082614 tumor angiogenesis Flashcards
vasculogenesis vs angiogenesis
vasculogenesis is when precursors of endothelial cells differentiate, mobilizing cells from bone marrow
angiogenesis is when there’s sprouting from existing vasculature (as in wound healing)
role of tip and stalk cells in angiogenesis
tip cell will lead the formation of new vessel, whereas stalk cells will follow the tip cells and proliferate after it
angiogenesis process
growth factors need be present. then ECM of blood vessel needs to degrade. then endothelial cel (tip cell) needs to cut off contact with nearby cells and change polarity, then stalk cells need to replicate following path paved by tip cells
on an adjacent vessel, a tip cell needs to do the same process and somewhere in between these two newly created vessels will forge
what causes angiogenesis to be initiated in cancer?
hypoxia-causes cascade–master transcriptional factor HIF1alpha (normally degraded) is stabilized and dimerizes with HIF-1beta, both go to nucleus to cause transcription of VEGF—>induces surrounding endothelial cells to proliferate
tumor vasculature vs normal vasculature?
tumor vasculature is tortuous and chaotic
tumor secretes more growth factors than normal endothelial cells so creates hyperactivated state and these growth factors will induce leakage of blood components-tumor vessels don’t have pericytes along ENTIRE length of vessel. so there’s holes that can leak out contents or for metastasis to occur
what are lymphatics in tumor beds like?
they don’t work very well so they are enlarged, so it is a large presence in the tumor–means you can’t introduce drugs into the tumor core due to the pressure
what is the angiogenic switch?
MMP-9 protein, which is secreted by mast cells and macrophages, which are activated to secrete it by the bone marrow
MMP-9 will enable VEGF to be un-sequestered and be active
another possible angiogenic switch?
activators (like VEGFs) and inhibitors (like angiostatin, collagen IV) in the matrix–they are originally part of bigger fragments but when they are cleaved into their component parts, they become active–at that point then, it is a balance btwn activators and inhibitors
VEGF’s role in angiogenesis
it is a potent permeability factor that makes vessels incredibly leaky, also (for VEGFR2) has multiple residues in tyrosine kinase receptor that do multiple diff things
VEGFR3
primarily involved in lymphatics–lymphangiogenesis
VEGFR1
poorly studied
Notch protein role in angiogenesis
it, when cleaved, will have fragment that activates gene expression for cell to cell communication
anti angiogenic strategies
relieving the pressure from lymphatics
block lymphatics and prevent tumor from getting out
prevent recruitment of fibroblasts
target VEGF
inhibit bone marrow involvement in vasculogenesis
inhibit stromal cells to improve drug delivery
strategies to target VEGF
soluble VEGF receptors
anti-BEGF antibodies
small molecule VEGF receptor inhibitors
anti-angiogenic therapy had limitations how?
resistance mechanisms
