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MM22 Cancer Cell Biology 1 (ii) (Hallmarks of Cancer (6 original…
MM22 Cancer Cell Biology 1 (ii)
Hallmarks of Cancer
essential alterations in cell physiology
6 original biological capabilities
growth signal autonomy
sustained proliferative signalling, not dependent on ext signals
evading growth suppressors (inhibition signals)
evasion of apoptosis (resisting cell death)
unlimited/infinite replicative potential
immortality via increased telomerase expression
maintains telomeres
TTAGGG repeat
highly conserved
prevent nuclease attacks
length of each chain supposed to shorten after each replication
potential therapeutic target
inducing angiogenesis
tumour forms its own blood supply
altered balance between angiogenic inducers + inhibitors
invasion + metastasis
mutations involving cell-cell/extracellular adhesion
2 extra hallmarks added (emerging hallmarks)
not proven to be in every cancer yet
deregulating cellular energetics
altered metabolism -> growth advantage
avoiding immune destruction
hallmarks facilitated by 2 enabling factors
genomic instability + mutation
universal feature of all tumour cells
microsatellite instability: MMR defects
chromo instability: abnormal karyotype/rearrangements
tumour-promoting inflamm
Tumour Supressor gene inactivation
deletion (loss of normal allele -> loss of heterozygosity in someone with inherited mutation)
point mutations
silent (still codes for same AA, no inactivation)
nonsense (early stop codon)
missence (different AA)
conservative (new AA has similar properties to old AA, usually no inactivation)
non-conservative (new AA has different properties to old AA)
promotor methylation (transcriptional silencing)
post-transcriptional silencing (via miRNA)
Retinoblastoma
rare childhood cancer of retina
mutated/deleted Rb ->active E2F
sporadic (usually just 1 eye)
familial
germline mutation + sporadic mutation (2 hit hypothesis)
more common
multiple tumours in both eyes
Proto-oncogenes
code for GFs, cell surface GF Rs, intracellular signal transduction molecules (Abl, Ras), TFs (Jun, fos, MYCN), cell cycle proteins (cyclins, CDKs, kinase inhibitors, apoptosis inhibitors -> BCL2)
can be overactivated by
point mutation
Ras SNP in 20-30% of all cancers
prevents GTP hydrolysis, constitutively active
in EGFR
gene amplification (e.g. in MYCN)
200 MYCN copies in neuroblastoma (paed cancer of symp NS)
poor prognosis
potential therapeutic target
chromo rearrangement
BCR-ABL
t(9;22) (robertsonian)
philadelphia chromo
constitutively active tyrosine kinase
chronic myeloid leukemia
treatment = imatinib
IgH-BCL2
t(14;18)
massive Bcl2 transcription
follicular lymphoma (translocation present in 90% of cases)
IgH = immunoglobulin heavy enhancer