Myeloma-induced osteolytic bone lesions were reduced by suppressing expression of thymidine phosphorylase (TP), according to Huan Liu of the University of Texas MD Anderson Cancer Center in Houston and associates.
In osteoblast progenitors, methylation of alpha-1/runt-related transcription factor 2 (RUNX2) and osterix was upregulated by TP, resulting in decreased bone formation. TP also upregulated methylation of interferon regulatory factor 8 (IRF8) and enhanced nuclear factor of activated T cells, cytoplasmic 1 protein (NFATc1), which increased bone resorption. Thymidine was catalyzed into thymine and 2-deoxy-d-ribose, which bound to integrins alphavbeta3 and alpha5beta1, activated PI3K/Akt signaling, and increased DNA methyltransferase 3A (DNMT3A) expression, the investigators found.
In an experiment, myeloma was established in severe combined immunodeficient mice, and the mice were injected with ARP-1 cells, which produce high levels of TP. The mice were then treated with 7-deazaxanthine or tipiracil hydrochloride, which reduced ARP-1-induced bone lesions, DNMT3A expression, and 2DDR levels in the serum of tumor-bearing mice.
“This model could facilitate the translation of these inhibitors into human studies of myeloma bone disease. Because TP is often expressed by other malignancies including breast, prostate, and lung cancer, these findings may also have broader implications for the genesis of bone metastasis caused by these and other tumors,” the investigators concluded.
Find the full study in Science Translational Medicine (doi:10.1126/scitranslmed.aad8949)