Chapter 12 Flashcards
Define angiogenesis
The growth of new vessels from larger pre-existing vessels. It plays an nb role in cancer progression.
What is the precursor cells of the endothelial cell?
Hemangioblasts.
Define vasculogenesis (different than angiogenesis)
de novo formation of a primitive vascular network.
Name and describe the 4 steps of angiogenesis
1) vasodilation and vascular permeability.
occurs primarily in response to NO which upregulates VEGF. Increased vascular permeability leads to plasma proteins leaving the vessels to lay a new matrix on which the endothelial cells can sprout and spread on to.
2) basement membrane degradation.
needed for cells to migrate into extracellular space. MMPs are nb in this step, also for release of GFs from the ECM, such as bFGF, VEGF and IGF-1.
3) endothelial cell proliferation and migration.
tubules first form as cords lacking a lumen. Then VEGF and angiopoietins are nb for lumen formation, support cell recruitment and vessel formation. TSP-1 inhibits lumen formation.
4) support cell recruitment and vessel fusion.
mature bvs require recruitment of support cells such as pericytes and smooth m cells (for small and large vessels respectively). Final stages of new capillary growth where vessels fuse to form closed loops and deliver circulation to newly vascularized areas (this latter part is poorly understood).
What % of endothelial cells in the normal adult are undergoing cell %? (1%, 0.1%, 0.01%)
Name 2 tissue states and 1 normal organ in which angiogenesis is commonly found.
0.01%
Female repro organs. Wound healing, growing tissues
What 2 growth factors are very important in wound healing? Hypoxia leads to increased expression of _____.
FGF 1 and 2
VEGF
Describe alpha V beta 3.
Specifically what type of molecule is it?
What is its role in angiogenesis?
Its an integrin.
Nb for allowing endothelial cell migration into fibrin/fibrinogen clot
There are ___ members of the VEGF family whose effects are primarily mediated by ___ different receptors. List which ligands bind which receptor.
5
A - binds 1 + 2 + heparin sulfate prots of ECM B - binds 1 + neuropilin-1 C - mostly 3 but also 2 D - 2 + 3 E - 2
Name the VEGF receptors and their alternate names.
What type of receptor are they?
Where are they normally expressed?
VEGFR-1 (Flt-1)
VEGFR-2 (Flk-1)
VEGFR-3 (Flt-4)
Tyrosine kinases
VEGFR 1 and 2 - endothelial cells
VEGFR 3 - lymphatics
Describe angiopoietins - what is function, how many of them are there, etc?
What are their receptors?
A family of ligands for the Tie family of receptors. They are RTKs that are primarily expressed in endothelial cells altho they may also be found on endothelial precursor cells.
Ang 1-4 all bind to Tie 2 (not Tie 1)
The angiopoietins are not mitogenic but regulate other cell processes such as cell migration, cell survival and tubule formation
What type of receptors are ephrins? What is their normal function?
Ephrins = RTKs
Involved in the differentiation of venous vs arteriole development
At what distance from BVs can you find viable cells?
100-200 micrometers
Describe angiogenic switch?
disruption of the balance bt pro and anti-angiogenic factors can lead to the start of angiogenesis.
Describe tumor BVs. ie How doe they differ from normal bvs? Where do new cells for making tumor BVs come from?
tortuous, dilated, irregular shape
dead ended and leaky
tumor cells can be a part of the vessel wall
new cells can be recruited from endothelial precursors from bm
Name 3-5 GFs that upregulate angiogenesis.
VEGF bFGF IL-8 placental GF TGF-beta
Name 2-3 angiogenic inhibitors
TSP-1
maspin
INF-alpha
What role does Ras play in tumor angiogensis?
Elevated H-ras levels have been associated w/ increased angiogenesis by inhibiting TSP-1
Hypoxia increases expression of ____ and ____
VEGF and HIF1-alpha
What is the role of HIF1 alpha?
It is a transcription factor. Increases VEGF production.
What is the name of the BM progenitors that can act as precursors for endothelial cells?
Name 2 factors nb in mobilization of these an nb for making new vessels.
CEPs - circulating endothelial precursors
VEGF and MMP-9
Lymphatic vessels are lined by endothelial cells are are more/less leaky than BVs?
more
Which VEGF is nb for lymphatic development? What is its ligand?
VEGF-C (and D) and VEGFR-3
Name the 2 broad categories of angiogenesis inhibitors and how they inhibit angiogensis.
DIRECT - such as Vitaxin and Angiostatin inhibit endothelial cell function directly by preventing cell migration, proliferation or invasion of cell death.
INDIRECT - block expression or activity of tumor derived factors that are responsible for inducting an angiogenic response
Name 2 endogenous angiogenic inhibitors and where they come from (what is their precursor?).
ANGIOSTATIN from ECM (specifically plasminogen)
ENDOSTATIN from ECM (specifically from collagen type XVIII)
Others include PEX from MMP2
Describe the function of TSP-1.
How is it regulated (what up-regulates and what downregulates it?)
Inhibits MMP-9 (which releases VEGF from ECM)
Upregulated by tumor supressor p53 and PTEN
Downregulated by oncogenes such as ras, myc, src, jun
Name 3 pharmacologic inhibitors of angiogenesis and their MOA
Thalidomide - decreased bFGF, VEGF, TNF-alpha
Bevacizumab - small molecule inhibitor of VEGFR, PDGFR
IFNalpha - inhibits endothelial cell migration, downregulation of bFGF
Vitaxin - blocks endothelial cell adhesion and apoptosis
Batimastat/Marimastat - MMP inhibitors that block endothelial & tumor cell invasion.
What is metronomic therapy?
How is it administered and why?
Give examples of 2 drugs that have been used in this fashion.
Best to use antiangiogenic meds at low constant level w/o stopping to avoid a period of revascularization.
ex: cytoxan, velban
MMPs are increased/decreased in an aggressive tumor.
Natural MMP inhibitors are____.
Name at least 2 drugs developed to inhibit MMPs.
Increased
TIMPs
Marimastat/Batimastat
Integrins___ and ____ are nb in vessel development. One in particular is attractive in tumor treatment because _________.
What is the name of the drug that is a monoclonal aby that inhibits this integrin?
Alpha V beta 3
Alpha V beta 5
Increased expression on proliferating tumor vessels but decreased on normal resting endothelium
Vitaxin
What is Avastin?
Bevacizumab, mAb anti-VEGF
How does response to antiangiogenic tx vary from that seen in traditional chemo?
much slower response
What are some theoretical problems w/ tx w/ antiangiogenic medications?
Tumor cells increase apoptosis resistance bc of fewer BVs which leads to hypoxia leading to development of resistance to other treatments such as chemo or RT
Wound healing impairment
What is Endoglin?
Transmembrane endothelial receptor expressed in tumor associated angiogenic vascular endothelium and binds to TGF-beta
