Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma.
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.
Kobayashi
Eisuke
E
Chemotherapy Division, National Cancer Centre Research Institute, Chuo-ku, Tokyo, Japan.
Masuda
Mari
M
Nakayama
Robert
R
Ichikawa
Hitoshi
H
Satow
Reiko
R
Shitashige
Miki
M
Honda
Kazufumi
K
Yamaguchi
Umio
U
Shoji
Ayako
A
Tochigi
Naobumi
N
Morioka
Hideo
H
Toyama
Yoshiaki
Y
Hirohashi
Setsuo
S
Kawai
Akira
A
Yamada
Tesshi
T
D000293:Adolescent; D000328:Adult; D001124:Argininosuccinate Synthase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002648:Child; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012516:Osteosarcoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D014407:Tumor Cells, Cultured; D055815:Young Adult
D014408:Biomarkers, Tumor; D001124:Argininosuccinate Synthase