;11)(q21;q23) del(12)(p11;p13)
t(8;14)(q24;q32) t(11;14)(p13;q11)
t(8;22)(q24;q11) t(1;19)(q23;p13)
t(2;8)(p12;q24) Trisomy 21
t(9;22)(q34;q11)
Abnormality
t(8;14)(q24;q32)
Lymphoma t(8;22)(q24;q11)
t(2;8)(p12;q24)
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Primary Chromosomal Aberrations
in Solid Tumors
Tumor Abnormality
Lipoma t(3;12)(q27-28;q14-15)
Ewings sarcoma t(11;22)(q24;q12)
Renal carcinoma t or del(3)(p11-21)
Wilms tumor t or del(11)(p13)
Bladder carcinoma Changes of chromosome 1, i(5p)
Breast cancer Changes of chromosome 1, t or del(16q)
Ovarian cancer Changes of chromosome 1
Germ cell tumor of testis i(12p)
Meningioma Monosomy 22, del(22q)
Neuroblastoma del(1)(p13-32)
Retinoblastoma del(13)(q14)
Malignant melanoma t or del(6q)/i(6p)
t or del(1)(p12-22)
Uterine carcinoma Changes of chromosome 1
Note : t, translocation; del, deletion; i, isochromosome 18
Hereditary forms of cancers
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Adenoma-Carcinoma Sequence
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Control cell proliferation
and differentiation
ONCOGENE
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Genes involved in cancer
Neoplastic transformation involves :
oncogene
tumor suppressor genes
mutator genes
apoptotic
Activation of oncogenes :
play a predominant role in the formation of cancer
development
Protooncogene Oncogene
Tumor Suppressor Gene Inactive
TUMOR
When ???
1. Deletion / Point Mutation
2. Gene Amplification
3. Chromosome Rearrangement
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Protoonkogen Onkogen
PROTOONKOGEN
Growth-factor
GTP-binding Membrane/cyto-
receptors acting
proteins skeleton-associated
via tyrosine-
specific protein- tyrosine-specific [ myc ]
kinase activity protein kinases [ fos ]
[ jun ]
Thyroid hormone
[ fes ] [ raf ]
receptor [ erbA ]
Nuclear protein
Burkitts lymphoma
Chronic Myelogenous
Leukemia
Gene Amplification
Suppressor
Gene
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Tumor Suppresor Gen
RETINOBLASTOMA
a childhood cancer
occur in two forms
affects the retina
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Hereditary retinoblastoma :
Non-hereditary retinoblastoma :
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Deletion of 13q14 in Retinoblastomas
The phosphorylation
state of the RB
Position of protein varies
RB1 gene throughout the cell
cycle and correlates
with its capacity to
interact with the
transcription factors
and with viral
Chromosome Chromosome 13 oncoproteins.
13 deleted for the
region containing
the RB1 gene 40
RB
G0 No transcription
Mode of Action E2F DP-1
of RB
RB
G1 E2F
No transcription
DP-1
Cyclin D1/CDK4-6
Transcription
Cyclin E/CDK2 P P
RB E2F DP-1
S
TTTCGCGC
P
Cyclin A/CDK2
P P Phosphorylation
During G1, cyclin D1/CDK4-
of RB is
RB
G2 During
6
maintained
and cyclin
G0 and
by
E/CDK2
Gcyclin
1 RB is
underphosphorylated
phosphorylate
A/CDK2 until mitosis
RB andwhen
and
E2F-
P
is is
1
it bound
released
dephosphorylated
to the
to interact
E2F-1
transcription
with
ready and
either
promote
tofactor
re-enter G1
Dephosphorylation M RB complexed
transcription
or to go intowith
the
fromDP-1.
stationary
genes
necessary for S phase.
phase.
RB
G0 G1 E2F
No transcription
DP-1 41
Tumor suppressor p53
P53 halts progression
when DNA damaged
to give cell time to
repair or
triggers apoptosis of
damaged cell by
activating Bcl-2 causing
mitochondria to
release cytochrome C
and activate caspase
system
If damaged (mutated)
cell moves to S phase
then it may replicate
DNA lesion
Mode of Action of p53
p53 gene
? p53
?
STABILIZATION
WAF1/CIP1 gene
p21 APOPTOSIS
DNA REPAIR
CYC CYC
CDK CDK
STOP
Kinase No kinase G1 S
GO
activity activity
M G2
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Apoptosis
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Regulation of cell death
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THE OUTLINE OF APOPTOSIS
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TARGET STRATEGIS TERAPI KANKER
Hambat Transduksi
Siklus Sel Sinyal
Pertumbuhan
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ChemoTx research
<1990 1980-2000 2000-2010 >2010
Sifat Eksploratif Eksploratif Targeted Targeted
Strategi Screening Activity Guided Metabolomics AB-conjugate
screening based-
screening
Jangka waktu > 30 th 10-20 th < 10 th < 5 tahun
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