Tumour Angiogenesis, Invasion & Metastasis Flashcards
Describe the growth of malignant tumours
Malignant tumours = Unlimited growth as long as an adequate blood supply is available
(Benign tumours = self-limited growth)
Malignant tumour invasion
Tumour cells migrate into the surrounding stroma and spread through vascular/lymphatics to distant organs
What is metastasis?
Metastasis = Tumour cells spread from the primary site to form secondary tumours at other sites
What is involved in cancer metastasis?
Cancer metastasis - sequential, interlinked, selective steps (+ some stochastic elements)
Describe the influence of each metastatic cascade step in cancer
Each step is potentially rate limiting; failure of tumor cell to complete any step impedes that part of the process
Outline the key steps of cancer progression
- Transformation: Extensive mutagenic and epigenetic changes followed by clonal selection
- Angiogenesis - overcomes the limitations caused by hypoxia
- Motility + Invasion: Epithelial -> mesenchymal transition (invasive properties allowing intravasation + extravasation)
- Metastasis: Colonisation of target organs (expand from micrometastases)
What is angiogenesis?
Angiogenesis = 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 vasculogenesis?
developmental vasculogenesis = organ growth
What is the function of normal angiogenesis?
Normal angiogenesis:
- Wound repair
- Ovarian cycle(egg release)
- Placenta during pregnancy
What is the consequence of tumour angiogenesis (pathological angiogenesis)?
tumour angiogenesis = ocular and inflammatory disorders
How long can tumours survive without a blood supply?
Tumours won’t grow >1-2mm3 without their own blood supply before they become hypoxic
Tumours become hypoxic at 1-2mm3
Describe a tumour in situ (benign)
Cancers in situ remain differentiated
Describe the structure of an invasive cancer
Invasive cancers:
- lose their rigid structure
- ↑ blood vessel density within the tumour
Outline the stimulus of tumour angiogenic factor release
- Small tumour (<1-2mm^3) is self-sustaining
- Tumour become hypoxic - As it grows, inner tumour cells ↑ distance from nearest capillary
- Angiogenic switch occurs - stimulates production of vascular growth factors (e.g. VEGF)
- VEGF(cytokine) diffuses out to initiate endothelial cell proliferation (in nearby capillaries) = forms vessels around the tumour
Describe the role of hypoxia in tumour angiogenesis
Hypoxia is a strong stimulus for tumour angiogenesis
What is hypoxia?
Hypoxia = Insufficient oxygen is delivered to tissues.
↑ distance of tissue from capillary = hypoxia.
Hypoxia is a strong stimulus for tumour angiogenesis.
-Low oxygen tension <1% O2
What is the consequence of hypoxia in tumour tissue?
Hypoxia in tumour tissue - Activates gene transcription for proteins involved in angiogenesis, tumour cell migration and metastasis
What are angiogenic factors?
Angiogenic factors = Proteins produced by tumour cells that stimulate the directional growth of endothelial cells:
- Vascular Endothelial Growth Factor (VEGF)
- Fibroblast Growth Factor 2 (FGF 2)
- Placental growth factor (PlGF)
- Angiopoietin 2 (Ang 2)
Name some angiogenic factors
Vascular Endothelial Growth Factor (VEGF)
Fibroblast Growth Factor-2 (FGF-2)
Placental Growth Factor (PlGF)
Angiopoietin 2 (Ang 2)
Transforming Growth Factor-β (TGF- β)
How are angiogenic factors stored and released?
Angiogenic 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 (MMP-2)
Outline the process of tumour angiogenesis
- Tumour releases VEGF - acts on VEGFR on 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: A tyrosine-kinase receptor that dimerises upon ligand binding
What is the effect of VEGF binding?
VEGF binding to VEGFRs on vascular endothelial cells=
- Activate RAS/MEK, AKT, PKB and PKC pathways
- Ca2+ release and endothelial cell proliferation
What are the requirements for metastasis to occur?
- ↑ mechanical pressure caused by rapid cellular proliferation
- ↑ motility of the malignant cells (epithelial -> mesenchymal transition)
- ↑ production of degradative enzymes by both tumour cells and stromal cells
What is lost during epithelial-mesenchymal transition?
Epithelial-mesenchymal transition = Loss of:
- Epithelial shape + cell polarity (Beta-catenin, claudin-1)
- 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?
Epithelial-mesenchymal transition cell adhesion molecules:
- E-cadherins
- Integrins
Outline the effect of E-M transition on E-cadherins
E->M transition = E-Cadherins are 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?
E->M transition = Integrins are upregulated: - 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?
Stromal cells = fibroblasts, macrophages, mast cells
Stromal cells release factors e.g. 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(e.g. TGFβ1)
How efficient is metastasis?
Metastasis 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
Mechanical Hypothesis of Pattern of Tumour Spread (Metastasis)
Anatomical considerations: Blood and lymphatic systems, entrapment in capillary beds (20-30µm carcinoma cell, ~8µm capillary)
Seed and Soil Hypothesis of Pattern of Tumour Spread (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?
Targeted therapy to angiogenic factors (e.g. VEGF)
How successfully is cell motility targeted in cancer prevention?
No success with targeting cell-cell adhesion molecules or integrins
What is Judah Folkman’s hypothesis on tumour growth?
Tumour growth is dependent on new blood vessel growth
If tumor remains in the non-vascularized dormant state, metastases may not arise
What is the significance of Folkman’s hypothesis?
Paradigm shift in cancer therapy
Both the tumour and microvascular compartment are valid therapeutic targets
What is a common pathological(tumour) angiogenesis?
Kidney cancer/renal cell carcinoma is a highly angiogenic and metastatic tumour
What is avastin?
Avastin = First specific anti-angiogenesis drug
Used for
- Colorectal cancer
- Lung cancer
- Kidney cancer
- Ovarian cancer
- Eye diseases
Outline the mechanism of action of avastin
Avastin:
- monoclonal antibody
- binds to VEGF
- prevents VEGF binding to VEGF receptors
Hypoxia is a strong stimulus for ………
tumour angiogenesis
