Bone metastasis in breast cancer: The story of RANK-Ligand

Abstract

The primary cellular mechanism responsible for osteolytic bone metastases is osteoclastic activation. Preclinical models have shown that breast cancer cells can produce parathyroid hormone-related protein (PTHrP), and other osteolytic molecules, which stimulate excessive osteoclastic bone resorption and establishment of osteolytic lesions. It has been shown that PTHrP by itself cannot directly induce osteoclastic activation, but it mediates its effect through the transactivation of RANK-ligand (RANKL) gene on stromal and osteoblastic cells. Accordingly RANKL up-regulation has been considered as a prerequisite in virtually all conditions of cancer induced bone destruction. Hence, therapeutic targeting of RANKL seems to be a rational approach to treat or even to prevent the process of bone metastases. In this review, we will focus on the unique patho-physiological aspects related to the evolution of bone metastases in breast cancer, emphasizing the pivotal role of RANKL and some other key molecules in osteoclastic bone resorption. We will discuss the therapeutic interventions using bisphosphonates and RANKL inhibitors in patients with bone metastases and the outcome of this novel approach.

Stromal cells in tumor microenvironment and breast cancer

“…In addition, CD4 + FOXP3 + Treg cells, recruited by CCL5 secreted from CAFs, also promoted lung metastasis by secreting receptor activator of nuclear factor-κB (RANK) ligand (RANKL) [51]. Interestingly, when breast cancer cells homed to the bone marrow through CXCL12/CXCR4 interaction caused by stem cells and circulating leukocytes [52], osteoclastic activation was induced by parathyroid hormone-related protein (PTHrP) and other soluble mediators released from the metastatic cells [53], at the same time, bone derived TGF-β also enhanced this process and tumor growth in a TGF-β-RANKL- PTHrP manner [54]. Besides, CCL18 from tumor associated macrophages (TAMs) also promote metastasis in breast cancer via PITPNM3 [55].…”

Bone health in breast cancer patients: A comprehensive statement by CECOG/SAKK Intergroup

“…Signaling through RANK leads to differentiation of osteoclast progenitors, formation of mature activated osteoclasts and increased survival of activated osteoclasts. Stimulatory effects of RANKL on osteoclasts are opposed by OPG, which is also secreted by the osteoblasts and stromal cells, and functions as a soluble decoy receptor for RANKL [73]. OPG competes with RANK for RANKL, thus it prevents the RANKLeRANK interaction on the osteoclast cell membrane, leading to cessation of osteoclastogenesis and bone resorption.…”

“…OPG competes with RANK for RANKL, thus it prevents the RANKLeRANK interaction on the osteoclast cell membrane, leading to cessation of osteoclastogenesis and bone resorption. Conceptually, the level of osteoclastogenesis and bone remodeling is primarily regulated by the RANKL/OPG ratio, in as much as a relative increase of RANKL results in excessive bone resorption while a relative increase in OPG inhibits resorption [73].…”

“…Furthermore, OPG is not specific to RANKL, as it can also block TRAIL [TNF related apoptosis inducing ligand], which is a principal mediator of tumor cell death induced by the host immune cells [101]. Therefore and as an alternative approach, an antibody specific to RANKL (Denosumab) was developed, which simulates the beneficial effects of OPG on bone health while avoiding any potential reaction with TRAIL [73]. Denosumab is a fully human monoclonal antibody that binds with a very high affinity and specificity to RANKL, with no detectable neutralizing antibodies in treated patients.…”

The Osteoblastic and Osteoclastic Interactions in Spinal Metastases Secondary to Prostate Cancer

“…RANKL is essential for differentiation, activation, and survival of osteoclasts 67. The release of RANKL from tumor cells into the bone microenvironment has been suggested to simulate osteoblast-derived activation of osteoclasts, leading to bone destruction in skeletal metastasis in PC 88,89…”