Loss of Osteoclasts Contributes to Development of Osteosarcoma Pulmonary Metastases

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 18; pp. 7063 - 7072
• Main Authors: ENDO-MUNOZ, Liliana, CUMMING, Andrew, DICKINSON, Ian, GUMINSKI, Alexander, SAUNDERS, Nicholas A, RICKWOOD, Danny, WILSON, Danielle, CUEVA, Claudia, NG, Charlotte, STRUTTON, Geoffrey, IAN CASSADY, A, EVDOKIOU, Andreas, SOMMERVILLE, Scott
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2010
• Subjects: Acid Phosphatase - biosynthesis; Adolescent; Adult; Aged; Animals; Antineoplastic agents; Biological and medical sciences; Biopsy; Bone Neoplasms - enzymology; Bone Neoplasms - pathology; Child; Diseases of the osteoarticular system; Female; Humans; Isoenzymes - biosynthesis; Lung Neoplasms - enzymology; Lung Neoplasms - secondary; Male; Medical sciences; Mice; Mice, Inbred BALB C; Middle Aged; Osteoclasts - enzymology; Osteoclasts - pathology; Osteosarcoma - enzymology; Osteosarcoma - pathology; Osteosarcoma - secondary; Pharmacology. Drug treatments; Tartrate-Resistant Acid Phosphatase; Tumors; Tumors of striated muscle and skeleton; Young Adult; Osteoarticular system; Sarcoma; Osteosarcoma; Lung; Diseases of the osteoarticular system; Development; Osteoclast; Bone; Malignant tumor; Metastasis; Respiratory system; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-09-4291

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.