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

Benjamin Navet (1) , Kosei Ando (2) , Jorge William Vargas-Franco (3, 1) , Régis Brion (1) , Jérôme Amiaud (1) , Kanji Mori (4) , Hideo Yagita (5) , Christopher G Mueller (6) , Franck Verrecchia (1) , Clotilde Dumars (2) , Marie-Françoise Heymann (7) , Dominique Heymann (7) , Frederic Lezot (1)

1 Phy-Os - Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238]
2 PhAN - Physiopathologie des Adaptations Nutritionnelles
3 Department of Basic Studies [Medellin, AA, Colombia]
4 Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives
5 Department of Immunology
6 ICT - Immunologie et chimie thérapeutiques
7 LabCT - Laboratoire de Biologie des Cancers et de Théranostic [St Herblain, Nantes]

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.

Mots clés: RANKL/RANK; osteosarcoma; metastases; bone; T-lymphocyte

Domaines: Médecine humaine et pathologie; Organes des sens; Cancer

Benjamin Navet, Kosei Ando, Jorge William Vargas-Franco, Régis Brion, Jérôme Amiaud, et al.. The Intrinsic and Extrinsic Implications of RANKL/RANK Signaling in Osteosarcoma: From Tumor Initiation to Lung Metastases. Cancers, 2018, 10 (11), pp.398. ⟨10.3390/cancers10110398⟩. ⟨inserm-02102610⟩