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Immunohistochemical analysis of the expression of cancer-associated fibroblast markers in esophageal cancer with and without neoadjuvant therapy

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Abstract

Esophageal carcinoma (EC) is one of the most aggressive human malignancies with high rates of resistance to conventional anticancer treatment. Cancer-associated fibroblasts (CAFs) are an important part of the tumor microenvironment and associated with tumor progression. COL11A1, SPARC, and CD90 have been identified as rather specific CAF markers, with COL11A1 expression particularly shown to influence response to chemotherapy. We investigated the impact of CAFs in esophageal cancer with a special focus on response to neoadjuvant treatment (nTX). Two collections of esophageal carcinomas were investigated: 164 cases treated with primary resection and 256 cases receiving nTX before resection. The expression of CAF markers was determined using next-generation tissue microarray (ngTMA®) technology and immunohistochemistry. The presence of COL11A1 and SPARC in fibroblasts within both primary resected cases and nTX-treated cases was associated with unfavorable clinicopathological variables such as higher (y)pT category and lymphatic invasion (p<0.001 each). The presence of COL11A1-positive CAFs was associated with worse overall survival in primary resected cases (HR: 2.162, p = 0.004, CI 95% 1.275–3.686). While in tumors showing regression after nTX, COL11A1-positive CAFs were detected less frequently, SPARC-positive CAFs were enriched after nTX, in both responding and non-responding patients (p < 0.001). Our results support the concept of CAFs as an important factor of tumor promotion and maintenance in EC. The population of CAFs increases with tumor progression and decreases, partly depending on the subtype, after regression following nTX. CAFs may serve as potential target for future therapeutic approaches for these highly aggressive tumors.

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Acknowledgments

The authors would like to acknowledge Translational Research Unit at the Institute of Pathology, University of Bern (Switzerland), for excellent technical assistance and Prof. Dr. Inti Zlobec and Lester Thoo for revision and critical reading of the manuscript.

Funding

This work was supported by the Stiftung Krebshilfe (Switzerland) and Dr. Hans Altschüler Stiftung (Switzerland).

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Authors and Affiliations

  1. Institute of Pathology, University of Bern, Murtenstrasse 31, 3008, Bern, Switzerland

    José A. Galván, Julia Wiprächtiger & Rupert Langer

  2. Institute of Pathology, Technische Universität München, München, Germany

    Julia Slotta-Huspenina

  3. Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, München, Germany

    Marcus Feith

  4. Department of Surgery, RoMED Klinikum, Rosenheim, Germany

    Katja Ott

  5. Department of Visceral Surgery and Medicine, University Hospital of Bern, University of Bern, Bern, Switzerland

    Dino Kröll & Christian A. Seiler

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  1. José A. Galván
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Contributions

JAG and RL conceived and planned the study. JSH, MF, KO, DK, and CAS provided the human tissue samples. JW and RL selected the human tissue samples and performed the annotations of the TMA cores. JAG constructed the ngTMAs and carried out the immunostainings. JW and JAG carried out the scoring and supervised by RL. JAG carried out the statistical analysis. JAG and RL contributed to the interpretation of the results. JAG wrote the manuscript with the support of RL. All authors provided critical feedback and helped shape the manuscript.

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Correspondence to José A. Galván.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of local ethics commission (Kantonale Ethikkommission Bern, Switzerland, 200/14 and Medizinische Fakultät of the Technische Universität München, 2056/08) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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The authors declare that they have no conflicts of interest.

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Galván, J.A., Wiprächtiger, J., Slotta-Huspenina, J. et al. Immunohistochemical analysis of the expression of cancer-associated fibroblast markers in esophageal cancer with and without neoadjuvant therapy. Virchows Arch 476, 725–734 (2020). https://doi.org/10.1007/s00428-019-02714-6

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