title: 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 efficient 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 effect 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 significantly smaller in the latter. CXCR4 pharmacological inhibition by Plerixafor further reduced lung metastases in CXCR4(+/-) mice, preserving the pulmonary architecture (4.18 ± 1.38 mm(2) vs. 1.11 ± 0.60 mm(2), 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 findings argue in favor of a specific role of CXCR4 expressed in stromal cells that condition the pro-tumor microenvironment. In this scenario, CXCR4 antagonists will target neoplastic cells as well as the pro-tumor stromal microenvironment.
authors.affiliation: Department of Oncological Immunology, National Cancer Institute G. Pascale, Via Semmola., 80131 Naples, Italy.
authors.forename: Crescenzo
authors.initials: C
authors.lastname: D'Alterio
authors.forename: Antonio
authors.initials: A
authors.lastname: Barbieri
authors.forename: Luigi
authors.initials: L
authors.lastname: Portella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palma
authors.forename: Marianeve
authors.initials: M
authors.lastname: Polimeno
authors.forename: Anna
authors.initials: A
authors.lastname: Riccio
authors.forename: Caterina
authors.initials: C
authors.lastname: Ieranò
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.forename: Giosuè
authors.initials: G
authors.lastname: Scognamiglio
authors.forename: Jane
authors.initials: J
authors.lastname: Bryce
authors.forename: Antonio
authors.initials: A
authors.lastname: Luciano
authors.forename: Domenica
authors.initials: D
authors.lastname: Rea
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000032:analysis / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001596:Benzylamines; D000080027:Cyclams; D005260:Female; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology; D006571:Heterocyclic Compounds / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000276:immunology* / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000276:immunology; D017154:Stromal Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D000950:Antigens, Ly; D000970:Antineoplastic Agents; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; C480309:Ly6G antigen, mouse; D019718:Receptors, CXCR4; C088327:plerixafor