L23: Tumour Angiogenesis, Invasion & Metastasis Flashcards
What are the characteristics of malignant tumours?
→growth
→invasiveness
→metastasis
What are the key steps in cancer progression?
→transformation
→angiogenesis
→motility and invasion
→metastasis
What happens in transformation in cancer progression?
→extensive mutagenic
→epigenetic changes
→clonal selection
What happens in angiogenesis of cancer progression?
→new blood vessel formation (overcomes limitations imposed by hypoxia
What happens in motility and invasion in cancer progression?
→epithelial to mesenchymal transition
What is metastasis?
→colonisation of target organs (ability to expand from micrometastases)
What is the difference between 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 three types of angiogenesis and what does each lead to?
→Developmental/ vasculogenesis= organ growth
→Normal
angiogenesis= wound repair, placenta
→Pathological angiogenesis= tumour angiogenesis
What is the maximum size of tumours without their own blood supply?
→1-2 mm3
Describe the angiogenic process
→Tumour switches on expression of angiogenic genes/factors
→they initiate new blood vessel growth
→New network of blood vessels grows in and around the tumour
→increasing the delivery of oxygen and nutrients
that allows it to increase growth
→provides a route for cells to shed off and spread
What allows directional growth of new vessels toward a tumour?
→Chemotaxis signals
What is a strong stimulus for tumour angiogenesis?
→hypoxia→
What is hypoxia?
→low oxygen tension <1% O2
What genes are activated by hypoxia?→
→VEGF
→GLUT-1
→u-PAR
→PAI-1
What are the 4 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
How are factors that stimulate directional growth of endothelial cells found in the cells?
→stored bound to components of the extracellular matrix
How are factors that stimulate directional growth of endothelial cells activated?
→Matrix metalloproteinase 2 (MMP-2)
What do matrix metalloproteinase?
→proliferation,
→migration
→invasion
Describe the signalling of Vascular endothelial growth factor
→VEGF binds to VEGF-R2 on endothelial cells
→VEGF/VEGF-R2 dimerizes at the plasma membrane and recruits cofactors
→subsequently activate 3 major signal transduction pathways
What are the pathways that VEGF activate?
→cell survival,
→vascular permeability,
→gene expression
→cell proliferation
What are the three 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 epithelial mesenchymal transition?
→ epithelial cells lose their cell polarity and cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells
What do epithelial cells lose in EMT and what do they lead to?
→β-catenin, claudin-1=Epithelial shape and cell polarity
→Cytokeratin intermediate filament expression
→E-cadherin= Epithelial adherens junction protein
What do epithelial cells acquire during EMT?
→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 are E-cadhedrins?
→Homotypic adhesion molecule (adhesion of cells with the same cadherin)
→Calcium-dependent
What is the function of E-cadherins?→
→Inhibits invasiveness
→Binds β-catenin
What does loss of E-cadherins lead to?
→disrupted cell-cell adhesion
→loss of contact inhibition
→cells grown on top of each other as opposed to a monolayer
What are some factors released by stromal cells?
→angiogenic factors,
→growth factors, cytokines,
→proteases
→u-PA
What is uPA?
→Urokinase-type plasminogen activator
→plasmin production
What roles does plasmin play in tumour progression?
→activates matrix metalloproteinases (MMPs),
→permit invasion by degrading extracellular matrix
→release matrix-bound angiogenic factors such as transforming growth factor-β1 (TGF-β1)
→ allows cells to migrate
What does uPA do to latent cancer cells?
→activates latent cancer cells
What is the different between intravasation and extravasation?
→intravasation= entry of tumor cells into the circulation
→extravasation= exit of tumor cells from the circulation
What are common sites of tumour metastasis for breast cancer?
→lung
→brain
→liver
→bone
What are common sites of tumour metastasis for lung cancer?
adrenal gland
What are common sites of tumour metastasis for gastric cancer?
→oesophagus
→stomach
What are common sites of tumour metastasis for prostate cancer?
→bone
What are the two hypotheses to explain the pattern of tumour spread?
→mechanical
→seed and soil
→Genetic alterations acquired during progression allow tumour cells to metastasize
What is the mechanical hypothesis of tumour spread pattern?
→metastasis is determined by the pattern of blood flow
→entrapment in capillary beds
Explain the seed and soil hypothesis of tumour spread pattern
→Specific adhesions between tumour cells and endothelial cells in the target organ create a favourable environment in the target organ for colonisation
What aspect of cancer progression has been successfully addressed?
→tumour angiogenesis
What types of cancer is Avastin used for?
→colorectal,
→lung, kidney
→ovarian cancersand eye diseases
Describe the mechanism of Avastin/ Bevacizumab
→a monoclonal antibody
→binds to VEGF
→prevents VEGF binding to VEGF receptors on endothelial cells
