and HBeAg(-) patients - World Journal of Gastroenterology

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Online Submissions: http://www.wjgnet.com/1007-9327office wjg@wjgnet.com doi:10.3748/wjg.v17.i6.727 ORIGINAL ARTICLE Prediction of gastric cancer metastasis through urinary metabolomic investigation using GC/MS Jun-Duo Hu, Hui-Qing Tang, Qiang Zhang, Jing Fan, Jing Hong, Jian-Zhong Gu, Jin-Lian Chen Jun-Duo Hu, Medical College, Soochow University, Suzhou 215213, Jiangsu Province, China Jun-Duo Hu, Department of Gastroenterology, Shanghai Sixth People’s Hospital, Shanghai 200233, China Hui-Qing Tang, Jian-Zhong Gu, Shanghai Laboratory Animal Center, Chinese Academy of Sciences, Shanghai 201615, China Qiang Zhang, Jing Fan, Jing Hong, Jin-Lian Chen, Department of Gastroenterology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai 200233, China Author contributions: Chen JL designed and conducted the study; Hu JD analyzed the data and prepared the manuscript; Fan J, Hong J, Tang HQ and Gu JZ established the animal model; Hu JD, Zhang Q and Chen JL did the metabolomic analyses; all authors were involved in reviewing, interpreting the results and drafting the manuscript. Supported by The Key Program of Science and Technology Commission of Shanghai Municipality, Project No. 09JC1411600; and Natural Science Foundation of Shanghai, No. 08ZR1411300 Correspondence to: Jin-Lian Chen, MD, Professor, Department of Gastroenterology, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai 200233, China. wqq_021002@163.com Telephone: +86-21-64369181 Fax: +86-21-64369181 Received: August 14, 2010 Revised: September 29, 2010 Accepted: October 6, 2010 Published online: February 14, 2011 Abstract AIM: To gain new insights into tumor metabolism and to identify possible biomarkers with potential diagnostic values to predict tumor metastasis. METHODS: Human gastric cancer SGC-7901 cells were implanted into 24 severe combined immune deficiency (SCID) mice, which were randomly divided into metastasis group (n = 8), non-metastasis group (n = 8), and normal group (n = 8). Urinary metabolomic information was obtained by gas chromatography/mass spectrometry (GC/MS). RESULTS: There were significant metabolic differences among the three groups (t test, P < 0.05). Ten WJG|www.wjgnet.com 727 World J Gastroenterol 2011 February 14; 17(6): 727-734 ISSN 1007-9327 (print) ISSN 2219-2840 (online) © 2011 Baishideng. All rights reserved. selected metabolites were different between normal and cancer groups (non-metastasis and metastasis groups), and seven metabolites were also different between non-metastasis and metastasis groups. Two diagnostic models for gastric cancer and metastasis were constructed respectively by the principal component analysis (PCA). These PCA models were confirmed by corresponding receiver operating characteristic analysis (area under the curve = 1.00). CONCLUSION: The urinary metabolomic profile is different, and the selected metabolites might be instructive to clinical diagnosis or screening metastasis for gastric cancer. © 2011 Baishideng. All rights reserved. Key words: Metabolomic profile; Gastric cancer; Metastasis; Biomarker; Gas chromatography/mass spectrometry Peer reviewers: Dr. Cuneyt Kayaalp, MD, Professor, Department of General Surgery, Staff Surgeon of Gastrointestinal Surgery, Turgut Ozal Medical Center, Inonu University, Malatya 44315, Turkey; Kevin Michael Reavis, MD, Assistant Clinic Professor, Department of Surgery, Division of Gastrointestinal Surgery, University of California, Irvine Medical Center, 333 City Boulevard West, Suite 850, Orange, CA 92868, United States Hu JD, Tang HQ, Zhang Q, Fan J, Hong J, Gu JZ, Chen JL. Prediction of gastric cancer metastasis through urinary metabolomic investigation using GC/MS. World J Gastroenterol 2011; 17(6): 727-734 Available from: URL: http://www.wjgnet.com/1007-9327/full/v17/i6/727.htm DOI: http://dx.doi. org/10.3748/wjg.v17.i6.727 INTRODUCTION Gastric cancer is the second leading cause of cancer death worldwide, and in many Asian countries, such as China [1,2] . Until now, there has been no effective treatment for gastric cancer. Even among patients undergoing gastrectomy, February 14, 2011|Volume 17|Issue 6|
Hu JD et al . Urinary metabolomic profile and gastric cancer because of locoregional relapse and distant metastases, the 5-year survival rates remain disappointing [3] . Early dissemination of the disease through the lymphatic system, blood and peritoneum has limited the therapeutic effects of optimal surgery, except in patients with relatively early-stage tumors [4] . Therefore, it is significant to establish an accurate early diagnosis of gastric cancer. Currently, the diagnosis or screening of gastric cancer or tumor recurrence mainly depends on endoscopy and pathological examinations. The ratio for identifying early gastric cancer with endoscopy is higher than that with X-ray [5] , and the diagnosis of gastric cancer using endoscopy is more accurate [6] . Nevertheless, the results of endoscopy are easily affected by artificial factors (e.g. the experience of the endoscopist). Over the past years, epidemiological data have shown that Helicobacter pylori (H. pylori) infection is strongly associated with the development of gastric cancer [1] , and H. pylori eradication may be considered as a strategy to prevent gastric cancer [7] . In addition, investigation of gastric cancer tissues and some biomarkers have been used for screening gastric cancer [8-13] . However, compared with tissues and serum, the markers acquired from urine are noninvasive and convenient, especially in the patients with recurrent gastric cancer. The urinary metabolic profiling could be used to get urinary metabolites as gastric cancer or tumor recurrence biomarkers. Metabolomics is a post-genomic research field for analysis of low molecular weight compounds in biological systems [14] , and offers an analysis of metabolite level changes in biological samples [15] . In recent years, studies of metabolomics used in various diseases have been conducted, such as stomach cancer [16] , lung cancer [17] , renal cancer [18,19] , brain tumors [20] , and colorectal cancer [21-24] . Nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) are the most commonly employed techniques for measuring the metabolome [14] . MSbased techniques, including gas chromatography/mass spectrometry (GC/MS), GC-MS/MS, liquid chromatography/mass spectrometry (LC-MS) and LC-MS/MS, are among the most efficient and versatile for quantitative analysis of endogenous and exogenous substances in biological samples [25] . Because of its peak resolution, high sensitivity and reproducibility, GC/MS has been well established and widely utilized in metabolomics [26-28] . In this study, we have established a human gastric cancer non-metastasis model and a metastasis model using severe combined immune deficiency (SCID) mice, and deployed GC/MS following chemical derivatization to profile the mouse model urinary specimens and their matched urine. The metabolic differences among the three groups were characterized by principal components analysis (PCA). On the basis of its results, we expected that the potential metabolic biomarkers could be found in mice for early diagnosis and screening the metastasis or the recurrence of gastric cancer. MATERIALS AND METHODS Chemicals and materials Tetrahydrofuran (THF) and bis-(trimethylsilyl)-trifluoroacetamide (BSTFA) were obtained from Sigma Chemical WJG|www.wjgnet.com Co. (St Louis, MO, USA). Vacuum dryer was purchased from Shanghai NOTED Technologies. All other reagents were obtained from Sinopharm Chemical Reagent Co. Ltd. Animal models Male SCID mice were acquired from Shanghai Experimental Animal Center of Chinese Academy of Sciences. Animals used were 6-wk old and weighed 20-25 g. Animal and experimental procedures were performed according to the relative ethical regulations for the care and use of laboratory animals of our university. Human gastric cancer SGC-7901 (Shanghai Cancer Institute), a poorlydifferentiated adenocarcinoma line, was originally derived from a primary tumor and maintained by passage in the subcutis of nude mice. Tumors were cut out aseptically. Necrotic tissues were cut and the reserved healthy tumor tissues were scissor minced into pieces (about 3 mm × 4 mm in diameter) in Hank’s balanced salt solution. Each tumor piece was weighed and adjusted to be approximately 100 mg. All animals were randomly divided into metastasis group (n = 8), non-metastasis group (n = 8), and normal group (n = 8). Animal models were made using orthotopic implantation of histologically intact tissue of human gastric cancer [29] . Mice were anesthetized with 4.3% trichloraldehyde hydrate. An incision of the metastatic group and the normal group was made through the left upper abdominal pararectal line. Then peritoneal cavity was carefully exposed and a part of serosal membrane in the middle of the greater curvature of stomach was mechanically injured by scissors. A tumor piece of 100 mg was fixed on each injured site of the serosal surface of the metastatic group, while normal control mice received no tumor implantation. The stomach was then returned to the peritoneal cavity, and the abdominal wall and skin were closed. An incision of the non-metastatic group was made at the left oxter. A tumor piece of 100 mg was fixed under the skin. All animals were sent to the breeding room after becoming conscious. Specimen collection and pathological examination Six weeks after implantation, all mice were housed in metabolic cages and maintained in an air conditioned room (24 ± 2℃). They were only allowed free access to water during urine sample collection (8:00 pm that day to 8:00 am the next day). All animal urine was collected in frozen tubes at the sixth week after implantation, and immediately stored at -80℃ until processing. The specimens were collected at the same time. Then all mice were killed, tumors growing on the stomach wall were resected and fixed in 4% formalin, and processed for routine paraffin embedding after careful macroscopic examination. In order to evaluate histologically for liver metastasis or lymph node metastasis or other organ metastasis under microscope, four-micron-thick sections were stained with hematoxylin and eosin, then observed by a blinded pathologist. Sample pretreatment and derivatization Each urinary specimen was transferred to a glass cen- 728 February 14, 2011|Volume 17|Issue 6|
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World Journal of Gastroenterology W
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Robert JL Fraser, Daw Park Jacob Ge
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Italy Donato F Altomare, Bari Piero
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Page 9 and 10: S Contents EDITORIAL REVIEW ORIGINA
Page 11 and 12: Contents ACKNOWLEDGMENTS APPENDIX A
Page 13 and 14: Jahn KA et al . Colon cancer and li
Page 23 and 24: Săftoiu A. Imaging techniques in E
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Goenka MK et al . Capsule endoscopy
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Tatsuki M et al . Hypermagnesemia a
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Chang CC et al . Parity and gastric
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Chang CC et al . Parity and gastric
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Zhang XQ et al . EEA model of guine
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Table 3 Measurement of common bile
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Zhang XQ et al . EEA model of guine
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Zhao R et al . Gene expression anal
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Zhao R et al . Gene expression anal
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Qiu HB et al . HBV infection and li
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Qiu HB et al . HBV infection and li
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