Molecular Mechanisms Of Neoplasia In Practice

Question 0

Mediators of growth control

Answer 0

Secreted growth factors 
Environmental growth inhibitory factors 
Levels of secreted growth inhibitors 
Intrinsic program of differentiation/apoptosis 
Tumour immune response

Question 1

Tumour origin

Answer 1

Arise from normal tissue-> majority epithelium-> exposed to outside world-> higher turnover rate
Most tumours recapitulate their original tissue-> different cell actions

Question 2

Tumour growth characteristics

Answer 2

For a tumour to develop-> subversion of growth control mechanisms
For a tumour to survive and become malignant needs to acquire:
-> limitless replication/immortality-> insensitive to anti growth, self sufficiency in growth signals
-> angiogenesis
-> invasion and metastasis

Question 3

Tumourigenesis

Answer 3

Cells squire new features
Acquisition of these new features is mediated through disrupting gene function
Limited to host genome
Occur through mutation-> sequence change, gene amplification, gene deletion, gene sil envying
-> results in either change in protein structure/levels-> gain or loss of function-> oncogenes or tumour suppressors

Question 4

Self sufficiency of growth signals

Answer 4

Mutations that cause:
-> increased secretion of growth factors
-> up regulation of growth factor receptors-> doesn’t require receptor
-> activation of growth factor receptors-> in places they aren’t usually present
Examples:
Insulin like growth factor IGF2-> up regulated in wilms tumour
cErbB2 (EGFR) -> up regulated in breast cancer
Mutation in TK domain of c-kit (receptor for stem cell factor) in GISTS-> activation of growth factor receptor

Question 5

Evasion of apoptosis

Answer 5

• > up regulation of anti-apoptotic factors -> Bcl2 is up regulated in follicular lymphoma due to translocation
• > down regulation of pro-apoptotic factors-> cascade 3 is down regulated in colorectal tumours
• > loss of function of pro-apoptotic factors-> Tp53 is mutated in colorectal cancers

Question 6

Refining diagnosis

Answer 6

Identifying mutations characteristic of tumour type-> use in diagnostic test -> c-kit in gastrointestinal stromal tumours, t(9;22) in chronic myeloid leukaemia
Identifying genetic subgroups within a morphologically uniform group of tumours-> different prognosis
Identify new prognostic factors-> loss of 18q is poor prognostic marker in early stage colorectal cancer, n-myc level is important in neuralblastoma

Question 7

Refining treatment

Answer 7

Identifying mutations which predict response to particular treatment
-> c-kit mutations activate the tyrosine kinase domain-> treat with gleevec which is a tyrosine kinase inhibitor
-> only glialblastomas showing methylation of MGMT gene are responsive to temozolamide
Identifying therapeutic targets
-> 15-29% of breast cancer have amplification of c-ErbB2 (HER-2) gene-> targeted by Herceptin
-> most colorectal cancers express VEGF-H targeted by bevacizumab