Tumour angiogenesis invasion and metastasis Flashcards
What are the characteristics of malignant tumours?
→ 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 to overcome 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?
- Developmental/ vasculogenesis → leads to organ growth
- Normal angiogenesis → Wound repair placenta during pregnancy, ovarian cycles
- 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 – low oxygen tension <1% O2 Increases with increasing distance from capillaries
→ Hypoxia is a strong stimulus for tumour angiogenesis
→ 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:
1. Vascular Endothelial Growth Factor (VEGF)
2. Fibroblast Growth Factor 2 (FGF 2)
3. Placental growth factor (PlGF)
4. 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 ultimately 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?
→ 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
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:
→ monoclonal antibody
→ binds to VEGF
→ prevents VEGF binding to VEGF receptors on endothelial cells
so essentially stops tumour growing/spreading/ get a decrease in angiogenesis
