Tumor Angiogenesis Flashcards
Define angiogenesis
The sprouting of vessels from established vasculature (sometimes referred to in the context of remodeling)
Define vasculogenesis
The de novo differentiation of precursor cells to differentiated endothelial cells and the assembly of them into vessels (often associated during embryonic development)
What are characteristics of abnormal vasculature?
- leaky blood vessels (tortuous and dilated)
- haphazard vessel interconnection pattern
- aberrant morphology of endothelial cell lining
- pericytes are loosely attached or absent
- basement membrane is thick, thin, or absent
**tumor vascular beds are highly unstructured and chaotic
What would be the benefit of halting tumor angiogenesis?
Would be able to keep the tumor dormant (cannot increase growth without angiogenic switch)
Define angiogenic switch
A discrete step in tumor development that can occur at different stages in the tumor progression pathway depending on the nature of the tumor and its microenvironment
**Not sure what triggers the switch… hypoxia maybe?
What maintains vessel growth homeostasis?
A balance betwee pro- and anti-angiogenic molecules
Give characteristics of a stalk cell
- Proliferate when stimulated with VEGF-A
- Form vascular lumen
- Establish firm adherens junctions (between cells)
- Deposit basement membrane
- Can be induced to become new tip cells
Give characteristics of a tip cell
- RARELY proliferates
- Single highly polarized endothelial cells
- Numerour actin rich filopodia protrusions
- Induced by VEGF-A (receptor on filopodia)
- Lacks vascular lumen
- Specialized for guided migration
What are the two main signaling pathways studied extensively in tip versus stalk cell specification?
VEGF and Notch signaling pathways
Describe the VEGF signaling pathway
VEGF binds one of many variations of the receptor (tyrosine kinase receptors) which trigger migration, proliferation, cell survival and vascular permeability of the endothelial cell
**neurophillins (e.g. NRP2) help the process
Describe the notch signaling pathway
Ligand binds the notch receptor, stimulating proteases which cleave off the “NICD”… The “Notch Intracellular Domain” translocates to the nucleus and influences transcription
**notch signaling mediates lateral inhibition (e.g. helps formation of arteries and veins in pairs)
What are the general steps to form a stable vessel?
- Select a tip cell (most VEGF, gradient downwards)
- Tip cell guidance and stalk elongation
- Sprout fusion and lumen formation -> perfusion
- Maturation and quiescence of phalanx cells
What is the idea of metronomic chemotherapy?
Give low dose (lower than maximum tolerable dose MTD) therapy each day without giving breaks
**often given with combinational attacks (e.g. anti-angiogenic, pro-apoptotic, etc)
What role do normal endothelial cells play in metronomic therapy?
They are partly responsible for the therapy’s effectiveness because of their ability to better recover under the metronomic schedule than the conventional chemo schedule
What is vessel normalization?
To correct the structure and function of tumor vessels we then are able to deliver drugs and perhaps even contain the tumor from spreading
What are the features of a tumor vascular bed?
- Spatial/temporal heterogeneity in tumor blood flow
- Pressure (tumor cells are tightly packed) compresses blood and lymph vessels -> impairs flow and therefore immune function
- Hypoxia renders tumor cells resistant to radiation and cytotoxic drugs
**All of these select for more malignant cells with increased metastatic potential
What is the “normalization window”
The narrow therapeutic dose and schedule that is right for each individual patient for vessel normalization therapy
How has wet-AMD benefitted from angiogenesis research?
It has been shown that wet age-related macular degeneration (AMD) benefits from blood vessel reduction accomplished by injection of anti-VEGF
