Inhibition of stromal CXCR4 impairs development of lung metastases

Abstract

Compelling evidence has emerged in recent years indicating that stromal cells play a critical role in disease progression. CXCR4 is a G-protein-coupled receptor with a major role in lymphocyte homing. Its ligand, CXCL12, is a highly eYcient chemotactic factor for T cells, monocytes, pre-B cells, dendritic cells and myeloid bone marrow-derived cells (BMDCs). In addition, the CXCR4-CXCL12 axis plays a central role in tumor growth and metastasis. To evaluate the eVect of genetic CXCR4 reduction on metastasis development, murine melanoma B16 cells were injected into the tail vein of C57BL/6 CXCR4+/+ and CXCR4+/- mice in the presence of the CXCR4 inhibitor, Plerixafor (previously named AMD3100). Although lung metastases developed in wild-type CXCR4+/+ and heterozygote CXCR4+/- mice, nodules were signiWcantly smaller in the latter. CXCR4 pharmacological inhibition by Plerixafor further reduced lung metastases in CXCR4+/- mice, preserving the pulmonary architecture (4.18 $ 1.38 mm2 vs. 1.11 $ 0.60 mm2, p = 0.038). A reduction in LY6G-positive myeloid/granulocytic cells and in p38 MAPK activation was detected in lungs from CXCR4+/- mice compared to CXCR4+/+ mice [LY6G-positive myeloid CXCR4+/- vs. CXCR4+/+ (p = 0.0004); CXCR4+/+ vs. CXCR4+/+ Plerixafor-treated (p = 0.0031)] suggesting that CXCR4 reduction on myeloid-derived cells reduced their recruitment to the lung, consequently impairing lung metastases. Our Wndings argue in favor of a speciWc role of CXCR4 expressed in stromal cells that condition the protumor microenvironment. In this scenario, CXCR4 antagonists will target neoplastic cells as well as the pro-tumor stromal microenvironment. © Springer-Verlag 2012.