Bone is a common site for
cancer metastasis. To create space for their growth,
cancer cells stimulate bone resorbing osteoclasts.
Cytokine RANKL is a key osteoclast activator, while
osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic
tumor burden in bone. However, OPG produced locally by
cancer cells was shown to enhance
osteolysis and
tumor growth. We propose that OPG produced by
cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the
tumor and towards the bone tissue, resulting in faster resorption and
tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL,
PTHrP, osteoclasts,
tumor and bone mass. We demonstrate that at lower expression rates,
tumor-derived OPG enhances the chemotactic RANKL gradient and
osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases
osteolysis and
tumor burden. Moreover,
tumor expression of a soluble mediator inducing RANKL in the host tissue, such as
PTHrP, is important for correct orientation of the RANKL gradient. A meta-analysis of OPG, RANKL and
PTHrP expression in normal prostate,
carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic
prostate cancer, and positive correlation between OPG and
PTHrP in metastatic
prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and
ligands, and can be applied to other systems involving regulation of spatially anisotropic processes.