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

2. 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

3. 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-)

4. Chemokines in Angiogenesis

5. 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

6. 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

7. 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

8. Extracellular Matrix Remodeling

9. 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

10. 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

11. Extracellular Matrix Remodeling

13. Cell Involvement