Virchows Archiv

, Volume 475, Issue 4, pp 479–488 | Cite as

Comprehensive in situ analysis of ALDH1 and SOX2 reveals increased expression of stem cell markers in high-grade serous carcinomas compared to low-grade serous carcinomas and atypical proliferative serous tumors

  • Anna Katharina FischerEmail author
  • Deborah L. Pham
  • Hans Bösmüller
  • Claudia Lengerke
  • Philipp Wagner
  • Cornelia Bachmann
  • Christine Beschorner
  • Sven Perner
  • Stefan Kommoss
  • Falko Fend
  • Annette StaeblerEmail author
Original Article


Recent studies have shown that re-expression of stem cell factors contribute to pathogenesis, therapy resistance, and recurrent disease in ovarian carcinomas. In this study, we compare the expression and co-expression of stem cell markers ALDH1 and SOX2 in different types of serous ovarian tumors. A total of 215 serous ovarian tumors (161 high-grade serous carcinomas (HGSC), 17 low-grade serous carcinomas (LGSC), 37 atypical proliferative serous tumors (APST)), and 10 cases of serous tubal intraepithelial carcinoma (STIC) were analyzed. Double immunostaining experiments addressed the association of cell proliferation (Ki67) with ALDH1 and the potential co-expression of SOX2 and ALDH1. The prognostic effect was analyzed in the cohort of HGSC. Expression of ALDH1and/or SOX2 was detected with increased frequency in HGSC (88.8%), compared with LGSC (70.5%) and APST (36.4%), while ALDH1 alone was significantly more frequently expressed in LGSC. The majority of all tumor types showed expression of ALDH1 and SOX2 in different cells. Only a minority of HGSC (4.6%) and STIC (20%) showed SOX2/ALDH1 co-expression in > 10% of tumor cells. Double staining also revealed that ALDH1 is associated with the non-proliferating Ki67-negative fraction consistent with a stem cell phenotype. Co-expression of ALDH1 and SOX2 or ALDH1 and Ki67 has no effect on survival. Expression of stem cell factors ALDH1 and/or SOX2 shows increased frequency in high-grade serous ovarian carcinomas compared to low-grade carcinomas and borderline tumors, supporting the concept that stem cell markers play different biological roles in low-grade versus high-grade serous neoplasia of the ovary.


Ovarian neoplasms Cancer stem cells Proliferation SOX2 ALDH1 



We thank Anne Adam and the members of the laboratory staff at the Institute of Pathology in Tuebingen for expert technical support.


AF and AS were involved in all aspects of the study including collecting and choosing material for TMA construction, analyzing immunohistochemistry, interpreting the data, statistical analysis, and writing the manuscript. They were expanding TMAs previously constructed by Deborah Pham.

CB constructed the TMAs.

PW, SK, and CB provided patient tissue and clinical data.

SP and FF were involved in establishing immunohistochemistry, study design, and writing of the manuscript.

CL and HB were involved in the study design and writing of the manuscript.

AS oversaw and coordinated the work performed.

Funding information

Annette Staebler has received funding by the DFG (Deutsche Forschungsgemeinschaft, Collaborative Research Center SFB 685).

Compliance with ethical standards

The study is in agreement with the guidelines of local ethics committee and was approved (Nr. 645/2012/BO2). This study was approved by the institutional ethics review board of the University Hospital Tuebingen.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

428_2019_2647_MOESM1_ESM.docx (6.3 mb)
ESM 1 (DOCX 6412 kb)


  1. 1.
    Bowen NJ, Walker LD, Matyunina LV, Logani S, Totten KA, Benigno BB, McDonald JF (2009) Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells. BMC Med Genet 2:71. CrossRefGoogle Scholar
  2. 2.
    Crum CP, Herfs M, Ning G, Bijron JG, Howitt BE, Jimenez CA, Hanamornroongruang S, McKeon FD, Xian W (2013) Through the glass darkly: intraepithelial neoplasia, top-down differentiation, and the road to ovarian cancer. J Pathol 231(4):402–412. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
  4. 4.
    McAuliffe SM, Morgan SL, Wyant GA, Tran LT, Muto KW, Chen YS, Chin KT, Partridge JC, Poole BB, Cheng KH, Daggett J Jr, Cullen K, Kantoff E, Hasselbatt K, Berkowitz J, Muto MG, Berkowitz RS, Aster JC, Matulonis UA, Dinulescu DM (2012) Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc Natl Acad Sci U S A 109(43):E2939–E2948. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cannistra SA (2004) Cancer of the ovary. N Engl J Med 351(24):2519–2529. CrossRefPubMedGoogle Scholar
  6. 6.
    Kurman RJ, Shih Ie M (2008) Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications. Int J Gynecol Pathol 27(2):151–160. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ahmed N, Abubaker K, Findlay J, Quinn M (2013) Cancerous ovarian stem cells: obscure targets for therapy but relevant to chemoresistance. J Cell Biochem 114(1):21–34. CrossRefPubMedGoogle Scholar
  8. 8.
    Folkins AK, Saleemuddin A, Garrett LA, Garber JE, Muto MG, Tworoger SS, Crum CP (2009) Epidemiologic correlates of ovarian cortical inclusion cysts (CICs) support a dual precursor pathway to pelvic epithelial cancer. Gynecol Oncol 115(1):108–111. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Silva IA, Bai S, McLean K, Yang K, Griffith K, Thomas D, Ginestier C, Johnston C, Kueck A, Reynolds RK, Wicha MS, Buckanovich RJ (2011) Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res 71(11):3991–4001. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Abelson S, Shamai Y, Berger L, Shouval R, Skorecki K, Tzukerman M (2012) Intratumoral heterogeneity in the self-renewal and tumorigenic differentiation of ovarian cancer. Stem Cells 30(3):415–424. CrossRefPubMedGoogle Scholar
  11. 11.
    Flesken-Nikitin A, Hwang CI, Cheng CY, Michurina TV, Enikolopov G, Nikitin AY (2013) Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature 495(7440):241–245. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cariati M, Purushotham AD (2008) Stem cells and breast cancer. Histopathology 52(1):99–107. CrossRefPubMedGoogle Scholar
  13. 13.
    Tang C, Ang BT, Pervaiz S (2007) Cancer stem cell: target for anti-cancer therapy. FASEB J 21(14):3777–3785. CrossRefPubMedGoogle Scholar
  14. 14.
    Hu Y, Fu L (2012) Targeting cancer stem cells: a new therapy to cure cancer patients. Am J Cancer Res 2(3):340–356PubMedPubMedCentralGoogle Scholar
  15. 15.
    Kuroda T, Hirohashi Y, Torigoe T, Yasuda K, Takahashi A, Asanuma H, Morita R, Mariya T, Asano T, Mizuuchi M, Saito T, Sato N (2013) ALDH1-high ovarian cancer stem-like cells can be isolated from serous and clear cell adenocarcinoma cells, and ALDH1 high expression is associated with poor prognosis. PLoS One 8(6):e65158. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bareiss PM, Paczulla A, Wang H, Schairer R, Wiehr S, Kohlhofer U, Rothfuss OC, Fischer A, Perner S, Staebler A, Wallwiener D, Fend F, Fehm T, Pichler B, Kanz L, Quintanilla-Martinez L, Schulze-Osthoff K, Essmann F, Lengerke C (2013) SOX2 expression associates with stem cell state in human ovarian carcinoma. Cancer Res 73(17):5544–5555. CrossRefPubMedGoogle Scholar
  17. 17.
    Ye F, Li Y, Hu Y, Zhou C, Hu Y, Chen H (2011) Expression of Sox2 in human ovarian epithelial carcinoma. J Cancer Res Clin Oncol 137(1):131–137. CrossRefPubMedGoogle Scholar
  18. 18.
    Long KB, Hornick JL (2009) SOX2 is highly expressed in squamous cell carcinomas of the gastrointestinal tract. Hum Pathol 40(12):1768–1773. CrossRefPubMedGoogle Scholar
  19. 19.
    Sanada Y, Yoshida K, Konishi K, Oeda M, Ohara M, Tsutani Y (2006) Expression of gastric mucin MUC5AC and gastric transcription factor SOX2 in ampulla of vater adenocarcinoma: comparison between expression patterns and histologic subtypes. Oncol Rep 15(5):1157–1161PubMedGoogle Scholar
  20. 20.
    Rodriguez-Pinilla SM, Sarrio D, Moreno-Bueno G, Rodriguez-Gil Y, Martinez MA, Hernandez L, Hardisson D, Reis-Filho JS, Palacios J (2007) Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol 20(4):474–481. CrossRefPubMedGoogle Scholar
  21. 21.
    Pham DL, Scheble V, Bareiss P, Fischer A, Beschorner C, Adam A, Bachmann C, Neubauer H, Boesmueller H, Kanz L, Wallwiener D, Fend F, Lengerke C, Perner S, Fehm T, Staebler A (2013) SOX2 expression and prognostic significance in ovarian carcinoma. Int J Gynecol Pathol 32(4):358–367. CrossRefPubMedGoogle Scholar
  22. 22.
    He QZ, Luo XZ, Wang K, Zhou Q, Ao H, Yang Y, Li SX, Li Y, Zhu HT, Duan T (2014) Isolation and characterization of cancer stem cells from high-grade serous ovarian carcinomas. Cell Physiol Biochem 33(1):173–184. CrossRefPubMedGoogle Scholar
  23. 23.
    Orford KW, Scadden DT (2008) Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet 9(2):115–128. CrossRefPubMedGoogle Scholar
  24. 24.
    Kim J, Coffey DM, Creighton CJ, Yu Z, Hawkins SM, Matzuk MM (2012) High-grade serous ovarian cancer arises from fallopian tube in a mouse model. Proc Natl Acad Sci U S A 109(10):3921–3926. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. CrossRefGoogle Scholar
  26. 26.
    Chen X, Zhang J, Zhang Z, Li H, Cheng W, Liu J (2013) Cancer stem cells, epithelial-mesenchymal transition, and drug resistance in high-grade ovarian serous carcinoma. Hum Pathol 44(11):2373–2384. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Deng S, Yang X, Lassus H, Liang S, Kaur S, Ye Q, Li C, Wang LP, Roby KF, Orsulic S, Connolly DC, Zhang Y, Montone K, Butzow R, Coukos G, Zhang L (2010) Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers. PLoS One 5(4):e10277. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Landen CN Jr, Goodman B, Katre AA, Steg AD, Nick AM, Stone RL, Miller LD, Mejia PV, Jennings NB, Gershenson DM, Bast RC Jr, Coleman RL, Lopez-Berestein G, Sood AK (2010) Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Mol Cancer Ther 9(12):3186–3199. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Chui MH, Wang Y, Wu RC, Seidman J, Kurman RJ, Wang TL, Shih Ie M (2015) Loss of ALDH1A1 expression is an early event in the pathogenesis of ovarian high-grade serous carcinoma. Mod Pathol 28(3):437–445. CrossRefPubMedGoogle Scholar
  30. 30.
    Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456(7222):593–598. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Li H, Bitler BG, Vathipadiekal V, Maradeo ME, Slifker M, Creasy CL, Tummino PJ, Cairns P, Birrer MJ, Zhang R (2012) ALDH1A1 is a novel EZH2 target gene in epithelial ovarian cancer identified by genome-wide approaches. Cancer Prev Res (Phila) 5(3):484–491. CrossRefGoogle Scholar
  32. 32.
    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(6):817–823. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Liebscher CA, Prinzler J, Sinn BV, Budczies J, Denkert C, Noske A, Sehouli J, Braicu EI, Dietel M, Darb-Esfahani S (2013) Aldehyde dehydrogenase 1/epidermal growth factor receptor coexpression is characteristic of a highly aggressive, poor-prognosis subgroup of high-grade serous ovarian carcinoma. Hum Pathol 44(8):1465–1471. CrossRefPubMedGoogle Scholar
  34. 34.
    Hellner K, Miranda F, Fotso Chedom D, Herrero-Gonzalez S, Hayden DM, Tearle R, Artibani M, KaramiNejadRanjbar M, Williams R, Gaitskell K, Elorbany S, Xu R, Laios A, Buiga P, Ahmed K, Dhar S, Zhang RY, Campo L, Myers KA, Lozano M, Ruiz-Miro M, Gatius S, Mota A, Moreno-Bueno G, Matias-Guiu X, Benitez J, Witty L, McVean G, Leedham S, Tomlinson I, Drmanac R, Cazier JB, Klein R, Dunne K, Bast RC Jr, Kennedy SH, Hassan B, Lise S, Garcia MJ, Peters BA, Yau C, Sauka-Spengler T, Ahmed AA (2016) Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: discovery and validation studies. EBioMedicine 10:137–149. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lengerke C, Fehm T, Kurth R, Neubauer H, Scheble V, Muller F, Schneider F, Petersen K, Wallwiener D, Kanz L, Fend F, Perner S, Bareiss PM, Staebler A (2011) Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma. BMC Cancer 11:42. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of Pathology and NeuropathologyUniversity of TuebingenTuebingenGermany
  2. 2.Institute of PathologyLudwigs-Maximilians University of MunichMunichGermany
  3. 3.Division of Clinical Hematology and Department of Biomedicine, University Hospital BaselUniversity of BaselBaselSwitzerland
  4. 4.Women’s HospitalUniversity of TuebingenTuebingenGermany
  5. 5.Institute of Pathology, University Hospital Schleswig-HolsteinLuebeckGermany

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