Tumour Angiogenesis, Invasion & Metastasis Flashcards
What are the 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
What are the key steps in cancer progression?
Transformation: extensive mutagenic and epigenetic changes followed by clonal selection Angiogenesis: new blood vessel formation (overcomes limitations imposed by hypoxia) Motility and invasion: epithelial to mesenchymal transition (invasive properties allowing intravasation into circulation and extravasation from circulation to tissues) Metastasis: colonisation of target organs (ability to expand from micrometatases) starts with a healthy cell having acquired oncogenes or lost tumour suppressor genes! then that ‘unhealthy’ cell starts to build up in numbers/clones. Then it becomes limited in terms of oxygen etc so the formed tumour switches on the process of angiogenesis. A nearby capillary (to the tumour) sprouts out new vessels towards the tumour which gives it access to more nutrients and therefore can expand further. Tumour acquires new blood vessel network and evade into the circulation, arrest in different capillary beds as the tumour spreads (colonisation)
What is the definition of angiogenesis and vasculogenesis?
Angiogenesis is the formation of new blood vessels from pre-existing vessels Vasculogenesis is the formation of new blood vessels from progenitors
What are the different types of angiogenesis and what do they lead to the formation of?
1.Developmental/ vasculogenesis…. leads to organ growth 2.Normal angiogenesis…….Wound repair placenta during pregnancy, ovarian cycles 3.Pathological angiogenesis Tumour angiogenesis ocular and inflammatory disorders (Tumours will generally not grow beyond a size of about 1-2 mm3 without their own blood supply)
Summarise Angiogenesis process
Small tumour eventually gets to a large enough size when 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 (tumour angiogenesis) increasing the delivery of oxygen and nutrients that allows it to increase growth and provides a route for cells to shed off and spread
What does tumour hypoxia act as?
Hypoxia is a strong stimulus for tumour angiogenesis Hypoxia – low oxygen tension <1% O2 Increases with increasing distance from capillaries Activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis Some tumour cells produce factors that stimulate the directional growth of endothelial cells: Vascular Endothelial Growth Factor (VEGF) Fibroblast Growth Factor 2 (FGF 2) Placental growth factor (PlGF) Angiopoietin 2 (Ang 2) These factors are secreted by tumour cells or are stored bound to components of the extracellular matrix and may be released by enzymes called matrix metalloproteinases: Matrix metalloproteinase 2 (MMP-2)
How does VEGF signalling work? (+image summarising effects)
(VEGF (and Ang-2) are examples of factors that get released by the tumour and bind to receptors attached on endothelial cells) VEGF: VEGF binds to VEGF-R2 (has many receptors but R2 is an example main one) on endothelial cells VEGF/VEGF-R2 dimerizes at the plasma membrane and recruits cofactors that subsequently activate 3 major signal transduction pathways Ultimately, VEGF activates cell survival, vascular permeability, gene expression and cell proliferation All of these pathways are essential for angiogenesis
VEGF is a growth factor with tyrosine kinase activity that then activates 3 downstream pathways that are vital for increased cell growth, proliferation, survival etc that can ultimatley lead to angiogenesis
What are some mechanisms involved in tumour cell motility and invasion?
- Increased mechanical pressure caused by rapid cellular proliferation
- Increased motility of the malignant cells (epithelial to mesenchymal transition) (EMT)
- Increased production of degradative enzymes by both tumour cells and stromal cells
What is Epithelial-Mesenchymal Transition (EMT)?
It is a phenotypic switch of the cells
It includes the loss of:
Epithelial shape and cell polarity (β-catenin, claudin-1- downregulation in proteins maintaining epithelial cells)
Cytokeratin intermediate filament expression
Epithelial adherens junction protein (E-cadherin)
It includes the 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)
What do E-cadherins do?
- Homotypic adhesion molecule (adhesion of cells with the same cadherin)
- Calcium-dependent
- Inhibits invasiveness
- Binds β-catenin
A loss/mutation in E-cadherin can lead to disrupted cell-cell adhesion and loss of contact inhibition so cells end up growing on top of each other
How can stromal cells contribute to the progression of tumours?
Factors released by stromal cells (macrophages, mast cells, fibroblasts) include angiogenic factors, growth factors, cytokines, proteases
Example: Urokinase-type plasminogen activator (uPA); activated by tumour cells - resulting in plasmin production
Plasmin activates matrix metalloproteinases (MMPs), which permit invasion by degrading extracellular matrix (ECM) and releasing matrix-bound angiogenic factors such as transforming growth factor-β1 (TGF-β1)
What steps are involved in cancer dissemination? (image)
The overall process is highly inefficient:
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)
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
What is Avastin? Who developed it?
ØFirst specific anti-angiogenesis drug
Øin 2013 was the second biggest selling oncology product
ØApproved for colorectal, lung, kidney and ovarian cancers and eye diseases
Napoleone Ferrara who developed the drug at Genentech, California won both the Lasker prize in 2010 and the $3 million Breakthrough Prize in Life Sciences in 2013
Avastin:
Ømonoclonal antibody
Øbinds to VEGF
Øprevents VEGF binding to VEGF receptors on endothelial cells
so essentially stops tumour growing/spreading/ get a decrease in angiogenesis
