Tissue metabolic profiling of lymph node metastasis of colorectal cancer assessed by 1H NMR

Zhang,Hailong; Qiao,Liang; Li,Xiaopeng; Wan,Yang; Yang,Li; Wang,Huijuan

doi:10.3892/or.2016.5175

Tissue metabolic profiling of lymph node metastasis of colorectal cancer assessed by 1H NMR

Authors:
- Hailong Zhang
- Liang Qiao
- Xiaopeng Li
- Yang Wan
- Li Yang
- Huijuan Wang
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Affiliations: Henan Engineering Laboratory of Antibody Medicine, Henan International United Laboratory of Antibody Medicine, Key Laboratory of Cellular and Molecular Immunology, Medical College, Henan University, Kaifeng, Henan 475004, P.R. China, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China, Chengdu Jinkai Biotechnology Co., Ltd., Chengdu, Sichuan 610041, P.R. China, State Key Laboratory of Biotherapy and Cancer Center, West China School of Pharmacy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, P.R. China
Published online on: October 14, 2016 https://doi.org/10.3892/or.2016.5175
Pages: 3436-3448

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Abstract

Lymph node metastasis is a decisive prognostic and therapeutic staging factor for colorectal cancer (CRC), which is one of the most prevalent types of cancer and a malignant tumor. The metabolic profiling of tissue samples from a large cohort of lymph node non‑metastatic CRC patients (n=73), lymph node metastatic CRC patients (n=52) and normal controls (n=41) was performed using 1H nuclear magnetic resonance (NMR) together with multivariate statistical analyses. Excellent separation was obtained between CRC patients and normal controls, and CRC patients were also perfectly classified according to lymph node metastasis. Forty‑two distinguishing metabolites were identified, which revealed disturbance of glycolysis, glutaminolysis, fatty acid metabolism, choline metabolism and amino acids, suggesting that cellular functions in energy production, macromolecular synthesis, oxidative stress and immune escape of cancer cells are affected in CRC. In total, 10 tissue metabolites were significantly disturbed between non‑metastatic and metastatic CRC patients. The present study firstly staged CRC patients by lymph node metastasis by metabolomic approach. The identified metabolites may be associated with the neoplasia, invasion and metastasis of the tumor. The results suggest the promising application of these metabolites in clinical therapy, and further understanding of the related mechanism warrants further investigation.

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1	Weitz J, Koch M, Debus J, Höhler T, Galle PR and Büchler MW: Colorectal cancer. Lancet. 365:153–165. 2005. View Article : Google Scholar : PubMed/NCBI
2	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
3	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
4	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
5	Abstracts from the 38th annual meeting of the society of general internal medicine. J Gen Intern Med. 30:(Suppl 2). 45–551. 2015. View Article : Google Scholar : PubMed/NCBI
6	Warburg O: On the origin of cancer cells. Science. 123:309–314. 1956. View Article : Google Scholar : PubMed/NCBI
7	Muñoz-Pinedo C, El Mjiyad N and Ricci JE: Cancer metabolism: Current perspectives and future directions. Cell Death Dis. 3:e2482012. View Article : Google Scholar : PubMed/NCBI
8	Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB and Mootha VK: Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 336:1040–1044. 2012. View Article : Google Scholar : PubMed/NCBI
9	Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM, et al: Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 207:339–344. 2010. View Article : Google Scholar : PubMed/NCBI
10	Fiehn O: Metabolomics - the link between genotypes and phenotypes. Plant Mol Biol. 48:155–171. 2002. View Article : Google Scholar : PubMed/NCBI
11	Song H, Wang L, Liu HL, Wu XB, Wang HS, Liu ZH, Li Y, Diao DC, Chen HL and Peng JS: Tissue metabolomic fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity. Oncol Rep. 26:431–438. 2011.PubMed/NCBI
12	Nicholson JK, Connelly J, Lindon JC and Holmes E: Metabonomics: A platform for studying drug toxicity and gene function. Nat Rev Drug Discov. 1:153–161. 2002. View Article : Google Scholar : PubMed/NCBI
13	Qiu Y, Cai G, Zhou B, Li D, Zhao A, Xie G, Li H, Cai S, Xie D, Huang C, et al: A distinct metabolic signature of human colorectal cancer with prognostic potential. Clin Cancer Res. 20:2136–2146. 2014. View Article : Google Scholar : PubMed/NCBI
14	Jung J, Jung Y, Bang EJ, Cho SI, Jang YJ, Kwak JM, Ryu H, Park S and Hwang GS: Noninvasive diagnosis and evaluation of curative surgery for gastric cancer by using NMR-based metabolomic profiling. Ann Surg Oncol. 21:(Suppl 4). S736–S742. 2014. View Article : Google Scholar : PubMed/NCBI
15	Li Y, Song X, Zhao X, Zou L and Xu G: Serum metabolic profiling study of lung cancer using ultra high performance liquid chromatography/quadrupole time-of-flight mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 966:147–153. 2014. View Article : Google Scholar : PubMed/NCBI
16	Chen C, Deng L, Wei S, Gowda GA Nagana, Gu H, Chiorean EG, Abu Zaid M, Harrison ML, Pekny JF, Loehrer PJ, et al: Exploring metabolic profile differences between colorectal polyp patients and controls using seemingly unrelated regression. J Proteome Res. 14:2492–2499. 2015. View Article : Google Scholar : PubMed/NCBI
17	Ganti S, Taylor SL, Abu Aboud O, Yang J, Evans C, Osier MV, Alexander DC, Kim K and Weiss RH: Kidney tumor biomarkers revealed by simultaneous multiple matrix metabolomics analysis. Cancer Res. 72:3471–3479. 2012. View Article : Google Scholar : PubMed/NCBI
18	Griffin JL and Shockcor JP: Metabolic profiles of cancer cells. Nat Rev Cancer. 4:551–561. 2004. View Article : Google Scholar : PubMed/NCBI
19	Zhu J, Djukovic D, Deng L, Gu H, Himmati F, Chiorean EG and Raftery D: Colorectal cancer detection using targeted serum metabolic profiling. J Proteome Res. 13:4120–4130. 2014. View Article : Google Scholar : PubMed/NCBI
20	Nuñez-Sánchez MA, García-Villalba R, Monedero-Saiz T, García-Talavera NV, Gómez-Sánchez MB, Sánchez-Álvarez C, García-Albert AM, Rodríguez-Gil FJ, Ruiz-Marín M, Pastor-Quirante FA, et al: Targeted metabolic profiling of pomegranate polyphenols and urolithins in plasma, urine and colon tissues from colorectal cancer patients. Mol Nutr Food Res. 58:1199–1211. 2014. View Article : Google Scholar : PubMed/NCBI
21	Cheng Y, Xie G, Chen T, Qiu Y, Zou X, Zheng M, Tan B, Feng B, Dong T, He P, et al: Distinct urinary metabolic profile of human colorectal cancer. J Proteome Res. 11:1354–1363. 2012. View Article : Google Scholar : PubMed/NCBI
22	Beckonert O, Keun HC, Ebbels TM, Bundy J, Holmes E, Lindon JC and Nicholson JK: Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat Protoc. 2:2692–2703. 2007. View Article : Google Scholar : PubMed/NCBI
23	Hu Z, Deng Y, Hu C, Deng P, Bu Q, Yan G, Zhou J, Shao X, Zhao J, Li Y, et al: ¹H NMR-based metabonomic analysis of brain in rats of morphine dependence and withdrawal intervention. Behav Brain Res. 231:11–19. 2012. View Article : Google Scholar : PubMed/NCBI
24	Wang H, Wang L, Zhang H, Deng P, Chen J, Zhou B, Hu J, Zou J, Lu W, Xiang P, et al: ¹H NMR-based metabolic profiling of human rectal cancer tissue. Mol Cancer. 12:1212013. View Article : Google Scholar : PubMed/NCBI
25	Feng J, Liu H, Bhakoo KK, Lu L and Chen Z: A metabonomic analysis of organ specific response to USPIO administration. Biomaterials. 32:6558–6569. 2011. View Article : Google Scholar : PubMed/NCBI
26	Gu Y, Chen T, Fu S, Sun X, Wang L, Wang J, Lu Y, Ding S, Ruan G, Teng L, et al: Perioperative dynamics and significance of amino acid profiles in patients with cancer. J Transl Med. 13:352015. View Article : Google Scholar : PubMed/NCBI
27	Martínez-Zaguilán R, Seftor EA, Seftor RE, Chu YW, Gillies RJ and Hendrix MJ: Acidic pH enhances the invasive behavior of human melanoma cells. Clin Exp Metastasis. 14:176–186. 1996. View Article : Google Scholar : PubMed/NCBI
28	Williams MD, Zhang X, Park JJ, Siems WF, Gang DR, Resar LM, Reeves R and Hill HH Jr: Characterizing metabolic changes in human colorectal cancer. Anal Bioanal Chem. 407:4581–4595. 2015. View Article : Google Scholar : PubMed/NCBI
29	Heiden MG Vander, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
30	Daye D and Wellen KE: Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol. 23:362–369. 2012. View Article : Google Scholar : PubMed/NCBI
31	Holst S, Stavenhagen K, Balog CI, Koeleman CA, McDonnell LM, Mayboroda OA, Verhoeven A, Mesker WE, Tollenaar RA, Deelder AM, et al: Investigations on aberrant glycosylation of glycosphingolipids in colorectal cancer tissues using liquid chromatography and matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS). Mol Cell Proteomics. 12:3081–3093. 2013. View Article : Google Scholar : PubMed/NCBI
32	Ni Y, Xie G and Jia W: Metabonomics of human colorectal cancer: New approaches for early diagnosis and biomarker discovery. J Proteome Res. 13:3857–3870. 2014. View Article : Google Scholar : PubMed/NCBI
33	Schlappack OK, Zimmermann A and Hill RP: Glucose starvation and acidosis: Effect on experimental metastatic potential, DNA content and MTX resistance of murine tumour cells. Br J Cancer. 64:663–670. 1991. View Article : Google Scholar : PubMed/NCBI
34	Dang CV: Links between metabolism and cancer. Genes Dev. 26:877–890. 2012. View Article : Google Scholar : PubMed/NCBI
35	Pan T, Gao L, Wu G, Shen G, Xie S, Wen H, Yang J, Zhou Y, Tu Z and Qian W: Elevated expression of glutaminase confers glucose utilization via glutaminolysis in prostate cancer. Biochem Biophys Res Commun. 456:452–458. 2015. View Article : Google Scholar : PubMed/NCBI
36	Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E and Vousden KH: Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature. 493:542–546. 2013. View Article : Google Scholar : PubMed/NCBI
37	Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, et al: Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 43:869–874. 2011. View Article : Google Scholar : PubMed/NCBI
38	Locasale JW and Cantley LC: Genetic selection for enhanced serine metabolism in cancer development. Cell Cycle. 10:3812–3813. 2011. View Article : Google Scholar : PubMed/NCBI
39	Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, et al: Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 476:346–350. 2011. View Article : Google Scholar : PubMed/NCBI
40	Khan AP, Rajendiran TM, Ateeq B, Asangani IA, Athanikar JN, Yocum AK, Mehra R, Siddiqui J, Palapattu G, Wei JT, et al: The role of sarcosine metabolism in prostate cancer progression. Neoplasia. 15:491–501. 2013. View Article : Google Scholar : PubMed/NCBI
41	Baum CE, Price DK and Figg WD: Sarcosine as a potential prostate cancer biomarker and therapeutic target. Cancer Biol Ther. 9:341–342. 2010. View Article : Google Scholar : PubMed/NCBI
42	Cha YJ, Kim H, Jung WH and Koo JS: Expression of sarcosine metabolism-related proteins according to metastatic site in breast cancer. Int J Clin Exp Pathol. 7:7824–7833. 2014.PubMed/NCBI
43	Cha YJ, Jung WH, Cho NH and Koo JS: Expression of sarcosine metabolism-related proteins in invasive lobular carcinoma: Comparison to invasive ductal carcinoma. Yonsei Med J. 56:598–607. 2015. View Article : Google Scholar : PubMed/NCBI
44	Glunde K, Bhujwalla ZM and Ronen SM: Choline metabolism in malignant transformation. Nat Rev Cancer. 11:835–848. 2011.PubMed/NCBI
45	Lin JK and Ho YS: Hepatotoxicity and hepatocarcinogenicity in rats fed squid with or without exogenous nitrite. Food Chem Toxicol. 30:695–702. 1992. View Article : Google Scholar : PubMed/NCBI
46	Lin PC, Lin JK, Lin CH, Lin HH, Yang SH, Jiang JK, Chen WS, Chou CC, Tsai SF and Chang SC: Clinical relevance of plasma DNA methylation in colorectal cancer patients identified by using a genome-wide high-resolution array. Ann Surg Oncol. 22:(Suppl 3). S1419–S1427. 2015. View Article : Google Scholar : PubMed/NCBI
47	Michailidi C, Theocharis S, Tsourouflis G, Pletsa V, Kouraklis G, Patsouris E, Papavassiliou AG and Troungos C: Expression and promoter methylation status of hMLH1, MGMT, APC, and CDH1 genes in patients with colon adenocarcinoma. Exp Biol Med (Maywood). 240:1599–1605. 2015. View Article : Google Scholar : PubMed/NCBI
48	Nakamura K, Yamashita K, Sawaki H, Waraya M, Katoh H, Nakayama N, Kawamata H, Nishimiya H, Ema A, Narimatsu H, et al: Aberrant methylation of GCNT2 is tightly related to lymph node metastasis of primary CRC. Anticancer Res. 35:1411–1421. 2015.PubMed/NCBI
49	Hinnebusch BF, Meng S, Wu JT, Archer SY and Hodin RA: The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. J Nutr. 132:1012–1017. 2002.PubMed/NCBI
50	Lan A, Lagadic-Gossmann D, Lemaire C, Brenner C and Jan G: Acidic extracellular pH shifts colorectal cancer cell death from apoptosis to necrosis upon exposure to propionate and acetate, major end-products of the human probiotic propionibacteria. Apoptosis. 12:573–591. 2007. View Article : Google Scholar : PubMed/NCBI
51	Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, Walters H, Tantawy MN, Fu A, Manning HC, et al: Acetate dependence of tumors. Cell. 159:1591–1602. 2014. View Article : Google Scholar : PubMed/NCBI
52	Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, Nannepaga S, Piccirillo SG, Kovacs Z, Foong C, et al: Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell. 159:1603–1614. 2014. View Article : Google Scholar : PubMed/NCBI
53	Chen R, Xu M, Nagati JS, Hogg RT, Das A, Gerard RD and Garcia JA: The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment. PLoS One. 10:e01165152015. View Article : Google Scholar : PubMed/NCBI
54	Marques C, Oliveira CS, Alves S, Chaves SR, Coutinho OP, Côrte-Real M and Preto A: Acetate-induced apoptosis in colorectal carcinoma cells involves lysosomal membrane permeabilization and cathepsin D release. Cell Death Dis. 4:e5072013. View Article : Google Scholar : PubMed/NCBI
55	Oliveira CS, Pereira H, Alves S, Castro L, Baltazar F, Chaves SR, Preto A and Côrte-Real M: Cathepsin D protects colorectal cancer cells from acetate-induced apoptosis through autophagy-independent degradation of damaged mitochondria. Cell Death Dis. 6:e17882015. View Article : Google Scholar : PubMed/NCBI
56	Nogueira V and Hay N: Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy. Clin Cancer Res. 19:4309–4314. 2013. View Article : Google Scholar : PubMed/NCBI
57	Glasauer A and Chandel NS: Targeting antioxidants for cancer therapy. Biochem Pharmacol. 92:90–101. 2014. View Article : Google Scholar : PubMed/NCBI
58	Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR and Chandel NS: Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA. 107:8788–8793. 2010. View Article : Google Scholar : PubMed/NCBI
59	Moon DO, Kim MO, Choi YH, Hyun JW, Chang WY and Kim GY: Butein induces G(2)/M phase arrest and apoptosis in human hepatoma cancer cells through ROS generation. Cancer Lett. 288:204–213. 2010. View Article : Google Scholar : PubMed/NCBI
60	Fiser B, Szori M, Jójárt B, Izsák R, Csizmadia IG and Viskolcz B: Antioxidant potential of glutathione: A theoretical study. J Phys Chem B. 115:11269–11277. 2011. View Article : Google Scholar : PubMed/NCBI
61	Teoh-Fitzgerald ML, Fitzgerald MP, Zhong W, Askeland RW and Domann FE: Epigenetic reprogramming governs EcSOD expression during human mammary epithelial cell differentiation, tumorigenesis and metastasis. Oncogene. 33:358–368. 2014. View Article : Google Scholar : PubMed/NCBI
62	Silani V: Editorial on the original article entitled ‘Genetic validation of a therapeutic target in a mouse model of ALS’ published in the Science Translational Medicine on August 6, 2014. Ann Transl Med. 3:(Suppl 1). S272015.PubMed/NCBI
63	Chiang YT, Yen YW and Lo CL: Reactive oxygen species and glutathione dual redox-responsive micelles for selective cytotoxicity of cancer. Biomaterials. 61:150–161. 2015. View Article : Google Scholar : PubMed/NCBI
64	Qiao YL, Dawsey SM, Kamangar F, Fan JH, Abnet CC, Sun XD, Johnson LL, Gail MH, Dong ZW, Yu B, et al: Total and cancer mortality after supplementation with vitamins and minerals: Follow-up of the Linxian General Population Nutrition Intervention Trial. J Natl Cancer Inst. 101:507–518. 2009. View Article : Google Scholar : PubMed/NCBI
65	Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, Minasian LM, Ford LG, Parnes HL, Gaziano JM, et al: Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 306:1549–1556. 2011. View Article : Google Scholar : PubMed/NCBI
66	Brosnan JT and Brosnan ME: Branched-chain amino acids: Enzyme and substrate regulation. J Nutr. 136:(Suppl). 207S–211S. 2006.PubMed/NCBI
67	Zhu X, Herrera G and Ochoa JB: Immunosupression and infection after major surgery: A nutritional deficiency. Crit Care Clin. 26:491–500. 2010. View Article : Google Scholar : PubMed/NCBI
68	Phillips MM, Sheaff MT and Szlosarek PW: Targeting arginine-dependent cancers with arginine-degrading enzymes: Opportunities and challenges. Cancer Res Treat. 45:251–262. 2013. View Article : Google Scholar : PubMed/NCBI
69	Platten M, Wick W and Van den Eynde BJ: Tryptophan catabolism in cancer: Beyond IDO and tryptophan depletion. Cancer Res. 72:5435–5440. 2012. View Article : Google Scholar : PubMed/NCBI