Loss of osteoclasts contributes to development of osteosarcoma pulmonary metastases.
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.
Endo-Munoz
Liliana
L
The University of Queensland, Level 4, R Wing, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia.
Cumming
Andrew
A
Rickwood
Danny
D
Wilson
Danielle
D
Cueva
Claudia
C
Ng
Charlotte
C
Strutton
Geoffrey
G
Cassady
A Ian
AI
Evdokiou
Andreas
A
Sommerville
Scott
S
Dickinson
Ian
I
Guminski
Alexander
A
Saunders
Nicholas A
NA
D000135:Acid Phosphatase / Q000096:biosynthesis; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001706:Biopsy; D001859:Bone Neoplasms / Q000201:enzymology / Q000473:pathology*; D002648:Child; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000201:enzymology / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology*; D012516:Osteosarcoma / Q000201:enzymology / Q000473:pathology* / Q000556:secondary*; D000071681:Tartrate-Resistant Acid Phosphatase; D055815:Young Adult
D007527:Isoenzymes; C000605510:ACP5 protein, human; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase