Cellular pathology: Tumour Angiogenesis, Invasion & Metastasis Flashcards
1
Q
What are some characteristics of malignant tumours?
A
- Ability to grow - Unlimited growth (not self-limited as in benign tumours) as long as an adequate blood supply is available
- Invasiveness - Migration of tumour cells into surronding stroma where they’re free to spread via vascular or lymphatic vessels to distant organs
- Ability to metastasize - Spread of tumour cells from the primary site to form secondary tumours at other sites in the body
2
Q
Describe the sequential steps involved in metastasis
A
- Tumour cells become motile and invade capillaries/lymphatic vessels (intravasation)
- Tumour cells are transported via bloodstream/lymphatic vessels around body
- Eventually tumour cells embolize in capillaries of partcular organ (e.g. lungs or liver)
- Tumour cells move out of capillaries/lymphatic vessesl into organ parenchyma (extravasation)
- Tumour cells then respond to microenvironment within organ leading to proliferation and angiogenesis to occur
- Mestatic colonization occurs causing secondary metastases to form from micrometas in particular organ away from site of primary mestastes
3
Q
What is angiogenesis?
A
- The formation of new blood vessels from pre-existing ones
4
Q
What are the different types of angiogenesis?
A
- Developmental/vasculogenesis - Organ growth
- Normal angiogenesis - Wound repair
- Pathological angiogenesis - Tumour angiogenesis
5
Q
Why does tumour angiogenesis need to occur?
A
- Because as the tumour grows some tumour cells will move away from the nearest blood vessel and so won’t be near enough to receive sufficient oxygen and nutrients
- So new blood vessels ned to be formed so all cells of tumour are near enought to a blood vessel
6
Q
Briefly explain the process of tumour angiogenesis
A
- Once tumour grows to size where it has insufficient oxygen/nutrient supply the angiogenic switch within the tumour will be switched on
- This causes the tumour to release pro-angiogenic factors e.g. Vascular endothelial growth factor (VEGF)
- Pro-angiogenic factors will cause growth and migration of endothelial cells in existing blood vessels in a process called sprouting
- Sprouting results in formation of new blood vessels around the tumour
7
Q
How does tumour hypoxia lead to tumour angiogenesis?
A
- Tumour cells that are hypoxic, have an oxygen tension of < 1%, will begin to transcribe genes involved in angiogenesis, e.g. VEGF, as well as other genes involved in tumour cell migration and mestatses
- mRNA from these genes will be translated to produce proteins which will go on to intiate tumour angiogenesis as well as other processes
8
Q
Give some examples of pro-angiogeneic factors
A
- Vascular Endothelial Growth Factor (VEGF)
- Fibroblast Growth Factor-2 (FGF-2)
- Transforming Growth Factor-β (TGF- β)
- Hepatocyte growth factor/scatter factor (HGF/SF)
9
Q
Explain the vsacular endothelial growth factor siganllign pathway
A
- A molecule of VEGF binds to two VEGFR-2 recptors, a tyrosine kinase receptor, which leads to dimerization and then autophosphorylation
- Proteins such as VEGF-receptor activated factor (VRAP) bind to the phosphorylated receptor and cause activation of RAS
- RAS phosphorylates RAF, RAF phosphorylates MEK, which itself phosphorylates MAPK
- MAPK will phosphorylate transcription factors that promote expression of genes important for cell proliferation - this leads to angiogenesis
- PI3K, Phosphoinositide 3-kinase, is activated which phosphorylates and activates protein kinase B (PKB or AKT)
- AKT promotes cell survival which leads to angiogenesis
- Phospholipase C is also activated which leads to production of IP3 and DAG
- DAG activates protein kinase C which promotes cell proliferation and increased vasopermeability
- IP3 leads to increased Ca2+ release from endoplasmic reticulum
- Ca2+ leads to increased activation of nitric oxide synthase (NOS) which goes on to produce nitric oxide
- Nitric oxide also increases vasopermiability
10
Q
In order for a tumour to metastasize they need to become more motile and invasive. What are some mechanisms tumour cells use to become more motile and invasive?
A
- Increased mechanical pressure caused by rapid cellular proliferation
- Increased motility of the malignant cells (epithelial to mesenchymal transition)
- Increased production of degradative enzymes by both tumour cells and stromal cells
11
Q
Explain the process of epithelial - mesenchymal transition
A
- Specific epithelial cancer cell genes begin to be downregulated which results in the loss of cell-cell adhesion molecules such as E-cadherin
- Epithelial cancer cells also upregulate particular pathways which results in them transforming into mesenchymal cancer cells.
- These pathways include: PI3K/AKT pathway and the TGF-β
- The upregulation of these pathways results in the production of proteins such as: N-cadherin, Fibronectin and MMPs
- All these changes mean that the cancer cell is now more mobiule and invasive
12
Q
Summarise the changes that occur during the epithelial - mesenchymal transition
A
-
Loss of:
- Epithelial shape and cell polarity
- Cytokeratin intermediate filament expression
- Epithelial adherens junction protein (E-cadherin)
-
Acquisition of:
- Fibroblast-like shape and motility
- Invasiveness
- Vimentin intermediate filament expression
- Mesenchymal gene expression (fibronectin, PDGF receptor, αvβ6 integrin)
- Protease secretion (MMP-2, MMP-9)
13
Q
What is E-cadherin and what is its normal function?
A
- E-cadherins are transmembrane gylcoproteins that bind to β-catenin in order to facilitate homotypic cell adhesion (adhesion of cells with the same cadherin)
- E-cadherins are calcium dependent
14
Q
How does E-cadherin inhibit invasiveness?
A
- Presence of E-cadherin between cells allows a cell to recognise when it is too close to another cell
- This results in the two cells downregulating proliferation or to stop moving towards each other - this process is called contact inhibition
15
Q
How does loss or mutation of E-cadherin allow for a tumour to become invasive?
A
- Loss/mutation of E-cadherin means that cells aren’t able to recognise where they are in relation to other cells
- This means cells aren’t able to stop proliferating in response to being too close to another cell so they grow on top of each other (loss of contact inhibition)
- In a tumour this loss of contact inhibition allows for the tumour cells to proliferate and invade other tissues
16
Q
What are integrins and what is their normal function?
A
- Integrins are a family of heterodimers made up of a range of α and β subunits.
- Integrins facilitate heterotypic adhesion of cells to specific parts of the extracellular matrix e.g. collagen, fibronectin, laminin
- They also facilitate extracellular signal transduction
17
Q
How do tumour cells use integrins to become more invasive?
A
- In tumour cells there’s altered integrin expression which results in modified membrane distribution and also allows for the tumour cells to adhere to different extracellular matrixes
18
Q
Explain the role that stromal cells play in tumour progression
A
- Tumour cells induce stromal cells to release factors such as pro-angiogenic factors, growth factors, cytokines and proteases which all help tumour grow or become more invasive
- One of the factors released is Urokinase-type plasminogen activator (uPA)
- uPA is activated by tumour cells which results in plasmin production
- Plasmin activates matrix metalloproteinases (MMPs), which degrade the extracellular matrix (ECM) thus releasing matrix-bound pro-angiogenic factors
19
Q
Apart from degrading the extracellular matrix, how else do matrix metalloproteinases (MMPs) help with tumour cell progression?
A
- Matrix metalloproteinases can cleave the extracellular domain of E-cadherin which results in the loss of contact inhibition within the tumour cells
- Loss of contact inhibition allows tumour cells to contunously proliferate and invade into other tissues
20
Q
Is the process of tumour mestatsis an efficient process?
A
- Overall the process is highly inefficient
- Although most umour cells can extravasate (move from a blood/lymphatic vessel into an organ) successfully (>80%), the last two steps are very inefficient.
- Only <0.02% of cells actually form micrometastases.
21
Q
For some common cancer types name some of the most common areas of tumour metasasis
A
- Breast cancer - Can metastasize in the brain, lungs, liver
- Colorectal cancer - Can metastasize in colon, lungs
- Gastric cancer - Can metasasize in stomach, oesophagus or lungs
- Lung cancer - Can metasasize in brain, liver or adrenal gland
- Pancreatic cancer - Can metasasize in pancreas, liver or lungs
- Prostate cancer - Can metastasize in prostate galnd
22
Q
What are the names of the 2 hypothesise on why particular tumours mestatsize in particular organs?
A
- Mechanical hypothesis
- Seed and soil hypothesis
23
Q
What does the mechanical hypothesis state?
A
- States that particular tumour metasasize in specific areas because of anatomical considerations - E.g. where is the closest supply of bood and lymphatic systems
24
Q
What does the seed and soil hypothesis state?
A
- States that specific adhesions between tumour cells and endothelial cells in the target organ, create a favourable environment in the target organ for colonisation
25
Q
What does the angiogenesis hypothesis state?
A
- States that tumour growth dependent on new blood vessel growth (angiogenesis) and so if angiogenesis could be halted eventually tumour cells will not metastasize
26
Q
Name a specific anti-angiogeneic drug
A
- Avastin
27
Q
Explain the mechanism of action of avastin
A
- Avastin is a monoclonal antibody which binds to VEGF
- This prevents VEGF binding to VEGF receptors on endothelial cells
- This prevents the induction of all of the VEGF signal transduction pathways which are needed in the process of angiogenesis
