Chemokines

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

Classes of ChemokinesClasses 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 ChemokineMelanoma CXCL1, 2, 3Pancreatic CXCL1, 2, 8Ovarian CXCL8Gastrointestinal CXCL2, 5, 6Bronchogenic Cancer CXCL5, 8Prostate CXCL8Glioblastoma CXCL8Head and Neck CXCL5, 8, 14Renal 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