TY - JOUR
T1 - The chemokine receptor CXCR4 strongly promotes neuroblastoma primary tumour and metastatic growth, but not invasion
AU - Meier, Roland
AU - Mühlethaler-Mottet, Annick
AU - Flahaut, Marjorie
AU - Coulon, Aurélie
AU - Fusco, Carlo
AU - Louache, Fawzia
AU - Auderset, Katya
AU - Bourloud, Katia Balmas
AU - Daudigeos, Estelle
AU - Ruegg, Curzio
AU - Vassal, Gilles
AU - Gross, Nicole
AU - Joseph, Jean Marc
PY - 2007/10/10
Y1 - 2007/10/10
N2 - 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 CXR4/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 NO 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.
AB - 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 CXR4/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 NO 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.
UR - http://www.scopus.com/inward/record.url?scp=42449114361&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0001016
DO - 10.1371/journal.pone.0001016
M3 - Article
C2 - 17925864
AN - SCOPUS:42449114361
SN - 1932-6203
VL - 2
JO - PLoS ONE
JF - PLoS ONE
IS - 10
M1 - e1016
ER -