title: The CXCR4/CXCR7/CXCL12 Axis Is Involved in a Secondary but Complex Control of Neuroblastoma Metastatic Cell Homing.
abstract: Neuroblastoma (NB) is one of the most deadly solid tumors of the young child, for which new efficient and targeted therapies are strongly needed. The CXCR4/CXCR7/CXCL12 chemokine axis has been involved in the progression and organ-specific dissemination of various cancers. In NB, CXCR4 expression was shown to be associated to highly aggressive undifferentiated tumors, while CXCR7 expression was detected in more differentiated and mature neuroblastic tumors. As investigated in vivo, using an orthotopic model of tumor cell implantation of chemokine receptor-overexpressing NB cells (IGR-NB8), the CXCR4/CXCR7/CXCL12 axis was shown to regulate NB primary and secondary growth, although without any apparent influence on organ selective metastasis. In the present study, we addressed the selective role of CXCR4 and CXCR7 receptors in the homing phase of metastatic dissemination using an intravenous model of tumor cell implantation. Tail vein injection into NOD-scid-gamma mice of transduced IGR-NB8 cells overexpressing CXCR4, CXCR7, or both receptors revealed that all transduced cell variants preferentially invaded the adrenal gland and typical NB metastatic target organs, such as the liver and the bone marrow. However, CXCR4 expression favored NB cell dissemination to the liver and the lungs, while CXCR7 was able to strongly promote NB cell homing to the adrenal gland and the liver. Finally, coexpression of CXCR4 and CXCR7 receptors significantly and selectively increased NB dissemination toward the bone marrow. In conclusion, CXCR4 and CXCR7 receptors may be involved in a complex and organ-dependent control of NB growth and selective homing, making these receptors and their inhibitors potential new therapeutic targets.
authors.affiliation: Department of Pediatrics, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Annick
authors.initials: A
authors.lastname: Mühlethaler-Mottet
authors.affiliation: Department of Pediatrics, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Liberman
authors.affiliation: Department of Pediatrics, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Kelly
authors.initials: K
authors.lastname: Ascenção
authors.affiliation: Department of Pediatrics, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Flahaut
authors.affiliation: Department of Pediatrics, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Katia
authors.initials: K
authors.lastname: Balmas Bourloud
authors.affiliation: Department of Pathology, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Pu
authors.initials: P
authors.lastname: Yan
authors.affiliation: Department of Pediatrics, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jauquier
authors.affiliation: Department of Pediatrics, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Gross
authors.affiliation: Department of Pediatrics, University Hospital CHUV, University of Lausanne, Lausanne, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Joseph
mesh_terms: D000311:Adrenal Glands / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D054387:Receptors, CXCR / Q000096:biosynthesis* / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: C501896:ACKR3 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D054387:Receptors, CXCR; D019718:Receptors, CXCR4