angiogenesis – Flashcards
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| what is associated with the "bad" aspect of angiogenesis? |
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| neoplasm formation |
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| what is associated with the "good" aspect of angiogenesis? |
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| blood vessels providing growing organs with needed O2 and promoting organ morphogenesis |
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| what is an important link in terms of endothelial and blood cell origin and angiogeneisis? |
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| blood vessels derive from endothelial precursors which share an origin with hematopoietic precursors |
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| how does angiogenesis start? |
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| a laying down of primitive blood vessels that progress into fragile, immature capillaries and then arteries and veins |
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| how do blood vessels differentiate into arteries? |
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| arteries are endothelial cell channels that become covered by pericytes and smooth muscle cells that provide strength and regulation of vessel perfusion |
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| are BV usually dividing in adults? what kinds of stimuli are involved? |
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| no most BV in adults are quiescent in adulthood, and need to be stimulated to divide by things such injury (hypoxia/inflammation) or tumors secreting growth factor |
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| where do you see angiogenesis in the adult human? |
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| in the cycling ovary and placenta |
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| what happens if the stimulus for angiogenesis is excessive? |
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| angiogenesis can occur in malignant ocular (diabetic retinopathy) and inflammatory disorders |
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| what are the endothelial cell precursors involved in vasculogenesis? |
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| angioblasts form a primitive vascular network during embryonic development |
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| how does angiogenesis often happen in adults? |
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| BV formation in adults can be due to branching and extension of adjacent BV (parent BV), which then recruits endothelial progenitor cells from the bone marrow |
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| what is angiogenesis critical for? |
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| chronic inflammation, fibrosis, tumor growth and vasculization of ischemic tissue |
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| what are the 2 endothelial precursor cells involved in angiogenesis? |
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| hemangioblasts and angioblasts |
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| what do hemangioblasts do in terms of angiogenesis? |
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| hemangioblasts link hematopoietic and vascular systems during embryonic development by producing both hematopoietic stem cells and angioblasts, (more immature/primitive types of cells) |
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| what do angioblasts do in terms of angiogenesis? |
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| hemangioblasts make angioblasts that proliferate and migrate to peripheral sites, differentiating into endothelial cells that form arteries, veins, and lymphatics; as well as pericytes and smooth muscle cells, (more specialized cells) |
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| where are angioblasts stored, for how long? do they express markers? |
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| in adult bone marrow, until they are recruited to tissue to proliferate and initiate angiogenesis. they express markers for hematopoietic stem cells and endothelial specific markers. |
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| what processes do angioblasts usually participate in? |
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| replacement of lost endothelial cells, reendothelization of vascular implants, healing of cutaneous wounds and tumor formation |
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| what kinds of changes do you see with preexisting BV undergoing angiogenesis? |
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| vasodilation, increased vascular permeability, degradation of the ECM, which allows for the budding off and migration of endothelial cells |
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| what can stimulate angiogensis from preexisting BVs? |
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| vasodilation from nitric oxide and increases in vascular permeability due to VEGF (vascular endothelial growth factor) |
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| what do you see in early angiogensis from preexisting BVs? |
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| proteolytic degradation of the basement membrane and disruption of cell-cell contact between endothelial cells by the plasminogen activator. migration of endothelial cells toward the angiocentric stimulus and subsequent endothelial cell maturation |
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| what is the needs to happen keep vascular neoplasms from forming? |
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| inhibition of growth and remodeling into capilllary tubes |
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| what cells are recruited to support the endothelial tube and form the mature BV? |
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| periendothelial cells |
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| what is VEGF secreted by? what kind of receptor does bind to/where are its receptors? |
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| VEGF is secreted by mesenchymal and stromal cells. VEGFR-2 is a tyrosine kinase receptor present on both endothelial cells and their precursors. |
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| what is the action of VEGF/VEGFR-2 interaction on endothelial cell precursors? |
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| ECPs are stimulated to migrate from the bone marrow and increase proliferation of cells at sites of angiogenesis forming a delicate network that matures |
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| what growth factor enhances endothelial proliferation, differentiation and migration? (know for boards etc...) |
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| FGF-2 (fibroblast growth factor), which helps the process of angiogenesis from preexisting vessels along via stimulation of proliferation and mobilization of endothelial cells to sprout new capillaries |
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| secretion of what helps recruit what that stabilizes blood vessel formation? |
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| angiopoietins 1,2, PDGF, and TGF beta (transforming growth factor) participate in stabilization including recruitment of pericytes, smooth muscle cells and ECM disruption |
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| what does angiopoietin 1 do in term of angiogenesis? |
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| angiopoietin 1 interacts with a receptor on endothelial cells called Tie 2 which leads to recruitment of periendothelial cells |
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| what does PDGF do in term of angiogenesis? |
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| PDGF recruits smooth muscle cells |
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| what does TGF beta do in term of angiogenesis? |
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| helps stabilize newly formed BVs |
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| what does the interaction of Ang1/Tie2 do in term of angiogenesis? |
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| Ang1/Tie2 interaction mediates vessel maturation and maintains endothelial quiescence, (turns off proliferation in favor of maturation) |
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| what does the interaction of Ang2/Tie2 do in term of angiogenesis? |
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| Ang2/Tie2 loosens endothelial cells, making them more responsive to VEGF and inhibitors of angiogenesis, (2-fold role depending on what is needed at the time |
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| what do integrins do in terms of angiogenesis? |
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| integrins help form and maintain new blood vessels |
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| what does the process of angiogenesis require in terms of endothelial cells? |
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| mobility and migration |
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| what role do matricellular proteins play in extracellular matrix proliferation? |
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| matricellular proteins destabilize the cell matrix interaction and promote angiogenesis |
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| what role do proteinases play in extracellular matrix proliferation and what are some examples? can they secrete growth factors? |
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| plasminogen activator and metalloproteinases remodel tissues during endothelial invasion, also releasing VEGF and FGF-2 |
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| unless tumors are well vascularized, what diameter can they not grow past? |
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| 1-2mm |
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| what does perfusion supply in terms of tumor angiogenesis? how can newly formed endothelial cells stimulate the growth of adjacent tumor cells? |
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| perfusion supplies nutrient and O2 and newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors and PDGF |
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| what does angiogenesis allow in tumor formation? |
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| metastasis to highly vascular organs such as the liver/lungs |
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| how does increased VEGF affect tumors? |
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| tumor vessels are irregularly shaped and leak b/c of high VEGF. they may also grow continously. |
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| what do tumors have high serum+urine levels of in CA pts? |
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| VEGF and bFGF |
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| what is the angiogenic switch? what may it involve? what does treatment of the tumor before this allow? |
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| when cells in the tumor change to an angiogenic phenotype. it may involve increased production of angiogenic factors (VEGF)/loss of angiogenic inhibitors. treatment of the tumor before the angiogenic switch greatly increases the likelihood of pt survival |
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| what do tumors produce in terms of the angiogenic switch? |
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| tumors may produce anti angiogenic molecules to tip the balance of pro and antiangiogenic stimuli (angiostatin, endostatin, and tumstatin are produced in response to the tumor), in favor of angiogenesis -> increased tumor formation |
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| what kinds of things does VEGF stimulate via multiple downstream signaling pathways in endothelial cells? |
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| vasc. permability, endothelial cell survival, proliferation and migration |
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| what is an important process in the formation of malignant tumors? |
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| angiogenesis, (formation of new BVs from existing ones |
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| is there an association between VEGF and angiogenesis, malignancy, and metastatsis? |
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| yes |
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| what growth factor is a potent and predominant factor in angiogenesis? |
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| VEGF |
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| angiogenesis is one of the 6 aquired cellular capabilities leading to malignant growth, what are the other 5? |
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| evading apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion & metastasis, and limitless replication potential |
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| why is sustained angiogenesis so important for tumor growth? |
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| tumors are very metabolically hungry and need oxygen and nutrients |
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| what are the 4 major steps of endothelial cells in angiogenesis? is VEGF involved? |
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| 1) breaking through of basal lamina that envelops existing blood vessels (so blood vessels can progress out) 2) migration towards source angiogenic signal 3) proliferation 4) formations of tubes. yes VEGF is involved. |
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| what does the angiogenic switch being turned on result in? |
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| neovascularization |
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| to what point can tumors grow before they need angiogenesis? |
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| 2 mm |
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| since VEGF is continously expressed throughout the entire tumor life cycle should it be targeted for anti-tumor activity? |
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| yes, direct and continous VEGF inhibition is an important antitumor strategy |
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| how does VEGF enact cell proliferation (endothelial cells,pericytes, etc)? |
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| through activation of mitogen-activated protein kinases |
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| how does VEGF enact cell permeability? |
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| through vesicovascular organelles, endothelial fenestrations, and opening of junctions between adjacent endothelial cells |
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| how does VEGF enact invasion? |
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| induction of metalloproteinases uPA, uPAR, TTPA |
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| how does VEGF enact migration? |
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| induction of FAK, release of nitric oxide |
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| how does VEGF enact survival? |
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| inihbition of caspases, induction of anti-apoptotic factors such as Bcl2, survivin |
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| how does VEGF enact activation? |
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| upregulation of integrin expression, alteration of cell cytoskeleton |
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| can hypoxia induce VEGF? |
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| yes, VEGF gene expression is upregulated in reponse to hypoxic condition. (if there is a decrease in O2, cells try to increase O2) |
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| how do oncogenes/tumor suppressor affect VEGF production? |
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| oncogenes but also tumor suppressor genes are associated with increased VEGF production |
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| can cellular receptors being over-expressed or activated lead to higher levels of VEGF? which ones? |
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| yes, EGFR, HER-2, IGF-1R are examples |
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| how do COX-2 and PDGF affect the VEGF pathway? |
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| both COX-2 and PDGF induce VEGF production |
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| how do various VEGF ligans express their angiogenic effects? |
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| by binding to specific primary VEGF receptors on the endothelial cell surface. |
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| can VEGF effect lymphangiogenesis? |
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| VEGF can also effect lymphangiogenesis as well as angiogenesis/vasculogenesis,(can allow tumors to metastasize via the lymph system) |
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| are VEGF receptors on tumor cells? |
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| yes |
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| what is the most important VEGF receptor? why? |
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| VEGFR-2 is the most important VEGF receptor in tumor angiogenesis and it mediates the majority of VEGF angiogenic effects |
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| where is VEGFR-3 important? what is it associated with therefore? **remember this |
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| lymphatic endothelial cells. it is thus associated with lymph node metastasis |
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| what is VEGFR-1 associated with? is it thought to be critical to pathogenic angiogenesis? |
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| VEGFR-1 is crucial to embryonic angiogenesis, but it does not appear to be critical in pathogenic angiogenesis, (mostly physiologic) |
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| what prognosis is VEGF overexpression on solid tumors associated with? |
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| poor |
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| once VEGF stimulates tumor angiogenesis, is it a survival factor for existing tumor vasculature? what does it stimulate? |
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| yes. it stimulates blood vessel formation towards the tumor via disruption of the ECM, basement membrane, the bone marrow will be stimulated to produce more endothelial precursor cells and angioblasts. VEGFR-3 brings in lymphatics, (through which, metastasis can occur) |
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| how do most carcinomas spread vs most sarcomas? |
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| most carcinomas spread through the lymphatics while most sarcomas spread through the hematogenous route |
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| b/c VEGF is a potent permeability factor and stimulates vascular permeability small blood vessels, can it induce abnormal vasculature? what does this result in? |
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| yes, this can result in leaky vasculature/increases in interstitial pressure creating an environment for more endothelial cell growth |
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| what is a problematic side effect of VEGF inducing higher interstitial pressure in tumors? |
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| high interstitial pressure may impede delivery of therapeutic agents to tumors |
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| can tumor cells prevent immune response to tumors? |
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| yes, tumors have multiple mechanisms to avoid immune response such as inhibition of dendritic cells and other APCs that stimulate B & T cells |
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| can VEGF help tumors resist an immune response? |
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| yes, VEGF can prevent functional maturation of dendritic cells, (tumor secretion of VEGF may help suppress the immune antitumoral response) |
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| is angiogenesis an important process to the growth of malignant tumors? |
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| yes |
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| is the VEGF ligand a key mediator of angiogenesis? |
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| yes |
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| has VEGF overexpression been associated with poor prognosis in a variety of solid tumors? |
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| yes, , with VGFR-2 being the most prominent receptor, (but 3 is important in lymphangiogenesis***) |
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| does the VEGF ligand have multiple effects on the tumor microenvironment? |
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| yes, increases vascular permeability, helps breakdown ECM |
