Caecinogenesis The Molecular Basis Of Cancer
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Transcript of Caecinogenesis The Molecular Basis Of Cancer
Caecinogenesis The Molecular Basis Of
Cancer
Fadwa Jameel Altaf Layalh S. Ab dullah
Osama NassifAli 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 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
Most tumor cells are monoclonal 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
Principles of Carcinogenesis
Neoplastic transformation is a progressive process involving multiple “hits” or genetic changes.
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
Transformation Growth of transformed cells Invasion of tumor cells into the
surrounding tissues Metastasis of tumor cells to distant
sites
Hallmarks of Cancer
1. Self sufficiency in growth factors2. Insensitivity to growth-inhibitory
signals3. Evasion of apoptosis4. Limitless replicative potential5. Sustained angiogenesis6. Ability to invade and metastasize
Six fundamental changes of cell Six fundamental changes of cell PhysiologyPhysiology
Self-Sufficiency In Growth Signals
Oncogenes
promote autonomous cell growth in cancer cells by:
Point MutationsChromosomal Translocations
Gene Amplification
Activation of Oncogenes
Point Mutations The RAS gene is an oncogene that becomes
activated by a point mutation. Chromosomal Translocations
Translocation of chromosome 9 and 22 in CML creating a fusion gene that produces an activated tyrosine kinase.
Gene Amplification Specific oncogenes such as N-myc and C-neu
are amplified in neuroblastoma and breast cancer respectively.
Self-Sufficiency In Growth Signals
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
Growth Factors 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
Growth Factor Receptors
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
30% OF ALL TUMORS
Activation of
MAP kinase pathway
BCR-ABL HYBRID GENE
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
Self-Sufficiency In Growth Signals
(Oncogenes) Growth Factors
Growth Factor Receptors Signal transducing Proteins
Nuclear transcription factors Cyclins & cyclin- dependent
kinases
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.