Hallmarks of cancer Flashcards
The 6 cellular hallmarks of cancers
- Can evade inhibitory growth signals.
- Grows without growth signals
- Angiogenesis
- Invasion and metastasis
- Evades apoptosis
- Unlimited replication
Oncogenes
- Definition
- Examples
Normal genes that is pro-malignant when mutated.
Mutations lead to:
- Unregulated angiogenesis
- Continuous replication/ growth
- Invasion, metastasis
Genes are dominant
- Only one allele mutation required for oncogenic effect
- But it is not inherited like this
Examples
- erB2/ Her2 (epidermal growth factor)
- Ras
Tumour suppressor genes
- Definition
- Examples
Definition
- Genes that regulate anti-malignant processes
- Involved in: apoptosis, DNA repairs, cell cycle regulation, growth inhibition.
Genes are recessive
- Requires two alleles to be mutated
- Can be inherited.
Examples
- p53
- APC
- BRCA1, 2
- retinoblastoma (Rb)
Viruses and cancer
Certain viruses predisposes to certain cancers.
HPV 16, 18
- Viral DNA inserts itself into host DNA
- Stimulates production of proteins that makes cells pro-malignant
Adult T cell lymphoma
- HTLV-1
Burkitt’s lymphoma
- EBV
Hepatocellular cancer
- Hep B, C
HPV and cervical carcinoma
HPV 16, 18
viral dna inserts itself into host DNA and stimulates proteins that make cell pro-malignant
E6
- degrades p53
E7
- inactivates Rb by phosphorylating it
Virus associated with Adult T cell lymphoma
HTLV-1 (human T cell leukaemia virus type 1)
Virus associated with Burkitt’s lymphoma
EBV
ErbB-1
Epidermal growth factor gene
Protein
- Transmembrane, activated by EGF
- Tyrosine kinase receptor- autophosphorylation
- Stimulates downstream signalling–> RAS-MAPK (mitogen activated protein kinase)
Oncogene when mutated
- Stimulates persistent replication and growth
erB2/ her2
Human epidermal growth factor receptor
- Oncogene
When mutated, predisposes to breast cancer (25%)
Cancer is more resistant to treatment and more aggressive.
Ras
GTPase that is involved in cell proliferation
- When mutated, becomes oncogenic
In mutation:
- GTPase loses function and RAS is constantly active
- Found in 1/3 of all cancers
p53
Tumour suppressor protein involve in regulate cell growth
- Mutated in half of cancers
Involved in
- apoptosis
- cell cycle crest
- DNA repair
- Angiogenesis
Mutation leads to
- Increased mutation rate of cell’s DNA
- Reduced apoptosis
- Persistent angiogenesis
- increased tumour growth
Li-Fraumeni syndrome
Autosomal dominant condition
- Germline mutation of p53
Predisposes to several cancers (SBLA)
- Sarcoma
- Breast
- Leukaemia
- Adrenal
APC
Tumour suppressor protein
- Pro-oncogene
Germline mutation associated with familial adenomatous polyposis
(FAP)
- Predisposes to colorectal cancer
Spontaneous mutation associated with colorectal cancer.
Familial adenomatous polyposis (FAP)
Autosomal dominant inheritance
Predisposes to developing colorectal cancer through formation of colonic polyps
Multistep carcinogenesis of colorectal cancer
Non-hereditary mutations and environmental stresses leading to development of cancer
- APC mutation= small adenoma
- K-ras/ DCC mutation= large adenoma
- p53 mutation= carcinoma
- Aneuploidy= metastasis
Hallmark: Grows without influence of growth signals
EGFR is stimulated despite lack of ligand due to mutation.
Examples of inhibitory growth signals
Down regulation of growth receptors.
Inactivation/ degradation of signalling proteins
Inhibition of kinase signalling (phosphates)
Competition with growth-mediating proteins
Inhibition of transcription
Tumour’s ability to evade apoptosis
Pro-apoptotic signals are deficient
- i.e Caspases, cytokines
- Bax, p53
Anti-apoptotic signals upregulated
- Bcl-2
Unlimited replication in tumours
Telomerase is upregulated
- Telomeres are longer so becomes anti-apoptotic
Angiogenesis in tumours
VEGF is unregulated
- Can produce vessels as it grows.
Anti-angiogenesis factors are down regulated
Tumours Invasion and metastasis into other tissues.
Tumour cells express abnormal integrins
- breaks from inter/extracellular connections
Matrix metalloproteases facilitates invasion
TIMPsi nhibits invasion
MMP-TIMPs balance is abnormal in tumours
Evidence for cancer clonality
All cells in a cancer carry the same founding mutation
- Philadelphia mutation in CML
Lyonisation of the same X chromosome in cancer cells, in women
- G6PD polymorphism
Multiple myeloma patients
- Monoclonal Ig on protein electrophoresis
- Light chain restriction
Cancer stem cells can reproduce the cancer
- Transplantation study of cancer cells in animals.
Darwinian selection of cancer cells
Increasingly malignant sub-clones of cancer cells arise from ‘selective pressures’ (i.e chemothreapy)
- Selects out cells with additional mutations and growth advantages.
This further leads to invasion and metastasis
- Due to increased genetic and chromosomal instability.
Where is p53 gene located?
Short arm (p) of chromosome 17.
Factors that trigger P53 (5)
DNA damage
Abnormal growth signals
Oncogene activation
Cell stress
- Hypoxia
- Nucleotide depletion
Function of P53 (4))
Cell cycle arrest
Apoptosis
DNA repair
Inhibition of angiogenesis
