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

Cancers

Christopher G. Mueller¹  Hideo Yagita²  Kanji Mori³  Marie-Françoise Heymann⁴  Dominique Heymann⁴  Jérome Amiaud⁵  Franck Verrecchia⁵  Frédéric Lézot⁵  Régis Brion⁵  Jorge William Vargas-Franco⁵  Clotilde Dumars⁵  Benjamin Navet⁵  Kosei Ando⁵ 

[1] CNRS, UPR 9021, Institut de Biologie Moléculaire et Cellulaire (IBMC), Laboratoire Immunologie et Chimie Thérapeutiques, Université de Strasbourg, F-67084 Strasbourg, France;Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan;Department of Orthopedic Surgery, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan;INSERM, LEA Sarcoma Research Unit, Department of Oncology and Human Metabolism, Medical School, University of Sheffield, Sheffield S10 2RX, UK;INSERM, UMR 1238, Faculté de Médecine, Université de Nantes, F-44035 Nantes, France;

关键词: RANKL/RANK;    osteosarcoma;    metastases;    bone;    T-lymphocyte;   

DOI  :  10.3390/cancers10110398

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown