Vascular Disease and Cancer Flashcards
Blood vessel components
endothelium
extracellular matrix layer
smooth muscle
nervous system connections
The vascular network
Made of veins, arteries and capillaries:
- Artery = high pressure (80-120mm Hg)
- Veins = low pressure (20-30mm Hg)
Blood vessel wall structure
Lumen –> endothelium –> elastica interna –> smooth muscle cells –> Adventitia
Vasculogenesis
Devloping new blood vessel networks:
1) Vascular stem cells (hemangioblasts) congregate
2) Develop networks that lay the foundations of new blood vessels
3) Outward sprouting = angiogenesis
4) Inward sprouting = intussusception
5) bridging within vessels
Angiogenesis
Sprouting new blood vessels from pre-existing ones using the VEGF-A growth factor
Role of endothelial cells in Angiogenesis
Angiogenesis is driven by endothelial-based proliferation, migration & movement (supported by other cell types like pericytes or smooth muscle)
- Directed angiogenesis by ‘Tip cells’ using projections to detect medium and lead new vessel growth
- Cells encounter different protein signalling molecules triggering vascular tube growth
Endothelial cell features
Unique cells displaying cell surface receptors to engage with growth factors
- cell adhesion
- respond to growth factors via cell surface receptors
Key functions of endothelial adhesion
- provides intercellular barrier
- regulates movement of molecules and cells
- barrier function helps regulate angiogenesis and vasculogenesis
Cancer’s interaction with vascular network
Cancers grow until it subverts nearby blood vessels
- allows for metastasis and forming secondary tumours
- increases nutrient supply to facilitate cancer growth
Cancer Immune Surveillance Evasion
New turmour cells form after ‘transformation’ events, when an impaired immune system allows the escape of cancer cells
- leads to cancer growth
- Increases secretion of pro-angiogenic growth factors (critical switch during hypoxia)
- angiogenesis and neovascularisation leads to metastasis
Hypoxia stimulating angiogenesis
Low O2 levels (hypoxia) = <5% O2 compared to tissues
1) Hypoxia Inducible Factor 1a is stabilised by hypoxia so it doesn’t get ubiquitinated and degraded
2) HIF1a gets translocated into the nucleus and binds with cofactors HIF1b and Cbp/p300
3) HIF1a complex acts as a transcription factor binding to hypoxia response elements (HRE) to promote VEGFA production/secretion
How VEGFA drives angiogenesis
VEGFA binds to VEGFR2 receptors on endothelial cell surface to trigger downstream signalling cascade that promote angiogenesis
- Target for treating epithelial cancer (Avastin, VEGF trap eye, Sutent)
Endothelial VEGF-binding membrane proteins
Receptor TKs:
- VEGFR1,2&3 (binding triggers kinase activation)
Non-RTK accessory receptors:
- Neuropilin-1&2 (may bind RTKs as secondary event)
Different outcomes of VEGF system depending on epithelial cell’s condition
If cells are engaged (high cell-cell contact)
- promotes cell survival
If cells are spaced (low cell-cell contact)
- promotes growth
Other receptor activation alter angiogenic signalling
- e.g. notch receptor activation = negative regulatory signal (anti-VEGF treatment)
The ‘Angiogenic Switch’ alters cellular metabolism
- promotes oxidative metabolism in oxygen-rich revascularised tissue
The Warburg Effect
Normal cells use oxidative phosphorylation to produce ATP from glucose metabolism
In cancer cells, aerobic glycolysis is used instead
- Less efficient
- Produces ATP quickly with less metabolic control needed
