Deciphering the ovarian cancer ascites fluid peptidome

Clinical Proteomics

Vathany Kulasingam¹  Eleftherios P Diamandis²  Christopher R Smith²  Felix Leung²  Anand Bery¹ 

[1] Department of Clinical Biochemistry, University Health Network, Toronto, ON, Canada;Department of Pathology and Laboratory Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

关键词: Peptidome;    Ascites fluid;    Ovarian cancer;    Mass spectrometry;    Early diagnosis;    Biomarker;   

Others  :  802773
DOI  :  10.1186/1559-0275-11-13

 received in 2013-09-30, accepted in 2014-01-24,  发布年份 2014

【 摘 要 】

Background

Conventional proteomic approaches have thus far been unable to identify novel serum biomarkers for ovarian cancer that are more sensitive and specific than the current clinically used marker, CA-125. Because endogenous peptides are smaller and may enter the circulation more easily than proteins, a focus on the low-molecular-weight region may reveal novel biomarkers with enhanced sensitivity and specificity. In this study, we deciphered the peptidome of ascites fluid from 3 ovarian cancer patients and 3 benign individuals (ascites fluid from patients with liver cirrhosis).

Results

Following ultrafiltration of the ascites fluids to remove larger proteins, each filtrate was subjected to solid phase extraction and fractionated using strong cation exchange chromatography. The resultant fractions were analyzed using an Orbitrap mass spectrometer. We identified over 2000 unique endogenous peptides derived from 259 proteins. We then catalogued over 777 peptides that were found only in ovarian cancer ascites. Our list of peptides found in ovarian cancer specimens includes fragments derived from the proteins vitronectin, transketolase and haptoglobin.

Conclusions

Peptidomics may uncover previously undiscovered disease-specific endogenous peptides that warrant further investigation as biomarkers for ovarian cancer.

【 授权许可】

   
2014 Bery et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Diamandis EP: Cancer biomarkers: can we turn recent failures into success? J Natl Cancer Inst 2010, 102:1462-1467.
• [2]Fredolini C, Meani F, Luchini A, Zhou W, Russo P, Ross M, Patanarut A, Tamburro D, Gambara G, Ornstein D, Odicino F, Ragnoli M, Ravaggi A, Novelli F, Collura D, D’Urso L, Muto G, Belluco C, Pecorelli S, Liotta L, Petricoin EF 3rd: Investigation of the ovarian and prostate cancer peptidome for candidate early detection markers using a novel nanoparticle biomarker capture technology. AAPS J 2010, 12:504-518.
• [3]Leichtle A, Dufour JF, Fiedler GM: Potentials and pitfalls of clinical peptidomics and metabolomics. Swiss Med Wkly 2013, 143:0.
• [4]Kulasingam V, Diamandis EP: Strategies for discovering novel cancer biomarkers through utilization of emerging technologies. Nat Clin Pract Oncol 2008, 5:588-599.
• [5]Liotta LA, Ferrari M, Petricoin E: Clinical proteomics: written in blood. Nature 2003, 425:905.
• [6]Hu L, Ye M, Zou H: Recent advances in mass spectrometry-based peptidome analysis. Expert Rev Proteomics 2009, 6:433-447.
• [7]Tammen H, Zucht HD, Budde P: Oncopeptidomics–a commentary on opportunities and limitations. Cancer Lett 2007, 249:80-86.
• [8]Villanueva J, Shaffer DR, Philip J, Chaparro CA, Erdjument-Bromage H, Olshen AB, Fleisher M, Lilja H, Brogi E, Boyd J, Sanchez-Carbayo M, Holland EC, Cordon-Cardo C, Scher HI, Tempst P: Differential exoprotease activities confer tumor-specific serum peptidome patterns. J Clin Invest 2006, 116:271-284.
• [9]Fiedler GM, Leichtle AB, Kase J, Baumann S, Ceglarek U, Felix K, Conrad T, Witzigmann H, Weimann A, Schutte C, Hauss J, Buchler M, Thiery J: Serum peptidome profiling revealed platelet factor 4 as a potential discriminating Peptide associated with pancreatic cancer. Clin Cancer Res 2009, 15:3812-3819.
• [10]Lopez MF, Mikulskis A, Kuzdzal S, Golenko E, Petricoin EF 3rd, Liotta LA, Patton WF, Whiteley GR, Rosenblatt K, Gurnani P, Nandi A, Neill S, Cullen S, O’Gorman M, Sarracino D, Lynch C, Johnson A, McKenzie W, Fishman D: A novel, high-throughput workflow for discovery and identification of serum carrier protein-bound peptide biomarker candidates in ovarian cancer samples. Clin Chem 2007, 53:1067-1074.
• [11]Bhoola S, Hoskins WJ: Diagnosis and management of epithelial ovarian cancer. Obstet Gynecol 2006, 107:1399-1410.
• [12]Leung F, Diamandis EP, Kulasingam V: From bench to bedside: discovery of ovarian cancer biomarkers using high-throughput technologies in the past decade. Biomark Med 2012, 6:613-625.
• [13]Diamandis EP, Yousef GM: Human tissue kallikreins: a family of new cancer biomarkers. Clin Chem 2002, 48:1198-1205.
• [14]Attallah AM, Badr El-Din NK, Omran MM, Farid K, El-Wahab AH, El-Bendary M, El-Dosoky I: Assessment of matrix metalloproteinase-1 for marking liver cirrhosis in chronic hepatitis C patients. Egypt J Immunol 2011, 18:33-42.
• [15]Caramelo C, Fernandez-Gallardo S, Santos JC, Inarrea P, Sanchez-Crespo M, Lopez-Novoa JM, Hernando L: Increased levels of platelet-activating factor in blood from patients with cirrhosis of the liver. Eur J Clin Invest 1987, 17:7-11.
• [16]El-Gindy I, El Rahman AT, El-Alim MA, Zaki SS: Diagnostic potential of serum matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 as non-invasive markers of hepatic fibrosis in patients with HCV related chronic liver disease. Egypt J Immunol 2003, 10:27-35.
• [17]Lichtinghagen R, Breitenstein K, Arndt B, Kuhbacher T, Boker KH: Comparison of matrix metalloproteinase expression in normal and cirrhotic human liver. Virchows Arch 1998, 432:153-158.
• [18]Kuk C, Kulasingam V, Gunawardana CG, Smith CR, Batruch I, Diamandis EP: Mining the ovarian cancer ascites proteome for potential ovarian cancer biomarkers. Mol Cell Proteomics 2009, 8:661-669.
• [19]Siwy J, Mullen W, Golovko I, Franke J, Zurbig P: Human urinary peptide database for multiple disease biomarker discovery. Proteomics Clin Appl 2011, 5:367-374.
• [20]Lorkova L, Pospisilova J, Lacheta J, Leahomschi S, Zivny J, Cibula D, Zivny J, Petrak J: Decreased concentrations of retinol-binding protein 4 in sera of epithelial ovarian cancer patients: a potential biomarker identified by proteomics. Oncol Rep 2012, 27:318-324.
• [21]Camuzcuoglu H, Arioz DT, Toy H, Kurt S, Celik H, Erel O: Serum paraoxonase and arylesterase activities in patients with epithelial ovarian cancer. Gynecol Oncol 2009, 112:481-485.
• [22]Agachan B, Yilmaz H, Ergen HA, Karaali ZE, Isbir T: Paraoxonase (PON1) 55 and 192 polymorphism and its effects to oxidant-antioxidant system in turkish patients with type 2 diabetes mellitus. Physiol Res 2005, 54:287-293.
• [23]Lurie G, Wilkens LR, Thompson PJ, McDuffie KE, Carney ME, Terada KY, Goodman MT: Genetic polymorphisms in the Paraoxonase 1 gene and risk of ovarian epithelial carcinoma. Cancer Epidemiol Biomarkers Prev 2008, 17:2070-2077.
• [24]Wu J, Xie X, Nie S, Buckanovich RJ, Lubman DM: Altered Expression of Sialylated Glycoproteins in Ovarian Cancer Sera Using Lectin-based ELISA Assay and Quantitative Glycoproteomics Analysis. J Proteome Res 2013, 12:3342-3352.
• [25]Szala A, Sawicki S, Swierzko AS, Szemraj J, Sniadecki M, Michalski M, Kaluzynski A, Lukasiewicz J, Maciejewska A, Wydra D, Kilpatrick DC, Matsushita M, Cedzynski M: Ficolin-2 and ficolin-3 in women with malignant and benign ovarian tumours. Cancer Immunol Immunother 2013, 62:1411-1419.
• [26]Wu J, Xie X, Liu Y, He J, Benitez R, Buckanovich RJ, Lubman DM: Identification and confirmation of differentially expressed fucosylated glycoproteins in the serum of ovarian cancer patients using a lectin array and LC-MS/MS. J Proteome Res 2012, 11:4541-4552.
• [27]Carduner L, Agniel R, Kellouche S, Picot CR, Blanc-Fournier C, Leroy-Dudal J, Carreiras F: Ovarian cancer ascites-derived vitronectin and fibronectin: Combined purification, molecular features and effects on cell response. Biochim Biophys Acta 2013, 1830:4885-4897.
• [28]Kenny HA, Kaur S, Coussens LM, Lengyel E: The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin. J Clin Invest 2008, 118:1367-1379.
• [29]Tang H, Yao L, Tao X, Yu Y, Chen M, Zhang R, Xu C: miR-9 functions as a tumor suppressor in ovarian serous carcinoma by targeting TLN1. Int J Mol Med 2013, 32:381-388.
• [30]Pan S, Cheng L, White JT, Lu W, Utleg AG, Yan X, Urban ND, Drescher CW, Hood L, Lin B: Quantitative proteomics analysis integrated with microarray data reveals that extracellular matrix proteins, catenins, and p53 binding protein 1 are important for chemotherapy response in ovarian cancers. OMICS 2009, 13:345-354.
• [31]Krockenberger M, Honig A, Rieger L, Coy JF, Sutterlin M, Kapp M, Horn E, Dietl J, Kammerer U: Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of distant metastases. Int J Gynecol Cancer 2007, 17:101-106.
• [32]Beratis NG, Kaperonis A, Eliopoulou MI, Kourounis G, Tzingounis VA: Increased activity of lysosomal enzymes in the peritoneal fluid of patients with gynecologic cancers and pelvic inflammatory disease. J Cancer Res Clin Oncol 2005, 131:371-376.
• [33]Mandato VD, Magnani E, Abrate M, Casali B, Nicoli D, Farnetti E, Formisano D, Pirillo D, Ciarlini G, De Iaco P, Strada I, Zamagni C, La Sala GB: Haptoglobin phenotype and epithelial ovarian cancer. Anticancer Res 2012, 32:4353-4358.
• [34]Zhao C, Annamalai L, Guo C, Kothandaraman N, Koh SC, Zhang H, Biswas A, Choolani M: Circulating haptoglobin is an independent prognostic factor in the sera of patients with epithelial ovarian cancer. Neoplasia 2007, 9:1-7.