ONCOGENESIS
CANCER : Cancrum – Latin
Karkinoma- Greek
Karkitakam
Crab : can move anyside Swollen veins around the area
resembles a crabs limbs
Cancer from epithelial tissue ; carcinoma
Cancer from connective tissue ; Sarcoma
BRIEF CONTENTS
Carcinogenesis: Initiation of a tumor
Oncogenesis : maintainance and subseqent evolution of a
tumor.
Tumorigenesis: Initial formation of a tumor in the body.
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DEFINITION
Oncogenesis or tumorigenesis:-
normal cells are transformed into cancer cells.
The process is characterized by changes at the cellular, genetic, and
epigenetic levels and abnormal cell division.
Tumor growth depends on
1. Cellular proliferation
Proliferation co-efficient
cells in cycle : Resting cells
2. Apoptosis : Lack of oxygen,nutrition &immunological
destruction
Doubling time: Time taken by a tumor to double its
mass.
In human cancers 10-450 days(mean 100)
ONCOGENESIS – MULTISTEP PROCESS
Features of Malignant Transformation
In cell culture – form multi layers
LACK OFCONTACT INHIBITION
LOSS OF ANCHORAGE DEPENDENCE IN TISSUE
CULTURE
METASTASIS & SECONDARIES
METABOLIC ALTERATIONS
APOPTOSIS
ONCO FETAL ANTIGENS –DE-DIFFERENTIATION
ONCOGEN : AGENT CAPABLE OF PRODUCING A
CANCER.
ONCOGENES: GENES WITH A POTENTIAL TO
CAUSE CANCER
PROTO ONCOGENES : GENE INVOLVED IN
NORMAL CELL GROWTH.ON MUTATIONS
BECOMES ONCOGENES
TUMOR SUPRESSOR GENES: GENES THAT
REGULATES CELLS DURING CELL DIVISION AND
REPLICATION
ONCOGENES - TYPES
ONCOGENES - TYPES
CANCER ETIOLOGY & MECHANISMS
Physical carcinogenesis(Radiation hazards)
Chemical Carcinogenesis
Biologic carcinogenesis(Oncogenic Viruses)
CANCER ETIOLOGY & MECHANISMS
Radiation hazards:-
CANCER ETIOLOGY & MECHANISMS
Radiation hazards:-
Radiant energy – UV rays, X- rays, and γ-rays
Direct effects
Pyrimidinedimers(2 adjacent pyrimidine nucleotides)
DNA cross linking
Indirect effects
Produce free radicals like Hydroxyl ions, superoxide radicals that
interact with DNA and other macromolecules
CHEMICAL CARCINOGENESIS
CANCER ETIOLOGY & MECHANISMS
Chemical carcinogenesis:-
CANCER ETIOLOGY & MECHANISMS
Chemical carcinogenesis:-
Neoplastic transformation produced by chemicals is a dynamic
multi step process
Initiation – rapid & irreversible
They are not transformed cells
Do not have growth autonomy
Give rise to tumors when stimulated by the promoting
agents
Promotion
Bring tumor induction in previously initiated cell
Transmit a message across the plasma membrane to the
interior cell called as transmembrane signal transduction
which produces alterations in gene expression
CANCER ETIOLOGY & MECHANISMS
Chemical carcinogenesis:-
CANCER ETIOLOGY & MECHANISMS
Chemical carcinogenesis:-
CANCER ETIOLOGY & MECHANISMS
Oncogenic virus:-
CANCER ETIOLOGY & MECHANISMS
Oncogenic virus:-
RETROVIRAL TRANSDUCTION
CANCER ETIOLOGY & MECHANISMS
Oncogenic virus:-
CANCER ETIOLOGY & MECHANISMS
Oncogenic virus:-
ONCOGENES VS TUMOR SUPPRESSOR GENES
ONCOGENES & PROTONCOGENES
• Products of many oncogenes are polypeptide growth
factors
– e.g. sis gene produces PDGF
• Act as receptors for growth factors
– Ex: erb-B produces receptor for EGF.
• Some act on key intracellular pathways
– Ex: src product tyrosine kinase enzyme phosphorylates tyr
residue-activation of intracellular events.
Mutagens
Carcinogens
Viruses
Irradiation
Genetic
predisposition
Normal Transformi
Cellular
protooncog ng
Oncogene
ene Oncogene
Altered
cellular
Protooncogene To Oncogene Conversion functions
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‘Spontaneous
neoplasm’
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Protooncogene To Oncogene Conversion
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Protooncogene To Oncogene Conversion – Translocation
(Burkitt’s lymphoma)
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Protooncogene To Oncogene Conversion – Translocation
(Chronic myeloid leukaemia)
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Protooncogene To Oncogene Conversion – Translocation
(Chronic myeloid leukaemia)
Activate protooncogenes through structural alterations in
their encoded proteins
C-ras :bladder cancer ( at position 12 of p21)
B-raf – Melanoma, Colon carcinoma
changes valine residue at 599 to glutamic acid
(V599E)
Deregulating genes involved in cell proliferation,
survival
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Protooncogene To Oncogene Conversion – Point mutations
• Expansion in copy number of a
protooncogene.
• Results in double minute chrom.
&homogeneous staining regions.
myc- small-cell lung cancer ,cervical
cancer, ovarian cancer
EGFR (ER BB1)- glioblastoma
ER BB2 (HER2/neu) – breast cancer
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Protooncogene To Oncogene Conversion – Gene amplification
ONCOGENE PRODUCTS
Apoptosis Growth
regulators
factors
Oncogene
products
Signal Growth
transducer factor
s receptors
Transcription
factors
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GROWTH FACTORS
Extracellular signals to stimulate proliferation of target
cells (eg :PDGF,NGF,EGF,FGF)
sis oncogene of simian sarcoma virus structurally similar
to gene for PDGF-β
Overexpession induces transformation of fibroblasts
having PDGF receptors.
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Unregulated cell growth
β-CATENIN IN FAMILIAL ADENOMATOUS
POLYPOSIS
Growth factor receptors
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Examples of Receptor tyrosine kinases
ROLE OF VEGF-VEGFR INTERACTION IN ANGIOGENESIS
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VEGF=Vascular Endothelial Growth Factor
TRANSCRIPTION FACTORS
Nuclear proteins that regulate the expression of target
genes or gene families
Members of multigene families that share common
structural domains
Lymphoid cancers,Prostate cancer :Transcription factor
genes activated
In Ewing’s sarcoma : aberrant transcriptional activity of 44
fused proteins
TRANSCRIPTION FACTORS (contd…)
fos + jun transcription factor
AP1 transcription factor
Expression of genes that
control cell division
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SIGNAL TRANSDUCERS
Signal transduction pathways
Nonreceptor protein
GTP binding proteins
kinases
Tyrosine Serine/Threonine
kinases kinases Eg: H-ras,K-ras,N-
Eg:abl,lck,src Eg:raf-1,mos ras
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APOPTOSIS REGULATORS
bcl-2 gene in follicular b-cell
lymphomas
BCL-XL and BCL2
Inhibit Apoptosis
ONCOGENE – TARGETED THERAPIES
Drug Oncogene Tumor types
Retinoic acid PML/RARα Acute promyelocytic
leukemia
Herceptin erb-2 Breast cancer
Erbitux erbB Colorectal cancer
Imatinib abl Chronic myeloid
leukemia
kit Gastrointestinal
tumors(GISTS)
PDGFR GISTS,hypereosinophili
c syndrome
Gefitinib erbB Lung cancer
Erlotinib erbB Lung cancer
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Sorafenib raf Kidney cancer
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