Increased osteoclast activity is associated with aggressiveness of osteosarcoma.
Osteosarcoma (OS) is a highly malignant primary skeletal tumor with a striking tendency to rapidly destroy the surrounding bone and metastasize, since metastases are frequently present at clinical onset. The basis for the aggressiveness of this tumor is largely unknown. However, recent studies in in vivo models indicate that the anti-osteolytic drugs, bisphosphonates, can inhibit the tumor local expansion and the formation of metastases. We further investigated the association between the presence of active osteoclasts and the aggressiveness of OS. We evaluated the presence of osteoclasts and the mRNA of different osteoclast-related genes in tumor biopsies from 16 OS patients and in three OS cell lines and the serum levels of bone resorption markers in the same series and in 28 other patients. Tumor-associated osteoclasts were found in 63 and 75% of cases by histological and mRNA analysis. Among different serum markers, only MMP-9 was significantly higher in OS cases (p=0.0001), whereas TRACP 5b was significantly higher in metastatic patients compared to nonmetastatic patients (p=0.0509). Serum TRACP 5b was significantly correlated to serum NTX (p<0.0001) and cathepsin K mRNA in tumor tissues (p=0.0153). In 8 patients we also analyzed TRACP 5b serum level at follow-up and we verified a significant decrease of TRACP 5b after primary tumor removal (p=0.0117). In conclusion, tumor-infiltrating osteoclasts are frequently found in OS and increased serum TRACP 5b levels and the presence of active osteoclast at primary sites were positively associated with tumor aggressiveness.
Avnet
Sofia
S
Laboratory for Pathophysiology, Istituti Ortopedici Rizzoli, 40136 Bologna, Italy. sofia.avnet@ior.it
Longhi
Alessandra
A
Salerno
Manuela
M
Halleen
Jussi M
JM
Perut
Francesca
F
Granchi
Donatella
D
Ferrari
Stefano
S
Bertoni
Franco
F
Giunti
Armando
A
Baldini
Nicola
N
D000135:Acid Phosphatase / Q000097:blood; D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D024042:Collagen Type I / Q000097:blood; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007527:Isoenzymes / Q000097:blood; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D009361:Neoplasm Invasiveness; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D010455:Peptides / Q000097:blood; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D013997:Time Factors; D055815:Young Adult
D015415:Biomarkers; D024042:Collagen Type I; C508600:IL6 protein, human; D015850:Interleukin-6; D007527:Isoenzymes; C473449:PTH1R protein, human; D044162:Parathyroid Hormone-Related Protein; D010455:Peptides; D053245:RANK Ligand; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; C505688:TNFSF11 protein, human; C052929:collagen type I trimeric cross-linked peptide; D016173:Macrophage Colony-Stimulating Factor; C000605510:ACP5 protein, human; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; D020780:Matrix Metalloproteinase 9