Angiogenesis Flashcards
What is angiogenesis?
Formation of new blood vessels
What is angiogenesis controlled by? Name examples
controlled by chemical signal
-VEGF
Name 6 types of alternative vessel recruitment
- sprouting angiogensis
- vasculogenesis
- intussusception
- vessel co-option
- vasculkar mimicry
- tumor stem cell to ec differentiation
How does vessel intussusception work?
splitting of pre-existing vessels
how does vessel co-option work?
cancer cells grow around and co-opt existing vasculature
How does vascular mimicry work?
cancer cells get incorporated into the blood vessel wall
Name the 7 steps of tumor angiogenesis (sprouting)
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- hypoxia
- ECM degradation
- tipp cell migration
- tube formation
- regulation of vessel size
- pericyte recruitment
- tumor angiogenesis
What is hypoxia? What is affected by it?
physiological state characterized by decreased oxygen levels in organs and tissues –>
O2 concentration <= 2 %
–>cell proliferation, differentiation, metabolism and pH homeostasis affected
Why is tumor growth restricted at 1-2 mm3? What is the work around?
Metabolic demands are restricted due to the diffusion limit of oxygen and nutrients –> alteration of the cancer metabolism to support continous growth
How can proliferation and apoptosis be studied in cell culture?
use of Spheroids
Which cellular system increases oxygen level in the cell
Hypoxia induciblke factor (HIF)
What role does HIF play in tumor?
- promotes EMT
- ECM changes: remodelling and angiogenesis induction
- metabolic changes/tumor growth; anaerobic pathway, pentose phosphat pathway
- cancer stem cells dedifferentiate, self-renew and surve/are immortalized
How is HIF regulated?
by O2 concentration
O2 normal = HIF degradation
O2 low (hypoxia) = work as Transcription factors –> gene expression (e.g VEGF)
What is the role of VEGF?
-transcription activated by HIF
-stimulate cellular responses by binding to VEGF-Receptor on cell surface
-involved in vasculogenesis and angiogenesis
What type of receptor is the VEGF-Receptor?
Tyrosine kinase
What are tipp cells? What are they activated by?
endothelial cells that spearhead the vascular sprouts activated by VEGF
What are tipp cells required for?
to create new connections between different sprouts to generate an interconnected and functioanl vascular network
What is the role of the ECM and how is it degraded?
ECM supports adhesion of cells and transmits signals through cell-surface adhesion receptors
Matrix-Metalloproteases are endopeptidases that degrade ECM
What is required for tipp cell formation?
-VEGF
-pericyte detachment
-ECM remodelling
-Loosening of junctions
What are pericytes?
multi-functional cells of the microcirculation that wrap around the endothelial cells
What are the functions of pericytes?
-regulation of blood flow
-angiogenesis
-structural stabilization
-vascular permeability
What is necessary for pericyte detachment?
-pro-angiogenic factors (VEGF and Ang2)
-PDGF for activation and recruitment of pericytes
-vascular growth factors (Ang) –> ligate to endothelial cell tyrosine kinase receptor Tie2
what are stalk cells?
cell that follows the tipp cells
What is the function of stalk cells?
ensure trhe stability of new sprout and form the nascent vascular lumen
What are the characteristics of stalk cells?
-produce fewer filopodia
-highly proliferative
-establish adherent and tight junctions
How do tipp and stalk cell communicate?
-tipp cell express DLL4 –> bind to Notch on follower stalk cell
-Notch is cleaved in stalk cells –> VEGFR2/3 expression decreased and VEGFR1 expression increased
-VEGFR is released by stalk cells and binds VEGF molecules to b ind VEGF signaling
-enhancement by Jag1 expression by stalk cells which negatively regulate Notch
Which gradient plays a role in tipp cell attraction?
VEGF gradient
What are endothelial progenitor cells?
subtype of stem cells which can differentiate into mature epithelial cells
How can endothelial progenitor cells be mobilized from bone marrow to peripheral blood in tumors?
tumor secreted cytokines
