title: The chemokine receptor CXCR4 strongly promotes neuroblastoma primary tumour and metastatic growth, but not invasion.
abstract: Neuroblastoma (NB) is a heterogeneous, and particularly malignant childhood neoplasm in its higher stages, with a propensity to form metastasis in selected organs, in particular liver and bone marrow, and for which there is still no efficient treatment available beyond surgery. Recent evidence indicates that the CXCR4/CXCL12 chemokine/receptor axis may be involved in promoting NB invasion and metastasis. In this study, we explored the potential role of CXCR4 in the malignant behaviour of NB, using a combination of in vitro functional analyses and in vivo growth and metastasis assessment in an orthotopic NB mouse model. We show here that CXCR4 overexpression in non-metastatic CXCR4-negative NB cells IGR-NB8 and in moderately metastatic, CXCR4 expressing NB cells IGR-N91, strongly increased tumour growth of primary tumours and liver metastases, without altering the frequency or the pattern of metastasis. Moreover shRNA-mediated knock-down experiments confirmed our observations by showing that silencing CXCR4 in NB cells impairs in vitro and almost abrogates in vivo growth. High levels of CXCL12 were detected in the mouse adrenal gland (the primary tumour site), and in the liver suggesting a paracrine effect of host-derived CXCL12 on NB growth. In conclusion, this study reveals a yet unreported NB-specific predominant growth and survival-promoting role of CXCR4, which warrants a critical reconsideration of the role of CXCR4 in the malignant behaviour of NB and other cancers.
authors.affiliation: Department of Paediatrics, Paediatric Oncology Research, University Hospital Centre Hospitalier Universitaire Vaudois Lausanne, Lausanne, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Meier
authors.forename: Annick
authors.initials: A
authors.lastname: Mühlethaler-Mottet
authors.forename: Marjorie
authors.initials: M
authors.lastname: Flahaut
authors.forename: Aurélie
authors.initials: A
authors.lastname: Coulon
authors.forename: Carlo
authors.initials: C
authors.lastname: Fusco
authors.forename: Fawzia
authors.initials: F
authors.lastname: Louache
authors.forename: Katya
authors.initials: K
authors.lastname: Auderset
authors.forename: Katia Balmas
authors.initials: KB
authors.lastname: Bourloud
authors.forename: Estelle
authors.initials: E
authors.lastname: Daudigeos
authors.forename: Curzio
authors.initials: C
authors.lastname: Ruegg
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
authors.forename: Nicole
authors.initials: N
authors.lastname: Gross
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Joseph
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism / Q000502:physiology*
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4