Cancer Immunology, Immunotherapy

, Volume 62, Issue 10, pp 1609–1618

Reduced expression of NGEP is associated with high-grade prostate cancers: a tissue microarray analysis

  • Monireh Mohsenzadegan
  • Zahra Madjd
  • Mojgan Asgari
  • Maryam Abolhasani
  • Mehdi Shekarabi
  • Jaleh Taeb
  • Ahmad Shariftabrizi
Original Article

Abstract

New gene expressed in prostate (NGEP) is a newly diagnosed prostate-specific gene that is expressed only in normal prostate and prostate cancer cells. Discovery of tissue-specific markers may promote the development of novel targets for immunotherapy of prostate cancer. In the present study, the staining pattern and clinical significance of NGEP were evaluated in a series of prostate tissues composed of 123 prostate cancer, 19 high-grade prostatic intraepithelial neoplasia and 44 samples of benign prostate tissue included in tissue microarrays using immunohistochemistry. Our study demonstrated that NGEP localized mainly in the apical and lateral membranes and was also partially distributed in the cytoplasm of epithelial cells of normal prostate tissue. All of the examined prostate tissues expressed NGEP with a variety of intensities; the level of expression was significantly more in the benign prostate tissues compared to malignant prostate samples (P value <0.001). Among prostate adenocarcinoma samples, a significant and inverse correlation was observed between the intensity of NGEP expression and increased Gleason score (P = 0.007). Taken together, we found that NGEP protein is widely expressed in low-grade to high-grade prostate adenocarcinomas as well as benign prostate tissues, and the intensity of expression is inversely proportional to the level of malignancy. NGEP could be an attractive target for immune-based therapy of prostate cancer patients as an alternative to the conventional therapies particularly in indolent patients.

Keywords

NGEP Prostate cancer Immunotherapy Immunohistochemistry 

Abbreviations

Ano 7

Anoctamin 7

BPH

Benign prostatic hyperplasia

Epe

Extraprostatic extension

ESTs

Expressed sequence tags

FDA

Food and drug administration

HPIN

High-grade prostatic intraepithelial neoplasia

IHC

Immunohistochemistry

ISH

In situ hybridization

MAb

Monoclonal antibody

NGEP

New gene expressed in prostate

PBMC

Peripheral blood mononuclear cell

PCa

Prostate cancer

PSA

Prostate-specific antigen

PSMA

Prostate-specific membrane antigen

PSCA

Prostate stem cell antigen

TMA

Tissue macroarray

TRICOM

Triad of costimulatory molecules (B7.1, ICAM-1, LFA-3)

References

  1. 1.
    Vainio P, Lehtinen L, Mirtti T, Hilvo M, Seppanen-Laakso T, Virtanen J, Sankila A, Nordling S, Lundin J, Rannikko A, Oresic M, Kallioniemi O, Iljin K (2011) Phospholipase PLA2G7, associated with aggressive prostate cancer, promotes prostate cancer cell migration and invasion and is inhibited by statins. Oncotarget 2:1176–1190PubMedGoogle Scholar
  2. 2.
    Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Colombet M, Boyle P (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18:581–592PubMedCrossRefGoogle Scholar
  3. 3.
    Shanmugam A, Suriano R, Chaudhuri D, Rajoria S, George A, Mittelman A, Tiwari RK (2011) Identification of PSA peptide mimotopes using phage display peptide library. Peptides 32:1097–1102PubMedCrossRefGoogle Scholar
  4. 4.
    Crawford ED, Rosenblum M, Ziada AM, Lange PH (1999) Hormone refractory prostate cancer. Urology 54:1–7PubMedCrossRefGoogle Scholar
  5. 5.
    Gulley JL, Arlen PM, Bastian A, Morin S, Marte J, Beetham P, Tsang KY, Yokokawa J, Hodge JW, Menard C, Camphausen K, Coleman CN, Sullivan F, Steinberg SM, Schlom J, Dahut W (2005) Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res 11:3353–3362PubMedCrossRefGoogle Scholar
  6. 6.
    Karnes RJ, Whelan CM, Kwon ED (2006) Immunotherapy for prostate cancer. Curr Pharm Des 12:807–817PubMedCrossRefGoogle Scholar
  7. 7.
    Lechleider RJ, Arlen PM, Tsang KY, Steinberg SM, Yokokawa J, Cereda V, Camphausen K, Schlom J, Dahut WL, Gulley JL (2008) Safety and immunologic response of a viral vaccine to prostate-specific antigen in combination with radiation therapy when metronomic-dose interleukin 2 is used as an adjuvant. Clin Cancer Res 14:5284–5291PubMedCrossRefGoogle Scholar
  8. 8.
    Nesslinger NJ, Ng A, Tsang KY, Ferrara T, Schlom J, Gulley JL, Nelson BH (2010) A viral vaccine encoding prostate-specific antigen induces antigen spreading to a common set of self-proteins in prostate cancer patients. Clin Cancer Res 16:4046–4056PubMedCrossRefGoogle Scholar
  9. 9.
    Harada M, Noguchi M, Itoh K (2003) Target molecules in specific immunotherapy against prostate cancer. Int J Clin Oncol 8:193–199PubMedCrossRefGoogle Scholar
  10. 10.
    Slovin SF (2005) Targeting novel antigens for prostate cancer treatment: focus on prostate-specific membrane antigen. Expert Opin Ther Targets 9:561–570PubMedCrossRefGoogle Scholar
  11. 11.
    Arlen PM, Gulley JL, Tsang KY, Schlom J (2003) Strategies for the development of PSA-based vaccines for the treatment of advanced prostate cancer. Expert Rev Vaccines 2:483–493PubMedCrossRefGoogle Scholar
  12. 12.
    Israeli RS, Powell CT, Corr JG, Fair WR, Heston WD (1994) Expression of the prostate-specific membrane antigen. Cancer Res 54:1807–1811PubMedGoogle Scholar
  13. 13.
    Reiter RE, Gu Z, Watabe T, Thomas G, Szigeti K, Davis E, Wahl M, Nisitani S, Yamashiro J, Le Beau MM, Loda M, Witte ON (1998) Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc Natl Acad Sci U S A 95:1735–1740PubMedCrossRefGoogle Scholar
  14. 14.
    Carter RE, Feldman AR, Coyle JT (1996) Prostate-specific membrane antigen is a hydrolase with substrate and pharmacologic characteristics of a neuropeptidase. Proc Natl Acad Sci USA 93:749–753PubMedCrossRefGoogle Scholar
  15. 15.
    Yang WB, Cai F, Cheng CT, Cao G, Qing ZY (2009) Role of prostate stem cell antigen in human pancreatic carcinoma: a tissue microarray-based study. Nan Fang Yi Ke Da Xue Xue Bao 29:2135–2137PubMedGoogle Scholar
  16. 16.
    Bera TK, Das S, Maeda H, Beers R, Wolfgang CD, Kumar V, Hahn Y, Lee B, Pastan I (2004) NGEP, a gene encoding a membrane protein detected only in prostate cancer and normal prostate. Proc Natl Acad Sci U S A 101:3059–3064PubMedCrossRefGoogle Scholar
  17. 17.
    Duran C, Qu Z, Osunkoya AO, Cui Y, Hartzell HC (2012) ANOs 3–7 in the anoctamin/Tmem16 Cl channel family are intracellular proteins. Am J Physiol Cell Physiol 302:C482–C493PubMedCrossRefGoogle Scholar
  18. 18.
    Hartzell HC, Yu K, Xiao Q, Chien LT, Qu Z (2009) Anoctamin/TMEM16 family members are Ca2+-activated Cl channels. J Physiol 587:2127–2139PubMedCrossRefGoogle Scholar
  19. 19.
    Galindo BE, Vacquier VD (2005) Phylogeny of the TMEM16 protein family: some members are overexpressed in cancer. Int J Mol Med 16:919–924PubMedGoogle Scholar
  20. 20.
    Moyer BD, Hevezi P, Gao N, Lu M, Kalabat D, Soto H, Echeverri F, Laita B, Yeh SA, Zoller M, Zlotnik A (2009) Expression of genes encoding multi-transmembrane proteins in specific primate taste cell populations. PLoS ONE 4:e7682PubMedCrossRefGoogle Scholar
  21. 21.
    Das S, Hahn Y, Nagata S, Willingham MC, Bera TK, Lee B, Pastan I (2007) NGEP, a prostate-specific plasma membrane protein that promotes the association of LNCaP cells. Cancer Res 67:1594–1601PubMedCrossRefGoogle Scholar
  22. 22.
    Das S, Hahn Y, Walker DA, Nagata S, Willingham MC, Peehl DM, Bera TK, Lee B, Pastan I (2008) Topology of NGEP, a prostate-specific cell:cell junction protein widely expressed in many cancers of different grade level. Cancer Res 68:6306–6312PubMedCrossRefGoogle Scholar
  23. 23.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422PubMedCrossRefGoogle Scholar
  24. 24.
    Zhou G, Levitsky H (2012) Towards curative cancer immunotherapy: overcoming posttherapy tumor escape. Clin Dev Immunol 2012:124187PubMedCrossRefGoogle Scholar
  25. 25.
    Drake CG (2010) Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol 10:580–593PubMedCrossRefGoogle Scholar
  26. 26.
    Arlen PM, Kaufman HL, DiPaola RS (2005) Pox viral vaccine approaches. Semin Oncol 32:549–555CrossRefGoogle Scholar
  27. 27.
    Gerritsen WR (2012) The evolving role of immunotherapy in prostate cancer. Ann Oncol 23(Suppl 8):viii22–viii27PubMedCrossRefGoogle Scholar
  28. 28.
    Cereda V, Poole DJ, Palena C, Das S, Bera TK, Remondo C, Gulley JL, Arlen PM, Yokokawa J, Pastan I, Schlom J, Tsang KY (2010) New gene expressed in prostate: a potential target for T cell-mediated prostate cancer immunotherapy. Cancer Immunol Immunother 59:63–71PubMedCrossRefGoogle Scholar
  29. 29.
    Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL (2005) The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol 29:1228–1242PubMedCrossRefGoogle Scholar
  30. 30.
    Pierorazio PM, Walsh PC, Partin AW, Epstein JI (2013) Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int 111:753–760PubMedCrossRefGoogle Scholar
  31. 31.
    Ro YK, Lee S, Jeong CW, Hong SK, Byun SS, Lee SE (2012) Biochemical recurrence in Gleason score 7 prostate cancer in Korean men: significance of the primary Gleason grade. Korean J Urol 53:826–829PubMedCrossRefGoogle Scholar
  32. 32.
    Cheng L, Montironi R, Bostwick DG, Lopez-Beltran A, Berney DM (2012) Staging of prostate cancer. Histopathology 60:87–117PubMedCrossRefGoogle Scholar
  33. 33.
    Madjd Z, Karimi A, Molanae S, Asadi-Lari M (2011) BRCA1 protein expression level and CD44(+) phenotype in breast cancer patients. Cell J 13:155–162PubMedGoogle Scholar
  34. 34.
    Mehrazma M, Madjd Z, Kalantari E, Panahi M, Hendi A, Shariftabrizi A (2012) Expression of stem cell markers, CD133 and CD44, in pediatric solid tumors: a study using tissue microarray. Fetal Pediatr Pathol 32:192–204PubMedCrossRefGoogle Scholar
  35. 35.
    Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847PubMedCrossRefGoogle Scholar
  36. 36.
    McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr (1985) Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109:716–721PubMedGoogle Scholar
  37. 37.
    Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC (2005) Monoclonal antibody successes in the clinic. Nat Biotechnol 23:1073–1078PubMedCrossRefGoogle Scholar
  38. 38.
    Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ (2007) Immunotoxin treatment of cancer. Annu Rev Med 58:221–237PubMedCrossRefGoogle Scholar
  39. 39.
    Mhawech-Fauceglia P, Zhang S, Terracciano L, Sauter G, Chadhuri A, Herrmann FR, Penetrante R (2007) Prostate-specific membrane antigen (PSMA) protein expression in normal and neoplastic tissues and its sensitivity and specificity in prostate adenocarcinoma: an immunohistochemical study using multiple tumour tissue microarray technique. Histopathology 50:472–483PubMedCrossRefGoogle Scholar
  40. 40.
    Bahrenberg G, Brauers A, Joost HG, Jakse G (2000) Reduced expression of PSCA, a member of the LY-6 family of cell surface antigens, in bladder, esophagus, and stomach tumors. Biochem Biophys Res Commun 275:783–788PubMedCrossRefGoogle Scholar
  41. 41.
    Koh YT, Gray A, Higgins SA, Hubby B, Kast WM (2009) Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization. Prostate 69:571–584PubMedCrossRefGoogle Scholar
  42. 42.
    Ragde H, Cavanagh WA, Tjoa BA (2004) Dendritic cell based vaccines: progress in immunotherapy studies for prostate cancer. J Urol 172:2532–2538PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Monireh Mohsenzadegan
    • 1
    • 2
  • Zahra Madjd
    • 3
    • 5
  • Mojgan Asgari
    • 3
    • 4
  • Maryam Abolhasani
    • 3
    • 4
  • Mehdi Shekarabi
    • 2
  • Jaleh Taeb
    • 5
  • Ahmad Shariftabrizi
    • 3
    • 6
  1. 1.Immunology Research CentreIran University of Medical SciencesTehranIran
  2. 2.Department of ImmunologyIran University of Medical SciencesTehranIran
  3. 3.Department of Pathology, Oncopathology Research CentreIran University of Medical SciencesTehranIran
  4. 4.Department of Pathology, Hasheminejad Kidney CenterIran University of Medical SciencesTehranIran
  5. 5.Department of Molecular MedicineIran University of Medical SciencesTehranIran
  6. 6.Department of Pathology, Danbury HospitalYale UniversityDanburyUSA

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