Abstract
Pulmonary metastasis is the most significant prognostic determinant for osteosarcoma, but methods for its prediction and treatment have not been established. Using oligonucleotide microarrays, we compared the global gene expression of biopsy samples between seven osteosarcoma patients who developed pulmonary metastasis within 4 years after neoadjuvant chemotherapy and curative resection, and 12 patients who did not relapse. We identified argininosuccinate synthetase (ASS) as a gene differentially expressed with the highest statistical significance (Welch's t test, P = 2.2 x 10(-5)). Immunohistochemical analysis of an independent cohort of 62 osteosarcoma cases confirmed that reduced expression of ASS protein was significantly correlated with the development of pulmonary metastasis after surgery (log-rank test, P < 0.05). Cox regression analysis revealed that ASS was the sole significant predictive factor (P = 0.039; hazard ratio, 0.319; 95% confidence interval, 0.108-0.945). ASS is one of the enzymes required for the production of a nonessential amino acid, arginine. We showed that osteosarcoma cells lacking ASS expression were auxotrophic for arginine and underwent G(0)-G(1) arrest in arginine-free medium, suggesting that an arginine deprivation therapy could be effective in patients with osteosarcoma. Recently, phase I and II clinical trials in patients with melanoma and hepatocellular carcinoma have shown the safety and efficacy of plasma arginine depletion by stabilized arginine deiminase. Our data indicate that in patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention.
Highlights
Rare (200–300 newly diagnosed cases per year in Japan), osteosarcoma is the most frequent primary malignant bone tumor, developing mainly in the metaphysis of long bones of children and young adults
Development of lung metastasis is the most significant determinant of poor prognosis in osteosarcoma, followed by poor response to neoadjuvant chemotherapy [1]. Because such high-risk patients may derive some benefit from modification of their preoperative and postoperative therapeutics, the development of a reliable diagnostic method that can stratify osteosarcoma patients according to their likelihood of developing lung metastasis would be highly valuable
All of the 19 patients were
Summary
Rare (200–300 newly diagnosed cases per year in Japan), osteosarcoma is the most frequent primary malignant bone tumor, developing mainly in the metaphysis of long bones of children and young adults. A significant proportion of osteosarcoma patients develop metastasis even after curative resection of the primary tumor [1, 2]. Osteosarcoma patients with lung metastasis have a poor prognosis, with an overall survival rate of
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
