title: The metastatic behavior of osteosarcoma by gene expression and cytogenetic analyses.
abstract: Osteosarcoma is a malignant bone tumor with high metastatic potential. Metastasis at diagnosis is the most significant prognostic factor in predicting the clinical outcome of osteosarcoma. We compared the gene expression of metastases that were present at the time of initial diagnosis to those developed later in the course of the disease. We used quantitative real-time polymerase chain reaction to evaluate the gene expression of MDM2, CXCR4, RANKL, RB1, and OSTERIX in 98 samples of osteosarcoma taken from 47 patients (74 metastases and 24 primary tumors) and 30 nonmalignant lung tissues surrounding osteosarcoma metastases. In addition, we investigated the copy number changes of RB1 and MDM2 genes in 12 primary cultures of pulmonary metastases of osteosarcoma, using interphase fluorescence in situ hybridization. Metastases from metastatic patients at diagnosis were characterized by low expression of RB1 and RANKL (P = .0009 and P = .0109, respectively) and overexpression of CXCR4 and MDM2 (P = .0389 and P = .0325, respectively). The loss of RANKL and gain of CXCR4 could also be detected in the primary tumors of metastatic patients at diagnosis (P = .0121 and P = .0264, respectively). Thus, some early genetic events such as the loss of RANKL and the gain of CXCR4 expressions probably facilitate the metastatic progression concomitant with the primary tumor establishment, supporting the role of the CXCR4 receptor in directing osteosarcoma metastases to the lung. On the other hand, late events such as the loss of RB1 and gain of MDM2, crucial regulators of cell cycle, appear to be related to the final mechanisms contributing to the metastatic establishment of osteosarcoma.
authors.affiliation: Genetics Laboratory, Pediatric Oncology Institute (IOP/GRAACC/UNIFESP), Department of Pediatrics, Federal University of São Paulo, São Paulo 04023-062, Brazil. Electronic address: carolina.salinas@unifesp.br.
authors.forename: Carolina
authors.initials: C
authors.lastname: Salinas-Souza
authors.forename: Renato
authors.initials: R
authors.lastname: De Oliveira
authors.forename: Maria Teresa De Seixas
authors.initials: MT
authors.lastname: Alves
authors.forename: Reynaldo Jesus
authors.initials: RJ
authors.lastname: Garcia Filho
authors.forename: Antonio Sergio
authors.initials: AS
authors.lastname: Petrilli
authors.forename: Silvia Regina Caminada
authors.initials: SR
authors.lastname: Toledo
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D001938:Brazil / Q000453:epidemiology; D020732:Cytogenetic Analysis; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008297:Male; D012516:Osteosarcoma / Q000235:genetics / Q000556:secondary*; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C527276:CXCR4 protein, human; D053245:RANK Ligand; D019718:Receptors, CXCR4; D016160:Retinoblastoma Protein; C505688:TNFSF11 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: CXCR4; Cell culture; Fluorescence in situ hybridization; Gene expression; Lung metastasis; MDM2; Osteosarcoma