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Virchows Archiv

, Volume 464, Issue 4, pp 473–488 | Cite as

Stem cell marker-positive stellate cells and mast cells are reduced in benign-appearing bladder tissue in patients with urothelial carcinoma

  • Björn L. IsfossEmail author
  • Christer Busch
  • Helena Hermelin
  • Anette T. Vermedal
  • Marianne Kile
  • Geir J. Braathen
  • Bernard Majak
  • Aasmund Berner
Original Article

Abstract

Survival after invasive bladder cancer has improved less than that of other common non-skin cancers. In many types of malignancy, treatment failure has been attributed to therapy-resistant stem-like cancer cells. Our aim was therefore to determine identities of stem cell marker-positive cells in bladder cancer tissue and to investigate possible associations between these cells and different forms of bladder neoplasia. We investigated tissue from 52 patients with bladder neoplasia and 18 patients with benign bladder conditions, from a cohort that had been previously described with regard to diagnosis and outcome. The samples were analysed immunohistologically for the stem cell markers aldehyde dehydrogenase 1 A1 (ALDH1) and CD44, and markers of cell differentiation. The majority of stem cell marker-positive cells were located in connective tissue, and a smaller fraction in epithelial tissue. Stem cell marker-positive cells exhibiting possible stem cell characteristics included cells in deeper locations of benign and malignant epithelium, and sub-endothelial cells in patients with or without neoplasia. Stem cell marker-positive cells with non-stem cell character included stellate cells, mast cells, endothelial cells, foamy histiocytes, and neurons. Significantly, ALDH1+ stellate cells and ALDH1+ mast cells were reduced in number in stroma of benign-appearing mucosa of bladder cancer patients. The stem cell markers ALDH1 and CD44 label several types of differentiated cells in bladder tissue. ALDH1+ stellate cells and mast cells appear to be reduced in stroma of normal-appearing mucosa of bladder cancer patients, and may be part of a “field effect” in cancer-near areas.

Keywords

Bladder cancer Tumour microenvironment Stem cells Stellate cells Mast cells Aldehyde dehydrogenase CD44 

Notes

Acknowledgments

This study was financed by the Telemark Hospital Research and Development Fund. We thank Linda Røland Svensson at Telemark Hospital and Ulla Larsson Petterson at Akademiska Sjukhuset Uppsala for laboratory assistance, and ImaGene-iT AB in Sweden for image processing and figure compilation.

Acknowledgment of funding and grants

R&D Fund, Telemark Hospital, 3710 Skien, Norway

Disclosure of Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300PubMedCrossRefGoogle Scholar
  2. 2.
    Cancer in Norway 2011: Cancer incidence, mortality, survival and prevalence in Norway (2013) Cancer Registry of Norway, Institute of Population-based Cancer Research. http://kreftregisteret.no/Global/Cancer%20in%20Norway/2011/cin2011_with_special_issue-NORDCAN.pdf. Accessed 17 October 2013
  3. 3.
    Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R (2003) The health economics of bladder cancer. A comprehensive review of the published literature. Pharmacoeconomics 21:1315–1330PubMedCrossRefGoogle Scholar
  4. 4.
    Burnet NG, Jefferies SJ, Benson RJ, Hunt DP, Treasure FP (2005) Years of life lost (YLL) from cancer is an important measure of population burden—and should be considered when allocating research funds. Br J Cancer 92:241–245PubMedCentralPubMedGoogle Scholar
  5. 5.
    Young RH (2008) Non-neoplastic disorders of the urinary bladder. Histology. In: Bostwick DG, Cheng L (ed) In: Urologic Surgical Pathology, 2nd edn. Elsevier, pp 217-219Google Scholar
  6. 6.
    Isfoss BL (2011) The sensitivity of fluorescent-light cystoscopy for the detection of carcinoma in situ (CIS) of the bladder: a meta-analysis with comments on gold standard. BJU Int 108:1703–1707PubMedCrossRefGoogle Scholar
  7. 7.
    Althausen AF, Prout GR, Daly JJ (1976) Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 116:575–580PubMedGoogle Scholar
  8. 8.
    Soto EA, Friedell GH, Tiltman AJ (1997) Bladder cancer as seen in giant histologic sections. Cancer 39:447–455CrossRefGoogle Scholar
  9. 9.
    Koss LG, Nakanishi I, Freed SZ (1977) Nonpapillary carcinoma in situ and atypical hyperplasia in cancerous bladders. Further studies of surgically removed bladders by mapping. Urology 9:442–455PubMedCrossRefGoogle Scholar
  10. 10.
    Isfoss BL, Majak B, Busch C, Braathen GJ (2011) Diagnosis of intraurothelial neoplasia. Interobserver variation and the value of individual histopathologic attributes. Anal Quant Cytol Histol 33:75–81PubMedGoogle Scholar
  11. 11.
    Sylvester RJ, van der Mejden APM, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K (2006) Predicting recurrence and progression with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49:466–477PubMedCrossRefGoogle Scholar
  12. 12.
    Cheng L, Cheville JC, Neumann RM, Leibovich BC, Egan KS, Spotts BE, Bostwick DG (1999) Survival of patients with carcinoma in situ of the urinary bladder. Cancer 85:2469–2479PubMedCrossRefGoogle Scholar
  13. 13.
    Chade DC, Shariat SF, Godoy G, Savage CJ, Cronin AM, Bochner BH et al (2010) Clinical outcomes of primary bladder carcinoma in situ in a contemporary series. J Urol 184:74–80PubMedCrossRefGoogle Scholar
  14. 14.
    Cooper PH, Waisman J, Johnston WH, Skinner DG (1973) Severe atypia of transitional epithelium and carcinoma of the urinary bladder. Cancer 31:1055–1060PubMedCrossRefGoogle Scholar
  15. 15.
    Koss LG, Tiamson EM, Robbins MA (1974) Mapping cancerous and precancerous bladder changes. JAMA 227:281–286PubMedCrossRefGoogle Scholar
  16. 16.
    Farrow GM, Utz DC, Rife CC (1976) Morphological and clinical observations of patients with early bladder cancer treated with total cystectomy. Cancer Res 36:2495–2501PubMedGoogle Scholar
  17. 17.
    Farrow GM, Utz DC, Rife CC, Greene L (1977) Clinical observations on sixty-nine cases of in situ carcinoma of the urinary bladder. Cancer Res 27:2794–2798Google Scholar
  18. 18.
    Koss LG (1979) Mapping of the urinary bladder: its impact on the concepts of bladder cancer. Hum Pathol 10:533–548PubMedCrossRefGoogle Scholar
  19. 19.
    Brawn PN (1982) The origin of invasive carcinoma of the bladder. Cancer 50:515–519PubMedCrossRefGoogle Scholar
  20. 20.
    Clarke MF, Dick JE, Dirks PB, Eaves CH, Jamieson CHM, Jones DL et al (2006) Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res 66:9339–9344PubMedCrossRefGoogle Scholar
  21. 21.
    Gupta PB, Chaffer CI, Weinberg RA (2009) Cancer stem cells: mirage or reality? Nat Med 15:1010–2012PubMedCrossRefGoogle Scholar
  22. 22.
    Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y et al (2004) Characterization of clonigenic multiple myeloma cells. Blood 103:2332–2336PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    OBrien CA, Pollett A, Gallinger S, Dick JE (2006) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110CrossRefGoogle Scholar
  24. 24.
    Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 15:555–567CrossRefGoogle Scholar
  25. 25.
    Al-Hajj WMS, Benito-Hernandez MSJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. PNAS 100:3983–3988PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Rovira M, Scott SG, Liss AS, Jensen J, Thayer SP, Leach SD (2009) Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci U S A 107:75–80PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H et al (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 69:3382–3389PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Burger PE, Gupta R, Xiong X, Ontiveros CS, Salm SN, Moscatelli D, Wilson EL (2009) High aldehyde dehydrogenase activity: a novel functional marker of murine prostate stem/progenitor cells. Stem Cells 27:220–2228CrossRefGoogle Scholar
  29. 29.
    Su Y, Qiu Q, Zhang X, Jiang Z, Leng Q, Liu Z et al (2010) Aldehyde dehydrogenase 1 A1-positive cell population is enriched in tumor-initiating cells and associated with progression of bladder cancer. Cancer Epidemiol Biomarkers Prev 19:327–337PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Tagutchi T (2009) Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 15:4234–4241PubMedCrossRefGoogle Scholar
  31. 31.
    Duester G (2008) Retinoid acid synthesis and signaling during early organogenesis. Cell 134:921–931PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    The Human Protein Atlas (2013) CRABP1. The Swedish Human Protein Atlas Project. http://proteinatlas.org/ENSG00000166426. Accessed 17 Oct 2013
  33. 33.
    Isfoss BL, Majak B, Busch C, Braathen GJ (2011) Diagnosis of intraurothelial neoplasia. Interobserver variation and the value of individual histopathologic attributes. Anal Quant Cytol Histol 33:75–81PubMedGoogle Scholar
  34. 34.
    Epstein JI, Amin MB, Reuter VR, Mostofi FK (1998) The World Health Organization/International Society of Urological Pathology Consensus Classification of Urothelial (Transitional Cell) Neoplasms of the Urinary Bladder. Am J Surg Pathol 22:1435–1448PubMedCrossRefGoogle Scholar
  35. 35.
    Tumours of the urinary system (2004) In: Eble JN, Sauter G, Epstein JI and Sesterhenn IA (ed) WHO Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. IARCPress, Lyon, pp 89–157Google Scholar
  36. 36.
    van der Horst G, Bos L, van der Pluijm G (2012) Epithelial plasticity, cancer stem cells, and the tumor-supportive stroma in bladder carcinoma. Mol Cancer Res 10:995–1009PubMedCrossRefGoogle Scholar
  37. 37.
    Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS et al (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313PubMedCrossRefGoogle Scholar
  38. 38.
    Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S et al (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763–776PubMedCrossRefGoogle Scholar
  39. 39.
    Zhou Y, Pan P, Yao L, Meng S, Ping H, Niu N et al (2010) CD117-positive cells of the heart: progenitor cells or mast cells? J Histochem Cytochem 58:309–316PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Jain PC, Singh SN, Pratap VK, Lahiri B (1977) Connective tissue changes and mast cell variations in benign and malignant lesions of the uterine cervix. Int Surg 62:358–360PubMedGoogle Scholar
  41. 41.
    Dabiri S, Huntsman D, Makretsov N, Cheang M, Gilks B, Bajdik C et al (2004) The presence of stromal mast cells identifies a subset of invasive breast cancers with a favourable prognosis. Mod Pathol 17:690–695PubMedCrossRefGoogle Scholar
  42. 42.
    Nielsen HJ, Hansen U, Christensen IJ, Reimert CM, Brünner N, Moesgaard F (1999) Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue. J Pathol 189:487–495PubMedCrossRefGoogle Scholar
  43. 43.
    Fleischmann A, Schlomm T, Köllermann T, Sekulic N, Huland H, Mirlacher M et al (2009) Immunological microenvironment in prostate cancer. High mast cell densities are associated with favourable tumor characteristics and good prognosis. Prostate 69:976–981PubMedCrossRefGoogle Scholar
  44. 44.
    Carlini MJ, Dalurzo MC, Lastiri JM, Smith DE, Vasallo BC, Puricelli LI, Lauría de Cidre LS (2010) Mast cell phenotypes and microvessels in non-small cell lung cancer and its prognostic significance. Hum Pathol 41:697–705PubMedCrossRefGoogle Scholar
  45. 45.
    Norum KR (1984) The name of the perisinusoidal stellate cells, fat-storing cells, pericytes, vitamin A-storing cells of the liver. Kupffer Cell Bull 5:13Google Scholar
  46. 46.
    Wake K (1971) "Sternzellen" in the liver: Perisinusoidal cells with special reference to storage of vitamin A. Am J Anat 132:429–461PubMedCrossRefGoogle Scholar
  47. 47.
    Berkley HJ (1893) Studies in the histology of the liver. III. The perivascular cells of the rabbits liver. Anat Anz 8:787–792Google Scholar
  48. 48.
    Zimmerman KW (1923) Der feinere bau der blutkapillären. Z Anat 68:29–109CrossRefGoogle Scholar
  49. 49.
    Ito T (1951) Cytological studies on stellate cells of Kupffer and fat-storing cells in the capillary wall of the human liver. Acta Anat Nippon 26:2Google Scholar
  50. 50.
    Suzuki K (1958) A silver impregnation method in histology. Takeda Pharm Ind Ozaka 310–320Google Scholar
  51. 51.
    Bronfenmajer S, Schaffer F, Popper H (1966) Fat storing cells (lipocytes) in human liver. Arch Pathol 82:447–553PubMedGoogle Scholar
  52. 52.
    Yamada E, Hirosawa K (1976) The possible existence of a vitamin A-storing cell system. Cell Struct Funct 1:201–204CrossRefGoogle Scholar
  53. 53.
    Hruban Z, Russell RM, Boyer JL, Glagov S, Bagheri SA (1974) Ultrastructural changes in livers of two patients with hypervitaminosis A. Am J Pathol 76:451–468PubMedCentralPubMedGoogle Scholar
  54. 54.
    Nakane PK (1963) Ito’s "fat-storing cell" of the mouse liver. Anat Rec 145:265–266Google Scholar
  55. 55.
    Wake K (1980) Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol 66:303–353PubMedCrossRefGoogle Scholar
  56. 56.
    Nordlinder H, Eriksson U, Busch C (1991) Identification of extrahepatic stellate cells and the cell specific regulation of cellular retinol binding protein. Dissertation, Uppsala University. Acta Universitatis Upsaliensis nr. 284, paper 5Google Scholar
  57. 57.
    Nagy NE, Holven KB, Roos N, Senoo H, Kojima N, Norum KR, Blomhoff R (1997) Storage of vitamin A in extrahepatic cells in normal rats. J Lipid Res 38:645–658PubMedGoogle Scholar
  58. 58.
    Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A (2010) Understanding the "lethal" drivers of tumor-stroma co-evolution. Emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor microenvironment. Cancer Biol Ther 10:537–542PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Björn L. Isfoss
    • 1
    • 2
    Email author
  • Christer Busch
    • 3
  • Helena Hermelin
    • 4
  • Anette T. Vermedal
    • 1
  • Marianne Kile
    • 1
  • Geir J. Braathen
    • 5
    • 6
    • 7
  • Bernard Majak
    • 1
  • Aasmund Berner
    • 2
    • 8
  1. 1.Department of PathologyTelemark HospitalSkienNorway
  2. 2.Faculty of MedicineOslo UniversityOsloNorway
  3. 3.Department of Pathology & CytologyUniversity HospitalUppsalaSweden
  4. 4.Dalarnas ForskningslabFalunSweden
  5. 5.Department of Laboratory Medicine, Section of Medical GeneticsTelemark HospitalSkienNorway
  6. 6.Head and Neck Research Group, Research CentreAkershus University HospitalLørenskogNorway
  7. 7.Faculty Division Akershus University HospitalUniversity of OsloNordbyhagenNorway
  8. 8.Department of Pathology, RadiumhospitaletOslo University HospitalOsloNorway

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