Reduced Argininosuccinate Synthetase Is a Predictive Biomarker for the Development of Pulmonary Metastasis in Patients with Osteosarcoma

摘要: Pulmonary metastasis is the most significant prognostic determinant for osteosarcoma, but methods its prediction and treatment have not been established. Using oligonucleotide microarrays, we compared global gene expression of biopsy samples between seven osteosarcoma patients who developed pulmonary within 4 years after neoadjuvant chemotherapy curative resection, 12 did relapse. We identified argininosuccinate synthetase (ASS) as a differentially expressed with highest statistical significance (Welch's t test, P = 2.2 x 10(-5)). Immunohistochemical analysis an independent cohort 62 cases confirmed that reduced ASS protein was significantly correlated development surgery (log-rank < 0.05). Cox regression revealed sole predictive factor (P 0.039; hazard ratio, 0.319; 95% confidence interval, 0.108-0.945). one enzymes required production nonessential amino acid, arginine. showed cells lacking were auxotrophic arginine underwent G(0)-G(1) arrest in arginine-free medium, suggesting deprivation therapy could be effective osteosarcoma. Recently, phase I II clinical trials melanoma hepatocellular carcinoma shown safety efficacy plasma depletion by stabilized deiminase. Our data indicate only novel biomarker metastasis, also potential target pharmacologic intervention.