Tumour Angiogenesis, Invasion & Metastasis Flashcards
State the 3 major characteristics of malignant tumours
- Growth
- Invasiveness
- Metastasis
Describe the 3 major characteristics of malignant tumours
- Growth: Unlimited (not self-limited like benign T) - only if there is adequate blood supply
- Invasive: Migration of tumour cells into surrounding stroma - free to disseminate via vascular or lymphatic channels to distant organs
- Metastasis: Spread of tumour cells from the primary site - secondary tumours formed at other sites in the body
State the 4 key steps involved in cancer progression?
- Transformation: extensive mutagenic + epigenetic changes followed by clonal selection
- Angiogenesis: new blood vessel formation
- Motility and invasion: Epithelial to mesenchymal transition, invasive properties allowing intravation into circulation and extravation from circulation to tissues
- Metastasis: Colonisation of target organs, gives ability to expand from micrometastases
Define angiogenesis
Formation of new blood vessels from pre- existing vessels
Define vasculogenesis
Formation of new blood vessels from progenitors
State the 3 types of angiogenesis and their function?
- Developmental vasculogesis: Organ growth
- Normal Angiogenesis: wound repair, placenta during pregnancy, cycling ovary
- Pathological Angiogenesis: Tumour A ocular (eye) + inflammatory disorder
Describe the neovascularization of tumours?
- Natural formation of new blood vessels
- Infiltrate into tumour tissue
- Tumours won’t grow beyond a size of 1-2 mm3 without own blood supply
- So for context - There are three different pathways that comprise neovascularization: (1) vasculogenesis, (2) angiogenesis, and (3) arteriogenesis. [2]
Describe the process behind tumour angiogenesis?
- Small tumour grows to 1-2mm^3 when delivery of oxygen + nutrients from nearby capillaries becomes limiting (hypoxia) -> Tumour switches on expression of angiogenic genes/factors that initiate new blood vessel growth -> New network of blood vessels grows in + around the tumour (TA) -> the delivery of oxygen + nutrients -> increase growth + provides a route for cells to shed off & spread
Describe features of tumour hypoxia and what it activates?
- Low 02 tension < 1% -> Strong stimulus for tumour angiogenesis -> Increase distance from capillaries -> increase in Tumour hypoxia
- Activates transcription of genes involved in angiogenesis, tumour cell migration + metastasis
State what 4 Angiogenesis genes can be activated from tumour hypoxia?** check over
- Vascular endothelial growth factor
- Glucose transporter 1
- Urokinase plasminogen activator receptor
- Plasminogen activator inhibitor 1
State angiogenic factors that have a role aside from forming new blood vessels and describe how these factors are secreted?
- stimulate the directional growth of endothelial cells
- Vascular Endothelial Growth Factor, Fibroblast Growth Factor 2, Placental growth factor + Angiopoietin 2
- Factors are secreted by tumour cells or stored bound to components of the extracellular matrix + released via Matrix metalloproteinase 2 enzyme
Describe the Vascular endothelial growth factor (VEG) signalling pathway?
- VEGF binds to VEGF-R2 on endothelial cells
- VEGF/VEGF-R2 dimerizes at the plasma membrane + recruits cofactors
- Activate 3 major signal transduction pathways - cell survival, vascular permeability, gene expression + cell proliferation
- Required for angiogenesis
Describe the 3 functions of mechanisms of tumour cell motility and invasion?
- Mechanical pressure caused by rapid cellular proliferation
- Motility of the malignant cells (epithelial to mesenchymal transition)
- Production of degradative enzymes by both tumour cells and stromal cells
Describe the epithelial-mesenchymal transition mechanism?
- Transition of polarised epithelial cells via upregulaiton of marker genes to mesenchymal cells
- Epithelial P -> Loss of -> Epithelial shape and cell polarity (3-catenin, claudin-1), Cytokeratin intermediate filament expression + Epithelial adherens junction protein (E-cadherin) -> Acquisition of -> Fibroblast-like shape and motility, Invasiveness (gaps formed), Vimentin intermediate filament expression, Mesenchymal gene expression (fibronectin, PDGF receptor, avß6 integrin) + Protease secretion (MMP-2, MMP-9) -> M phenotype
Describe the role of E-cadherins in epithelial cells?
- Epithelial marker
- Homotypic adhesion molecule (adhesion of cells with the same cadherin)
- Calcium-dependent
- Inhibits invasiveness + Binds B-catenin
- Allows for cell-cell adhesion (^ density) + contact inhibition (monoloayer of cells formed)
Describe the contribution of stromal cells in tumour progression
Factors released by stromal cells (macrophages, mast cells, fibroblasts) include angiogenic factors, growth factors, cytokines, proteases
Describe the contribution of stromal cells in tumour progression and describe an example involved?
Urokinase-type plasminogen activator
- Activated by tumour cells
- Causes plasmin production
- Plasmin activates matrix metalloproteinases (MMPs)
- Allows invasion by degrading extracellular matrix (ECM) + releasing matrix- bound angiogenic factors such as transforming growth factor-B1.
Describe the steps involved in cancer dissemination from the point of primary tumour formation
- Primary tumour formation -> localized invasion -> Intravasation -> transport through circulation -> arrests in microvessels of various organs - extravasation -> formation of micrometastasis -› colonization (macrometastasis formation)
Describe the efficiency of the process?
- 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).
Describe 1 hypothesis that determine the pattern of tumour spread?
- Mechanical Hypothesis -> Anatomical considerations -> Blood and lymphatic systems, entrapment in capillary beds (20-30mm carcinoma cell, 8 Um capillary) + organs close by
Describe the other hypothesis that determine the pattern of tumour spread?
- 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 components of tumour angiogenesis, motility + invasion can be targeted to inhibit cancer and describe them?
- Only Tumour angiogenesis
- Success with targeted therapy to angiogenic factors like vascular endothelial growth factor
Name an anti-angiogenesis drug and its mechanism of action?
- Avastin
- monoclonal AB -> Binds VEGF -> prevents VEG binding to
VEG receptors on endothelial cells
