Chemokines A class of proteins secreted by cells which functions to attract cells

Classes of Chemokines Classes of Chemokines – defined by number and spacing of disulfide bridges -Net positive charge leads to interaction with the proteoglycans in tissues -Receptors are seven transmembrane domain G-protein couple molecules

Function of Chemokines Angiogenic or Angiostatic Angiogenic (pro-angiogenic) -Promote Angiogenesis -Contain a tripeptide proximal to the CXC motif -Glutamic Acid-Leucine-Arginine (ELR+) Angiostatic (anti-angiogenic) -Inhibit Angiogenesis -Does not contain the tripeptide (ELR-)

Chemokines in Angiogenesis

Angiogenic Chemokines -CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8 -CXCR2 is the only receptor needed for endothelial cell chemotaxis -Antibodies boung to CXCR2 blocks endothelial cell response -DARC is a decoy receptor that can bind CXCL1, CXCL5, CXCL8 to remove excess Chemokines

Angiostatic Chemokines -CXCL4, CXCL9, CXCL10, CXCL11, CXCL14 -IFN-inducible -CXCR3 (G protein-coupled receptor is the major receptor for CXCL9, CXCL10, CXCL11 Alternative splicing of CXCR3 results in 3 different splice variants, CXCR3A, CXCR3B, CXCR3-alt -CXCR3B strongly binds CXCL4

CXCL in Cancers Cancer Chemokine Melanoma CXCL1, 2, 3 Pancreatic CXCL1, 2, 8 Ovarian CXCL8 Gastrointestinal CXCL2, 5, 6 Bronchogenic Cancer CXCL5, 8 Prostate CXCL8 Glioblastoma CXCL8 Head and Neck CXCL5, 8, 14 Renal Cell CXCL1, 3, 5, 8

Extracellular Matrix Remodeling

Extracellular Matrix Remodeling -ECM remodeling is controlled by MMPs that cleave ECM components that are needed for angiogenesis activation -MMP-mediated degradation of collagen leads to exposure of the Arg-Gly-Asp sites needed for integrin binding

Integrins -Optimal growth factor stimulation often relies on integrin-mediated adhesion to an appropriate ECM protein -αvβ3 association with VEGFR-2 promotes full activation of each receptor leading to maximal angiogenesis

Extracellular Matrix Remodeling

Cell Involvement