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Myeloma enzyme makes way for metastasis
Bone tissue is built up by osteoblasts and broken down by osteoclasts in a balanced remodeling process. In metastatic cancer, however, the balance is tipped, leading to the formation of cancerous growths in the bone. Attempts to prevent metastasis have not been successful in the clinic; thus, Liu and colleagues set out in search of a new pathway to target. The authors found that an enzyme produced by myeloma cells, called thymidine phosphorylase (TP), suppressed osteoblast activity (new bone formation) and enhanced osteoclast activity (bone resorption). Inhibiting TP reduced the incidence of myeloma-induced osteolytic bone lesions, suggesting a new target for translation to the clinic, especially because certain TP inhibitors are already approved for human use.
Myelomatous bone disease is characterized by the development of lytic bone lesions and a concomitant reduction in bone formation, leading to chronic bone pain and fractures. To understand the underlying mechanism, we investigated the contribution of myeloma-expressed thymidine phosphorylase (TP) to bone lesions. In osteoblast progenitors, TP up-regulated the methylation of RUNX2 and osterix, leading to decreased bone formation. In osteoclast progenitors, TP up-regulated the methylation of IRF8 and thereby enhanced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1 protein), leading to increased bone resorption. TP reversibly catalyzes thymidine into thymine and 2-deoxy-d-ribose (2DDR). Myeloma-secreted 2DDR bound to integrin αVβ3/α5β1 in the progenitors, activated PI3K (phosphoinositide 3-kinase)/Akt signaling, and increased DNMT3A (DNA methyltransferase 3A) expression, resulting in hypermethylation of RUNX2, osterix, and IRF8. This study elucidates an important mechanism for myeloma-induced bone lesions, suggesting that targeting TP may be a viable approach to healing resorbed bone in patients. Because TP overexpression is common in bone-metastatic tumors, our findings could have additional mechanistic implications.
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