PBL2 Flashcards
What is metastasis?
spread of a tumour to and growth at ectopic sites via blood, lymphatics, intraepithelial route, or transcoelomic.
What is invasion?
growth by infiltration and destruction of surrounding tissues.
Define carcinoma
malignant tumour derived from epithelial cells
Define sarcoma
malignant tumour derived from mesenchymal cells
Define melanoma
malignant tumour derived from neural crest cells (melanocytes)
Define leukaemia
malignant tumour derived from circulating white blood cells
Define lymphoma
malignant tumour derived from lymphocytes
What is the basement membrane?
The basement membrane delineates epithelial/endothelial tissues
- a layer of extracellular matrix, made up of fibronectin, type IV collagen and laminin
How is the basement membrane made?
It is secreted by basal epithelial cells/endothelial cells
What is the significance of the BM in cancer?
The basement membrane acts as a primary barrier against the spread of cancerous cells, especially
carcinomas.
What are the requirements for a cell to metastasise?
Neoplastic cells have to develop several attributes in order to metastasise
- reduced cell-cell adhesion
- altered cell-substratum adhesion
- increased motility
- increased proteolytic ability
- ability to intravasate and extravasate
- ability to proliferate
What is E-cadherin?
(epithelial cadherin) is a a structure that is
used to connect adjacent epithelial cells together.
What is e-cadherin’s role in metastasis?
Loss of this epithelial adhesion molecule helps to
enable metastasis by disrupting the intercellular
contact, this is an early step in the metastatic
dissemination
E-Cadherin is calcium-dependent. Some tumours
(e.g. diffuse-type gastric tumours), there is ‘exon
skipping’ which is when the axons encoding for the calcium binding domain are missing.
So, for carcinomas and melanomas, the cancer cells acquire the ability to ‘unglue’ via mutations/
epigenetic alterations in E-Cadherin, or in molecules that regulate/interact with it.
What are integrins?
Integrins are cell-surface molecules that bind to
extracellular matrix molecules.
Where are integrins found?
Integrins are found in basal epithelial cells and in focal
adhesions of migrating cells.
What is the role of integrins in metastasis?
Specific integrins seem to promote invasion & metastasis. Possible mechanisms:
• ↓ Adhesion to the basement membrane surrounding the epithelium
• ↑ Migration through stroma
• ↑ Adhesion to the basement membrane or endothelial cells of blood vessels.
What is hepatocyte growth factor?
HGF or “scatter factor” can induce epithelial cells to
dissociate and scatter in culture
HGF is a mitogen and a motogen (motility factor). It is
produced by the stromal cells in a tumour.
What is HGF’s role in metastasis?
HGF binds to c-met (a receptor tyrosine kinase).
Activation of c-met leads to ↑ tyrosine phosphorylation of
β-catenin which disrupts E-Cadherin-mediated
adhesion
Describe the tumour microenvironment
Tumour cells do not act in isolation, but rather subsist in a rich microenvironment provided by:
• Fibroblasts
• Endothelial cells
• Pericytes (cells that wrap around endothelial cells of
blood vessels)
• Leukocytes
• Tumour-associates vasculature.
These secrete various factors including growth factors,
chemokines and enzymes that the tumour stroma can
take advantage of.
Describe how a neoplastic cell develops increased proteolytic ability
The production of proteolytic enzymes that degrade the environment, especially the ECM are important in metastasis e.g. matrix metalloproteinases (MMPs), which degrade type IV collagen in the
basement membrane.
(Other classes of enzymes are serine proteases., e.g. urokinase plasminogen activator (uPA) & plasmin)
What is the function of VEGF?
VEGF (Vascular Endothelial Growth Factor)
The VEGF binds to VEGF receptors on nearby endothelial cells, causing the endothelial cells to migrate
towards the tumour and start forming new blood vessels.
What is the role of VEGF in metastasis?
Tumour cells can express VEGF if they are hypoxic i.e. starved of oxygen, creating new vessels
newly forming vessels are weak and leaky, allowing fibrinogen to leak out. This is
converted to fibrin by pro-coagulants released from the TME. The fibrin
forms a clot, which provides a good surface for endothelial to grow onto
How does a neoplastic cell develop the ability to intravasate and extravasate?
thought to exploit abilities of WBCs
Lymphocytes have the ability to intravasate and extravasate due to role in immune surveillance (“lymphocyte homing”)
WBCs transiently bind to endothelial cells via selectin molecules, allowing them to bind and
roll onto endothelial cells and start to intravasate/extravasate
What are the two hypothesis for proliferation?
1 - seed and soil
2 - mechanical
Describe the seed and soil hypothesis
proposed organ-preference patterns of tumour metastasis are the
product of favourable interactions between metastatic tumour cells (the “seed”) and their organ
microenvironment (the “soil”).
What is tissue tropism?
Preferential growth in different sites
What are the possible mechanisms for tissue tropism
Selective adhesion to endothelium of target organs (selectins , CD44 variants)
• Selective response to GFs at ectopic site – e.g., PTHRP and IL-11 allow breast cancer cells to establish
osteolytic metastases
• Selective migration to CK source (differential CKR expression)
• Factors released by tumour cells cause changes in microenvironment at secondary sites, creating premetastatic
niche
• Balance of local angiogenic factors versus systemic anti-angiogenic factors (angiostatin & endostatin)
What is BRAF?
B-Raf is a member of the Raf kinase family which are a family of growth signal transduction protein
kinases
What is the normal role of BRAF
This protein plays a role in regulating the MAP kinase/ERKs signalling pathway, which affects cell
division, differentiation, and secretion
What is BRAFs role in cancer?
Approximately 40-60% of melanomas contain a mutation in the oncogene that encodes BRAF that
leads to constitutive activation of downstream signalling in the MAP kinase pathway.
What is vemurafenib?
- Drugs attack the BRAF protein directly - Vemurafenib is a reversible, ATP-competitive inhibitor of the kinase domain of BRAF
- drugs shrink tumours in about half of the people whose metastatic melanoma has a BRAF gene change.
- can prolong the time before tumours start growing again and help some patients live
longer, although the melanoma typically starts growing again.
What are the three stages of immune surveillance in cancer?
- elimination
- equilibrium
- escape
Describe the elimination stage of immune surveillance
The immune system recognises and
destroys potential tumour cells before they start to
metastasise
Describe the equilibrium stage in immune surveillance
phase follows when elimination is not entirely successful. During the equilibrium phase, a process known as cancer immunoediting continuously shapes the properties of the tumour cells that survive
Describe the escape stage in immune surveillance
tumour cells that have accumulated sufficient mutations elude the attentions of the immune system and grow
unimpeded to become clinical detectable
What is the principle immune mechanism of tumour eradication?
- killing of tumour cells by cytotoxic T cells (CD8+) specific for tumour antigens
How is the cytotoxic T cell response induced?
recognition of tumour antigens on host
APCs, which ingest tumour cells or their antigens and present the antigens to T cells via MHC Class 1.
What are the current immunotherapeutic approaches to treat diseases?
- cytokine therapy
- antigen targeted immunotherapy
- cell based therapies
Describe cytokine therapy
- IFN α/β:
• Interferon α/β is the seen as the ‘gold standard’ for CML (chronic myeloid leukaemia) until imatinib
was found.
• It affects MHC Class 1 expression and cell division.
• It prolongs survival and stabilises disease in cancers such as RCC (renal cell carcinoma). - IL-2
• Therapy of RCC (renal cell carcinoma) and metastatic melanoma
• Thought to promote expansion of tumour-specific T cells.
Describe antigen targeted immunotherapy
Pre-formed antibodies (monoclonal antibodies - mab) can target cancel cells directly and mediate
tumour destruction.
Administration of monoclonal antibodies which target either tumour-specific or over-expressed antigens,
or block inhibitor receptors (anti-CTLA4)
What are the methods in which monocloncal antibodies can kill tumour cells
- apoptosis induction
- complement-mediated cytotoxicity
- Antibody dependent celluylar cytotoxicity
- Conjugated to toxin/isotope
How does ipilimumab work?
CD28 is an ‘on-switch’ for CTL’s
CTLA4 is an ‘off-switch’ for CTL’s and is often up regulated by cancer cells
Ipilimumab blocks the CTLA 4 antigen to enhance inflammation and block the immunosuppressive
effects
Ipilimumab also increases the number of active T cells
What are the side effects of ipilimumab?
But this may also result in loss of some peripheral tolerance, for example, in the gut the CTL’s are
physiologically switched off to prevent them from digesting the gut when faced with a foreign
ingested substance. The MAb may lead to blistering of the gut and other adverse gut responses if
its CTL’s are switched on also.
How does nivolumab work?
Nivolumab is an anti-PD-L1 monoclonal antibody.
The pathway includes two proteins called programmed death-1 (PD-1), expressed on the surface of immune cells, and programmed death ligand-1 (PD-L1), expressed on
cancer cells.
When PD-1 and PD-L1 join together, they form a
biochemical “shield” protecting tumour cells from being destroyed by
the immune system.
If cells display this, then the PD-1 receptor on the T cell gets activated and it will initiate programmed cell death of the T cell.
However Nivolumab blocks this, and allows the T cell to function
What are the different cell based therapies in cancer?
- Haematopoietic Stem cells • Tumour-Infiltrating T cells (TILs) • Dendritic Cell Vaccines • NK cells • Gamma-delta T cells • Virus-specific T cells • Genetically engineered T cells.
What is depression?
Depression is a common mental disorder characterised by pervasive low mood, anhedonia (inability to
feel pleasure) and low energy.
What are the clinical features of depression?
Cognitive Features:
• Slowed speed of thought
• Reduced concentration and attention
• Reduced self-esteem and self-confidence
• Ideas of guilt and unworthiness
• Bleak and pessimistic views of the future
• Ideas or acts of self-harm or suicide
Biological Symptoms: • Sleep disturbance • Weight loss or gain • Constipation • Amenorrhea • Reduced libido (sex drive)
Psychotic Symptoms:
• Delusions - an idiosyncratic belief or impression maintained despite being contradicted by reality or a
rational argument.
• Hallucinations - hearing or seeing things that aren’t actually there/happening. (Often auditory)
What are the biological factors involved in the aetiology of depression
- Genetics
- Neurochemical theories (dopamine, serotonin, noradrenaline)
- Neuroendocrine theories (disrupted FPA/HPT axis)
What are the psychological factors involved in the aetiology of depression
- Psychodynamic
- Behavioural
- Cognitive
- Arbitrary inference
- Selective abstraction
- Magnification
- Minimisation
- Overgeneralisation
- Personalisation
What are the socialfactors involved in the aetiology of depression
- Predisposing
- Precipitating
How is depression investigated?
• Good clinical history, including drug history
• Risk assessment
• Blood tests may include blood glucose, U&Es, LFTs, TFTs, calcium levels, FBC and inflammatory
markers. Other tests may include magnesium levels, HIV or syphilis serology, or drug screening.
• Imaging (MRI or CT brain scanning)
What are the biological treatments for depression?
- SSRI
- TCA
- SNRI
- NASSA
- NRI
Give an example of an SSRI and its side effects
Fluoxetine
• Nausea, vomiting, agitation, sexual dysfunction, hyponatremia, sweating
Give an example of a TCA and its side effects
Tricyclic Antidepressants (TCAs)
Amitriptyline
Anticholinergic effects, sedation, weight gain, sweating, hyponatremia, cardiotoxic effects,
hallucinations
Give an example of an SNRI and its side effects
Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs)
Venlafaxine
nausea, vomiting, agitation, sweating, sexual dysfunction, hypertension
Give an example of NASSAs and their side effects
Noradrenergic and Specific Serotonergic Antidepressants (NASSAs)
Mirtazepine
• Sedation, weight gain
Give an example of NARIs and its side effects
Noradrenergic Reuptake Inhibitors (NARIs)
Reboxetine
• Sweating, hypotension, anticholinergic effects
What are the psychological managements for depression?
- Behavioural therapy
- Cognitive therapy
- Psychotherapy
