Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma

Eisuke Kobayashi, Mari Masuda, Turrent Robert Nakayama, Hitoshi Ichikawa, Reiko Satow, Miki Shitashige, Kazufumi Honda, Umio Yamaguchi, Ayako Shoji, Naobumi Tochigi, Hideo Morioka, Yoshiaki Toyama, Setsuo Hirohashi, Akira Kawai, Tesshi Yamada

Research output: Contribution to journalArticle

67 Citations (Scopus)

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 × 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 G0-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.

Original languageEnglish
Pages (from-to)535-544
Number of pages10
JournalMolecular Cancer Therapeutics
Volume9
Issue number3
DOIs
Publication statusPublished - 2010 Mar

Fingerprint

Argininosuccinate Synthase
Osteosarcoma
Biomarkers
Arginine
Neoplasm Metastasis
Lung
Phase II Clinical Trials
Clinical Trials, Phase I
Oligonucleotide Array Sequence Analysis
Hepatocellular Carcinoma
Melanoma
Cohort Studies
Regression Analysis
Confidence Intervals
Biopsy
Safety
Gene Expression
Amino Acids
Recurrence
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma. / Kobayashi, Eisuke; Masuda, Mari; Nakayama, Turrent Robert; Ichikawa, Hitoshi; Satow, Reiko; Shitashige, Miki; Honda, Kazufumi; Yamaguchi, Umio; Shoji, Ayako; Tochigi, Naobumi; Morioka, Hideo; Toyama, Yoshiaki; Hirohashi, Setsuo; Kawai, Akira; Yamada, Tesshi.

In: Molecular Cancer Therapeutics, Vol. 9, No. 3, 03.2010, p. 535-544.

Research output: Contribution to journalArticle

Kobayashi, E, Masuda, M, Nakayama, TR, Ichikawa, H, Satow, R, Shitashige, M, Honda, K, Yamaguchi, U, Shoji, A, Tochigi, N, Morioka, H, Toyama, Y, Hirohashi, S, Kawai, A & Yamada, T 2010, 'Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma', Molecular Cancer Therapeutics, vol. 9, no. 3, pp. 535-544. https://doi.org/10.1158/1535-7163.MCT-09-0774
Kobayashi, Eisuke ; Masuda, Mari ; Nakayama, Turrent Robert ; Ichikawa, Hitoshi ; Satow, Reiko ; Shitashige, Miki ; Honda, Kazufumi ; Yamaguchi, Umio ; Shoji, Ayako ; Tochigi, Naobumi ; Morioka, Hideo ; Toyama, Yoshiaki ; Hirohashi, Setsuo ; Kawai, Akira ; Yamada, Tesshi. / Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 3. pp. 535-544.
@article{a3f2a5dc439146da95e241b4faf7426b,
title = "Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma",
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 × 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 G0-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.",
author = "Eisuke Kobayashi and Mari Masuda and Nakayama, {Turrent Robert} and Hitoshi Ichikawa and Reiko Satow and Miki Shitashige and Kazufumi Honda and Umio Yamaguchi and Ayako Shoji and Naobumi Tochigi and Hideo Morioka and Yoshiaki Toyama and Setsuo Hirohashi and Akira Kawai and Tesshi Yamada",
year = "2010",
month = "3",
doi = "10.1158/1535-7163.MCT-09-0774",
language = "English",
volume = "9",
pages = "535--544",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma

AU - Kobayashi, Eisuke

AU - Masuda, Mari

AU - Nakayama, Turrent Robert

AU - Ichikawa, Hitoshi

AU - Satow, Reiko

AU - Shitashige, Miki

AU - Honda, Kazufumi

AU - Yamaguchi, Umio

AU - Shoji, Ayako

AU - Tochigi, Naobumi

AU - Morioka, Hideo

AU - Toyama, Yoshiaki

AU - Hirohashi, Setsuo

AU - Kawai, Akira

AU - Yamada, Tesshi

PY - 2010/3

Y1 - 2010/3

N2 - 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 × 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 G0-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.

AB - 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 × 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 G0-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.

UR - http://www.scopus.com/inward/record.url?scp=77949735952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77949735952&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-09-0774

DO - 10.1158/1535-7163.MCT-09-0774

M3 - Article

VL - 9

SP - 535

EP - 544

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 3

ER -