Tumour Angiogenesis, Invasion And Metastasis Flashcards
What are the characteristics of malignant tumours?
Unlimited growth as long as adequate blood supply available
Invasiveness - tumour cells migrate to surrounding stroma and move through vascular/lymphatic channels to distant organs
Metastasis - spread of secondary tumours from primary site
What are the stages in cancer progressions to metastasis?
Transformation - mutagenic and epigenetic changes followed by clonal selection
Angiogenesis - new blood vessel formation overcoming limitation of hypoxia
Motility and invasion - epithelial to mesenchymal transition
Metastasis - colonise target organs
define angiogenesis
Formation of new blood vessels from PRE-EXISTING BLOOD VESSELS
What is vascularogenesis?
Formation of new blood vessels from its progenitors
What are the types of angiogenesis?
Developmental vasculogenesis e.g. for organ growth
Normal angiogenesis e.g. for wound repair, placenta during pregnancy
Pathological angiogenesis - tumour angiogenesis, ocular and inflammatory disorders
How big can tumours grow without own blood supply (own vessles infiltrating tumour)
1-2 mm
Describe the stages and process of tumour angiogenesis?
Small tumour gets large enough when delivery of oxygen from nearby capillaries is limiting
Tumour switches on angiogenic genes to release angiogenic factors that initiate new blood vessel growth
New network of blood vessels grow in and around tumour increasing delivery of oxygen and nutrients
What functions do the new blood vessels in the tumour have?
Provide oxygen and nutrients fro growth
Provides route for cells to shed off and enter circulation to spread
What causes tumour angiogenesis (stimulus)?
Hypoxia
How does increasing tumour size affect hypoxia?
Cells in tumour further away from capillaries becomes hypoxic (further distance from capillaries increase hypoxia)
Which target genes are activated for tumour angiogenesis once hypoxia stimulus is detected? !!!
VEGF - vascular endothelial growth factor - most imp growth factor for new blood vessel formation as its a stimulus for endothelial migration
GLUT-1 - glucose transporter 1 - for glucose uptake
More involved in invasion and metastasis
u-PAR - urokinase plasminogen activator receptor
PAI-1 - plasminogen activator inhibitor 1
name a few angiogenic factors (not genes that code for them) secreted by the tumour that stimulate direction growth of endothelial cells? !!!!
VEGF - vascular endothelial growth facor
FGF 2 - fibroblast growth factor 2
PIGF - placental growth factor
Ang 2 - angiopoietin 2
Where do the angiogenic factors that are secreted go?
Stored in extracellular matrix and released by enzymes called matrix metalloproteinases (MATRIX METALLOPROTEINASE 2 - MMP-2)
Describe the VEGF signalling stages in detail?!
VEGF binds to VEGF R2 on endothelial cells
VEGF/VEGF R2 dimerises at plasma membrane which recruits cofactors that activate major signal transduction pathway
Cell survivial, vascular permeability, gene expression and cell proliferation all activated by VEGF - processes all part of angiogenesis
What do all the different factors released by tumours do?
Endothelial proliferation + migration (all angiogenic factors cause this), and invasion(MMP2 causes this) (done by diff factors)
What are the 3 mechanisms for tumour cell motility and invasion?
Increased mechanical pressure due to rapid cellular proliferation
Increased motility of malignant cells (from epithelial to mesenchymal tissues allows cells to now move)
Increased production of degradative enzymes by tumour and stromal cells
What do tumour cells lose(downregulate) in epithelial mesenchymal transition (EMT)?
Downregulate genes that make epithelial markers such as e cadherin, b catenin, claudin 1
ultimately causing loss of:
Epithelial shape and cell polarity (loss of b catetnin and claudin 1)
Cytokeratin intermediate filament expression (required for structure of epthelial cell shape)
Epithelila adherns junction protein (e cadherin)
What do tumour cells upregulate in epithelial mesenchymal transition (EMT)?
Upregulates mesenchymal markers (epithelial cells acquire mesenchymal characteristics allowing them to become motile)
What is EMT?
Phenotypic switch of cell
epithelial cells los epithelial markers and gain mesenchymal markers to become mesenchymal cells
What do tumour cells acquire during EMT?
Fibroblast shape and motility - long and elongated, can spread, invade and move
Invasiveness
Vimentin intermediate filament expression
Mesenchymal gene expression (fibronectin, PDGF receptor, avb6 integrin)
Protease secretion
What are the markers of mesenchymal cells
N-cadherin
Vimentin
Fibronectin
What are the markers of epithelial cells?
E cadherin
B caterin
Claudin 1
What is E cadherin and where is it found?
On epithelial cells and are homotypic adhesion molecules
Homotypic because dimerises and binds to other cells with same cadherin
What is he purpose of E cadherin?
Inhibit invasiveness by maintainig contact inhibition (monolayer or cells)
What is the structure of e cadherin?
Extracellular domain binds to other e -cadherin
Intracellular domain binds to b catenin allowing for polarity and structure
What happens if loss of e -cadherin or mutation in e-cadherin
Loss of contact inhibition so cells grown on top of each toher - disrupted cell adhesion
What is e cadherin dependent on?
Calcium dependent
What are stromal cells and what do they release?
Macrophages, mast cells, fibroblasts
Factors released by them include angiogenic factors. growth factors, cytokines and proteases
What is stromal cells contribution to tumour progression?
Factors released incease motility of cancer cells, mainly uPA angiogenic factor (urokinase type plasminogen activator). uPA binds to tumour cells to become activated and produces plasmin which is involved in cancer progression
What does plasmin released due to uPA activation do to cancer progresion?
Plasmic activates matric metalloproteinases (MMPs) which permit invasion by degrading extravellular matrix and releases matrix bound angiogenic factors such as transforming growth factor B1 (TGF-B1)
What are the steps in cancer dissemination?
Primary tumour formation Localised invasion Intravasation Transport into circulation Arrest in microvessles in various organs Extravasation Formation of micrometasis Colonisation and formation of macrometasis (with blood vessels for itself)
Which parts of cancer dissemination doesnt happen often?
Formation of micormetastasis and colonisation leading to macrometastasis doesnt even througb extravasation is really efficient
What determine the pattern fo tumour spread?
Mechanical hypothesis
Seed and soil hypothesis
Where does breast cancer metastasis?
Lung, liver, bone and brain
Where does colorectal cancer merastasis ?
Liver and lung
Where does gastric (stomach) cancer metastasis?
Esophagus, lung and liver
Where does prostate cancer metastasis
Bone
Where does pancreatic cancer metastasis?
Liver and lung
Where does lung (non small cell) metastasis?
Adrenal gland, liver and brain
What is mechanical hypothesis for pattern of tumour spread, why certain cancers spread to certain organs?
Anatomical - blood and lymphatic systems
What is seed and soil hypothesis for pattern of tumour spread, why certain cancers spread to certain organs?
Specific adhesions between tumour cells and endothelial cells of target organ creating favourable environment in target organ for colonisation
- tumour cells needs genetic alterations during progression to metastasis though
What parts of cancer progression can be targetted to inhibit cancer?
Tumour angiogenesis
- the tumour itself and the microvascular compartments !!!!!!
Not successful
- Cell motility
- Invasion
What is avastin?
First anti-angiogenesis drug
- approved for colorectal, lung, kidney and ovarian cancers and eye diseases
