Tumour Angiogenesis, Invasion And Metastasis Flashcards
What are the characteristics of malignant tumours?
Growth
Invasiveness
Metastasis
What is the growth potential of a malignant tumour?
Unlimited as long as adequate blood supply is available
What is the invasiveness characteristic of a malignant tumour?
Migration of tumour cells into the surrounding stroma where they disseminate
What is the metastatic characteristic of a malignant tumour?
Spread of tumour cells from the primary site to form secondary tumours at other sites in the body
What are the key steps in cancer progression?
Transformation
Angiogenesis
Motility and invasion
Metastasis
What is transformation of a cancer?
Extensive mutagenic and epigenetic changes followed by clonal selection
What is angiogenesis?
New blood vessel formation from pre-existing vessels
What is vasculogenesis?
Formation of new blood vessels from progenitors
What are the types of angiogenesis?
Developmental (vasculogenesis)
Normal angiogenesis
Pathological angiogenesis
What is pathological angiogenesis?
Tumour angiogenesis
Seen in ocular and inflammatory disorders
When does normal angiogenesis occur?
Wound repair
Placenta furing pregnancy
Cycling ovary
What is the max. Size of a tumour without their own blood supply?
1-2mm^3 without their own organ blood supply
What are the steps in tumour angiogenesis?
Small tumour gets big enough to need its own blood supply
Tumour switches on expression of angiogenic genes/factors
New blood vessels grow in and around the tumour, increasing the delivery of oxygen
What is a strong stimulus for tumour angiogenesis?
Hypoxia
What genes are involved in angiogenesis?
Vascular endothelial growth
Glucose transporter 1
Urokinase plasminogen activator receptor
Plasminogen activator inhibitor 1
What does plasminogen activator 1 cause?
Invasion and metastasis
What factors stimulate the directional growth of endothelial cells (angiogenic factors)?
Vascular endothelial growth factor
Fibroblast growth factor 2
Placental growth factor
Angiopoietin 2
What are the angiogenic factors secreted by?
Tumour cells or components of the extracellular matrix
What does VEGF do?
activates cell survival, vascular permeability, gene expression and cell proliferation
What do you loose in the epithelial-mesenchymal transition?
Epithelial shape and polarity
Cytokeratin intermediate filament expression
Epithelial adherens junction position
What do you gain in the epithelial-mesenchymal transition?
Fibroblast-like shape and motility Invasiveness Vimentin intermediate filament expression Mesenchymal gene expression Protease secretion
What proteases are secreted in the epithelial-mesenchymal transition?
MMP-2 and MMP-9
What causes the loss of epithelial shape and cell polarity in the epithelial-mesenchymal transition?
Beta-catenin and cloudin-1
What causes the loss of epithelial adherens junction position in the epithelial-mesenchymal transition?
E-cadherin
What increases the gain of mesenchymal gene expression in the epithelial-mesenchymal transition?
Fibronectin, PDGF receptor, alpha 5 beta 6 integrin
What are E-cadherins?
Homotypic adhesion molecules
What are E-cadherins dependant on?
Calcium
What do E-cadherins inhibit?
Invasiveness
What does E-cadherin bind to?
Beta-katenin
What is contact inhibition?
Once cells have bound to other cells with the same cadherin, it signals for them not to migrate or proliferate
What forms a tumour mass?
When E-cadherin is lost in tumours, so you loose contact inhibition and cells grow on top of each other and proliferate
What factors are released by stromal cells?
Angiogenic factors, growth factors, cytokines and proteases
What does the tumour activation of urokinase-type plasminogen activator result in?
Plasmin production
What does plasmin activate?
Matrix metalloproteases
What do matrix metalloproteases do?
degrade extracellular matrix
release matrix-bound angiogenic factors
Which allows invasion
What is an example of a matrix bound angiogenic factor?
Transforming growth factor-beta1
What are the common sites of metastasis for breast cancer?
Lung
Liver
Brain
Bone
What are the hypotheses for pattern of tumour spread?
Mechanical hypothesis
Seed and soil hypothesis
Genetic alterations acquired during disease progression
What is the mechanical hypothesis for tumour spread?
Anatomical considerations like blood and lymphatic systems and entrapment in capillary beds
What is the seed and soil hypothesis for tumour spread?
Specific adhesions between tumour cells and endothelial cells in the target organ, creating a favourable environment in the target organ for colonisation
What tumour processes can be targeted to inhibit cancer?
Tumour angiogenesis
Cell motility
Invasion
What is avastin?
Monoclonal antibody drug that targets anti-angiogenesis
What types of cancer is avastin approved for?
Colorectal, lung, kidney, ovarian
How does avastin work?
Binds to VEGF and prevents it from binding to VEGF receptors on endothelial cells
What are the common sites of metastasis for breast cancer?
Lung
Liver
Brain
Bone
What are the common sites of metastasis for colorectal cancer?
Liver
lung
What are the common sites of metastasis for stomach cancer?
Oesophagus
Liver
Lung
What are the common sites of metastasis for lung cancer (non small-cell)?
Adrenal gland
Liver
Bone
Brain
What are the common sites of metastasis for pancreatic cancer?
Liver
Lung
What are the common sites of metastasis for prostate cancer?
Bone
