Angiogenesis

normoxic conditions

VHL degrades HIF during normoxia, makes for degradation

VEGF

cells monitor O2 tension through VHL proteins under hypoxic conditions VHL proteins signal for production and release of VEGF VEGF binds to receptors on the surface of endothelial cells stimulating their proliferation endothelial cells also migrate towards areas of higher VEGF concentration angiogenic factor

heterotypic interactions

heterogenous cell communication

what promotes angiogenesis?

hypoxia oncogenes

vasculature increases pressure

leakiness of tumor vasculature results in increased interstitial pressure lower pressure in tumor veins higher interstitial pressure lowers effective penetration of drugs

angiogenic switch

normal conditions prevent cells from triggering angiogenesis as tumors progress they gain the capacity to promote angiogenesis thus, overcoming the normal inhibition of angiogenesis

how are new vessels formed?

pre-existing vessels endothelial progenitor cells from the bone marrow

why do tumors induce angiogenesis?

provides nutrients required for cell growth provides a roadway for metastatic spread promotes tumor growth and spread

thrombospondin-1

secreted by many cell types is boudn to molecules in the ECM binds to receptors (cd36/47) on the surface of endothelial cells inhibits endothelial cell proliferation

stromal cells

streams cell release many cytokines and growth factors also produce MMPs and other proteases heterotypic interactions with storm enhance angiogenesis

VHL mutations

these mutations result in constitutively active HIF VHL and VEGF expression are inversely related

how far can tumors be from a blood vessel?

0.2 mm

angiogenesis pathway

1. hypoxic response elements cause tumor cells to up regulate pro-angiogenic factors 2. pro-angiogenic factors activate endothelial cells to increase proliferation 3. MMP are activated by tumor cells and endothelial cells to permit further endothelial cell growth and migration 4. Tumor vascularity is increased

tumor capillaries

3 times the diameter disorganized loosely associated parasites gaps between cells walls are more permeable higher interstitial fluid pressure poor lymphatic drainage

hypoxic conditions

HIF activates VEGF during hypoxia

when does angiogenesis happen?

embryonic development growth implantation of placenta uterine lining wound healing non-malignant disease: diabetic retinopathy, psoriasis, RA malignant disease: tumorogenesis

angiogenesis defined

growth of new blood vessels from preexisting blood vessels

can attract calls from distant sites (heterotypic interactions)

tumor cells may attract local endothelial cells, but can also attract precursor cells from distant sites like the bone marrow releases ECM bound angiogenic factors promotes endothelial cell migration through ECM allows for direct access of tumor to new vessels vasodilators are expressed chemokine and growth factors are also expressed

streams cells (heterotypic interactions)

tumor cells may attract other stream cell types that promote angiogenesis

degradation of the ECM and basement membrane (heterotypic interactions)

tumor cells may release enzymes, MMP, that degrade ECM and basement membrane releases ECM bound angiogenic factors promotes endothelial cell migration through ECM allows for direct access of tumor to new vessels

creating new vessels

tumors don't take over existing vessels they secrete angiogenic factors to stimulate the growth of new vessels from normal cells