Cancer part 2 Flashcards
How does a receptor tyrosine kinase become activated
ligand (such as growth factor) binds to the extracellular region, causes conformational change, binding induces dimerisation so two or more receptor molecules to come together and one receptor phosphorylates the intracellular domain of the other receptor. phosphorylates tyrosine acts as a docking site for signalling proteins
What are some examples of mechanisms of oncogenic activation of growth factor induced pathways
hyperactive mutant growth factor
elevated levels of normal growth factor
increased levels of RTK
mutation in RTK to be constituently active or hyperative
activation of RTK by a viral protein
loss of RTK regulatory elements
What do high levels of epidermal growth factor (EGFR) result in
associated with carcinomas, metastasis and resistance to treatment
Explain what happens when EGFR is activated to switch off the signal
activated EGFR recruits the ubiquitin ligament CBL which helps switch off the signal
receptor becomes ubiquitinylated and internalised
receptor is degraded by hydrolytic enzymes in the lysosomes
What pathways are activated when EGFR binds to its ligand
the RAS/RAF pathway
the P13/AKT pathway which is linked to cell proliferation
Which abnormalities in EGFR signalling pathway can result in cancer
increased EGF ligands
increased EGFR levels on the surface - can occur due to gene amplification, binding of p53
mutations giving rise to constantly active receptors
What is EGFR variant III?
loss of extracellular binding domain so loss of the ligand binding region. receptor can actively dimerise without the need for binding to a ligand
strongly and persistently activated the p13/AKT signalling pathway, increased cell survival, proliferation and motility
What type of mutations cause the drive of oncogenesis
gain of function mutations in signal transduction molecules (RAS, P13-kinase, RAF)
loss of function mutations in growth inhibitory molecules (p53, RB, PTEN)
What is the role of PTEN and what happens when it is lost
in response to activated growth factors, PIP2 is converted to PIP3 and PTEN switches off this pathway to dephosphorylate PIP3 to PIP2
loss of PTEN means cells are more motile and aggressively migrate to new sites (as PTEN is a growth inhibitory molecule)
What are the two routes of apoptosis and which is most commonly disrupted in cancer
intrinsic/mitochondrial
extrinsic/death receptor mediated
intrinsic is most commonly disrupted in cancer
What factors determine whether the intrinsic pathway for apoptosis is activated
depends on the release of cytochrome c from the mitochondria - regulated by a balance between pro-apoptotic and anti-apoptotic molecules
What are examples of pro-apoptotic molecules
BAX
BAK
BAD
p53
What are examples of anti-apoptotic molecules
BCL-2
BCL-XL
What is the pathway of intrinsic induction of apoptosis and which
cytochrome C is released and activated BAX or BAL
recruitment of procaspase 9 molecules to form the apoptosome
and becomes activated
caspase cascade leading to apoptosis
How can the intrinsic pathway be deregulated
overexpression of anti-apoptotic molecules due to activating mutations in these genes
loss of activity of pro-apoptotic molecules
What is the prostate gland?
Is a walnut size organ
Male sex gland
Produces prostatic fluid which mixes with sperm and seminal fluid to form semen
Controls the flow of urine
Development, maintenance and growth is dependent upon androgens i.e specifically testosterone
Sites below the bladder in the pelvis
What is the histology of normal prostate tissue?
Comprimised of a mixture of glandular tissue (30-40% and fibromuscular stroma (60-70%)
• 30-50 tubular glands- comprimised of two cell layer- low cuboidal epithelium, tall columnar epithelium
• Connective tissue
• Smooth muscle
• Overall surrounding capsule of connective tissue
What is begnin prostatic hyperplasia (BPH) , What are the symptoms?
Common with age
Non- malignant modular enlargement
Glandular tissue is hyperplasticity
Symptoms:
Difficulty in urinating
Leaking or dribbling urine
Urinary retention and infection
What is prostatic intraepithelial neoplasia (PIN)?
Dysplasia of the epithelial cells lining the glands- epithelial cells become crowded and irregularly spaced with nuclei that are hyperchromatic
- Likely precursor for prostate adenocarcinoma
Exist as low and high grade PIN
What is prostatic adenocarcinoma?
Numerous proliferative small gland with little stroma present
Graded on scoring system - i.e 1-5 based on cellular architecture patterns
PC is heterogenous
On the prostate cancer continuum - what does each stage entail?
Stage 1- cancer still contained
Stage 2- cancer has spread but remain in capsule
Stage 3- locally advanced- has escaped the capsule and spread to local areas
Stage 4- tumour spreads to other organs
What do prostate cancer cells secrete to promote bone remodelling?:
Growth factors including bone morphogenic proteins/ interleukins and parathyroid hormone
What is a marker for prostate cancer?
Prostate specific antigen (PSA)
What is prostate specific antigen?
Found in prostatic fluid (0.3-3mg/ml)
Aids in liquefaction of seminal fluid
Those with healthy prostate- little is detected in blood
In prostate cancer- increased levels can ve detected in blood- but is not cancer specific
What are risk factors of PC?
Having a prostate
Age- >65 years
Family hisotry
Genetics and ethnicity
Diet
What are oncogenes fusion proteins?
Arise due to chromosomal rearrangements and major player include to ETS family
They regulate cell proliferation, apoptosis and differentiation
Include ERG and ETVI
What is the role of the prostate gland
produces prostatic fluid which mixes with sperm and seminal fluid to form semen. controls the flow of urine and role in development, maintenance and growth (dependent on androgens)
What is the prostate tissue composed of (cell types)?
30-50 tubular glands. 2 cell layers - outer low cuboidal layer and inner tall columnar epithelial
an overall capsule of connective tissue
