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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

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Abstract

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.

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Acknowledgments

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

Contributions

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

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

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Authors and Affiliations

  1. Institute of Pathology and Neuropathology, University of Tuebingen, Liebermeisterstraße 8, 72076, Tuebingen, Germany

    Anna Katharina Fischer, Hans Bösmüller, Christine Beschorner, Falko Fend & Annette Staebler

  2. Institute of Pathology, Ludwigs-Maximilians University of Munich, Thalkirchner Straße 36, 80337, Munich, Germany

    Deborah L. Pham

  3. Division of Clinical Hematology and Department of Biomedicine, University Hospital Basel, University of Basel, Petersgraben 4, 4031, Basel, Switzerland

    Claudia Lengerke

  4. Women’s Hospital, University of Tuebingen, Calwerstraße 6, 72076, Tuebingen, Germany

    Philipp Wagner, Cornelia Bachmann & Stefan Kommoss

  5. Institute of Pathology, University Hospital Schleswig-Holstein, Campus Luebeck, 23538, Luebeck, Germany

    Sven Perner

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  1. Anna Katharina Fischer
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Correspondence to Anna Katharina Fischer or Annette Staebler.

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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.

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Fischer, A.K., Pham, D.L., Bösmüller, H. et al. 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. Virchows Arch 475, 479–488 (2019). https://doi.org/10.1007/s00428-019-02647-0

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