Skip to main content

Advertisement

SpringerLink
Log in

Investigation of the Ovarian and Prostate Cancer Peptidome for Candidate Early Detection Markers Using a Novel Nanoparticle Biomarker Capture Technology

  • Research Article
  • Theme: Fishing for the Hidden Proteome in Health and Disease: Focus on Drug Abuse
  • Published:
The AAPS Journal Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

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

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Crawford ED. Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology. 2009;73 Suppl 5:4–10.

    Article  Google Scholar 

  2. Barry MJ. Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med. 2001;344:1373–7.

    Article  PubMed  CAS  Google Scholar 

  3. 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.

    Article  PubMed  Google Scholar 

  4. 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.

    Article  PubMed  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

  7. Rosenthal AN, Menon U, Jacobs IJ. Screening for ovarian cancer. Clinical Obstetrics and Gynecology. 2006;49:433–47.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. Bast Jr RC. Status of tumor markers in ovarian cancer screening. J Clin Oncol. 2003;21 Suppl 10:200s–5s.

    Article  PubMed  Google Scholar 

  10. 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.

    Article  PubMed  CAS  Google Scholar 

  11. 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.

    Article  PubMed  Google Scholar 

  12. 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.

    Article  Google Scholar 

  13. 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.

    Article  PubMed  Google Scholar 

  14. 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.

    Article  PubMed  CAS  Google Scholar 

  15. Farina A, Dumonceau JM, Lescuyer P. Proteomic analysis of human bile and potential applications for cancer diagnosis. Expert Rev Proteomics. 2009;6:285–301.

    Article  PubMed  CAS  Google Scholar 

  16. Jamaspishvili T, Kral M, Khomeriki I, et al. Urine markers in monitoring for prostate cancer. Prostate Cancer Prostatic Dis. 2010;13:12–9.

    Article  PubMed  CAS  Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. Issaq HJ, Xiao Z, Veenstra TD. Serum and plasma proteomics. Chem Rev. 2007;107:3601–20. doi:10.1021/cr068287r.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. Gundry RL, Van Eyk JE. Unraveling the complexity of circulating forms of brain natriuretic peptide. Clin Chem. 2007;53:1181–2.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. 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.

    Article  PubMed  CAS  Google Scholar 

  24. Liotta LA, Ferrari M, Petricoin E. Clinical proteomics: written in blood. Nature. 2003;425:905.

    Article  PubMed  CAS  Google Scholar 

  25. 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.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. 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).

    Article  PubMed  CAS  Google Scholar 

  29. Ahmed FE. Sample preparation and fractionation for proteome analysis and cancer biomarker discovery by mass spectrometry. J Sep Sci. 2009;32:771–9.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. Streuli CH. Integrins and cell-fate determination. J Cell Sci. 2009;122:171–7.

    Article  PubMed  CAS  Google Scholar 

  32. Eliceiri BP. Integrin and growth factor receptor crosstalk. Circ Res. 2001;89:1104–10.

    Article  PubMed  CAS  Google Scholar 

  33. Danen EH, Yamada KM. Fibronectin, integrins, and growth control. J Cell Physiol. 2001;189:1–13.

    Article  PubMed  CAS  Google Scholar 

  34. Howe A, Aplin AE, Alahari SK, Juliano RL. Integrin signaling and cell growth control. Curr Opin Cell Biol. 1998;10:220–31.

    Article  PubMed  CAS  Google Scholar 

  35. Hall A. The cytoskeleton and cancer. Cancer Metastasis Rev. 2009;28:5–14.

    Article  PubMed  Google Scholar 

  36. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10:9–22.

    Article  PubMed  CAS  Google Scholar 

  37. Goel HL, Li J, Kogan S, Languino LR. Integrins in prostate cancer progression. Endocr Relat Cancer. 2008;15:657–64 (Epub 4 Jun 2008).

    Article  PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed  CAS  Google Scholar 

  39. Mizejewski GJ. Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med. 1999;222:124–38.

    Article  PubMed  CAS  Google Scholar 

  40. 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).

    Article  PubMed  CAS  Google Scholar 

  41. 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).

    Article  PubMed  CAS  Google Scholar 

  42. 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.

    Article  PubMed  CAS  Google Scholar 

  43. 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.

    Article  CAS  Google Scholar 

  44. 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.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. 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.

    Article  PubMed  CAS  Google Scholar 

  47. 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.

    Article  PubMed  CAS  Google Scholar 

  48. 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.

    Article  PubMed  CAS  Google Scholar 

  49. 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.

    PubMed  CAS  Google Scholar 

  50. 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).

    Article  PubMed  CAS  Google Scholar 

  51. 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.

    Article  PubMed  CAS  Google Scholar 

  52. Goodwin M, Yap AS. Classical cadherin adhesion molecules: coordinating cell adhesion, signaling and the cytoskeleton. J Mol Histol. 2004;35:839–44.

    Article  PubMed  CAS  Google Scholar 

  53. Felding-Habermann B, Cheresh DA. Vitronectin and its receptors. Curr Opin Cell Biol. 1993;5:864–8.

    Article  PubMed  CAS  Google Scholar 

  54. 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.

    Article  PubMed  CAS  Google Scholar 

  55. 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.

    PubMed  CAS  Google Scholar 

  56. Cooper CR, Chay CH, Pienta KJ. The role of alpha(v)beta(3) in prostate cancer progression. Cooper Neoplasia. 2002;4:191–4.

    Article  CAS  Google Scholar 

  57. 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.

    PubMed  CAS  Google Scholar 

  58. 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Department of Urology, S. Giovanni Bosco Hospital, Turin, Italy

    Claudia Fredolini, Devis Collura, Leonardo D’Urso & Giovanni Muto

  2. Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy

    Claudia Fredolini & Francesco Novelli

  3. Gynecology and Obstetrics Department, University of Brescia, Brescia, Italy

    Francesco Meani, Franco Odicino, Monica Ragnoli, Antonella Ravaggi & Sergio Pecorelli

  4. Chemistry and Biochemistry Department, George Mason University, Manassas, Virginia, USA

    Alexis Patanarut

  5. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

    Davide Tamburro

  6. Department of Urology, University of California at Irvine, Irvine, California, USA

    David Ornstein

  7. Center for the Applied Proteomics and Molecular Medicine, George Mason University, 10900 University Blvd, Room 181A Discovery Hall, Manassas, Virginia, 20110, USA

    Claudia Fredolini, Francesco Meani, Alessandra Luchini, Weidong Zhou, Paul Russo, Mark Ross, Alexis Patanarut, Davide Tamburro, Guido Gambara, Lance Liotta & Emanuel F. Petricoin III

  8. Department of Experimental Oncology 2, CRO-IRCSS, National Cancer Institute, Aviano, Italy

    Claudio Belluco

Authors
  1. Claudia Fredolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesco Meani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessandra Luchini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weidong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mark Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexis Patanarut
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Davide Tamburro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guido Gambara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David Ornstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Franco Odicino
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Monica Ragnoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Antonella Ravaggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Francesco Novelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Devis Collura
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Leonardo D’Urso
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Giovanni Muto
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Claudio Belluco
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Sergio Pecorelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Lance Liotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Emanuel F. Petricoin III
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emanuel F. Petricoin III.

Additional information

Guest Editors: Rao S. Rapaka, Lloyd D. Fricker, and Jonathan V. Sweedler

Claudia Fredolini and Francesco Meani equally contributed to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-010-9211-3

Key words

Search

Navigation