Abstract
We conducted a transcriptomic screen of osteosarcoma (OS) biopsies and found that expression of osteoclast-specific tartrate-resistant acid phosphatase 5 (ACP5/TRAP) is significantly downregulated in OS compared with nonmalignant bone (P < 0.0001). Moreover, lesions from OS patients with pulmonary metastases had 2-fold less ACP5/TRAP expression (P < 0.018) than lesions from patients without metastases. In addition, we found a direct correlation (P = 0.0166) between ACP5/TRAP expression and time to metastasis. Therefore, we examined whether metastasis-competent (MC) OS cells could induce loss of ACP5(+) osteoclasts and contribute to metastasis. We found that MC OS cell lines can inhibit osteoclastogenesis in vitro and in vivo. In addition, osteoclasts can inhibit the migration of MC OS cells in vitro. Finally, ablation of osteoclasts with zoledronic acid increases the number of metastatic lung lesions in an orthotopic OS model, whereas fulvestrant treatment increases osteoclast numbers and reduces metastatic lesions. These data indicate that the metastatic potential of OS is determined early in tumor development and that loss of osteoclasts in the primary lesion enhances OS metastasis.
Highlights
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents
receiver operating characteristic (ROC) curves showed an excellent predictive value for ACP5/TRAP expression in Nonmalignant bone (NB) and OS [AUC, 0.94; 95% confidence interval, 0.84–1.03] and NB and MC (AUC, 0.97; 95% CI, 0.91–1.04), and a good predictive value for NB and MI (AUC, 0.83; 95% CI, 0.57–1.10) and MI and MC (AUC, 0.83; 95% CI, 0.66–1.00)
The optimum statistical cutoff expression value was 3.28, indicating that lower ACP5/TRAP expression is more likely to occur in patients that will develop metastasis, and that ACP5/TRAP expression is useful in determining metastasis in OS
Summary
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Pulmonary metastasis is the leading cause of death and the most consistent factor for predicting negative patient outcome in OS [2]. Clinically detectable metastases may not be apparent at the time of diagnosis, and there is no reliable way of predicting outcome at the time of presentation. This is of considerable importance because the longterm survival of patients with metastases is only 10% to 20%. Identifying therapeutic targets and patients at risk of developing pulmonary metastases will allow these patients to be directed into more aggressive or targeted treatments
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