Current efforts to identify protein biomarkers of disease use mainly mass spectrometry (MS) to analyze tissue and blood specimens. The low-molecular-weight “peptidome” is an attractive information archive because of the facile nature by which the low-molecular-weight information freely crosses the endothelial cell barrier of the vasculature, which provides opportunity to measure disease microenvironment-associated protein analytes secreted or shed into the extracellular interstitium and from there into the circulation. However, identifying useful protein biomarkers (peptidomic or not) which could be useful to detect early detection/monitoring of disease, toxicity, doping, or drug abuse has been severely hampered because even the most sophisticated, high-resolution MS technologies have lower sensitivities than those of the immunoassays technologies now routinely used in clinical practice. Identification of novel low abundance biomarkers that are indicative of early-stage events that likely exist in the sub-nanogram per milliliter concentration range of known markers, such as prostate-specific antigen, cannot be readily detected by current MS technologies. We have developed a new nanoparticle technology that can, in one step, capture, concentrate, and separate the peptidome from high-abundance blood proteins. Herein, we describe an initial pilot study whereby the peptidome content of ovarian and prostate cancer patients is investigated with this method. Differentially abundant candidate peptidome biomarkers that appear to be specific for early-stage ovarian and prostate cancer have been identified and reveal the potential utility for this new methodology
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Crawford ED. Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology. 2009;73 Suppl 5:4–10.
Barry MJ. Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med. 2001;344:1373–7.
Schröder FH, Hugosson J, Roobol MJ, ERSPC Investigators, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320–8.
Roehrborn CG. The utility of serum prostatic-specific antigen in the management of men with benign prostatic hyperplasia. Int J Impot Res. 2008;20 Suppl 3:S19–26.
Thompson IA, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level of ≤4.0 ng per milliliter. N Engl J Med. 2004;350:2239–46.
Horner MJ, Ries LAG, Krapcho M, et al., editors. SEER Cancer Stat Fact Sheets. 2009, Bethesda, MD. National Cancer Institute. http://seer.cancer.gov/statfacts/html/ovary.html, accessed December 2, 2009.
Rosenthal AN, Menon U, Jacobs IJ. Screening for ovarian cancer. Clinical Obstetrics and Gynecology. 2006;49:433–47.
Duffy MJ, Bonfrer JM, Kulpa J, et al. CA125 in ovarian cancer. European Group on Tumor Markers guidelines for clinical use. Int J Gynecol Cancer. 2005;15:679–91.
Bast Jr RC. Status of tumor markers in ovarian cancer screening. J Clin Oncol. 2003;21 Suppl 10:200s–5s.
Azad NS, Rasool N, Annunziata CM, Minasian L, Whiteley G, Kohn EC. Proteomics in clinical trials and practice: present uses and future promise. Mol Cell Proteomics. 2006;5:1819–29.
Buys SS, Partridge E, Greene MH, et al. Ovarian cancer screening in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial. Am J Obstet Gynecol. 2005;193:1630–9.
Skates SJ, Menon U, MacDonald N, et al. Calculation of the risk of ovarian cancer from serial CA-125 values for preclinical detection in postmenopausal women. J Clin Oncol. 2003;21 Suppl 10:206–10s.
Menon U, Skates SJ, Lewis S, et al. Prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer. J Clin Oncol. 2005;23:7919–26.
Berven FS, Flikka K, Berle M, et al. Proteomic-based biomarker discovery with emphasis on cerebrospinal fluid and multiple sclerosis. Curr Pharm Biotechnol. 2006;7:147–58.
Farina A, Dumonceau JM, Lescuyer P. Proteomic analysis of human bile and potential applications for cancer diagnosis. Expert Rev Proteomics. 2009;6:285–301.
Jamaspishvili T, Kral M, Khomeriki I, et al. Urine markers in monitoring for prostate cancer. Prostate Cancer Prostatic Dis. 2010;13:12–9.
Drake RR, White KY, Fuller TW, Igwe E, Clements MA, Nyalwidhe JO, et al. Clinical collection and protein properties of expressed prostatic secretions as a source for biomarkers of prostatic disease. J Proteomics. 2009;72:907–17.
Issaq HJ, Xiao Z, Veenstra TD. Serum and plasma proteomics. Chem Rev. 2007;107:3601–20. doi:10.1021/cr068287r.
Zhou M, Lucas DA, Chan KC, Issaq HJ, Petricoin 3rd EF, Liotta LA, et al. An investigation into the human serum “interactome”. Electrophoresis. 2004;25:1289–98.
Wang YY, Cheng P, Chan DW. A simple affinity spin tube filter method for removing high-abundant common proteins or enriching low-abundant biomarkers for serum proteomic analysis. Proteomics. 2003;3:243–8.
Gundry RL, Van Eyk JE. Unraveling the complexity of circulating forms of brain natriuretic peptide. Clin Chem. 2007;53:1181–2.
Lowenthal MS, Mehta AI, Frogale K, Bandle RW, Araujo RP, Hood BL, et al. Analysis of albumin-associated peptides and proteins from ovarian cancer patients. Clin Chem. 2005;51:1933–45.
Tirumalai RS, Chan KC, Prieto DA, Issaq HJ, Conrads TP, Veenstra TD. Characterization of the low molecular weight human serum proteome. Mol Cell Proteomics. 2003;2:1096–103.
Liotta LA, Ferrari M, Petricoin E. Clinical proteomics: written in blood. Nature. 2003;425:905.
Rai AJ, Gelfand CA, Haywood BC, Warunek DJ, Yi J, Schuchard MD, et al. HUPO Plasma Proteome Project specimen collection and handling: towards the standardization of parameters for plasma proteome samples. Proteomics. 2005;5:3262–77.
Luchini A, Geho DH, Bishop B, et al. Smart hydrogel particles: biomarker harvesting: one-step affinity purification, size exclusion, and protection against degradation. Nano Lett. 2008;8:350–61.
Fredolini C, Meani F, Alex Reeder K, et al. Concentration and preservation of very low abundance biomarkers in urine, such as human growth hormone (hGH), by Cibacron Blue F3G-A loaded hydrogel particles. Nano Res. 2008;1:502–18.
Longo C, Patanarut A, George T, Bishop B, Zhou W, Fredolini C, et al. Core–shell hydrogel particles harvest, concentrate and preserve labile low abundance biomarkers. PLoS One. 2009;4(3):e4763 (Epub 2009 Mar 10.B).
Ahmed FE. Sample preparation and fractionation for proteome analysis and cancer biomarker discovery by mass spectrometry. J Sep Sci. 2009;32:771–9.
Mueller LN, Brusniak MY, Mani DR, Aebersold R. An assessment of software solutions for the analysis of mass spectrometry based quantitative proteomics data. J Proteome Res. 2008;7:51–61.
Streuli CH. Integrins and cell-fate determination. J Cell Sci. 2009;122:171–7.
Eliceiri BP. Integrin and growth factor receptor crosstalk. Circ Res. 2001;89:1104–10.
Danen EH, Yamada KM. Fibronectin, integrins, and growth control. J Cell Physiol. 2001;189:1–13.
Howe A, Aplin AE, Alahari SK, Juliano RL. Integrin signaling and cell growth control. Curr Opin Cell Biol. 1998;10:220–31.
Hall A. The cytoskeleton and cancer. Cancer Metastasis Rev. 2009;28:5–14.
Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10:9–22.
Goel HL, Li J, Kogan S, Languino LR. Integrins in prostate cancer progression. Endocr Relat Cancer. 2008;15:657–64 (Epub 4 Jun 2008).
Monniaux D, Huet-Calderwood C, Le Bellego F, Fabre S, Monget P, Calderwood DA. Integrins in the ovary. Semin Reprod Med. 2006;24:251–61.
Mizejewski GJ. Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med. 1999;222:124–38.
Weivoda S, Andersen JD, Skogen A, Schlievert PM, Fontana D, Schacker T, et al. ELISA for human serum leucine-rich alpha-2-glycoprotein-1 employing cytochrome c as the capturing ligand. J Immunol Methods. 2008;336:22–9 (Epub 4 Apr 2008).
Shirai R, Hirano F, Ohkura N, Ikeda K, Inoue S. Up-regulation of the expression of leucine-rich alpha(2)-glycoprotein in hepatocytes by the mediators of acute-phase response. Biochem Biophys Res Commun. 2009;382:776–9 (Epub 24 Mar 2009).
Andersen JD, Boylan KL, Xue FS, Anderson LB, Witthuhn BA, Markowski TW, et al. Identification of candidate biomarkers in ovarian cancer serum by depletion of highly abundant proteins and differential in-gel electrophoresis. Electrophoresis. 2010;31:599–610.
Kakisaka T, Kondo T, Okano T, Fujii K, Honda K, Endo M, et al. Plasma proteomics of pancreatic cancer patients by multi-dimensional liquid chromatography and two-dimensional difference gel electrophoresis (2D-DIGE): up-regulation of leucine-rich alpha-2-glycoprotein in pancreatic cancer. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences. 2007;852:257–67.
Kawakami T, Hoshida Y, Kanai F, Tanaka Y, Tateishi K, Ikenoue T, et al. Proteomic analysis of sera from hepatocellular carcinoma patients after radiofrequency ablation treatment. Proteomics. 2005;5:4287–95.
Okano T, Kondo T, Kakisaka T, Fujii K, Yamada M, Kato H, et al. Plasma proteomics of lung cancer by a linkage of multi-dimensional liquid chromatography and two-dimensional difference gel electrophoresis. Proteomics. 2006;6:3938–48.
Chen Y, Lim BK, Hashim OH. Different altered stage correlative expression of high abundance acute-phase proteins in sera of patients with epithelial ovarian carcinoma. J Hematol Oncol. 2009;2:37.
Chen Y, Lim BK, Peh SC, Abdul-Rahman PS. Hashim OH profiling of serum and tissue high abundance acute-phase proteins of patients with epithelial and germ line ovarian carcinoma. Proteome Sci. 2008;6:20.
Weivoda S, Andersen JD, Skogen A, Schlievert PM, Fontana D, et al. ELISA for human serum leucine-rich alpha-2-glycoprotein-1 employing cytochrome c as the capturing ligand. J Immunol Methods. 2008;336:22–9. Epub 2008 Apr 4.
Schwartz DR, Kardia SL, Shedden KA, Kuick R, Michailidis G, Taylor JM, et al. Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res. 2002;62:4722–9.
Paschos KA, Canovas D, Bird NC. The role of cell adhesion molecules in the progression of colorectal cancer and the development of liver metastasis. Cell Signal. 2009;21:665–74 (Epub 7 Jan 2009).
Heyman L, Leroy-Dudal J, Fernandes J, Seyer D, Dutoit S, Carreiras F. Mesothelial vitronectin stimulates migration of ovarian cancer cells. Cell Biol Int. 2010;34:493–502.
Goodwin M, Yap AS. Classical cadherin adhesion molecules: coordinating cell adhesion, signaling and the cytoskeleton. J Mol Histol. 2004;35:839–44.
Felding-Habermann B, Cheresh DA. Vitronectin and its receptors. Curr Opin Cell Biol. 1993;5:864–8.
De Wever O, Derycke L, Hendrix A, De Meerleer G, Godeau F, Depypere H, et al. Soluble cadherins as cancer biomarkers. Clin Exp Metastasis. 2007;24:685–97.
Hurt EM, Chan K, Serrat MA, Thomas SB, Veenstra TD, Farrar WL. Identification of vitronectin as an extrinsic inducer of cancer stem cell differentiation and tumor formation. Stem Cells. 2010;28:390–8.
Cooper CR, Chay CH, Pienta KJ. The role of alpha(v)beta(3) in prostate cancer progression. Cooper Neoplasia. 2002;4:191–4.
Kuefer R, Hofer MD, Gschwend JE, et al. The role of an 80 kDa fragment of E-cadherin in the metastatic progression of prostate cancer. Clin Cancer Res. 2003;9:6447–52.
Kuefer R, Hofer MD, Zorn CS, Engel O, Volkmer BG, Juarez-Brito MA, et al. Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer. Br J Cancer. 2005;92:2018–23.
The authors appreciate the generous support of Dr. Vikas Chandhoke and the Department of Life Sciences at George Mason University. This work was partly supported by the Italian Istituto Superiore di Sanita` in the framework Italy/USA cooperation agreement between the U.S. Department of Health and Human Services, George Mason University, and the Italian Ministry of Public Health. This work was partially supported by the U.S. Department of Energy grant no. 201270.
Claudia Fredolini and Francesco Meani equally contributed to this work.
Guest Editors: Rao S. Rapaka, Lloyd D. Fricker, and Jonathan V. Sweedler
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Fredolini, C., Meani, F., Luchini, A. et al. Investigation of the Ovarian and Prostate Cancer Peptidome for Candidate Early Detection Markers Using a Novel Nanoparticle Biomarker Capture Technology. AAPS J 12, 504–518 (2010). https://doi.org/10.1208/s12248-010-9211-3
- Mass spectrometry