Tumour Angiogeneis, Invasion And Metastasis Flashcards
What are characteristics of malignant tumours?
Growth
- unlimited growth as long as there’s a adequate blood supply is availability
Invasiveness
- migrational of tumour cells into surrounding stroma where they are free to disseminate
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
- Transformation
- extensive mutagenic and epigenetic changes followed by clonal selection - Angiogenesis
- new blood vessel formation - Motility and invasion
- epithelial to mesenchymal transition (invasive properties and extravasation from circulation to tissues) - Metastasis
- colonisation of target organs (ability to expand from micro metastases)
What is angiogenesis?
Formation of new blood vessels from pre existing vessels
What is vasculogenesis?
Formation of new blood vessels from progenitor cells
What are the 3 types of angiogenesis?
Developmental/vasculogenesis
- organ growth
Normal angiogenesis
- wound repair
- placenta during pregnancy
- cycling ovary
Pathological angiogenesis
- Tumour angiogenesis
- inflammatory disorders
What are the three stages of angiogenesis?
- Small tumour eventually gets large enough size where 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 increasing the delivery of oxygen and nutrients that allows it to grow and provides routes for cells to shed off and spread.
What is tumour hypoxia?
Hypoxia is a strong stimulus for tumour angiogenesis
Hypoxia is low oxygen tension < 1% and Increases with increasing distance from capillaries
This activates transcription of genes involves d in angiogenesis, tumour cell migration and metastasis
What are the genes activated as a result of tumour hypoxia?
VEGF (vascular endothelial growth factor)
GLUT-1 (glucose transporter 1)
u-PAR (urokinase plasminogen activator receptor)
PAI-1 (plasminogen activator inhibitor 1)
What are some examples of angiogenic factors?
VEGF (vascular endothelial growth factor)
FGF 2 (fibroblast growth factor 2)
PIGF (placental growth factor)
Ang 2 (Angiopoietin)
What is the function of angiogenic factors?
To stimulate the directional growth of epithelial cells
They are stored and bound to components of the extracellular matrix and may be released by matrix mtelloproteinases
Eg. Matrix metalloproteinase 2 (MMP-2)
Describe the VEGF signalling pathway
- VEGF binds to VEGF receptor 2 on endothelial cells
- The complex dimerises at the plasma membrane and recruits co factors
- That subsequently activate 3 major signal transduction pathways
- cell survival (PKB)
- gene expression (Ras and Raf)
- cell proliferation (PIP2 and DAG, IP3) - All of these pathways are essential for angiogenesis
What are the 3 mechanisms of timeout cell motility and invasion?
Increased mechanical pressure caused by rapid cellular proliferation
Increased motility of the malignant cells
Increased production of degradative enzymes by both tumour cells and strolls cells
What is lost during epithelial-mesenchymal transition (EMT)?
Epithelial shape and polarity is lost
Cyokeratin intermediate filament expression is lost
Epithelial adherents junction protein is lost
What is acquired in epithelial mesenchymal transition (EMT)?
Fibroblast like shape and motility
Invasiveness
Vimentin intermediate filament expression
Mesenchymal gene expression
Protease secretion
What are epithelial markers?
E-cadherin
Beta-catenin
Claudia-1
What are mesenchymal markers?
N-cadherin
Vimentin
Fibronectin
What are E cadherins in epithelial molecules?
Homotypic adhesion molecule (connects epithelial cells together)
Calcium-dependent
Inhibits invasiveness
Binds beta catenin
Without E cadherins cells would grow on top of eachother instead of being a mono layer of normal cells and cells become more motile.
How do stromal cells contribute to tumour formation?
Factors released by stromal cells include angiogenic factors, growth factors, cytokines, proteases
Eg. uPA release by stromal cells bind to receptors on cancer cells and become activated.
Resulting in plasmin production.
Plasmin activates MMPs which permit invasion by degrading the extracellular matrix and releasing angiogenic factors.
Plasmin also activates growth factors
What are the steps involved in cancer dissemination?
Primary tumour formation
Localisation invasion
Intravasation
Transport through circulation
Arrest in microvessels of various organs
Extravasation
Formation of a micro metastasis
Colonisation - formation of a macro metastasis
What are the two hypothesis to determining the pattern of tumour spread?
Mechanical hypothesis
Seed and soil hypothesis
What is the mechanical hypothesis?
Anatomical considerations: Blood and lymphatic systems, entrapment in capillary beds
What is the 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
What is the success rates of targeting tumour angiogenesis to inhibit cancer?
Success with targeted therapy to angiogenic factors like vascular endothelial growth factor
What is the success rates of targeting cell motility to inhibit cancer?
No success with targeting cell-cell adhesion molecules
What is the success rates of targeting invasion to inhibit cancer?
All clinical trials with matrix metalloproteinases have been unsuccessful in reducing tumour burden
What is Avastin?
First specific anti angiogenesis drug
Approved for colorectal, lung, kidney and ovarian cancers and eye disease.
It’s a monoclonal antibody
Describe the mechanism of action of Avastin
- Binds to VEGF
- Prevents VEGF binding to VEGF receptors on endothelial cells
- VEGF signal transmission inhibition (survival, angiogenesis, progression, metastasis)
