Abstract
Background
Head and neck cancers are the seventh most common type of cancer worldwide, with almost half of the cases affecting the oral cavity. Oral squamous cell carcinoma (OSCC) is the most common form of oral cancer, showing poor prognosis and high mortality. OSCC molecular pathogenesis is complex, resulting from a wide range of events that involve the interplay between genetic mutations and altered levels of transcripts, proteins, and metabolites. Metabolomics is a recently developed sub-area of omics sciences focused on the comprehensive analysis of small molecules involved in several biological pathways by high throughput technologies.
Aim of review
This review summarizes and evaluates studies focused on the metabolomics analysis of OSCC and oral premalignant disorders to better interpret the complex process of oral carcinogenesis. Additionally, the metabolic biomarkers signatures identified so far are also included. Moreover, we discuss the limitations of these studies and make suggestions for future investigations.
Key scientific concepts
Although many questions about the metabolic features of OSCC have already been answered in metabolomic studies, further validation and optimization are still required to translate these findings into clinical applications.
Similar content being viewed by others
References
Armitage, E. G., & Barbas, C. (2014). Metabolomics in cancer biomarker discovery: Current trends and future perspectives. Journal of Pharmaceutical and Biomedical Analysis, 87, 1–11. https://doi.org/10.1016/j.jpba.2013.08.041.
Al-Hebshi, N. N., Borgnakke, W. S., & Johnson, N. W. (2019). The microbiome of oral squamous cell carcinomas: a functional perspective. Current Oral Health Reports, 6, 145–160.
Bag, S., Banerjee, D. R., Basak, A., Das, A. K., Pal, M., Banerjee, R., et al. (2015). NMR ((1)H and (13)C) based signatures of abnormal choline metabolism in oral squamous cell carcinoma with no prominent Warburg effect. Biochemical and Biophysical Research Communications, 459(4), 574–578. https://doi.org/10.1016/j.bbrc.2015.02.149.
Beger, R. D. (2013). A review of applications of metabolomics in cancer. Metabolites, 3(3), 552–574. https://doi.org/10.3390/metabo3030552.
Beger, R. D., Dunn, W., Schmidt, M. A., Gross, S. S., Kirwan, J. A., Cascante, M., et al. (2016). Metabolomics enables precision medicine: “A White Paper, Community Perspective”. Metabolomics, 12(10), 149. https://doi.org/10.1007/s11306-016-1094-6.
Braakhuis, B. J., Tabor, M. P., Kummer, J. A., Leemans, C. R., & Brakenhoff, R. H. (2003). A genetic explanation of slaughter’s concept of field cancerization: Evidence and clinical implications. Cancer Research, 63(8), 1727–1730.
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424.
de Carvalho, A. C., Kowalski, L. P., Campos, A. H. J. F. M., Soares, F. A., Carvalho, A. L., & Vettore, A. L. (2012). Clinical significance of molecular alterations in histologically negative surgical margins of head and neck cancer patients. Oral Oncology, 48(3), 240–248. https://doi.org/10.1016/j.oraloncology.2011.10.018.
Chen, X., & Yu, D. (2019). Metabolomics study of oral cancers. Metabolomics, 15(2), 22. https://doi.org/10.1007/s11306-019-1483-8.
Cooke, M., Leeves, N., & White, C. (2003). Time profile of putrescine, cadaverine, indole and skatole in human saliva. Archives of Oral Biology, 48, 323–327.
Cramer, J. D., Burtness, B., Le, Q. T., & Ferris, R. L. (2019). The changing therapeutic landscape of head and neck cancer. Nature Reviews Clinical Oncology, 16(11), 669–683. https://doi.org/10.1038/s41571-019-0227-z.
DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., et al. (2007). Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. PNAS, 104(49), 19345–19350. https://doi.org/10.1073/pnas.0709747104.
Dettmer, K., Aronov, P. A., & Hammock, B. D. (2007). Mass spectrometry-based metabolomics. Mass Spectrometry Reviews, 26(1), 51–78. https://doi.org/10.1002/mas.20108.
Donczo, B., & Guttman, A. (2018). Biomedical analysis of formalin-fixed, paraffin-embedded tissue samples: The Holy Grail for molecular diagnostics. Journal of Pharmaceutical and Biomedical Analysis, 155, 125–134. https://doi.org/10.1016/j.jpba.2018.03.065.
Dotto, G. P., & Rustgi, A. K. (2016). Squamous cell cancers: A unified perspective on biology and genetics. Cancer Cell, 29(5), 622–637. https://doi.org/10.1016/j.ccell.2016.04.004.
Dudzik, D., Barbas-Bernardos, C., García, A., & Barbas, C. (2018). Quality assurance procedures for mass spectrometry untargeted metabolomics. A review. Journal of Pharmaceutical and Biomedical Analysis, 147, 149–173. https://doi.org/10.1016/j.jpba.2017.07.044.
El-Naggar, A. K., Chan, J. K., Grandis, J. R., Takata, T., & Slootweg, P. J. (2017). World Health Organization Classification of head and neck tumours. Lyon: International Agency for Research on Cancer.
Enomoto, Y., Kimoto, A., Suzuki, H., Nishiumi, S., Yoshida, M., & Komori, T. (2018). Exploring a novel screening method for patients with oral squamous cell carcinoma: A plasma metabolomics analysis. Kobe Journal of Medical Sciences, 64(1), E26–E35.
Gardner, A., Parkes, H. G., So, P.-W., & Carpenter, G. H. (2019). Determining bacterial and host contributions to the human salivary metabolome. Journal of Oral Microbiology, 11(1), 1617014. https://doi.org/10.1080/20002297.2019.1617014.
Glunde, K., Jacobs, M. A., & Bhujwalla, Z. (2006). Choline metabolism in cancer: implications for diagnosis and therapy. Expert Review of Molecular Diagnostics, 6(6), 821–829. https://doi.org/10.1586/14737159.6.6.821.
Goertzen, C., Mahdi, H., Laliberte, C., Meirson, T., Eymael, D., Gil-Henn, H., et al. (2018). Oral inflammation promotes oral squamous cell carcinoma invasion. Oncotarget, 9(49), 29047–29063.
Gupta, A., Gupta, S., & Mahdi, A. A. (2015). 1H NMR-derived serum metabolomics of leukoplakia and squamous cell carcinoma. Clinica Chimica Acta, 441, 47–55. https://doi.org/10.1016/j.cca.2014.12.003.
Hirschey, M. D., DeBerardinis, R. J., Diehl, A. M. E., Drew, J. E., Frezza, C., Green, M. F., et al. (2015). Dysregulated metabolism contributes to oncogenesis. Seminars in Cancer Biology, 35, S129–S150. https://doi.org/10.1016/j.semcancer.2015.10.002.
Hsu, C. W., Cheng, Y. T., Hsieh, Y. J., Chang, K. P., Hsueh, P. C., Chen, T. W., et al. (2019). Integrated analyses utilizing metabolomics and transcriptomics reveal perturbation of the polyamine pathway in oral cavity squamous cell carcinoma. Analytica Chimica Acta, 1050, 113–122. https://doi.org/10.1016/j.aca.2018.10.070.
Hu, S., Wang, J., Ji, E. H., Christison, T., Lopez, L., & Huang, Y. (2015). Targeted metabolomic analysis of head and neck cancer cells using high performance ion chromatography coupled with a Q Exactive HF Mass Spectrometer. Analytical Chemistry, 87(12), 6371–6379. https://doi.org/10.1021/acs.analchem.5b01350.
Ishikawa, S., Sugimoto, M., Edamatsu, K., Sugano, A., Kitabatake, K., & Iino, M. (2020). Discrimination of oral squamous cell carcinoma from oral lichen planus by salivary metabolomics. Oral Diseases, 26(1), 35–42. https://doi.org/10.1111/odi.13209.
Ishikawa, S., Sugimoto, M., Kitabatake, K., Sugano, A., Nakamura, M., Kaneko, M., et al. (2016). Identification of salivary metabolomic biomarkers for oral cancer screening. Scientific Reports, 6, 31520. https://doi.org/10.1038/srep31520.
Ishikawa, S., Sugimoto, M., Kitabatake, K., Tu, M., Sugano, A., Yamamori, I., et al. (2017). Effect of timing of collection of salivary metabolomic biomarkers on oral cancer detection. Amino Acids, 49(4), 761–770. https://doi.org/10.1007/s00726-017-2378-5.
Ishikawa, S., Wong, D. T. W., Sugimoto, M., Gleber-Netto, F. O., Li, F., Tu, M., et al. (2019). Identification of salivary metabolites for oral squamous cell carcinoma and oral epithelial dysplasia screening from persistent suspicious oral mucosal lesions. Clinical Oral Investigations, 23(9), 3557–3563. https://doi.org/10.1007/s00784-018-2777-3.
Javed, F., & Warnakulasuriya, S. (2016). Is there a relationship between periodontal disease and oral cancer? A systematic review of currently available evidence. Critical Reviews in Oncology/Hematology, 97, 197–205. https://doi.org/10.1016/j.critrevonc.2015.08.018.
Ji, E. H., Cui, L., Yuan, X., Cheng, S., Messadi, D., Yan, X., et al. (2017). Metabolomic analysis of human oral cancer cells with adenylate kinase 2 or phosphorylate glycerol kinase 1 inhibition. Journal of Cancer, 8(2), 298–304. https://doi.org/10.7150/jca.17521.
Kamarajan, P., Rajendiran, T. M., Kinchen, J., Bermúdez, M., Danciu, T., & Kapila, Y. L. (2017). Head and neck squamous cell carcinoma metabolism draws on glutaminolysis, and stemness is specifically regulated by glutaminolysis via aldehyde dehydrogenase. Journal of Proteome Research. https://doi.org/10.1021/acs.jproteome.6b00936.
Kelly, A. D., Breitkopf, S. B., Yuan, M., Goldsmith, J., Spentzos, D., & Asara, J. M. (2011). Metabolomic profiling from formalin-fixed, paraffin-embedded tumor tissue using targeted LC/MS/MS: Application in sarcoma. PLoS ONE. https://doi.org/10.1371/journal.pone.0025357.
Khanna, R., Kumar, K., & Roy, R. (2018). A case study of primary malignancy of buccal mucosa using proton HR-MAS NMR spectroscopy on tissue specimens. Journal of Oral Biology and Craniofacial Research, 8(1), 68–72. https://doi.org/10.1016/j.jobcr.2017.09.011.
Kirwan, J. A., Brennan, L., Broadhurst, D., Fiehn, O., Cascante, M., Dunn, W. B., et al. (2018). Preanalytical processing and biobanking procedures of biological samples for metabolomics research: A white paper, community perspective (for “Precision medicine and pharmacometabolomics task group”—The metabolomics society initiative). Clinical Chemistry, 64(8), 1158–1182. https://doi.org/10.1373/clinchem.2018.287045.
Knobloch, T. J., Ryan, N. M., Bruschweiler-Li, L., Wang, C., Bernier, M. C., Somogyi, A., et al. (2019). Metabolic regulation of glycolysis and AMP activated protein kinase pathways during black raspberry-mediated oral cancer chemoprevention. Metabolites. https://doi.org/10.3390/metabo9070140.
Koh, T., Murakami, Y., Tanaka, S., Machino, M., Onuma, H., Kaneko, M., et al. (2013). Changes of metabolic profiles in an oral squamous cell carcinoma cell line induced by eugenol. Vivo, 27(2), 233–243.
Kong, X., Yang, X., Zhou, J., Chen, S., Li, X., Jian, F., et al. (2015). Analysis of plasma metabolic biomarkers in the development of 4-nitroquinoline-1-oxide-induced oral carcinogenesis in rats. Oncology Letters, 9(1), 283–289. https://doi.org/10.3892/ol.2014.2619.
Lee, N., Jang, W. J., Seo, J. H., Lee, S., & Jeong, C. H. (2019). 2-deoxy-D-glucose-induced metabolic alteration in human oral squamous SCC15 cells: Involvement of N-glycosylation of Axl and met. Metabolites, 9(9), E188.
Liberti, M. V., & Locasale, J. W. (2016). The Warburg effect: How does it benefit cancer cells? Trends in Biochemical Sciences, 41(3), 211–218. https://doi.org/10.1016/j.tibs.2016.01.004.
Liebsch, C., Pitchika, V., Pink, C., Samietz, S., Kastenmüller, G., Artati, A., et al. (2019). The saliva metabolome in association to oral health status. Journal of Dental Research, 98(6), 642–651. https://doi.org/10.1177/0022034519842853.
Lohavanichbutr, P., Zhang, Y., Wang, P., Gu, H., Nagana Gowda, G. A., Djukovic, D., et al. (2018). Salivary metabolite profiling distinguishes patients with oral cavity squamous cell carcinoma from normal controls. PLoS ONE, 13(9), e0204249. https://doi.org/10.1371/journal.pone.0204249.
Lu, W., Su, X., Klein, M. S., Lewis, I. A., Fiehn, O., & Rabinowitz, J. D. (2017). Metabolite measurement: Pitfalls to avoid and practices to follow. Annual review of biochemistry, 86, 277–304. https://doi.org/10.1146/annurev-biochem-061516-044952.
Ly, A., Buck, A., Balluff, B., Sun, N., Gorzolka, K., Feuchtinger, A., et al. (2016). High-mass-resolution MALDI mass spectrometry imaging of metabolites from formalin-fixed paraffin-embedded tissue. Nature Protocols, 11(8), 1428–1443. https://doi.org/10.1038/nprot.2016.081.
Malik, U. U., Zarina, S., & Pennington, S. R. (2016). Oral squamous cell carcinoma: Key clinical questions, biomarker discovery, and the role of proteomics. Archives of Oral Biology, 63, 53–65. https://doi.org/10.1016/j.archoralbio.2015.11.017.
Moreno-Sánchez, R., Marín-Hernándeza, A., Saavedraa, E., Pardob, J. P., Ralphc, S. J., & Rodríguez-Enríqueza, S. (2014). Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism. The International Journal of Biochemistry & Cell Biology, 50, 10–23.
Morishima, H., Washio, J., Kitamura, J., Shinohara, Y., Takahashi, T., & Takahashi, N. (2017). Real-time monitoring system for evaluating the acid-producing activity of oral squamous cell carcinoma cells at different environmental pH. Scientific Reports, 7(1), 10092.
Musharraf, S. G., Shahid, N., Naqvi, S. M. A., Saleem, M., Siddiqui, A. J., & Ali, A. (2016). Metabolite profiling of preneoplastic and neoplastic lesions of oral cavity tissue samples revealed a biomarker pattern. Scientific Reports, 6, 38985. https://doi.org/10.1038/srep38985.
Naz, S., Moreira Dos Santos, D. C., García, A., & Barbas, C. (2014a). Analytical protocols based on LC-MS, GC-MS and CE-MS for nontargeted metabolomics of biological tissues. Bioanalysis, 6(12), 1657–1677. https://doi.org/10.4155/bio.14.119.
Naz, S., Vallejo, M., García, A., & Barbas, C. (2014b). Method validation strategies involved in non-targeted metabolomics. Journal of Chromatography A, 1353, 99–105. https://doi.org/10.1016/j.chroma.2014.04.071.
Ogawa, T., Washio, J., Takahashi, T., Echigo, S., & Takahashi, N. (2014). Glucose and glutamine metabolism in oral squamous cell carcinoma: Insight from a quantitative metabolomic approach. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 118(2), 218–225. https://doi.org/10.1016/j.oooo.2014.04.003.
Ohshima, M., Sugahara, K., Kasahara, K., & Katakura, A. (2017). Metabolomic analysis of the saliva of Japanese patients with oral squamous cell carcinoma. Oncology Reports, 37(5), 2727–2734. https://doi.org/10.3892/or.2017.5561.
Parlatescu, I., Gheorghe, C., Coculescu, E., & Tovaru, S. (2014). Oral leukoplakia—An update. Maedica, 9(1), 88–93.
Paul, A., Srivastava, S., Roy, R., Anand, A., Gaurav, K., Husain, N., et al. (2020). Malignancy prediction among tissues from Oral SCC patients including neck invasions: A 1H HRMAS NMR based metabolomic study. Metabolomics, 16(3), 38. https://doi.org/10.1007/s11306-020-01660-8.
Petersen, P. E. (2009). Oral cancer prevention and control—The approach of the World Health Organization. Oral Oncology, 45(4–5), 454–460. https://doi.org/10.1016/j.oraloncology.2008.05.023.
Rojo, D., Canuto, G. A. B., Castilho-Martins, E. A., Tavares, M. F. M., Barbas, C., López-Gonzálvez, Á., et al. (2015). A multiplatform metabolomic approach to the basis of antimonial action and resistance in Leishmania infantum. PLoS ONE, 10(7), e0130675. https://doi.org/10.1371/journal.pone.0130675.
Römisch-Margl, W., Prehn, C., Bogumil, R., Röhring, C., Suhre, K., & Adamski, J. (2012). Procedure for tissue sample preparation and metabolite extraction for high-throughput targeted metabolomics. Metabolomics, 8(1), 133–142. https://doi.org/10.1007/s11306-011-0293-4.
Sakagami, H., Shimada, C., Kanda, Y., Amano, O., Sugimoto, M., Ota, S., et al. (2015). Effects of 3-styrylchromones on metabolic profiles and cell death in oral squamous cell carcinoma cells. Toxicology Reports, 2, 1281–1290. https://doi.org/10.1016/j.toxrep.2015.09.009.
Sakagami, H., Sugimoto, M., Kanda, Y., Murakami, Y., Amano, O., Saitoh, J., et al. (2018). Changes in metabolic profiles of human oral cells by benzylidene ascorbates and eugenol. Medicines, 5(4), 116. https://doi.org/10.3390/medicines5040116.
Sakagami, H., Sugimoto, M., Tanaka, S., Onuma, H., Ota, S., Kaneko, M., et al. (2014). Metabolomic profiling of sodium fluoride-induced cytotoxicity in an oral squamous cell carcinoma cell line. Metabolomics, 10(2), 270–279. https://doi.org/10.1007/s11306-013-0576-z.
Sant’Anna-Silva, A. C. B., Santos, G. C., Campos, S. P. C., Gomes, A. M. O., Pérez-Valencia, J. A., & Rumjanek, F. D. (2018). Metabolic profile of oral squamous carcinoma cell lines relies on a higher demand of lipid metabolism in metastatic cells. Frontiers in Oncology, 8, 13. https://doi.org/10.3389/fonc.2018.00013.
Sarode, G., Sarode, S. C., Tupkari, J., & Patil, S. (2017). Is oral squamous cell carcinoma unique in terms of intra- and inter-tumoral heterogeneity? Translational Research in Oral Oncology, 2, 1–6. https://doi.org/10.1177/2057178x17703578.
Shahid, N., Iqbal, A., Siddiqui, A. J., Shoaib, M., & Musharraf, S. G. (2019). Plasma metabolite profiling and chemometric analyses of tobacco snuff dippers and patients with oral cancer: Relationship between metabolic signatures. Head and Neck, 41(2), 291–300. https://doi.org/10.1002/hed.25511.
Sharma, P. S., Nandimath, K. R., Hiremath, S. V., & Burde, K. (2020). Alteration of plasma free amino acids’ level in oral squamous cell carcinoma patients using High Performance Liquid Chromatography. Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 32(1), 65–71. https://doi.org/10.1016/j.ajoms.2019.07.003.
Shigeyama, H., Wang, T., Ichinose, M., Ansai, T., & Lee, S. W. (2019). Identification of volatile metabolites in human saliva from patients with oral squamous cell carcinoma via zeolite-based thin-film microextraction coupled with GC–MS. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 1104, 49–58. https://doi.org/10.1016/j.jchromb.2018.11.002.
Shin, J. M., Kamarajan, P., Fenno, J. C., Rickard, A. H., & Kapila, Y. L. (2016). Metabolomics of head and neck cancer: a mini-review. Frontiers in Physiology, 7, 526.
Song, X., Yang, X., Narayanan, R., Shankar, V., Ethiraj, S., Xiang, W., et al. (2020). Oral squamous cell carcinoma diagnosed from saliva metabolic profiling. PNAS. https://doi.org/10.1073/pnas.2001395117.
Speight, P. M., Khurram, S. A., & Kujan, O. (2018). Oral potentially malignant disorders: Risk of progression to malignancy. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 125(6), 612–627. https://doi.org/10.1016/j.oooo.2017.12.011.
Sridharan, G., Ramani, P., & Patankar, S. (2017). Serum metabolomics in oral leukoplakia and oral squamous cell carcinoma. Journal of Cancer Research and Therapeutics, 13(3), 556–561. https://doi.org/10.4103/jcrt.JCRT.
Sridharan, G., Ramani, P., Patankar, S., & Vijayaraghavan, R. (2019). Evaluation of salivary metabolomics in oral leukoplakia and oral squamous cell carcinoma. Journal of Oral Pathology & Medicine, 48(4), 299–306. https://doi.org/10.1111/jop.12835.
Srivastava, S., Roy, R., Gupta, V., Tiwari, A., Srivastava, A. N., & Sonkar, A. A. (2011). Proton HR-MAS MR spectroscopy of oral squamous cell carcinoma tissues: An ex vivo study to identify malignancy induced metabolic fingerprints. Metabolomics, 7(2), 278–288. https://doi.org/10.1007/s11306-010-0253-4.
Stanta, G., & Bonin, S. (2018). Overview on clinical relevance of intra-tumor heterogeneity. Frontiers in Medicine, 5, 85. https://doi.org/10.3389/fmed.2018.00085.
Sugimoto, M., Saruta, J., Matsuki, C., To, M., Onuma, H., Kaneko, M., et al. (2013). Physiological and environmental parameters associated with mass spectrometry-based salivary metabolomic profiles. Metabolomics, 9, 454–463. https://doi.org/10.1007/s11306-012-0464-y.
Sugimoto, M., Wong, D. T., Hirayama, A., Soga, T., & Tomitta, M. (2010). Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles. Metabolomics, 6(1), 78–95. https://doi.org/10.1007/s11306-009-0178-y.
Sumner, L. W., Amberg, A., Barrett, D., Beale, M. H., Beger, R., Daykin, C. A., et al. (2007). Proposed minimum reporting standards for chemical analysis Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI). Metabolomics, 3(3), 211–221. https://doi.org/10.1007/s11306-007-0082-2.
Takeda, I., Stretch, C., Barnaby, P., Bhatnager, K., Rankin, K., Fub, H., et al. (2009). Understanding the human salivary metabolome. NMR in Biomedicine, 22(6), 577–584. https://doi.org/10.1002/nbm.1369.
Tiziani, S., Lopes, V., & Günther, U. L. (2009). Early stage diagnosis of oral cancer using 1H NMR-Based metabolomics. Neoplasia, 11(3), 269–276. https://doi.org/10.1593/neo.81396.
Tripathi, P., Kamarajan, P., Somashekar, B. S., MacKinnon, N., Chinnayian, A. M., Kapila, Y. L., et al. (2012). Delineating metabolic signatures of head and neck squamous cell carcinoma: phospholipase A2, potential therapeutic target. The International Journal of Biochemistry & Cell Biology, 44(11), 1852–1861.
Tsai, C. K., Lin, C. Y., Kang, C. J., Liao, C.-T., Wang, W.-L., Chiang, M.-H., et al. (2020). Nuclear magnetic resonance metabolomics biomarkers for identifying high risk patients with extranodal extension in oral squamous cell carcinoma. Journal of Clinical Medicine, 9(4), E951. https://doi.org/10.3390/jcm9040951.
Wang, H., Chen, J., Feng, Y., Zhou, W., Zhang, J., Yu, Y., et al. (2015). 1H nuclear magnetic resonance-based extracellular metabolomic analysis of multidrug resistant Tca8113 oral squamous carcinoma cells. Oncology Letters, 9(6), 2551–2559. https://doi.org/10.3892/ol.2015.3128.
Wang, J., Christison, T. T., Misuno, K., Lopez, L., Huhmer, A. F., Huang, Y., et al. (2014a). Metabolomic profiling of anionic metabolites in head and neck cancer cells by capillary ion chromatography with orbitrap mass spectrometry. Analytical Chemistry, 86(10), 5116–5124. https://doi.org/10.1021/ac500951v.
Wang, Q., Gao, P., Cheng, F., Wang, X., & Duan, Y. (2014b). Measurement of salivary metabolite biomarkers for early monitoring of oral cancer with ultra performance liquid chromatography–mass spectrometry. Talanta, 119, 299–305. https://doi.org/10.1016/j.talanta.2013.11.008.
Wang, Q., Gao, P., Wang, X., & Duan, Y. (2014c). The early diagnosis and monitoring of squamous cell carcinoma via saliva metabolomics. Scientific Reports, 4, 6802. https://doi.org/10.1038/srep06802.
Wang, Q., Gao, P., Wang, X., & Duan, Y. (2014d). Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma. Clinica Chimica Acta, 427, 79–85. https://doi.org/10.1016/j.cca.2013.10.004.
Weckx, A., Riekert, M., Grandoch, A., Schick, V., Zöller, J. E., & Kreppel, M. (2019). Time to recurrence and patient survival in recurrent oral squamous cell carcinoma. Oral Oncology, 94, 8–13. https://doi.org/10.1016/j.oraloncology.2019.05.002.
Wei, J., Xie, G., Zhou, Z., Shi, P., Qiu, Y., Zheng, X., et al. (2011). Salivary metabolite signatures of oral cancer and leukoplakia. International Journal of Cancer, 129(9), 2207–2217. https://doi.org/10.1002/ijc.25881.
Wishart, D. S. (2016). Emerging applications of metabolomics in drug discovery and precision medicine. Nature Reviews Drug Discovery, 15(7), 473–484. https://doi.org/10.1038/nrd.2016.32.
Wojakowska, A., Marczak, Ł., Jelonek, K., Polanski, K., Widlak, P., & Pietrowska, M. (2015). An optimized method of metabolite extraction from formalin-fixed paraffin-embedded tissue for GC/MS analysis. PLoS ONE, 10(9), e0136902. https://doi.org/10.1371/journal.pone.0136902.
Xie, G. X., Chen, T. L., Qiu, Y. P., Shi, P., Zheng, X. J., Su, M. M., et al. (2012). Urine metabolite profiling offers potential early diagnosis of oral cancer. Metabolomics, 8, 220–231. https://doi.org/10.1007/s11306-011-0302-7.
Yan, S. K., Wei, B. J., Lin, Z. Y., Yang, Y., Zhou, Z. T., & Zhang, W. D. (2008). A metabonomic approach to the diagnosis of oral squamous cell carcinoma, oral lichen planus and oral leukoplakia. Oral Oncology, 44(5), 477–483. https://doi.org/10.1016/j.oraloncology.2007.06.007.
Yang, Q., Sun, H., Wang, X., Yu, X., Zhang, J., Guo, B., et al. (2020a). Metabolic changes during malignant transformation in primary cells of oral lichen planus: Succinate accumulation and tumour suppression. Journal of Cellular and Molecular Medicine, 24(2), 1179–1188. https://doi.org/10.1111/jcmm.14376.
Yang, X. H., Zhang, X. X., Jing, Y., Ding, L., Fu, Y., Wang, S., et al. (2019). Amino acids signatures of distance-related surgical margins of oral squamous cell carcinoma. EBioMedicine, 48, 81–91. https://doi.org/10.1016/j.ebiom.2019.10.005.
Yang, X. H., Jing, Y., Wang, S., Ding, F., Zhang, X. X., Chen, S., et al. (2020). Integrated non-targeted and targeted metabolomics uncovers amino acid markers of oral squamous cell carcinoma. Frontiers in Oncology, 10, 426.
Ye, G., Liu, Y., Yin, P., Zeng, Z., Huang, Q., Kong, H., et al. (2014). Study of induction chemotherapy efficacy in oral squamous cell carcinoma using pseudotargeted metabolomics. Journal of Proteome Research, 13(4), 1994–2004. https://doi.org/10.1021/pr4011298.
Yin, P., Lehmann, R., & Xu, G. (2017). Effects of pre-analytical processes on blood samples used in metabolomics studies. Analytical and Bioanalytical Chemistry, 407(17), 4879–4892. https://doi.org/10.1007/s00216-015-8565-x.
Yoshimura, N., Yamada, S.-I., Aizawa, H., Xiao, T., Nishimaki, F., & Kurita, H. (2019). Glycogen metabolism in an oral dysplastic/cancerous (iodine-negative) epithelium: Glycogen was consumed in the pentose phosphate pathway, not in glycolysis. Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 31(4), 288–294. https://doi.org/10.1016/j.ajoms.2019.01.002.
Yuan, M., Breitkopf, S. B., Yang, X., & Asara, J. M. (2012). A positive/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nature protocols, 7(5), 872–881. https://doi.org/10.1038/nprot.2012.024.
Zandberg, D. P., Tallon, L. J., Nagaraj, S., Sadzewicz, L. K., Zhang, Y., Strome, M. B., et al. (2019). Intratumor genetic heterogeneity in squamous cell carcinoma of the oral cavity. Head and Neck, 41(8), 2514–2524. https://doi.org/10.1002/hed.25719.
Zhang, A., Sun, H., & Wang, X. (2012). Saliva metabolomics opens door to biomarker discovery, disease diagnosis, and treatment. Applied Biochemistry and Biotechnology, 168(6), 1718–1727. https://doi.org/10.1007/s12010-012-9891-5.
Zhou, J., Xu, B., Huang, J., Jia, X., Xue, J., Shi, X., et al. (2009). 1H NMR-based metabonomic and pattern recognition analysis for detection of oral squamous cell carcinoma. Clinica Chimica Acta, 401(1–2), 8–13. https://doi.org/10.1016/j.cca.2008.10.030.
Funding
This study was financed in part by the Coordination for the Improvement of Higher Education Personnel (CAPES)/Brazil, Finance code 001. FFDA, RRMC and TSFP receive CAPES scholarship and JGV and LSDA receives (National Council for Scientific and Technological Development) CNPq/Brazil scholarship. CCG, FPF and RSG are research fellows at CNPq/Brazil.
Author information
Authors and Affiliations
Contributions
RSG conceptualized and refined research ideas. FFDA, JGV and LSDA conducted literature search and selected the studies to be included in the review. JGV, FFDA, LSDA, and TFSP drafted the manuscript and tables. TSFP, FFDA and JGV prepared the figures. All authors edited the manuscript. FFDA, GABC, JGV, and TFSP prepared Online Resources. GABC conducted chemical nomenclature standardization and established the criteria for the construction of Venn Diagrams and contributed with analytical chemistry expertise. TSFP, FPF, CCG and RSG contributed with oral pathology expertise. JGV, FFDA, TFSP, FPF, CCG, RRMC, GABC, and RSG reviewed critically the manuscript. All authors read and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
Jéssica Gardone Vitório, Filipe Fideles Duarte-Andrade, Thaís dos Santos Fontes Pereira, Felipe Paiva Fonseca, Larissa Stefhanne Damasceno Amorim, Roberta Rayra Martins-Chaves, Carolina Cavaliéri Gomes, Gisele André Baptista Canuto, and Ricardo Santiago Gomez declares that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
11306_2020_1727_MOESM2_ESM.xlsx
Online Resource 2. Single metabolic biomarkers for Oral Squamous Cell Carcinoma (OSCC) diagnosis proposed by metabolomic studies (XLSX 297 kb)
11306_2020_1727_MOESM4_ESM.tif
Online Resource 4. Convergences among studies employing distinct techniques to evaluate OSCC in comparison to healthy subjects Overlap among studies employing a. plasma, serum, and urine samples, b. tissue specimens, or c. saliva to uncover the metabolic landscape of OSCC utilizing different analytical platforms (TIF 1456 kb)
11306_2020_1727_MOESM5_ESM.tif
Online resource 5. Overlaps among salivary-based investigantions comparing OSCC and healthy subjects independently of the analytical platform that was employed Convergences among studies based on salivary samples. The article of Shigeyama et al. 2019 was not included in this Venn Diagram since it was the only one that evaluated exclusively volatile organic compounds. Given the higher number of publications using tissue samples and plasma, serum and urine, Venn diagrams were not constructed, and the overlaps are presented in the form of tables to facilitate interpretation. (TIF 1520 kb)
11306_2020_1727_MOESM6_ESM.docx
Online Resource 6. Overlaps among plasma, serum and urine-based investigations comparing OSCC and healthy controls (DOCX 16 kb)
Rights and permissions
About this article
Cite this article
Vitório, J.G., Duarte-Andrade, F.F., dos Santos Fontes Pereira, T. et al. Metabolic landscape of oral squamous cell carcinoma. Metabolomics 16, 105 (2020). https://doi.org/10.1007/s11306-020-01727-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11306-020-01727-6