Role of the RANK/RANKL Pathway in Multiple Myeloma

Abstract

Receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL, are expressed in a variety of tissues throughout the body; their primary role is in the regulation of bone remodeling and development of the immune system. Consistent with these functions, evidence exists for a role of RANK/RANKL in all stages of tumorigenesis, from cell proliferation and carcinogenesis to epithelial-mesenchymal transition to neoangiogenesis and intravasation to metastasis to bone resorption and tumor growth in bone. Results from current studies also point to a role of RANK/RANKL signaling in patients with multiple myeloma, who have increased serum levels of soluble RANKL and an imbalance in RANKL and osteoprotegerin. Current therapies for patients with multiple myeloma demonstrate that RANKL may be released by tumor cells or osteoprogenitor cells. This article will review currently available evidence supporting a role for RANK/RANKL signaling in tumorigenesis, with a focus on patients with multiple myeloma.

A predicted risk score based on the expression of 16 autophagy‑related genes for multiple myeloma survival

“…The role of autophagy in tumors is well known, and the function of autophagy in the development and treatment of MM has been previously reported (29)(30). However, the clinical significance of ARGs, particularly their prognostic effect in MM has not been extensively studied.…”

“…Autophagy has an important role in the pathogenesis of plasma cell development and MM, the incidence rate of which is estimated to be 2-3/100,000, and which mostly affects patients >40 years old (29)(30)(31). Generally, autophagy is considered to be involved in pro-survival mechanisms of MM cells and to interact with the ubiquitin-proteasome system to maintain homeostasis of MM cells via degraded and misfolded proteins for energy recovery (32)(33)(34)(35)(36).…”

RANKL biology: bone metabolism, the immune system, and beyond

“…Multiple myeloma is a malignant proliferative disease of plasma cells in the bone marrow and remains largely untreatable. Patients with multiple myeloma develop osteolytic lesions, which frequently lead to skeletal-related events, including hypercalcemia, spinal cord compression, and pathological fractures [105]. Therefore, preventing the progression of bone lesions is an important clinical issue in the treatment of myeloma.…”

A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in four European countries: Austria, Belgium, Greece, and Italy

“…Denosumab is a fully human monoclonal antibody targeting the receptor activator of nuclear factor-jB (RANK) ligand (RANKL) 17,22 . In addition to its involvement in bone complications, there is evidence to suggest that RANKL-RANK signaling may play a role in MM pathogenesis 20,28 . This hypothesis was supported by the 20090482 study, which suggested that, when used in addition to anti-MM treatment, denosumab improved median progression-free survival (PFS) by 10.7 months vs ZA; PFS was a pre-specified, exploratory endpoint (HR ¼ 0.82 [95% CI ¼ 0.68-0.99], p ¼ 0.036) 20 .…”