HTHSCI 1DT3 Lecture Notes - Lecture 18: Tumor Suppressor Gene, Radiation Therapy, Carmustine
23 Jun 2018
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Evasion of apoptosis
Limitless replicative potential
Sustained angiogenesis
Tissue invasion and metastasis.
Douglas Hanahan , Robert A. Weinberg
Hallmarks of Cancer
Cell Volume 144, Issue 5 2011 646 - 674
1. Self sufficiency in growth signals
2. Insensitivity to growth inhibitory signals
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Tissue invasion and metastasis
Parallel Pathways of Tumourigenesis
Douglas Hanahan , Robert A Weinberg Cell Volume 100, Issue 1 2000 57 - 70
Parallel Pathways of Tumorigenesis
Hallmark 1: Self-sufficiency in Growth Signals
Ability to maintain growth irrespective of extracellular growth signal changes (or reduction?)
Hallmark 1:
self sufficiency in growth signals
Normal cells
quiescent state active proliferative state
Growth signals
Types of proteins encodes by oncogenes
Many oncogenes mimic normal growth signals
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Hallmark 1:
self sufficiency in growth signals
Normal cells
quiescent state active proliferative state
Growth signals
Types of proteins encodes by oncogenes
Many oncogenes mimic normal growth signals
Mechanisms of oncogene activation
Hallmark 2: Insensitivity to Negative Signals
Inactivating mutations in Tumour Suppressor Genes:
Point mutations
Chromosome deletions
LOH
Altered methylation of promoters – epigenetics
Classic RB Gene:
Germline mutations in RB and one acquired somatic mutation leads to retinoblastoma
80% of small cell lung cancer have an RB mutation
P53 – 50-73% of all cancers have a p53 mutation (loss both or dominant negative).
Hallmark 3: Evasion of Apoptosis
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Hallmark 4: Acquisation of Limitless Proliferative Capacity
Normal cells have a finite replicative potential, 50-80 doublings (Hayflick 1997)
Due to chromosome shortening:
Results from the loss of telomeric DNA from ends of chromosome during each cycle.
Progressive loss through successive cycles of replication leads to inability to protect the
ends of chromosomal DNA.
Telomeres are maintained in most/all malignant cells - upregulation of telomerase.
Hallmark 4:
Acquisition of limitless proliferative capacity
Hallmark 5: Sustained Angiogenesis
Normal cells: angiogenesis is transitory and carefully regulated
Tumours: Shift this balance by increased gene transcription of VEGF and FGF1&2
Signals endothelial cell proliferation and growth of blood vessels.
Hallmark 6: Tissue Invasion and Metastasis
Hallmark 6:
Tissue invasion and metastasis
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Document Summary
Ability to maintain growth irrespective of extracellular growth signal changes (or reduction?) Inactivating mutations in tumour suppressor genes: o o o o. Germline mutations in rb and one acquired somatic mutation leads to retinoblastoma. 80% of small cell lung cancer have an rb mutation. P53 50-73% of all cancers have a p53 mutation (loss both or dominant negative). Normal cells have a finite replicative potential, 50-80 doublings (hayflick 1997) Results from the loss of telomeric dna from ends of chromosome during each cycle. Progressive loss through successive cycles of replication leads to inability to protect the ends of chromosomal dna. Telomeres are maintained in most/all malignant cells - upregulation of telomerase. Normal cells: angiogenesis is transitory and carefully regulated. Tumours: shift this balance by increased gene transcription of vegf and fgf1&2 o. Signals endothelial cell proliferation and growth of blood vessels. Cell volume 144, issue 5 2011 646 - 674. Prognosis related to many factors: age, location, histology.
