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Co-Expression of Putative Cancer Stem Cell Markers CD44 and CD133 in Prostate Carcinomas

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Pathology & Oncology Research

Abstract

Cancer stem cells (CSCs) are the main players of prostate tumorigenesis thus; characterization of CSCs can pave the way for understanding the early detection, drug resistance, metastasis and relapse. The current study was conducted to evaluate the expression level and clinical significance of the potential CSC markers CD44 and CD133 in a series of prostate tissues. One hundred and forty eight prostate tissues composed of prostate cancer (PCa), high-grade prostatic intraepithelial neoplasia (HGPIN), and benign prostate hyperplasia (BPH) were immunostained for the putative CSC markers CD44 and CD133. Subsequently, the correlation between the expression of these markers and the clinicopathological variables was examined. A higher level of CD44 expression was observed in 42% of PCa, 57% of HGPIN, and 42% BPH tissues. In the case of CD133 expression PCa, HGPIN, and BPH samples demonstrated high immunoreactivity in 46%, 43%, and 42% of cells, respectively. Statistical analysis showed an inverse significant correlation between CD44 expression with Gleason score of PCa (P = 0.02), while no significant correlation was observed between CD133 expression and clinicopathological parameters. A significant reciprocal correlation was observed between the expression of two putative CSC markers CD44 and CD133 in PCa specimens while not indicating clinical significance. Further clinical investigation is required to consider these markers as targets of new therapeutic strategies for PCa

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References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108

    Article  PubMed  Google Scholar 

  2. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    Article  PubMed  Google Scholar 

  3. Hurt EM, Kawasaki BT, Klarmann GJ, Thomas SB, Farrar WL (2008) CD44+ CD24− prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br J Cancer 98:756–765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Lippitt JM, Guzmán-Ramírez N, Hamdy FC, Eaton CL, Thalmann GN, Cecchini MG (2010) High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res 70:5163–5173

    Article  PubMed  Google Scholar 

  5. Dubrovska A, Elliott J, Salamone RJ, Kim S, Aimone LJ, Walker JR, Watson J, Sauveur-Michel M, Garcia-Echeverria C, Cho CY (2010) Combination therapy targeting both tumor-initiating and differentiated cell populations in prostate carcinoma. Clin Cancer Res 16:5692–5702

    Article  CAS  PubMed  Google Scholar 

  6. Rangwala F, Omenetti A, Diehl AM (2010) Cancer stem cells: repair gone awry? J Oncol 2011:465343

  7. Reyes EE, Kunovac SK, Duggan R, Kregel S, Griend DJV (2013) Growth kinetics of CD133-positive prostate cancer cells. Prostate 73:724–733

    Article  CAS  PubMed  Google Scholar 

  8. Ugolkov AV, Eisengart LJ, Luan C, Yang XJ (2011) Expression analysis of putative stem cell markers in human benign and malignant prostate. Prostate 71:18–25

    Article  PubMed  Google Scholar 

  9. AM DM, WG N, AK M, DS C (1998) Stem cell features of benign and malignant prostate epithelial cells. J Urol 160:2381–2392

    Article  Google Scholar 

  10. Tirino V, Desiderio V, Paino F, De Rosa A, Papaccio F, La Noce M, Laino L, De Francesco F, Papaccio G (2013) Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization. FASEB J 27:13–24

    Article  CAS  PubMed  Google Scholar 

  11. Marhaba R, Zöller M (2004) CD44 in cancer progression: adhesion, migration and growth regulation. J Mol Histol 35:211–231

    Article  CAS  PubMed  Google Scholar 

  12. Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG (2007) Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+ α2β1+ cell population is enriched in tumor-initiating cells. Cancer Res 67:6796–6805

    Article  CAS  PubMed  Google Scholar 

  13. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951

    Article  CAS  PubMed  Google Scholar 

  14. Marker PC 2007 Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells: Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, Reilly JG, Chandra D, Zhou J, Claypool K, Coghlan L, Tang DG, Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville, TX. In: Urologic Oncology: Seminars and Original Investigations,. vol 3. Elsevier, pp 277–278

  15. Nagabhushan M, Pretlow TG, Guo Y-J, Amini SB, Pretlow TP, Sy M-S (1996) Altered expression of CD44 in human prostate cancer during progression. Am J Clin Pathol 106:647–651

    Article  CAS  PubMed  Google Scholar 

  16. Kallakury BV, Yang F, Figge J, Smith KE, Kausik SJ, Tacy NJ, Fisher HA, Kaufman R, Figge H, Ross JS (1996) Decreased levels of CD44 protein and mRNA in prostate carcinoma: correlation with tumor grade and ploidy. Cancer 78:1461–1469

    Article  CAS  PubMed  Google Scholar 

  17. Simon RA, di Sant’Agnese PA, Huang L-S, Xu H, Yao JL, Yang Q, Liang S, Liu J, Yu R, Cheng L (2009) CD44 expression is a feature of prostatic small cell carcinoma and distinguishes it from its mimickers. Hum Pathol 40:252–258

    Article  CAS  PubMed  Google Scholar 

  18. Tirino V, Desiderio V, d’Aquino R, De Francesco F, Pirozzi G, Graziano A, Galderisi U, Cavaliere C, De Rosa A, Papaccio G (2008) Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS One 3:e3469

    Article  PubMed  PubMed Central  Google Scholar 

  19. Tirino V, Camerlingo R, Franco R, Malanga D, La Rocca A, Viglietto G, Rocco G, Pirozzi G (2009) The role of CD133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer. Eur J Cardiothorac Surg 36:446–453

    Article  PubMed  Google Scholar 

  20. Sabet MN, Rakhshan A, Erfani E, Madjd Z (2014) Co-expression of putative cancer stem cell markers, CD133 and nestin, in skin tumors. Asian Pac J Cancer Prev 15:8161–8169

    Article  PubMed  Google Scholar 

  21. Mehrazma M, Madjd Z, Kalantari E, Panahi M, Hendi A, Shariftabrizi A (2013) Expression of stem cell markers, CD133 and CD44, in pediatric solid tumors: a study using tissue microarray. Fetal Pediatr Pathol 32:192–204

    Article  CAS  PubMed  Google Scholar 

  22. Wognum AW, Eaves AC, Thomas TE (2003) Identification and isolation of hematopoietic stem cells. Arch Med Res 34:461–475

    Article  CAS  PubMed  Google Scholar 

  23. Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT (2004) CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 117:3539–3545

    Article  CAS  PubMed  Google Scholar 

  24. Miki J, Furusato B, Li H, Gu Y, Takahashi H, Egawa S, Sesterhenn IA, McLeod DG, Srivastava S, Rhim JS (2007) Identification of pPutative sStem cCell mMarkers, CD133 and CXCR4, in hTERT–Immortalized Primary Nonmalignant and Malignant Tumor-Derived Human Prostate Epithelial Cell Lines and in Prostate Cancer Specimens. Cancer Res 67:3153–3161

    Article  CAS  PubMed  Google Scholar 

  25. 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 29:1228–1242

    Article  PubMed  Google Scholar 

  26. Cheng L, Montironi R, Bostwick DG, Lopez-Beltran A, Berney DM (2012) Staging of prostate cancer. Histopathology 60:87–117. doi:10.1111/j.1365-2559.2011.04025.x

    Article  PubMed  Google Scholar 

  27. Madjd Z, Akbari ME, Zarnani AH, Khayamzadeh M, Kalantari E, Mojtabavi N (2013) Expression of EMSY, a novel BRCA2-link protein, is associated with lymph node metastasis and increased tumor size in breast carcinomas. Asian Pac J Cancer Prev 15:1783–1789

    Article  Google Scholar 

  28. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    CAS  PubMed  Google Scholar 

  29. Kalantari E, Saadi FH, Asgari M, Shariftabrizi A, Roudi R, Madjd Z (2016) Increased expression of ALDH1A1 in prostate cancer is correlated with tumor aggressiveness: a tissue microarray study of Iranian patients. Appl Immunohistochem Mol Morphol AIMM Off Publ Soc Appl Immunohistochem. doi:10.1097/PAI.0000000000000343

  30. Camp RL, Charette LA, Rimm DL (2000) Validation of tissue microarray technology in breast carcinoma. Lab Investig 80:1943–1949

    Article  CAS  PubMed  Google Scholar 

  31. Roudi R, Korourian A, Shariftabrizi A, Madjd Z (2015) Differential expression of cancer stem cell markers ALDH1 and CD133 in various lung cancer subtypes. Cancer Invest 33:294–302

  32. Madjd Z, Ramezani B, Molanae S, Asadi-Lari M (2012) High expression of stem cell marker ALDH1 is associated with reduced BRCA1 in invasive breast carcinomas. Asian Pac J Cancer Prev 13:2973–2978

    Article  PubMed  Google Scholar 

  33. Walker R (2006) Quantification of immunohistochemistry—issues concerning methods, utility and semiquantitative assessment I. Histopathology 49:406–410

    Article  CAS  PubMed  Google Scholar 

  34. Nagel H, Laskawi R, Wahlers A, Hemmerlein B (2004) Expression of matrix metalloproteinases MMP-2, MMP-9 and their tissue inhibitors TIMP-1,-2, and-3 in benign and malignant tumours of the salivary gland. Histopathology 44:222–231

    Article  CAS  PubMed  Google Scholar 

  35. Madjd Z, Pinder S, Paish C, Ellis I, Carmichael J, Durrant L (2003) Loss of CD59 expression in breast tumours correlates with poor survival. J Pathol 200:633–639

    Article  CAS  PubMed  Google Scholar 

  36. Mohsenzadegan M, Madjd Z, Asgari M, Abolhasani M, Shekarabi M, Taeb J, Shariftabrizi A (2013) Reduced expression of NGEP is associated with high-grade prostate cancers: a tissue microarray analysis. Cancer Immunol Immunother 62:1609–1618

    Article  CAS  PubMed  Google Scholar 

  37. Taeb J, Asgari M, Abolhasani M, Farajollahi MM, Madjd Z (2014) Expression of prostate stem cell antigen (PSCA) in prostate cancer: a tissue microarray study of Iranian patients. Pathology-research and. Practice 210:18–23

    CAS  Google Scholar 

  38. Kerfoot C, Huang W, Rotenberg SA (2004) Immunohistochemical analysis of advanced human breast carcinomas reveals downregulation of protein kinase Cα. J Histochem Cytochem 52:419–422

    Article  CAS  PubMed  Google Scholar 

  39. McCarty K Jr, Miller L, Cox E, Konrath J, McCarty K Sr (1985) Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109:716–721

    PubMed  Google Scholar 

  40. Sharma BK, Manglik V, Elias EG (2010) Immuno-expression of human melanoma stem cell markers in tissues at different stages of the disease. J Surg Res 163:e11–e15

    Article  CAS  PubMed  Google Scholar 

  41. Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci 100:15178–15183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chang B, Liu G, Xue F, Rosen DG, Xiao L, Wang X, Liu J (2009) ALDH1 expression correlates with favorable prognosis in ovarian cancers. Mod Pathol 22:817–823

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Nguyen LV, Vanner R, Dirks P, Eaves CJ (2012) Cancer stem cells: an evolving concept. Nat Rev Cancer 12:133–143

    CAS  PubMed  Google Scholar 

  44. Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, Schuster K, Shao C, Larsen JE, Sullivan LA (2010) Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Res 70:9937–9948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Castellón EA, Valenzuela R, Lillo J, Castillo V, Contreras HR, Gallegos I, Mercado A, Huidobro C (2012) Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis. Biol Res 45:297–305

    Article  PubMed  Google Scholar 

  46. Jaworska D, Król W, Szliszka E (2015) Prostate cancer stem cells: research advances. Int J Mol Sci 16:27433–27449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, Reilly J, Chandra D, Zhou J, Claypool K (2006) Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25:1696–1708

    Article  CAS  PubMed  Google Scholar 

  48. Paradis V, Eschwege P, Loric S, Dumas F, Ba N, Benoit G, Jardin A, Bedossa P (1998) De novo expression of CD44 in prostate carcinoma is correlated with systemic dissemination of prostate cancer. J Clin Pathol 51:798–802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. De Marzo AM, Bradshaw C, Sauvageot J, Epstein JI, Miller GJ (1998) CD44 and CD44v6 downregulation in clinical prostatic carcinoma: relation to Gleason grade and cytoarchitecture. Prostate 34:162–168

    Article  CAS  PubMed  Google Scholar 

  50. Corbeil D, Röper K, Fargeas CA, Joester A, Huttner WB (2001) Prominin: a story of cholesterol, plasma membrane protrusions and human pathology. Traffic 2:82–91

    Article  CAS  PubMed  Google Scholar 

  51. Wang C-C, De Marzo AM, Lotan TL, Epstein JI (2015) Overlap of CD44 expression between prostatic small cell carcinoma and acinar adenocarcinoma. Hum Pathol 46:554–557

    Article  CAS  PubMed  Google Scholar 

  52. Trerotola M, Rathore S, Goel HL, Li J, Alberti S, Piantelli M, Adams D, Jiang Z, Languino LR (2010) CD133, trop-2 and alpha2beta1 integrin surface receptors as markers of putative human prostate cancer stem cells. Am J Transl Res 2:135–144

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Bussolati B, Bruno S, Grange C, Buttiglieri S, Deregibus MC, Cantino D, Camussi G (2005) Isolation of renal progenitor cells from adult human kidney. Am J Pathol 166:545–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, Conticello C, Ruco L, Peschle C, De Maria R (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15:504–514

    Article  CAS  PubMed  Google Scholar 

  55. O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110

    Article  PubMed  Google Scholar 

  56. Ma S, Lee T, Zheng B, Chan K, Guan X (2008) CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27:1749–1758

    Article  CAS  PubMed  Google Scholar 

  57. Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, John SY (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67

    Article  PubMed  PubMed Central  Google Scholar 

  58. Vatansever H, Gumus B, Aydogdu O, Sivrikoz O, Türköz-Uluer E, Kivanç M, Ateşçi Y, Bugdayci H (2014) The role of stem/progenitor cells and Wnt/β-catenin signaling pathway in the patients with prostate cancer. Minerva urologica e nefrologica = The Italian journal of urology and nephrology 66:249–255

    CAS  PubMed  Google Scholar 

  59. Fargeas C, Huttner W, Corbeil D (2007) Nomenclature of prominin-1 (CD133) splice variants–an update. Tissue Antigens 69:602–606

    Article  CAS  PubMed  Google Scholar 

  60. Irollo E, Pirozzi G (2013) CD133: to be or not to be, is this the real question. Am J Transl Res 5:563–581

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by Iran University of Medical Sciences [Project 94-1207 and 1491 « Immunohistochemical expression of Cancer Stem Cell markers CD44 and CD133 in prostate cancer »].

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Correspondence to Mojgan Asgari or Zahra Madjd.

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Kalantari, E., Asgari, M., Nikpanah, S. et al. Co-Expression of Putative Cancer Stem Cell Markers CD44 and CD133 in Prostate Carcinomas. Pathol. Oncol. Res. 23, 793–802 (2017). https://doi.org/10.1007/s12253-016-0169-z

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  • DOI: https://doi.org/10.1007/s12253-016-0169-z

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