The anti-tumor effect of RANKL inhibition in malignant solid tumors – A systematic review

Abstract

At present, accumulating evidence suggests that inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) does not only induce an increase in bone mass and strength, but also has anti-tumor effects. Denosumab, an antibody targeting RANKL, is used to treat osteoporosis and to prevent skeletal related events (SREs) in patients with bone metastases originating from solid tumors. However, expression of RANKL and its receptor activator of nuclear factor kappa-B (RANK) is not solely restricted to cells involved in homeostasis of the bone and RANKL-RANK signalling appears to play a substantial role in many other processes in the body like mammary physiology, mammary tumorigenesis and the immune system. In pre-clinical models, RANKL inhibition has been shown to reduce skeletal tumor burden and distant metastases as well as to decrease mammary carcinogenesis. Clinically, RANKL inhibition improves bone-metastasis free survival in patients with prostate cancer and disease-free survival in patients with breast cancer. In addition, RANKL treatment may form a preventative strategy in patients at high risk for malignancies of the breast. Current clinical studies are evaluating the effect of denosumab on survival, the immune system and other biomarkers into a greater extent. To that purpose, a systematic review of the literature was performed and a narrative review synthesized, describing the present pre-clinical and clinical evidence of an anti-tumor effect of RANKL inhibition and the potential role of the immune system as one of the underlying mechanisms.

Capabilities of preoperative targeted therapy in treatment of bone metastases in renal cancer

“…Пазопаниб обеспечивает снижение активности остеокластогенеза за счет блока тирозинкиназ колониестимулирующего фактора макрофагов (M-CSF-R). Таким образом, интенсивность резорбции костной ткани снижается, процесс в метастатическом очаге стабилизируется, следовательно, уменьшается болевой синдром [11,12]. Снижение пролиферативной активности, миграции и проницаемости эндотелиальных клеток происходит за счет блока рецепторов VGEFR 1 и VGEFR 2.…”

Functional and Hybrid Imaging of Bone Metastases

“…In the commoner type of metastasis that is predominantly osteolytic, factors, such as parathyroid hormone‐related protein (PTHrP) derived from cancer cells, stimulate osteoblast production of the receptor activator of the nuclear factor‐κB ligand (RANKL), which in turn stimulates osteoclast maturation and activity . The increased osteoclast activity leads to increased local bone resorption at a greater rate than attempts at osteoblastic bone formation and repair, with net loss of bone.…”

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

“…It is worth noting that RANK and RANKL are also expressed in a wide variety of healthy tissues including breast, lymph nodes and the brain and are required for the normal functioning of these tissues, as well as in different types of cell, from cells in healthy tissues to cancerous and immune cells. Indeed, cancer cells use RANK and RANKL expression in their advantage for survival and migration . However although RANK/RANKL are expressed both in normal and neoplastic issues, such expression is differentiated.…”

“…Indeed, cancer cells use RANK and RANKL expression in their advantage for survival and migration. [33] However although RANK/RANKL are expressed both in normal and neoplastic issues, such expression is differentiated. For example, RANKL and RANK are expressed in the breast normal tissue but, conversely to RANK, an apparent loss of RANKL expression occurs in neoplastic breast tissue.…”