| RRC ID |
38169
|
| 著者 |
Kobayashi E, Masuda M, Nakayama R, Ichikawa H, Satow R, Shitashige M, Honda K, Yamaguchi U, Shoji A, Tochigi N, Morioka H, Toyama Y, Hirohashi S, Kawai A, Yamada T.
|
| タイトル |
Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma.
|
| ジャーナル |
Mol Cancer Ther
|
| 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.
|
| 巻・号 |
9(3)
|
| ページ |
535-44
|
| 公開日 |
2010-3-1
|
| DOI |
10.1158/1535-7163.MCT-09-0774
|
| PII |
1535-7163.MCT-09-0774
|
| PMID |
20159990
|
| MeSH |
Adolescent
Adult
Argininosuccinate Synthase / genetics*
Argininosuccinate Synthase / metabolism
Argininosuccinate Synthase / physiology
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Biomarkers, Tumor / physiology
Bone Neoplasms / diagnosis*
Bone Neoplasms / genetics
Bone Neoplasms / mortality
Bone Neoplasms / pathology
Child
Down-Regulation / physiology
Female
Gene Expression Profiling
Gene Expression Regulation, Enzymologic / physiology
Gene Expression Regulation, Neoplastic / physiology
Humans
Lung Neoplasms / diagnosis*
Lung Neoplasms / genetics
Lung Neoplasms / mortality
Lung Neoplasms / secondary*
Male
Oligonucleotide Array Sequence Analysis
Osteosarcoma / diagnosis*
Osteosarcoma / genetics
Osteosarcoma / mortality
Osteosarcoma / pathology
Prognosis
Tumor Cells, Cultured
Young Adult
|
| IF |
5.615
|
| 引用数 |
67
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
|
