Tumour Angiogenesis, Invasion & Metastasis Flashcards
Describe the growth of malignant tumours
Unlimited growth (not self-limited as in benign tumours) - as long as an adequate blood supply is available
Outline the invasiveness of malignant tumours
Migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs
What is metastasis?
Spread of tumour cells from the primary site to form secondary tumours at other sites in the body
What is involved in cancer metastasis?
Cancer metastasis consists of sequential, interlinked, and selective steps with some stochastic elements
Describe the influence of each metastatic cascade step in cancer
Each step is potentially rate limiting; failure of tumor cell completing any step effectively impedes that portion of the process
Outline the key steps of cancer progression
- Extensive mutagenic and epigenetic changes followed
by clonal selection - Angiogenesis (overcomes limitations imposed by
hypoxia) - Epithelial -> mesenchymal transition (invasive properties
allowing intravasation and extravasation) - Colonisation of target organs (ability to expand from
micrometastases) - Release of metastatic cells that acquire ability to
colonise
What is angiogenesis?
Angiogenesis is the formation of new blood vessels from pre-existing vessels
What is vasculogenesis?
Vasculogenesis is the formation of new blood vessels from progenitors
What is the role of developmental vasculogenesi?
organ growth
What is the function of normal angiogenesis?
- wound repair
- placenta during pregnancy
- cycling ovary
What is the consequence of tumour angiogenesis?
tumour angiogenesis
ocular and inflammatory disorders
How long can tumours survive without a blood supply?
Tumours will generally not grow beyond a size of about 1-2mm3 without their own blood supply before they become hypoxic
Describe a tumour in situ (beningn)
Cancers in situ remain differentiated
Describe the structure of an invasive cancer
Invasive cancers have a loss of their rigid structure and have an increase in blood vessel density within the tumour
Outline the stimulus of tumour angiogenic factor release
- Small tumour (not yet 1-2mm^3) is self sustaining
- Tumour become hypoxic as when it grows, areas of
tissue move away from nearest capillary - Angiogenic switch occurs stimulating production of
vascular growth factors e.g. (VEGF) - VEGF diffuses out as it’s a cytokine, to initiate
endothelial cells in nearby capillaries to proliferate and
form vessels around the tumour
Describe the role of hypoxia in tumour angiogenesis
Hypoxia is a strong stimulus for tumour angiogenesis
What is hypoxia?
Hypoxia – low oxygen tension <1% O2
Increases with increasing distance from capillaries
What is the consequence of hypoxia?
Activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis
What are angiogenic factors?
Some tumour cells produce factors that stimulate the directional growth of endothelial cells
Name some angiogenic factors
Vascular Endothelial Growth Factor (VEGF)
Fibroblast Growth Factor-2 (FGF-2)
Transforming Growth Factor-β (TGF- β)
Hepatocyte growth factor/scatter factor (HGF/SF)
How are angiogenic factors stored and released?
These factors are secreted by tumour cells or are stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases
Outline the process of tumour angiogenesis
- Tumour releases VEGF; acts on receptors within capillary
endothelial cells - Endothelial cells begin proliferating causing sprouts of
new vessels surrounding the tumour - Other factors FGF-2, PGF and matrix metalloproteinases
(MMPs) which are enzymes that facilitate invasion - In order for sprouting vessels to invade the ECM and
migrate they require enzymatic capacity mediated by
the upregulation of MMPs
Describe the structure of VEGFR
VEGFR is a tyrosine-kinase receptor that dimerises upon ligand binding
What is the effect of VEGF binding?
Activate RAS/MEK, AKT, PKB and PKC pathways
Ca2+ release and endothelial cell proliferation is also induced by VEGF binding
What are the requirements for metastasis to occur?
- 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
What is lost during epithelial-mesenchymal transition?
Loss of
- Epithelial shape and cell polarity
- Cytokeratin intermediate filament expression
- Epithelial adherens junction protein (E-cadherin)
What is acquired during epithelial-mesenchymal transition?
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)
What are the 2 crucial cell adhesion molecules affected during epithelial-mesenchymal transition
- E-cadherins
- Integrins
Outline the effect of E-M transition on E-cadherins
E-Cadherins (downregulated) - Homotypic adhesion molecule (adhesion of cells with the same cadherin) - Calcium-dependent - Inhibits invasiveness - Binds β-catenin
What is the effect of E-M transition on integrins?
Integrins (upregulation) - Heterodimers (α and β subunits) - Heterotypic adhesion molecule - Adhesion to extracellular matrix (via collagen, fibronectin, laminin) - Cell migration
What are the angiogenic factors released by stromal cells?
Factors released by stromal cells (macrophages, mast cells, fibroblasts) include angiogenic factors, growth factors, cytokines, proteases
Name an example of angiogenic factor released by stromal cells
Urokinase-type plasminogen activator (uPA); activated by tumour cells - resulting in plasmin production
What is the effect of plasmin production on cell invasion?
Plasmin activates matrix metalloproteinases (MMPs), which permit invasion by degrading extracellular matrix (ECM) thus releasing matrix-bound angiogenic factors
How efficient is metastasis?
The overall process is highly inefficient:
Tumour cells can extravasate successfully (>80%) but the last two steps are very inefficient (<0.02% of cells actually form micrometastases)
What are common sites of metastasis?
Lung and brain are common sites of primary tumour metastases
What is the mechanical hypothesis of tumour spread pattern?
Anatomical considerations: Blood and lymphatic systems, entrapment in capillary beds (20-30µm carcinoma cell, ~8µm capillary)
What is the seed and soil hypothesis of metastasis?
Specific adhesions between tumour cells and endothelial cells in target organ, create favourable environment in target organ for colonisation
Genetic alterations acquired during progression allow tumour cells to metastasize
How is tumour angiogenesis inhibited using treatments?
Success with targeted therapy to angiogenic factors like vascular endothelial growth factor
How successfully is cell motility targeted in cancer prevention?
No success with targeting cell-cell adhesion molecules or integrins
What is Judah Folkmans hypothesis on tumour growth?
Tumour growth dependent on new blood vessel growth
“If a tumor could be held indefinitely in the non-vascularized dormant state….it is possible that metastases will not arise”
What is the significance of Folkmans hypothesis?
Paradigm shift in cancer therapy
Both the tumour and microvascular compartment are valid therapeutic targets
What is a common pathological angiogenesis?
Kidney cancer/renal cell carcinoma is a highly angiogenic and metastatic tumour
What is avastin?
First specific anti-angiogenesis drug
in 2013 was the second biggest selling oncology produc
When is avastin used?
Approved for colorectal, lung, kidney and ovarian cancers and eye diseases
Outline the mechanism of action of avastin
Avastin:
- monoclonal antibody
- binds to VEGF
- prevents VEGF binding to VEGF receptors
