Multifunctional properties of RANKL/RANK in cell differentiation, proliferation and metastasis.

It is known that there are close relationships between bone destruction and tumor growth in bone metastasis. RANKL is a central factor in bone metastasis, inducing osteoclastogenesis mediated by its receptor RANK. Recent reports demonstrate that RANKL has important roles in organogenesis stimulating proliferation and differentiation of epithelial and stroma cells. RANKL is induced not only by cytokines and hormones but also by UV-irradiation, inflammation and carcinogens. Expression of RANK and RANKL is found in several human cancer cell lines, and RANK signaling stimulates proliferation, migration and epithelial-mesenchymal transition of cancer cells, which may be involved in metastasis via an autocrine/paracrine mechanism. RANKL regulates the number of Tregs that produce RANKL, which may affect cancer metastasis. In this review we discuss the multifunctional roles of RANKL/RANK in osteoclastogenesis, organogenesis, and the metastasis and tumorigenesis of cancer cells.