Tumour Angiogenesis, Invasion & Metastasis Flashcards
Describe growth as a characteristic of malignant tumours
Growth
Unlimited growth (not self-limited as in benign tumours) - as long as an adequate blood supply is available
Describe invasiveness as a characteristic of malignant tumours
Invasiveness
Migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs
Describe metastasis as a characteristic of malignant tumours
Metastasis
Spread of tumour cells from the primary site to form secondary tumours at other sites in the body
Summarise the key steps in cancer progression
Extensive mutagenic and epigenetic changes followed by clonal selection
Angiogenesis (overcomes limitations imposed by hypoxia)
Epithelial to mesenchymal transition (invasive properties allowing intravasation and extravasation)
Colonisation of target organs (ability to expand from micrometastases)
Release of metastatic cells that have acquired the ability to colonise
What is angiogenesis
Angiogenesis is the formation of new blood vessels from pre-existing vessels
What is vasculogenesis
Vasculogenesis is the formation of new blood vessels from progenitors
List then describe effects of the types of angiogenesis
Developmental/ vasculogenesis = organ growth
Normal
angiogenesis = wound repair
placenta during pregnancy
cycling ovary
Pathological angiogenesis = tumour angiogenesis
ocular and
inflammatory disorders
Describe tumour size limit
Tumours will generally not grow beyond a size of about 1-2mm3 without their own blood supply
Describe the process of angiogenesis
Small tumour releases angiogenic factors
Which leads to a sprouting capillary which in turn leads to a growing tumour due to the release of nutrients from blood and metastatic spread through the tumour
Define tumour hypoxia
Hypoxia is a strong stimulus for tumour angiogenesis
Hypoxia – low oxygen tension <1% O2
Describe link between tumour hypoxia and distance from capillary
Increases with increasing distance from capillaries
Describe effect of tumour hypoxia
Activates transcription of genes involved in angiogenesis, tumour cell migration and metastasis
List 4 angiogenic factors
Some tumour cells produce factors that stimulate the directional growth of endothelial cells:
Vascular Endothelial Growth Factor (VEGF)
Fibroblast Growth Factor-2 (FGF-2)
Transforming Growth Factor-β (TGF- β)
Hepatocyte growth factor/scatter factor (HGF/SF)
Describe secretion of angiogenic factors
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
Describe mechanisms of tumour cell motility and invasion
Increased mechanical pressure caused by rapid cellular proliferation
Increased motility of the malignant cells (epithelial to mesenchymal transition)
Increased production of degradative enzymes by both tumour cells and stromal cells
What is lost in epithelial-mesenchymal transition
Loss of
Epithelial shape and cell polarity
Cytokeratin intermediate filament expression
Epithelial adherens junction protein (E-cadherin)
What is acquired in epithelial-mesenchymal transition
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)
Describe the use of E-cadherins
E-Cadherins:
Homotypic adhesion molecule (adhesion of cells with the same cadherin)
Calcium-dependent
Inhibits invasiveness
Binds β-catenin
Describe the use of integrins
Integrins Heterodimers (α and β subunits) Heterotypic adhesion molecule Adhesion to extracellular matrix (via collagen, fibronectin, laminin) Cell migration
Explain effect of factors released by stromal cells by giving an example
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
Explain effect of plasmin
Plasmin activates matrix metalloproteinases (MMPs), which permit invasion by degrading extracellular matrix (ECM) thus releasing matrix-bound angiogenic factors
Describe cancer dissemination
Primary tumour formation → localized invasion → intravasation (interaction w/platelets, lymphocytes + other blood components) → transport through circulation → arrest in microvessels of various organs → extravasion → formation of metastasis →colonization - formation of macrometastasis
List sites of tumour metastasis
Breast Colorectal Gastric Lung (non-small cell) Pancreatic cell Prostate
Describe mechanical hypothesis
The ‘mechanical’ hypothesis states that metastasis is likely to occur at sites based on the pattern of blood flow
Anatomical considerations: Blood and lymphatic systems, entrapment in capillary beds (20-30µm carcinoma cell, ~8µm capillary)
Describe 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
The seed and soil hypothesis states that metastatic tumor cells will metastasize to a site where the local microenvironment is favorable
Describe the success in targeting tumour angiogenesis to inhibit cancer
Tumour angiogenesis
Success with targeted therapy to angiogenic factors like vascular endothelial growth factor
Describe the success in targeting cell motility to inhibit cancer
Cell motility
No success with targeting cell-cell adhesion molecules or integrins
Describe the success in targeting invasion to inhibit cancer
Invasion
All clinical trials with matrix metalloproteinases have been unsuccessful in reducing tumour burden!
Describe folmans’s work in the angiogenesis hypothesis
1971 – Angiogenesis hypothesis
Tumour growth dependent on new blood vessel growth
“If a tumor could be held indefinitely in the non-vascularized dormant state….it is possible that metastases will not arise”
Paradigm shift in cancer therapy
- Both the tumour and microvascular compartment are valid therapeutic targets
What is avastin - used for what?
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
Describe avastin’s mechanism
A monoclonal antibody
Which binds to VEGF
Prevents VEGF binding to VEGF receptors on endothelial cells
Leads to VEGF-signal transmission inhibition
= so no angiogenesis, progression, metastasis or survival
