cancer biology Flashcards
models for tumor propagations - At least two models put forward to account for heterogeneity & differences in tumour-regenerative
capacity:
1- — : mutant tumour cells with a growth advantage are selected and expanded. All cells in the dominant population have a similar potential for initiating tumour growth.
2. —— : - refers to a rare subset of
tumour cells that have the ability to self-renew and generate
diverse tumour cells
- Two models are not mutually exclusive, as CSCs themselves may undergo clonal evolution. Thus, secondary more dominant CSCs may emerge if a mutation confers more aggressive properties
clonal evolution model
cancer stem cells ( CSC) model
in colonal evolution model:
1- mutation 1 will have —- advantage of clone
2- mutation 2 has increased — to —-
3- mutation n will continue evolution by —-
then all of these mutations will lead to — as successive mutation gives the cell a —-
growth advantage
resistance
apoptosis
natural selection
maligant tumor
growth advantage
cancer stem cell model:
- tumor are functionally — and —
- tumours are composed of cells that — tumours aka —- and the cells the arise from the CSC but cant initiate tumours
- Frequency of CSC in a tumour is highly —
- CSC have been identified prospectively (e.g. Breast Cancer; ColonCancer; Leukemia; Prostate Cancer; Melanoma; Pancreatic Cancer & SomeMalignant Brain Tumours)
- CSCs may have different — to radiation or chemotherapy. Therefore significant — implications.
heterogeneous and hierarchical.
initiate( tumour
initiating cells or cancer stem cells [CSCs])
variable which is often low
sensitivities
clinical
- cancer stem cell hypothesis:
1- essential for the — and long term — of the tumor
2- responsible for — of the tumour - incapable of —- of the tumour
3- Perhaps — in some
cases, in others, further — is and is incapable of — the tumour
initiation n long term maintenance
expansion
long term maintenance
post-mitotic
proliferation
maintaining
mutations in 3 classes of genes can cause cancer as:
proto oncogenes
tumor supressor genes
care taker genes
1- proto oncogenes:
- normal activity is to promote —
- mutant form is –
- gain of function mutation create forms excessively —-
- A single mutant allele may affect —
2- tumor supressor TS gene:
- normal activity is to —– or promote –
- both alleles often — but — for some
- include genes that prevent inappropriate —- and promote — of damaged cells
3- care taker genes :
- ensures accurate —– , — , — of dna
- mutation of these genes leads to —
- example:
cell proliferation
oncogenes
active
cell phenotype
inhibit cell proliferation or promote apoptosis
inactivate
haploinsufficiency
cell cycle progression or apoptosis
replication repair and segregation
genomic instability
mismatch repair genes mlh1 and msh2
6 hallmarks of cancer:
1. —- :
– Normal cells need — signals from — factors to divide
– Cancer cells are not dependent on normal growth factor signalling
– Acquired mutations short-circuit growth factor pathways leading to unregulated growth
2.—– signals
3. Evasion of —
– Normal cells removed by apoptosis, often in response to —-
– Cancer cells evade apoptotic signals
4. —-
– Normal cells – finite number of cell doublings after which they become
senescent. —- of chromosomal ends (telomeres)
– Cancer cells maintain —- of telomeres
5. —-
– Altered balance between —- and — can activate the angiogenic switch
6. —- and —
– Mutations alter the activity of enzymes involved in invasion and alter molecules involved in — and —
growth signal autonomy
external
growth factor
Evasion of growth inhibitory signals
evasion of apoptosis
dna damage
Unlimited replicative potential
shortening
length
angiogenesis
angiogenic inducers and inhibitors
invasion n metastasis
cell-cell and cellular-extracellular adhesion
Tumour suppressor genes can be inactivated by:
1- —- aka loss of — gene copy and leads to —
2-
3-
4-
- Deletion (loss of functional gene copy; leads to ‘loss of heterozygosity’)
- Point mutation ( which can be silent nonsense or missense either conservative or non conservative )
- Methylation of promoter – transcriptional silencing
- miRNAs – post-transcriptional silencing
check slide 13
silencing of tumour supressor genes:
* —– is a rare childhood tumour of the retina
* Caused by mutation or deletion of —, which controls progression of —
* —- binds and inactivates — preventing it from interacting with the cell’s transcription machinery
* Both sporadic and familial retinoblastoma can occur
retinoblastoma
rb gene
cell cycle
Non-phosphorylated RB binds and inactivates E2F
check slide 14
- RB
- P53
- APC, and
- BRCA1
are all exmaples of
tumor supressor genes
fucntions of proto oncogenes:
- are — factors
- — receptors as EGFR
- —- molecules as ABL , RAS
- —- proteins including — factors as JUN, FOS, MYCN
- — proteins and cyclins, cdks, kinase inhibitors, apoptosis inhibitor e.g. BCL2
growth
cell surface
Intracellular signal transduction
DNA binding proteins including transcription factors
cell cycle
proto oncogenes can be activated by :
1- —- as RAS , EGFR
2- —- as MYCN
3- — :
- to create a —
- to place gene under control of —
- Point mutation or deletion - e.g. Ras, EGFR
- Gene amplification - e.g. MYCN
- Chromosome rearrangement
a. to create a new gene - e.g. BCR-ABL
b. to place gene under control of a strong promoter - e.g. IGH-BCL2
- Oncogene activation by point mutation:
- — oncogene controls intracellular signalling networks; resulting in transcription of genes promoting — and inhibition of —
-“off” state Ras is bound to —
* “on” state Ras is bound to —
* Mutated Ras prevents — hydrolysis to — , so constitutively active
RAS ( RAS mutated in 20 – 30% of all cancers)
cell divisions
apoptosis
guanosine diphosphate (GDP)
guanosine triphosphate (GTP)
gtp to gdp
- Oncogene activation by gene amplification:
- —- is an oncogenic transcription factor
* Alters expression of — ’s of genes
* — copies in neuroblastoma (a paediatric cancer arising from the sympathetic nervous system)
* —- is marker of poor prognosis
* MYCN — is important for determining optimal therapy
* Potential target for therapeutic intervention
MYCN ( in neuroblastoma )
100s
~200
MYCN amplification
status
- Oncogene activation by chromosome rearrangement ( Creating a novel chimeric gene)
Chronic myeloid leukaemia (CML)
Translocation (9;22) creating Philadelphia chromosome
Hybrid Bcr-Abl fusion protein has constitutively active tyrosine kinase
Treatment of CML with small molecule inhibitor of ABL-BCR tyrosine kinase - Imatinib
