Growth Factors And Receptors Flashcards
What are the three types of extracellular signals? Define each one
Endocrine - transported by the bloodstream to affect distant sites and tissues
Paracrine - molecules produced locally by one cell that have an effect on another
Autocrine - molecule produced locally and has an effect on the same cell
How are growth factors produced?
Synthesised as large precursors
Cleaved by protease so to monomers
How do growth factors exert their effects?
Bind to growth factor receptors in the cell membrane
Induce intracellular signal transducers which affect transcription factors
What can be the overall effects of growth factors?
Can stimulate or inhibit growth
Function of platelet-derived growth factor?
Stimulates proliferation of stromal cells and endothelial cells by paracrine mechanisms - important for angiogenesis
Where in platelets is PDGF found?
In their granules
N.B. can also be produced by non-platelets
Function of fibroblast growth factors?
Stimulate proliferation of fibroblasts, endothelial cells and smooth muscle cells - important for angiogenesis
Function of transforming growth factor α?
Induces epithelial development
Function of transforming growth factor β?
Acts as a growth inhibitor of epithelial cells
Stimulates growth of fibroblasts
Stimulates production of extracellular matrix by increasing synthesis and decreasing degradation
Blocks activation of lymphocytes and macrophages
Can stimulate angiogenesis
How do growth factor receptors transducer the signal?
Binding of the ligand (growth factor) causes a conformational change in the receptor which activates the cytoplasmic tail
Give some examples of growth factor receptors
Serine/threonine kinase
Tyrosine kinase receptor
What can drive growth of a tumour?
Changes in the growth factor receptors
How can cancer cells be stimulated by growth factors - like where do the growth factors come from?
Can be stimulated by systemic growth factors
Can produce their own growth factors
Induce surrounding benign cells to produce growth factors
Which growth factors can be used for angiogenesis?
PDGF
Fibroblast growth factors
What is HER2?
A gene that codes for a co-factor for EGFR and is seen in many breast cancers
Also now targeted in lung cancers
In cancer, what does transforming growth factor α do?
Induces epithelial development
In breast cancer
-responsible for autocrine growth stimulation
-mediate mitogenic effects of oestradiol
Function of transforming growth factor β in cancer?
Promote angiogenesis
Block them immune response
Inhibitory pathway often muted in cancer cells
What can bind to epidermal growth factor receptors?
EGF
TGF-α
What happens to EGFRs in many cancers? Which types in particular?
Amplified
Seen in squamous carcinomas and activating mutations in lung cancer
What can cause genetic changes to TGFβ receptor II?
Microsatellite instability - the condition of genetic hyper mutability that results from impaired DNA mismatch repair
What does the HER-2 receptor normally do?
Forms dimers with other type I tyrosine kinase receptors
What can happen to HER2 to lead to cancer?
High expression - get gene amplification and over-expression in adenocarcinomas
What can cause activation of PDGFR(B) receptor? Which cancers is it seen in?
Translocation between chromosomes 5 and 12 to form a fusion gene
An early event in development of chronic myeloid leukaemia
What are some hydrophobic growth regulatory molecules?
Steroids - androgens and oestrogens
Thyroid hormone
Retinoic acid (metabolised Vit A)
Which cancers are androgens and oestrogens promoters in?
Prostate cancer
Breast and endometrial cancer
How can vitamin A slow progression of acute myeloid leukaemia?
Metabolised to retinoic acid
Induces differentiation in cancer cells of AML - slowing disease progression
What are the three domains that steroid receptors share?
Hormone binding domain
DNA binding domain
Transactivating domain - induces transcription
What happens when a steroid bins to the receptor?
Steroid binds to receptor
Receptor binds to hormone response element in DNA
Transcription factors and RNA polymerase are recruited to initiate transcription of targeted genes
Protein is synthesised and get a functional response
What are the two types of oestrogen receptors and where are they present?
Classical or α form - present in breast, endometrium and myometrium
Secondary or β form - wider distribution
What happens when receptors are bound to the hormone?
Receptor forms dimers which may be homo or heterodimers (αα, ββ or αβ)
How are oestrogen receptors detected in tissue?
Immunohistochemistry - use routine pathology material
Name some of the receptors in the steroid receptor family
Glucocorticoids Progesterone Androgen Oestrogen Mineralocorticoids Thyroid Retinoic acid Vitamin D
How can mutations causing upregulation of EGFR be detected?
Detect mutations by qPCR or sequencing methods
How can detecting mutations activating EGFRs be a predictive marker of cancer? Which cancer is it used for?
Can target therapies - gefitnib
A minority of lung cancers
So in general, which two types of receptors can growth factors act on?
Transmembrane receptor with intracellular kinase domains
Directly on nuclear transcription factors
How can growth factors and receptors drive tumour growth?
If there is over expression of factors
Over expression of receptors
Alterations in receptors
What are the two main forms of extracellular signalling molecules and how do they exert their effect at the target site? Give examples for each
Polypeptides (growth factors) - act through receptors in the cell membrane eg hormones and cytokines
Low molecular weight molecules - traverse the cell membrane and bind to intracellular receptors eg steroid hormones
