RANK–RANKL signalling in cancer

Abstract

Oncogenic events combined with a favourable environment are the two main factors in the oncological process. The tumour microenvironment is composed of a complex, interconnected network of protagonists, including soluble factors such as cytokines, extracellular matrix components, interacting with fibroblasts, endothelial cells, immune cells and various specific cell types depending on the location of the cancer cells (e.g. pulmonary epithelium, osteoblasts). This diversity defines specific “niches” (e.g. vascular, immune, bone niches) involved in tumour growth and the metastatic process. These actors communicate together by direct intercellular communications and/or in an autocrine/paracrine/endocrine manner involving cytokines and growth factors. Among these glycoproteins, RANKL (receptor activator nuclear factor-κB ligand) and its receptor RANK (receptor activator nuclear factor), members of the TNF and TNFR superfamilies, have stimulated the interest of the scientific community. RANK is frequently expressed by cancer cells in contrast with RANKL which is frequently detected in the tumour microenvironment and together they participate in every step in cancer development. Their activities are markedly regulated by osteoprotegerin (OPG, a soluble decoy receptor) and its ligands, and by LGR4, a membrane receptor able to bind RANKL. The aim of the present review is to provide an overview of the functional implication of the RANK/RANKL system in cancer development, and to underline the most recent clinical studies.

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…These observations led to the development of a concept in which bone and immune tissues were functionally interconnected and it is at the origin of the "osteoimmunology" [25,26]. The RANKL/RANK/OPG system is associated to the pathogenesis of osteosarcoma [27][28][29], directly through RANK on the osteosarcoma cell surface [30] and indirectly by regulating osteoclast activities [31] and the tumor vascularization [32]. Based on this observation, a fully humanized antibody able to block specifically RANKL binding to RANK and to inhibit the RANKL-induced signalling has been developed and called Denosumab [33].…”

Carbon/Inorganic Hybrid Nanoarchitectures as Carriers for Signaling Elements in Electrochemical Immunosensors: First Biosensor for the Determination of the Inflammatory and Metastatic Processes Biomarker RANK‐ligand

“…Although the best‐known function of RANKL is the regulation of bone resorption, recent works report that it also plays an important role in tumorigenesis, facilitating tumor growth and the metastatic process by modulating immune response . Bone resorption is enhanced by the invasion of cancer cells and production of tumor‐associated factors (cytokines and growth factors) which in turn causes the release of more growth factors promoting tumor proliferation and initiation of the pre‐metastatic niches .…”

Immune Environment and Osteosarcoma

“…Lymphocytes are immune cells regulated by diverse cytokines, in particular the triad OPG/ RANK/RANKL, which represents a seting up a fertile soil for cancer cells as well [9]. Bone remodelling results from a balance between two opposite cellular activities: (i) osteoblasts in charge of the synthesis of new organic extracellular matrix, which will become progressively mineralized and (ii) osteoclasts specialised in the degradation of the mineralised extracellular matrix, process named bone resorption.…”

“…LGR4 expressed at the osteoclast/osteoclast precursor membrane is a negative regulator of RANKL-RANK activation (see review in Ref. [9]). It is widely accepted that the multiple components of the bone niche (e.g.…”

“…Bone remodelling results from a balance between two opposite cellular activities: (i) osteoblasts in charge of the synthesis of new organic extracellular matrix, which will become progressively mineralized and (ii) osteoclasts specialised in the degradation of the mineralised extracellular matrix, process named bone resorption. Osteoclastogenesis and osteoclast activities are regulated by a master cytokine called NF-κB Ligand (RANKL), member of the tumour necrosis factor (TNF) superfamily (oicial TNF nomenclature: TNFSF11) [9]. RANKL is a soluble and/ or membrane cytokine expressed by osteoblasts and stromal cells, binds to RANK a membrane receptor expressed at the surface of mature osteoclasts and their precursors.…”