Properties of RANKL/RANK in Differentiation and Metastasis
Properties of RANKL/RANK in Differentiation and Metastasis
Emerging evidence shows that RANKL, an essential factor for osteoclastogenesis, is a multifunctional protein. RANKL is involved not only in differentiation and function of osteoclasts but also in organogenesis and immunoregulation. RANKL has important roles in mammary gland development and formation of lymphoid organs by stimulating proliferation of epithelial cells and stroma cells or inducing differentiation of epithelial cells. Normal physiologic expression of RANKL is induced by cytokines and hormones. Pathologic RANKL expression is induced by inflammatory cytokines, hormone derivatives, UV-irradiation and immune reactions that may occur in the primary tumor site. Cancer cells express RANK and RANKL, and RANK expression is related to bone metastasis and aggressive properties of cancer. Downstream of RANK, activation of NF-κB leads to proliferation of epithelial cells as a consequence of cyclin D and Id2 expression, which are increased in cancer cells. RANKL also induces migration of cancer cells in an ERK1/2 and c-Src-dependent manner and RANKL induces EMT of epithelial cells mediated by NF-κB signaling. These data suggest that RANKL is involved not only in bone destruction in metastasis but also in initiation of metastasis. In addition, RANKL regulates the number of Tregs that control immune responses in tumor progression and metastasis. Recent successful clinical trials of denosumab confirmed the importance of the RANKL/RANK axis in the incidence of SRE in some bone metastatic tumors.
Conclusion
Emerging evidence shows that RANKL, an essential factor for osteoclastogenesis, is a multifunctional protein. RANKL is involved not only in differentiation and function of osteoclasts but also in organogenesis and immunoregulation. RANKL has important roles in mammary gland development and formation of lymphoid organs by stimulating proliferation of epithelial cells and stroma cells or inducing differentiation of epithelial cells. Normal physiologic expression of RANKL is induced by cytokines and hormones. Pathologic RANKL expression is induced by inflammatory cytokines, hormone derivatives, UV-irradiation and immune reactions that may occur in the primary tumor site. Cancer cells express RANK and RANKL, and RANK expression is related to bone metastasis and aggressive properties of cancer. Downstream of RANK, activation of NF-κB leads to proliferation of epithelial cells as a consequence of cyclin D and Id2 expression, which are increased in cancer cells. RANKL also induces migration of cancer cells in an ERK1/2 and c-Src-dependent manner and RANKL induces EMT of epithelial cells mediated by NF-κB signaling. These data suggest that RANKL is involved not only in bone destruction in metastasis but also in initiation of metastasis. In addition, RANKL regulates the number of Tregs that control immune responses in tumor progression and metastasis. Recent successful clinical trials of denosumab confirmed the importance of the RANKL/RANK axis in the incidence of SRE in some bone metastatic tumors.
