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

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.

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

“…In OS this signaling pathway is fully deregulated. In particular, OPG expression is frequently altered in several types of cell tumor including OS cells [46]. Several in vitro and in vivo studies demonstrated that OPG is able to increase tumor volume and development suggesting that it could serve as survival factor for OS cells and an important marker of cancer progression [47].…”

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

“…Nevertheless, one might address the importance of RANK signaling in OS cells, which derived from cells committed in differentiation pathway between MSCs or pre-osteoblasts towards mature osteoblasts [58]. In this context, Navet et al investigated the role of RANK overexpression in OS cell lines and during OS development in immune-deficient mice [59]. Activation of the RANKL-RANK pathway in these OS cell lines did not change cell proliferation or The TGF-β family comprises at least 30 members in humans [46].…”

Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies

“…Malignant osteosarcoma cells share characteristics of immature osteoblasts, suggesting that an aberrant osteoblast-like cell is the cell of origin for osteosarcoma [34]. Osteosarcomas express high levels of RANK, RANKL, and OPG, implying a global dysregulation in signalling between osteoblasts and osteoclasts [35]. Signalling pathways involved in normal bone development, such as Hedgehog (Hh), Notch, and WNT, have also been implicated in osteosarcoma pathogenesis [21].…”