Receptor activator of nuclear factor-kappa B ligand (RANKL) stimulates bone-associated tumors through functional
RANK expressed on bone-associated cancer cells?
Primary and secondary bone tumors clearly
deteriorate quality of life and the activity of daily living
of patients. These undesirable diseases become a major
social and economic burden. As both primary and
secondary bone tumors develop in the unique bone
tissue, it is therefore necessary to understand bone cell
biology in tumor bone environment. Recent findings of
the Receptor Activator of Nuclear Factor-kB ligand
(RANKL)/RANK/osteoprotegerin (OPG) molecular
triad, the key regulators of bone remodeling, opened new
era of bone research. Although RANK is an essential
receptor for osteoclast formation, activation and
survival, functional RANK expression has been recently
identified on several bone-associated tumor cells. When
RANK is expressed on secondary bone tumor cells, it is
implicated in tumor cell migration, whereas this is not
the case for primary bone tumors. In any case, RANK is
not involved in RANK-positive cell proliferation or
death. In two models of bone metastases secondary to
melanoma or prostate carcinoma, in vivo neutralization of RANKL by OPG resulted in complete protection from
paralysis, due to metastases of vertebral body, and a
marked reduction in tumor burden in bones, but not in
other organs. OPG also decreased tumor formation and
tumor burden in a mouse model of primary bone tumor,
osteosarcoma. In all these models, tumor cells express
RANK. These data revealed that local differentiation
factors, such as RANKL, play an important role in cell
migration in a metastatic tissue-specific manner. These
findings substantiate the novel direct role of RANKL/RANK in bone-associated tumors, and its
capability of representing new therapeutic targets