tumour angiogenesis Flashcards
What are some characteristics of malignant tumour?
- growth - unlimited growth (not self-limited like in benign)
- invasiveness - migration of tumour to cells into the surrounding stroma.
- metastasis- spread of tumour from primary site to form secondary tumours at other sites.
What are key steps in cancer progression-sequential process of metastasis?
- Transformation : extensive mutagenic and epigentic changes followed by clonal selection
- Angiogenesis: new blood vessel formation (overcomes limitations imposed by hypoxia, lack of O2 would have killed the tumour)
- Motility and invasion: epithelial to mesenchymal transition (invasive properties allowing intravasation into circulation and extravasation from circulation to tissue)
- Metastasis: colonisation of target organs (ability to expand from micrometastases)
What is tumour angiogenesis?
-angiogenesis = formation of new blood vessels from pre existing vessels.
- -small tumour eventually gets large and demands for O2 and nutrients increases
- tumour switches on expression of angiogenic factors that initiate blood vessels growth
- growth of new vessels around tumours, allow transport of O2 need for tumour to grow are called tumour angiogenesis.
- it can shred and travel in blood to metastasis.
What is vasculogenesis?
formation of new blood vessels from progenitor cells.
What are good and bad types of angiogenesis?
Good
- developmental/ vasculogenesis
- organ growth - normal angiogenesis
- wound repair
- placenta during pregnancy
Bad
- pathological angiogenesis
- tumour angiogenesis
- ocular(eyes)
- inflammatory disorders
How does hypoxia occur?
- hypoxia is a strong stimulus for tumour angiogenesis
- hypoxia <1% O2
- increase 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 factors (VEGF)
- fibroblast growth factor 2 (FGF 2)
- placental growth factor (PIGF)
- angiopoietin 2 (Ang 2)
these factors are secreted by tumour cells upon hypoxia
enzymes called matrix metalloproteinases also stimulate angiogenesis.
outline the vascular endothelial growth factor (VEGF)signalling?
- VEGF binds to its receptor on endothelial cells
- VEGF/VEGF -R2 dimerizes at the plasma membrane and recruits cofactors
- subsequently activate 3 major signal transduction pathways
- ultimately through these pathways VEGF activates cell survival, vascular permability, gene expression and cell proliferation
- all of these are essential for angiogenesis
++PIP2 for cell proliferation, PKB for cell survival and Ras/Raf for gene cell expression.
What is EMT?
- epithelial to mesenchymal transition
- EMT is a process by which epithelial cells
Lose:
- epithelial shape and cell polarity (beta catnin, claudin-1)
- cytokeratin intermediate filament expression
- epithelial adherens junctions (E-cadherin)
Gain migratory and invasive properties:
- fibroblast- like shape and motility
- invasiveness
- vimentin intermediate filament expression
- mesenchymal gene expression (fibronectin, PDGF receptor, avb6 integrins)
- protease secretion (MMP-2, MMP-9)
What are 3 epithelial markers essential for their structure, shape and cell polarity?
- E-cadherin
- beta -catenin
3.claudin-1
When these factors are down regulated , switch from epithelial -> mesenchymal
what are 3 mesenchymal markers?
- N-cadherin
2.Vimentin - fibronectin
these factors are upregulated , swithc from epithelial ->mesenchymal
How do E-cadherins maintain cell adhesion and polarity of typical epithelial cells?
- homotypic adhesion molecule (adhesion of cells with same cadherin) form dimers between cells.
- calcium dependent
- binds beta catenin
how does contact inhibition maintain monolayer in normal cells?
Normal cells:
- when E cadherins bind two cells
- contact inhibition prevents proliferation to maintain monolayer of normal cell.
Loss of E cadherin due to mutation:
- loss of cadherin = loss of adhesion properties
- distupted cell-cell adhesion/ contact
- no contact inhibition
- cells grow on top of each other.
How do stromal cell contribute to tumour progression?
- factors released by stromal cells (macrophages. mast cells, fibroblasts) include angiogenic factors, growth factors, cytokines, proteases.
- protease uPA factor activated by tumour cells converts plasminogen to plasmin
- plasmin activates matrix metalloproteinases (converts pro MMPs -> MMPs ), MMPs degrade extra cellular matrix (ECM) and release matrix -bound and angiogenic factors such as transforming growth factor -beta 1 (TGF- beta 1)
What is an example of protease factor released from stromal cells?
Urokinase-type plasminogen activator(uPA);
- activated by tumour cells
- resulting in plasmin production
