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Band 3 ectopic expression in colorectal cancer induces an increase in erythrocyte membrane-bound IgG and may cause immune-related anemia

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Abstract

Autoimmune hemolytic anemia (AIHA) is a rare comorbidity in colorectal cancer (CRC) and has an unknown etiology. Previously, we described an AIHA case secondary to CRC with ectopic band 3 expression. Herein, we investigated ectopic band 3 expression and erythrocyte membrane-bound IgG in a CRC cohort. Between September 2016 and August 2018, 50 patients with CRC and 26 healthy controls were enrolled in the present study. The expression of band 3 and SLC4A1 mRNA was observed in 97% of CRC surgical specimens. Although clinical AIHA was not observed in any patient with CRC, a direct antiglobulin test was positive in 10 of the patients in the CRC group (p = 0.01). Flow cytometry revealed significantly increased erythrocyte membrane-bound IgG among patients with CRC compared to healthy controls (mean ± standard deviation; 38.8 ± 4.7 vs. 29.9 ± 15.6, p = 0.012). Normocytic anemia was observed, including in cases negative for fecal occult blood, suggesting a shortened erythrocyte life-span due to increased membrane-bound IgG. Immunoprecipitation revealed increased anti-band 3 autoantibodies in patients’ sera. Mouse experiments recapitulated this phenomenon. We also confirmed that band 3 expression is controlled by 5′AMP-activated protein kinase under hypoxic conditions. These findings increase our understanding of the etiology of cancer-related anemia.

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Acknowledgements

We would like to thank Dr. Kimindo Kumagai of the Hyogo Prefecture Health Promotion Association for his contribution to the enrollment of healthy controls. We would also like to thank Drs. Atsushi Shiozaki, Michihiro Kudou and Mitsuo Kishimoto of Kyoto Prefectural University of Medicine for their advice on immunohistochemical staining techniques. We thank Dr. Toshiyuki Ikemoto of Shiga University of Medical Science and Hiroko Tanada of Osaka Medical College for providing technical advice on flow cytometry.

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Authors and Affiliations

  1. Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital, Kobe, Hyogo, Japan

    Akihito Kitao, Keiji Kurata, Hiroshi Matsuoka & Hironobu Minami

  2. Department of Transfusion Medicine and Cell Therapy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

    Shinichiro Kawamoto, Ikuyo Hayakawa & Hironobu Minami

  3. Department of Diagnostic Pathology, Kohnan Hospital, Kobe, Hyogo, Japan

    Takashi Yamasaki

  4. Department of Surgery, Asahikawa Medical University Hospital, Asahikawa, Hokkaido, Japan

    Yasuo Sumi

  5. Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Hospital, Kobe, Hyogo, Japan

    Yoshihiro Kakeji

  6. Center for Community Medicine, Jichi Medical University Hospital, Shimotsuke, Tochigi, Japan

    Toyomi Kamesaki

Authors
  1. Akihito Kitao
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  2. Shinichiro Kawamoto
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  3. Keiji Kurata
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  4. Ikuyo Hayakawa
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  5. Takashi Yamasaki
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  8. Yoshihiro Kakeji
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  9. Toyomi Kamesaki
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Contributions

AK collected the data, performed experiments, analyzed the results and drafted the initial manuscript. SK designed the study, performed experiments and proofread the manuscript. KK and IH collected the data. TY performed pathological investigations. HM, YS, YK collected the data. TK designed the study and reviewed the manuscript. HM reviewed the manuscript. This manuscript was approved by all authors.

Corresponding author

Correspondence to Shinichiro Kawamoto.

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Conflict of interest

This work was supported by JSPS KAKENHI Grant Number JP18K07297. The study was also supported by Astellas Pharma Inc., Ltd.; Eisai Co., Ltd.; MSD; Kyowa Hakko Kirin Co. Ltd.; and Chugai Pharmaceutical Co., Ltd.

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Kitao, A., Kawamoto, S., Kurata, K. et al. Band 3 ectopic expression in colorectal cancer induces an increase in erythrocyte membrane-bound IgG and may cause immune-related anemia. Int J Hematol 111, 657–666 (2020). https://doi.org/10.1007/s12185-020-02831-y

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  • DOI: https://doi.org/10.1007/s12185-020-02831-y

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