Format

Send to

Choose Destination
Cancers (Basel). 2018 Oct 24;10(11). pii: E398. doi: 10.3390/cancers10110398.

The Intrinsic and Extrinsic Implications of RANKL/RANK Signaling in Osteosarcoma: From Tumor Initiation to Lung Metastases.

Author information

1
INSERM, UMR 1238, Faculté de Médecine, Université de Nantes, F-44035 Nantes, France. Benjamin.navet@univ-nantes.fr.
2
INSERM, UMR 1238, Faculté de Médecine, Université de Nantes, F-44035 Nantes, France. kosei@belle.shiga-med.ac.jp.
3
Department of Orthopedic Surgery, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. kosei@belle.shiga-med.ac.jp.
4
INSERM, UMR 1238, Faculté de Médecine, Université de Nantes, F-44035 Nantes, France. jorge.vargas@udea.edu.co.
5
Department of Basic Studies, Faculty of Odontology, University of Antioquia, Medellin AA 1226, Colombia. jorge.vargas@udea.edu.co.
6
INSERM, UMR 1238, Faculté de Médecine, Université de Nantes, F-44035 Nantes, France. regis.brion@univ-nantes.fr.
7
Centre Hospitalier Universitaire, Hôtel Dieu, F-44035 Nantes, France. regis.brion@univ-nantes.fr.
8
INSERM, UMR 1238, Faculté de Médecine, Université de Nantes, F-44035 Nantes, France. jerome.amiaud@univ-nantes.fr.
9
Department of Orthopedic Surgery, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. kanchi@belle.shiga-med.ac.jp.
10
Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan. hyagita@med.juntendo.ac.jp.
11
CNRS, UPR 9021, Institut de Biologie Moléculaire et Cellulaire (IBMC), Laboratoire Immunologie et Chimie Thérapeutiques, Université de Strasbourg, F-67084 Strasbourg, France. c.mueller@ibmc-cnrs.unistra.fr.
12
INSERM, UMR 1238, Faculté de Médecine, Université de Nantes, F-44035 Nantes, France. franck.verrecchia@univ-nantes.fr.
13
INSERM, UMR 1238, Faculté de Médecine, Université de Nantes, F-44035 Nantes, France. clotilde.dumarsbarsi@ch-bretagne-atlantique.fr.
14
Centre Hospitalier Universitaire, Hôtel Dieu, F-44035 Nantes, France. clotilde.dumarsbarsi@ch-bretagne-atlantique.fr.
15
INSERM, LEA Sarcoma Research Unit, Department of Oncology and Human Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UK. marie-francoise.heymann@ico.unicancer.fr.
16
INSERM, UMR 1232, LabCT, Université de Nantes, Institut de Cancérologie de l'Ouest, site René Gauducheau, F-44805 Saint-Herblain, France. marie-francoise.heymann@ico.unicancer.fr.
17
INSERM, LEA Sarcoma Research Unit, Department of Oncology and Human Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UK. dominique.heymann@univ-nantes.fr.
18
INSERM, UMR 1232, LabCT, Université de Nantes, Institut de Cancérologie de l'Ouest, site René Gauducheau, F-44805 Saint-Herblain, France. dominique.heymann@univ-nantes.fr.
19
INSERM, UMR 1238, Faculté de Médecine, Université de Nantes, F-44035 Nantes, France. frederic.lezot@univ-nantes.fr.

Abstract

Background: Osteosarcoma is the most frequent form of malignant pediatric bone tumor. Despite the current therapeutic arsenal, patient life-expectancy remains low if metastases are detected at the time of diagnosis, justifying research into better knowledge at all stages of osteosarcoma ontogenesis and identification of new therapeutic targets. Receptor Activator of Nuclear factor κB (RANK)expression has been reported in osteosarcoma cells, raising the question of Receptor Activator of Nuclear factor κB Ligand (RANKL)/RANK signaling implications in these tumor cells (intrinsic), in addition to previously reported implications through osteoclast activation in the tumor microenvironment (extrinsic). Methods: Based on in vitro and in vivo experimentations using human and mouse osteosarcoma cell lines, the consequences on the main cellular processes of RANK expression in osteosarcoma cells were analyzed. Results: The results revealed that RANK expression had no impact on cell proliferation and tumor growth, but stimulated cellular differentiation and, in an immune-compromised environment, increased the number of lung metastases. The analysis of RANKL, RANK and osteoprotegerin (OPG) expressions in biopsies of a cohort of patients revealed that while RANK expression in osteosarcoma cells was not significantly different between patients with or without metastases at the time of diagnosis, the OPG/RANK ratio decreased significantly. Conclusion: Altogether, these results are in favor of RANKL-RANK signaling inhibition as an adjuvant for the treatment of osteosarcoma.

KEYWORDS:

RANKL/RANK; T-lymphocyte; bone; metastases; osteosarcoma

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center