Molecular Pathways: Osteoclast-Dependent and Osteoclast-Independent Roles of the RANKL/RANK/OPG Pathway in Tumorigenesis and Metastasis

Abstract

Receptor activator of nuclear factor-kappa B ligand (RANKL) is a TNF ligand superfamily member that is essential for the formation, activation, and function of osteoclasts. RANKL functions via its cognate receptor RANK, and it is inhibited by the soluble decoy receptor osteoprotegerin (OPG). In skeletal metastases, the ratio of RANKL to OPG is upregulated, which leads to increased osteoclast-mediated bone destruction. These changes in the bone microenvironment not only compromise the structural integrity of bone, leading to severe clinical morbidities, but have also been implicated in establishment of de novo bone metastasis and the progression of existing skeletal tumors. Evaluation of RANKL inhibitors, including the fully human anti-RANKL antibody denosumab, in patients with cancer has shown reductions in tumor-induced bone resorption activity and successful management of skeletal complications of bone metastases. RANKL also functions as a major paracrine effector of the mitogenic action of progesterone in mouse mammary epithelium, and it has a role in ovarian hormone-dependent expansion and regenerative potential of mammary stem cells. RANKL inhibition attenuates mammary tumorigenesis and pulmonary metastases in mouse models. These data suggest that the contribution of progesterone to increased mammary cancer incidence is mediated, at least in part, by RANKL-dependent changes in the mammary epithelium; RANKL also directly promotes distant metastases. In summary, the antitumor and antimetastatic effects of RANKL inhibition can occur by at least 2 distinct mechanisms, one in the bone via osteoclast-dependent effects, and the second via direct effects on the tumor cells of various origins and/or mammary epithelium. Clin Cancer Res; 18(2); 326-35. Ó2011 AACR.

Mechanisms of multiple myeloma bone disease

“…35,45 The impact of denosumab, a human monoclonal antibody to RANKL, on bone metastases in patients with breast and prostate cancer, treatment-induced bone disease due to prostate cancer, and osteoporosis has been evaluated. 46 Denosumab treatment resulted in a statistically significant improvement in bone mineral density in patients with non-metastatic prostate or breast cancer. 47,48 In addition, the prostate cancer patients receiving denosumab had a reduced incidence of new vertebral fractures at 36 months.…”

Metastatic Tumors to the Jaws and Mouth

“…Receptor activator of nuclear factor-kappa B ligand (RANKL) is essential for the formation, activation, and function of osteoclasts. RANKL functions via its cognate receptor RANK, and it is inhibited by the soluble decoy receptor osteoprotegerin (OPG) [42] (Fig. 2).…”

“…Understanding the key pathways regulating homing, colonization and proliferation of MTC in the bone is relevant for the recently development of targeted therapies targeted mainly against OPG/RANK/RANKL pathway, PTHrP, chemokines, and chemokines receptors. The most investigated classes of bone-targeted agents that have an inhibitory effect on osteolysis are the bisphosphonates and the monoclonal antibody against RANKL, denosumab [42]. Even in osteoblastic bone metastases from prostate cancer, there is an increased bone resorption phase providing the rationale for treatment with osteoclast-targeted agents [47,48].…”

Contrôle de la croissance et de la dissémination tumorales par le microenvironnement

“…Le traitement de patients atteints de métastases osseuses par le denosumab 1 qui, en ciblant le microenvironnement osseux, augmente leur chance de survie, illustre ce point [35]. Cependant, cette caractérisa-tion promet d'être ardue en raison de la multitude de microenvironnements tumoraux spécifiques, qui évo-luent de manière dynamique dans le temps et diffèrent selon les types de tumeur et vraisemblablement selon les patients concernés.…”