Tumour Angiogenesis, Invasion and Metastasis Flashcards
What are the characteristics of Malignant tumours
Growth:
- Unlimited growth (not self-limited as in benign tumours) - as long as an adequate blood supply is
available
Invasiveness: - Migration of tumour cells into the surrounding stroma
where they are free to disseminate via vascular or
lymphatic channels to distant organs
Metastasis:
- Spread of tumour cells from the primary site to form
secondary tumours at other sites in the body
Describe the key steps in cancer progression
1) Transformation:
- extensive mutagenic and epigenetic changes followed by clonal selection
2) Angiogenesis:
- new blood vessel formation (overcomes limitations imposed by hypoxia)
3) Motility and invasion:
- epithelial to mesenchymal transition (invasive properties
allowing intravasation into circulation and extravasation
from circulation to tissues)
4) Metastasis:
- colonisation of target organs (ability to expand from micrometastases)
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 are the types of angiogenesis
Developmental/Vasculogenesis:
- Organ growth
Normal angiogenesis:
- Wound repair placenta during pregnancy cycling ovary
Pathological angiogenesis:
- Tumour angiogenesis ocular and inflammatory disorders
Describe neovascularisation of tumours
- Numerous blood vessels have infiltrated into the tumour tissue
- Tumours will generally not grow beyond a size of 1-2mm3 without their own blood supply
Describe the steps of tumour angiogenesis
- Small tumour eventually gets to a large enough size when delivery of oxygen and nutrients from nearby capillaries becomes limiting
- Tumour switches on expression of angiogenic genes/factors that initiate new blood vessel growth
- New network of blood vessels grows in and around the tumour (tumour angiogenesis) increasing the delivery of oxygen and nutrients that allows it to increase growth and provides a route for cells to shed off and spread
What is tumour hypoxia
- Hypoxia is a strong stimulus for tumour angiogenesis
- Hypoxia – low oxygen tension <1% O
2 - Increases with increasing distance from capillaries
- Activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis
What are some angiogenic factors
- Vascular Endothelial Growth Factor (VEGF)
- Fibroblast Growth Factor 2 (FGF 2)
- Placental growth factor (PlGF)
- Angiopoietin 2 (Ang 2)
- Matrix metalloproteinase 2 (MMP-2)
Describe the Vascular endothelial growth factor signalling pathway
- VEGF binds to VEGF-R2 on endothelial cells
- VEGF/VEGF-R2 dimerizes at the plasma membrane and recruits cofactors that subsequently activate 3 major signal transduction pathways
- Ultimately, VEGF activates cell survival, vascular permeability, gene expression and cell proliferation
- All of these pathways are essential for angiogenesis
what causes tumour cell motility and invasion
- 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 happens in the Epithelial-Mesenchymal Transition
Loss of:
- Epithelial shape and cell polarity (β-catenin, claudin-1)
- 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)
What are E-cadherins
- Homotypic adhesion molecule (adhesion of
cells with the same cadherin) - Calcium-dependent
- Inhibits invasiveness
- Binds β-catenin
Loss of e-cadherins makes cells continuously proliferate, as there is a lack of contact inhibition pathway
How does stromal cells contribute to cancer cell progression
- Factors released by stromal cells
(macrophages, mast cells, fibroblasts) include angiogenic
factors, growth factors, cytokines,
proteases - E.g: Urokinase-type
plasminogen activator (uPA); activated by tumour cells - resulting in plasmin production - Plasmin activates matrix metalloproteinases (MMPs), which permit invasion by degrading extracellular matrix (ECM) and releasing matrix- bound angiogenic factors such as transforming growth factor-β1 (TGF-β1)
What are the steps involved in cancer dissemination
- Primary tumour formation
- Localised invasion
- Intravasation - Interaction with platelets, lymphocytes and other blood components
- Transport through circulation
- Arrest in micro vessels of various organs
- Extravasation
- Formation os a micrometastasis
- Colonisation - formation of a macro metastasis
