Although originally identified as mediators of inflammation, it is now apparent 
that chemokines play a fundamental role in tissue development. In this study, 
ELR(+)-CXC chemokine family members CXCL2 and CXCL7, along with their preferred 
receptor CXCR2, were expressed at the earliest stages of metanephric development 
in the rat, and signaling through this receptor was required for the survival 
and maintenance of the undifferentiated metanephric mesenchyme (MM). A specific 
antagonist of the CXCR2 receptor SB225002 induced apoptosis in this population 
but did not affect more mature structures or cells in the ureteric bud. CXCL7 
treatment of isolated MM elicited an angiogenic response by upregulation of 
matrix metalloprotease 9 and endothelial and mesangial markers 
(platelet-endothelial cell adhesion molecule, Megsin, Thy-1, PDGF receptor 
alpha, and vascular alpha-actin) and induced SB225002-sensitive cell invasion 
through a matrix. Because Wilms' tumor cells may similarly depend on CXCR2 
signaling for survival, primary tumor samples were analyzed, and 15 of 16 Wilms' 
tumors were found to be CXCR2 positive, whereas grossly normal kidney tissues 
from tumor patients or renal cell carcinomas were CXCR2 negative. Furthermore, 
cell lines derived from Wilms' tumors but not those from renal cell carcinomas 
were sensitive to SB225002-induced apoptosis. These data provide evidence for a 
prosurvival and proangiogenic role of ELR(+)-CXC chemokines and their receptor 
CXCR2 during metanephric development and suggest a novel mechanism for 
chemotherapeutic intervention in Wilms' tumor.