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Erschienen in: Gastric Cancer 5/2020

26.03.2020 | Original Article

Metabolomic profiling of gastric cancer tissues identified potential biomarkers for predicting peritoneal recurrence

verfasst von: Sanae Kaji, Tomoyuki Irino, Masatoshi Kusuhara, Rie Makuuchi, Yushi Yamakawa, Masanori Tokunaga, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Kenjiro Kami, Yoshiaki Ohashi, Shun Zhang, Hajime Orita, Hyeon-Cheol Lee-Okada, Tetsu Fukunaga, Masanori Terashima

Erschienen in: Gastric Cancer | Ausgabe 5/2020

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Abstract

Background

Metabolomics is useful for analyzing the nutrients necessary for cancer progression, as the proliferation is regulated by available nutrients. We studied the metabolomic profile of gastric cancer (GC) tissue to elucidate the associations between metabolism and recurrence.

Methods

Cancer and adjacent non-cancerous tissues were obtained in a pair-wise manner from 140 patients with GC who underwent gastrectomy. Frozen tissues were homogenized and analyzed by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Metabolites were further assessed based on the presence or absence of recurrence.

Results

Ninety-three metabolites were quantified. In cancer tissues, the lactate level was significantly higher and the adenylate energy charge was lower than in non-cancerous tissues. The Asp, β-Ala, GDP, and Gly levels were significantly lower in patients with recurrence than in those without. Based on ROC analyses to determine the cut-off values of the four metabolites, patients were categorized into groups at high risk and low risk of peritoneal recurrence. Logistic regression and Cox proportional hazard analyses identified β-Ala as an independent predictor of peritoneal recurrence (hazard ratio [HR] 5.21 [95% confidence interval 1.07–35.89], p = 0.029) and an independent prognostic factor for the overall survival (HR 3.44 [95% CI 1.65–7.14], p < 0.001).

Conclusions

The metabolomic profiles of cancer tissues differed from those of non-cancerous tissues. In addition, four metabolites were significantly associated with recurrence in GC. β-Ala was both a significant predictor of peritoneal recurrence and a prognostic factor.
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Literatur
1.
Zurück zum Zitat Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang X-S, et al. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). The Lancet. 2015;385(9972):977–1010.CrossRef Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang X-S, et al. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). The Lancet. 2015;385(9972):977–1010.CrossRef
2.
Zurück zum Zitat Takahashi T, Saikawa Y, Kitagawa Y. Gastric cancer: current status of diagnosis and treatment. Cancers (Basel). 2013;5(1):48–63.CrossRef Takahashi T, Saikawa Y, Kitagawa Y. Gastric cancer: current status of diagnosis and treatment. Cancers (Basel). 2013;5(1):48–63.CrossRef
3.
Zurück zum Zitat Shiozaki H, Elimova E, Slack RS, Chen HC, Staerkel GA, Sneige N, et al. Prognosis of gastric adenocarcinoma patients with various burdens of peritoneal metastases. J Surg Oncol. 2016;113(1):29–35.PubMedCrossRef Shiozaki H, Elimova E, Slack RS, Chen HC, Staerkel GA, Sneige N, et al. Prognosis of gastric adenocarcinoma patients with various burdens of peritoneal metastases. J Surg Oncol. 2016;113(1):29–35.PubMedCrossRef
4.
Zurück zum Zitat Katai H, Ishikawa T, Akazawa K, Isobe Y, Miyashiro I, Oda I, et al. Five-year survival analysis of surgically resected gastric cancer cases in Japan: a retrospective analysis of more than 100,000 patients from the nationwide registry of the Japanese Gastric Cancer Association (2001–2007). Gastric Cancer. 2018;21(1):144–54.PubMedCrossRef Katai H, Ishikawa T, Akazawa K, Isobe Y, Miyashiro I, Oda I, et al. Five-year survival analysis of surgically resected gastric cancer cases in Japan: a retrospective analysis of more than 100,000 patients from the nationwide registry of the Japanese Gastric Cancer Association (2001–2007). Gastric Cancer. 2018;21(1):144–54.PubMedCrossRef
5.
Zurück zum Zitat Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. The Lancet. 2016;388(10060):2654–64.CrossRef Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. The Lancet. 2016;388(10060):2654–64.CrossRef
6.
Zurück zum Zitat Miki Y, Tokunaga M, Tanizawa Y, Bando E, Kawamura T, Terashima M. Staging Laparoscopy for Patients with cM0, Type 4, and Large Type 3 Gastric Cancer. World J Surg. 2015;39(11):2742–7.PubMedCrossRef Miki Y, Tokunaga M, Tanizawa Y, Bando E, Kawamura T, Terashima M. Staging Laparoscopy for Patients with cM0, Type 4, and Large Type 3 Gastric Cancer. World J Surg. 2015;39(11):2742–7.PubMedCrossRef
7.
Zurück zum Zitat Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med. 2014;20(10):1193–8.PubMedPubMedCentralCrossRef Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med. 2014;20(10):1193–8.PubMedPubMedCentralCrossRef
8.
Zurück zum Zitat Battini S, Faitot F, Imperiale A, Cicek AE, Heimburger C, Averous G, et al. Metabolomics approaches in pancreatic adenocarcinoma: tumor metabolism profiling predicts clinical outcome of patients. BMC Med. 2017;15(1):56.PubMedPubMedCentralCrossRef Battini S, Faitot F, Imperiale A, Cicek AE, Heimburger C, Averous G, et al. Metabolomics approaches in pancreatic adenocarcinoma: tumor metabolism profiling predicts clinical outcome of patients. BMC Med. 2017;15(1):56.PubMedPubMedCentralCrossRef
9.
Zurück zum Zitat Farid SG, Morris-Stiff G. "OMICS" technologies and their role in foregut primary malignancies. Curr Probl Surg. 2015;52(10):409–41.PubMedCrossRef Farid SG, Morris-Stiff G. "OMICS" technologies and their role in foregut primary malignancies. Curr Probl Surg. 2015;52(10):409–41.PubMedCrossRef
10.
Zurück zum Zitat Abbassi-Ghadi N, Kumar S, Huang J, Goldin R, Takats Z, Hanna GB. Metabolomic profiling of oesophago-gastric cancer: a systematic review. Eur J Cancer. 2013;49(17):3625–37.PubMedCrossRef Abbassi-Ghadi N, Kumar S, Huang J, Goldin R, Takats Z, Hanna GB. Metabolomic profiling of oesophago-gastric cancer: a systematic review. Eur J Cancer. 2013;49(17):3625–37.PubMedCrossRef
11.
Zurück zum Zitat Hirayama A, Kami K, Sugimoto M, Sugawara M, Toki N, Onozuka H, et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 2009;69(11):4918–25.PubMedCrossRef Hirayama A, Kami K, Sugimoto M, Sugawara M, Toki N, Onozuka H, et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 2009;69(11):4918–25.PubMedCrossRef
12.
Zurück zum Zitat Hur H, Paik MJ, Xuan Y, Nguyen DT, Ham IH, Yun J, et al. Quantitative measurement of organic acids in tissues from gastric cancer patients indicates increased glucose metabolism in gastric cancer. PLoS ONE. 2014;9(6):e98581.PubMedPubMedCentralCrossRef Hur H, Paik MJ, Xuan Y, Nguyen DT, Ham IH, Yun J, et al. Quantitative measurement of organic acids in tissues from gastric cancer patients indicates increased glucose metabolism in gastric cancer. PLoS ONE. 2014;9(6):e98581.PubMedPubMedCentralCrossRef
13.
Zurück zum Zitat Song H, Wang L, Liu HL, Wu XB, Wang HS, Liu ZH, et al. Tissue metabolomic fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity. Oncol Rep. 2011;26(2):431–8.PubMed Song H, Wang L, Liu HL, Wu XB, Wang HS, Liu ZH, et al. Tissue metabolomic fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity. Oncol Rep. 2011;26(2):431–8.PubMed
14.
Zurück zum Zitat Wu H, Xue R, Tang Z, Deng C, Liu T, Zeng H, et al. Metabolomic investigation of gastric cancer tissue using gas chromatography/mass spectrometry. Anal Bioanal Chem. 2009;396(4):1385–95.PubMedCrossRef Wu H, Xue R, Tang Z, Deng C, Liu T, Zeng H, et al. Metabolomic investigation of gastric cancer tissue using gas chromatography/mass spectrometry. Anal Bioanal Chem. 2009;396(4):1385–95.PubMedCrossRef
16.
Zurück zum Zitat Chen XD, Mao CC, Wu RS, Zhang WT, Lin J, Sun XW, et al. Use of the combination of the preoperative platelet-to-lymphocyte ratio and tumor characteristics to predict peritoneal metastasis in patients with gastric cancer. PLoS ONE. 2017;12(4):e0175074.PubMedPubMedCentralCrossRef Chen XD, Mao CC, Wu RS, Zhang WT, Lin J, Sun XW, et al. Use of the combination of the preoperative platelet-to-lymphocyte ratio and tumor characteristics to predict peritoneal metastasis in patients with gastric cancer. PLoS ONE. 2017;12(4):e0175074.PubMedPubMedCentralCrossRef
17.
Zurück zum Zitat Association JGC. Japanese classification of gastric carcinoma. 15th ed. Tokyo: Kanehara Publisher; 2017. Association JGC. Japanese classification of gastric carcinoma. 15th ed. Tokyo: Kanehara Publisher; 2017.
18.
Zurück zum Zitat Ohashi T, Komatsu S, Ichikawa D, Kosuga T, Okamoto K, Arita T, et al. Monitoring with sensitive tumor markers contributes to decision-making and better prognosis in gastric cancer patients with peritoneal recurrence. Int J Clin Oncol. 2017;22(5):897–904.PubMedCrossRef Ohashi T, Komatsu S, Ichikawa D, Kosuga T, Okamoto K, Arita T, et al. Monitoring with sensitive tumor markers contributes to decision-making and better prognosis in gastric cancer patients with peritoneal recurrence. Int J Clin Oncol. 2017;22(5):897–904.PubMedCrossRef
19.
Zurück zum Zitat Ooga T, Sato H, Nagashima A, Sasaki K, Tomita M, Soga T, et al. Metabolomic anatomy of an animal model revealing homeostatic imbalances in dyslipidaemia. Mol BioSyst. 2011;7(4):1217–23.PubMedCrossRef Ooga T, Sato H, Nagashima A, Sasaki K, Tomita M, Soga T, et al. Metabolomic anatomy of an animal model revealing homeostatic imbalances in dyslipidaemia. Mol BioSyst. 2011;7(4):1217–23.PubMedCrossRef
20.
Zurück zum Zitat Sugimoto M, Wong DT, Hirayama A, Soga T, Tomita M. Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles. Metabolomics. 2010;6(1):78–95.PubMedCrossRef Sugimoto M, Wong DT, Hirayama A, Soga T, Tomita M. Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles. Metabolomics. 2010;6(1):78–95.PubMedCrossRef
21.
Zurück zum Zitat Yamamoto H, Fujimori T, Sato H, Ishikawa G, Kami K, Ohashi Y. Statistical hypothesis testing of factor loading in principal component analysis and its application to metabolite set enrichment analysis. BMC Bioinform. 2014;15:51.CrossRef Yamamoto H, Fujimori T, Sato H, Ishikawa G, Kami K, Ohashi Y. Statistical hypothesis testing of factor loading in principal component analysis and its application to metabolite set enrichment analysis. BMC Bioinform. 2014;15:51.CrossRef
22.
Zurück zum Zitat Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, NY). 2009;324(5930):1029–33.CrossRef Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, NY). 2009;324(5930):1029–33.CrossRef
23.
Zurück zum Zitat Iovine B, Iannella ML, Nocella F, Pricolo MR, Bevilacqua MA. Carnosine inhibits KRAS-mediated HCT116 proliferation by affecting ATP and ROS production. Cancer Lett. 2012;315(2):122–8.PubMedCrossRef Iovine B, Iannella ML, Nocella F, Pricolo MR, Bevilacqua MA. Carnosine inhibits KRAS-mediated HCT116 proliferation by affecting ATP and ROS production. Cancer Lett. 2012;315(2):122–8.PubMedCrossRef
24.
Zurück zum Zitat Vaughan RA, Gannon NP, Garcia-Smith R, Licon-Munoz Y, Barberena MA, Bisoffi M, et al. beta-alanine suppresses malignant breast epithelial cell aggressiveness through alterations in metabolism and cellular acidity in vitro. Mol Cancer. 2014;13:14.PubMedPubMedCentralCrossRef Vaughan RA, Gannon NP, Garcia-Smith R, Licon-Munoz Y, Barberena MA, Bisoffi M, et al. beta-alanine suppresses malignant breast epithelial cell aggressiveness through alterations in metabolism and cellular acidity in vitro. Mol Cancer. 2014;13:14.PubMedPubMedCentralCrossRef
25.
Zurück zum Zitat Li S, Chen P, Zheng K, Wang W, Pei Y, Qiu E, et al. beta-Alanine mediated inhibition of PTHR1suppresses the proliferation, invasion and tumorigenesis in metastatic human osteosarcoma U2OS cells. Int J Biol Macromol. 2018;111:1255–63.PubMedCrossRef Li S, Chen P, Zheng K, Wang W, Pei Y, Qiu E, et al. beta-Alanine mediated inhibition of PTHR1suppresses the proliferation, invasion and tumorigenesis in metastatic human osteosarcoma U2OS cells. Int J Biol Macromol. 2018;111:1255–63.PubMedCrossRef
27.
Zurück zum Zitat Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev. 2017;276(1):121–44.PubMedPubMedCentralCrossRef Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev. 2017;276(1):121–44.PubMedPubMedCentralCrossRef
28.
Zurück zum Zitat Cappellari AR, Rockenbach L, Dietrich F, Clarimundo V, Glaser T, Braganhol E, et al. Characterization of ectonucleotidases in human medulloblastoma cell lines: ecto-5'NT/CD73 in metastasis as potential prognostic factor. PLoS ONE. 2012;7(10):e47468.PubMedPubMedCentralCrossRef Cappellari AR, Rockenbach L, Dietrich F, Clarimundo V, Glaser T, Braganhol E, et al. Characterization of ectonucleotidases in human medulloblastoma cell lines: ecto-5'NT/CD73 in metastasis as potential prognostic factor. PLoS ONE. 2012;7(10):e47468.PubMedPubMedCentralCrossRef
29.
Zurück zum Zitat Yu J, Wang X, Lu Q, Wang J, Li L, Liao X, et al. Extracellular 5'-nucleotidase (CD73) promotes human breast cancer cells growth through AKT/GSK-3beta/beta-catenin/cyclinD1 signaling pathway. Int J Cancer. 2018;142(5):959–67.PubMedCrossRef Yu J, Wang X, Lu Q, Wang J, Li L, Liao X, et al. Extracellular 5'-nucleotidase (CD73) promotes human breast cancer cells growth through AKT/GSK-3beta/beta-catenin/cyclinD1 signaling pathway. Int J Cancer. 2018;142(5):959–67.PubMedCrossRef
Metadaten
Titel
Metabolomic profiling of gastric cancer tissues identified potential biomarkers for predicting peritoneal recurrence
verfasst von
Sanae Kaji
Tomoyuki Irino
Masatoshi Kusuhara
Rie Makuuchi
Yushi Yamakawa
Masanori Tokunaga
Yutaka Tanizawa
Etsuro Bando
Taiichi Kawamura
Kenjiro Kami
Yoshiaki Ohashi
Shun Zhang
Hajime Orita
Hyeon-Cheol Lee-Okada
Tetsu Fukunaga
Masanori Terashima
Publikationsdatum
26.03.2020
Verlag
Springer Singapore
Erschienen in
Gastric Cancer / Ausgabe 5/2020
Print ISSN: 1436-3291
Elektronische ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-020-01065-5

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