Transcript Self-Sufficiency In Growth Signals (Oncogenes) Growth Factors

Caecinogenesis
The Molecular Basis Of
Cancer
Fadwa Jameel Altaf
Layalh S. Ab dullah
Osama Nassif
Ali Sawan
Types of Normal Cellular
Genes
3 Normal regulatory genes;
Growth promoting protooncogene
Growth inhibiting tumor suppressor
gene
Gene regulate apoptosis
4 the category is DNA repair
gene
Molecular Basis Of
Cancer
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Nonlethal genetic damage lies at the
heart of carcinogenesis
Genetic hypothesis of cancer implies
that a tumor mass result from the
clonal expansion of a single progenitor
cell that incurred the genetic damage
Clonality of Neoplastic Cells
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Most tumor cells are monoclonal
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All tumor cells may possess a specific chromosomal
abnormality.
Unique rearrangement of immunoglobulin or T-cell
receptor genes in lymphoid tumors.
Tumor cell heterogeneity is common
 Clinical behavior is the best definition
of malignancy
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Principles of
Carcinogenesis
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Neoplastic transformation is a progressive
process involving multiple “hits” or genetic
changes.
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Alterations in DNA cause changes in one or both
of the following types of genes:
 Proto-oncogenes----Oncogene--(dominant)
 Tumor suppressor genes---TSG---- (recessive)
 Genes regulate apoptosis (dominant or
recessive)
 DNA repair genes
Tumor Development and
Growth
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Transformation
Growth of transformed cells
Invasion of tumor cells into the surrounding
tissues
Metastasis of tumor cells to distant sites
Hallmarks of Cancer
Six fundamental changes of cell Physiology
1.
2.
3.
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6.
Self sufficiency in growth factors
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replicative potential
Sustained angiogenesis
Ability to invade and metastasize
Self-Sufficiency In Growth
Signals
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Oncogenes
promote autonomous cell growth in cancer cells
by:
Point Mutations
Chromosomal Translocations
Gene Amplification
Activation of Oncogenes
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Point Mutations
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Chromosomal Translocations
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The RAS gene is an oncogene that becomes
activated by a point mutation.
Translocation of chromosome 9 and 22 in CML
creating a fusion gene that produces an activated
tyrosine kinase.
Gene Amplification
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Specific oncogenes such as N-myc and C-neu are
amplified in neuroblastoma and breast cancer
respectively.
Self-Sufficiency In Growth
Signals
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Oncogenes
promote autonomous cell growth in
cancer cells
Their product is called oncoproteins
Devoid of important regulatory elements &
their production does not depend on
growth factors or other external signals
Self-Sufficiency In Growth
Signals (Oncogenes)
Growth Factors
 Growth Factor Receptors
 Signal transducing Proteins
 Nuclear transcription factors
 Cyclins & cyclin- dependent
kinases
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Growth Factors
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Many cancer cells acquire growth
self-sufficiency, by acquiring the
ability to synthesize the same GF to
which they are responsive.
The growth factor itself is not
altered or mutant, but the product
of other oncogenes cause
overexpression of growth factors
Self-Sufficiency In Growth
Signals (Oncogenes)
Growth Factors
 Growth Factor Receptors
 Signal transducing Proteins
 Nuclear transcription factors
 Cyclins & cyclin- dependent
kinases
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Growth Factor
Receptors
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Mutations & pathologic overexpression
of normal forms of GFR have been detected in
several tumors.
Overexpression of GFR render tumor cells
hyperresponsive to normal level of GF
EGF receptor seen in 80% of sq cell ca of lung
 HER2 is amplified in 25%-30% of
adenocarcinoma of breast
Self-Sufficiency In Growth
Signals (Oncogenes)
Growth Factors
 Growth Factor Receptors
 Signal transducing Proteins
 Nuclear transcription factors
 Cyclins & cyclin- dependent
kinases
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30% OF ALL TUMORS
Activation of
MAP
kinase pathway
BCR-ABL HYBRID GENE
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Potenttyrosine
kinase activity
Impaired apoptosis
(Gleevec)ST1 571 is
effective in
treatment of CML
Self-Sufficiency In Growth
Signals (Oncogenes)
Growth Factors
 Growth Factor Receptors
 Signal transducing Proteins
 Nuclear transcription factors
 Cyclins & cyclin- dependent
kinases
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Self-Sufficiency In Growth
Signals (Oncogenes)
Growth Factors
 Growth Factor Receptors
 Signal transducing Proteins
 Nuclear transcription factors
 Cyclins & cyclin- dependent
kinases
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Cyclins
CyclinD overexpressed seen in
-Breast, esophagaus, liver, lymphoma
. Cyclin CDK4 amplification is seen in
-Melanoma, sarcoma, glioblastoma.
. Cyclin B,E,& CDKs occur in some
malignant neoplasm but they are less
frequant than cyclin D/CDK4.
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