tumour angiogenesis Flashcards
name 3 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
in order for cancer cells to form a micrometastisis, what needs to happen?
the cancer cells need to move out of the vessel so they can start to lodge and proliferate within a distant organ
summary of key steps in cancer progression
Extensive mutagenic and epigenetic changes followed by clonal selection
Angiogenesis (overcomes limitations imposed by hypoxia)
Epithelial to mesenchymal transition (invasive properties allowing intravasation and extravasation)
Colonisation of target organs (ability to expand from micrometastases)
Release of metastatic cells that have acquired the ability to colonise
What is angiogenesis?
the formation of new blood vessels from pre-existing vessels
What is vasculogenesis?
the formation of new blood vessels from progenitors
name 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
-can affect vessels in the eye, macular degeneration
why is neovascularisation of tumours essential?
because tumours will generally not grow beyond a size of about 1-2mm3 without their own blood supply
what happens in tumour angiogenesis?
small tumour near a capillary
- angiogenic switch, tumour secretes growth factors and angionenic factors (VGEF)
- initiates proliferation and migration of nearby endothelial cells, new vessels start to form from the nearby capillary around the tumour
- means the tumour can grow off at different angles - don’t stop mutating
- the cells can then escape from the primary tumour via the vascular network – metastatic spread
what is meant by tumour hypoxia and what happens as a result?
Hypoxia – low oxygen tension <1% O2
Increases with increasing distance from capillaries
hypoxia is a stimulus for GF’s to be released and activation of transcription of genes involved in angiogenesis, tumour cell migration and metastasis
hypoxia is a strong stimulus for?
tumour angiogenesis
what are angiogenic factors?
some tumour cells secrete factors that stimulate the directional growth of endothelial cells, or they are stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases
Vascular Endothelial Growth Factor (VEGF)
Fibroblast Growth Factor-2 (FGF-2)
Transforming Growth Factor-β (TGF- β)
Hepatocyte growth factor/scatter factor (HGF/SF)
-increase the ability of the tumour to spread
Vascular endothelial growth factor (VEGF) signalling
Cell signaling cascade activated when VGEF binds
Tyrosine kinase activator and this will stimulate many different processes within the cell
The RAS/MEK pathway
PKB cell survival pathway
PIP2 pathway will stimulate cell proliferation, and will cause release of NO, increasing angiogenesis
name some mechanisms of Tumour Cell Motility & 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
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)
Upregulation of fibroblast like genes that facilitate invasiveness
role of e-cadherins and how they are affected in cancer?
Calcium-dependent
Inhibits invasiveness
Binds β-catenin
contact inhibition
- stop proliferating if there’s a cell nearby, due to the cell to cell adhesions molecules called e-cadherins
- e-cadherin will contact and bind to an e-cadherin on another cell
- downregulation of proliferation in a normal cell
in CANCER:
- lose the e-cadherin (or its mutated so decreased expression) the cells cant recognise when they’re close to each other so cells start forming on top of each other and clumped together
- disrupted cell to cell adhesion
2 types of adhesion molecules?
e-cadherins and integrins
what are integrins?
- Heterodimers (α and β subunits)
- Heterotypic adhesion molecule
- Adhesion to extracellular matrix (via collagen, fibronectin, laminin)
- Cell migration
what is the stromal cell contribution to cancer?
stromal cells release angiogenic factors, growth factors, cytokines, proteases
example: Urokinase-type plasminogen activator (uPA) which is activated by tumour cells and results in plasmin production
Plasmin activates matrix metalloproteinases (MMPs), permitting invasion by degrading the extracellular matrix, releasing matrix-bound angiogenic factors
steps involved in cancer dissemination?
primary tumour formation, localised invasion, intravasation, transport through circulation, extravasation
cells extra-vasate to form a micro metastasis
- not a very efficient process, a lot of cells die
- but, formation of metastatic colonies can occur, killing someone
- once they invade, they can occupy a certain area
Tumour cells can extravasate successfully (>80%) but the last two steps are very inefficient (<0.02% of cells actually form micrometastases).
What Determines the Pattern of Tumour Spread?
Mechanical Hypothesis
Anatomical considerations: Blood and lymphatic systems, entrapment in capillary beds (20-30µm carcinoma cell, ~8µm capillary)
-based on what’s close by to the tumour
Seed and Soil Hypothesis
Specific adhesions between tumour cells and endothelial cells in the target organ, creating a favourable environment in the target organ for colonisation
Genetic alterations acquired during progression allow tumour cells to metastasize
Targeting tumour angiogenesis, cell motility & invasion to inhibit cancer?
Tumour angiogenesis
Success with targeted therapy to angiogenic factors like vascular endothelial growth factor
Cell motility
No success with targeting cell-cell adhesion molecules or integrins
Invasion
All clinical trials with matrix metalloproteinases have been unsuccessful in reducing tumour burden!
Kidney cancer/renal cell carcinoma
highly angiogenic and metastatic tumour
Avastin
First specific anti-angiogenesis drug, in 2013 was the second biggest selling oncology product
Approved for colorectal, lung, kidney and ovarian cancers and eye diseases
Mechanism of action of Avastin
monoclonal antibody
binds to VEGF
prevents VEGF binding to VEGF receptors on endothelial cells
-Prevents process of new blood vessel growth
