Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands.
CXCR7 binds chemokines CXCL11 (I-TAC) and CXCL12 (SDF-1) but does not act as a classical chemoattractant receptor. Using CCX771, a novel small molecule with high affinity and selectivity for CXCR7, we found that, although CXCR7 is dispensable for "bare filter" in vitro chemotaxis, CXCR7 plays an essential role in the CXCL12/CXCR4-mediated transendothelial migration (TEM) of CXCR4(+)CXCR7(+) human tumor cells. Importantly, although CXCL11 is unable to stimulate directly the migration of these cells, it acts as a potent antagonist of their CXCL12-induced TEM. Furthermore, even though this TEM is driven by CXCR4, the CXCR7 ligand CCX771 is substantially more potent at inhibiting it than the CXCR4 antagonist AMD3100, which is more than 100 times weaker at inhibiting TEM when compared with its ability to block bare filter chemotaxis. Far from being a "silent" receptor, we show that CXCR7 displays early hallmark events associated with intracellular signaling. Upon cognate chemokine binding, CXCR7 associates with beta-arrestin2, an interaction that can be blocked by CXCR7-specific mAbs. Remarkably, the synthetic CXCR7 ligand CCX771 also potently stimulates beta-arrestin2 recruitment to CXCR7, with greater potency and efficacy than the endogenous chemokine ligands. These results indicate that CXCR7 can regulate CXCL12-mediated migratory cues, and thus may play a critical role in driving CXCR4(+)CXCR7(+) tumor cell metastasis and tissue invasion. CXCR7 ligands, such as the chemokine CXCL11 and the newly described synthetic molecule CCX771, may represent novel therapeutic opportunities for the control of such cells.
Zabel
Brian A
BA
ChemoCentryx, Mountain View, CA 94043, USA. bzabel@chemocentryx.com
Wang
Yu
Y
Lewén
Susanna
S
Berahovich
Robert D
RD
Penfold
Mark E T
ME
Zhang
Penglie
P
Powers
Jay
J
Summers
Bretton C
BC
Miao
Zhenhua
Z
Zhao
Bin
B
Jalili
Ali
A
Janowska-Wieczorek
Anna
A
Jaen
Juan C
JC
Schall
Thomas J
TJ
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000276:immunology*; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008024:Ligands; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D020298:U937 Cells
C501896:ACKR3 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D054387:Receptors, CXCR; D019718:Receptors, CXCR4