Graeme Finlay 3 Flashcards
What are growth factors?
Things that normally regulate development, tissue maintenance, repair, cell survival, proliferation, differentiation and the function of those differentiated cells
What are the growth factors that are frequently over-active in cancer?
The insulin family (IGFs), TGFalpha (EGF family), PDGF, FGFs, HGF and TGF
What is PDGF?
Platlet-derived growth factor which can stimulate the proliferation of fibroblasts in vitro, it is found in the granules in platelets and promotes wound healing
What is TGFalpha?
Transforming growth factor alpha which is increased in expression by cells transformed by oncogenes
What are IGFs?
Insulin-like growth factors 1 and 2 bind to IGF-1 Receptor increasing cell survival as it prevents apoptosis. This is overexpressed in many tumour cells and important for growth as receptor knockouts cannot be transformed by oncogenes and siRNA knockouts stop proliferating
What is TGFbeta?
A widely expressed growth factor which effects processes such as embryogenesis, differentiation and wound healing. It is highly expressed in tumours where ti can modulate synthesis of ECM by fibroblasts to favour invasion, cause immunosuppression, induce angiogenesis and inhibit proliferation of normal epithelial cells and lymphocytes
What is the effect of TGFbeta on tumours?
It can act early to suppress tumour development and late to enhance it
What are autocrine loops with regards to growth factors?
Tumour cells often both express the growth factor and its receptor maintaining their own proliferation
What are the evidences for autocrine loops playing a role in cancer?
Cellular expression of both growth factor and receptor
Growth stimulation by purified growth factor or conditioned medium
Inhibition of proliferation by antibodies, antisense oligonucleotides to the growth factor or receptor
Constitutive receptor activation
Transgenic mice with inducible TGFalpha develop liver and mammary cancer
How does paracrine stimulation function in cancer?
Neighbouring cells are signalled by growth factor secretion such as in some breast cancers the source of IGFII is fibroblasts
How does juxtacrine signalling function in cancer?
There is an interaction between membrane bound growth factors and a receptor on adjacent cells
What are the 5 ways in which receptors for growth factors are over expressed in cancer?
Amplification, activating deletion of gene sequences, chimaeric receptors, amino acid substitions/deletions/additions, inactivating mutations
How do activating mutations occur to growth factor receptors in cancer?
ERBB1 loses exons 2-7 causing a receptor to lose its ligand binding domain allowing it to spontaneously dimerize and phosphorylate wild type EGFR generating constitutive tyrosine kinase activity
This mutant receptor causes a 4 times reduction in apoptosis, 2-3 times inreas in labellin index in vivo
How do chimaeric receptors function in cancer?
Many tyrosine kinases are activated by translocations where the ligand binding and transmembrane domain are replaced by fusion partner sequences causing redistribution of the receptor to the cytosol, dimerization due to fusion partner sequences and activation of the tyrosine kinase domain and downstream signalling molecules
How do amino acid substitutions/deletions/duplications function in cancer?
Occuring frequently in receptor tyrosine kinases EGFR mutations in lung cancer increase tyrosine kinase activity and promote cell viability
