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Identification and Characterization of CD107a as a Marker of Low Reactive Oxygen Species in Chemoresistant Cells in Colorectal Cancer

  • Colorectal Cancer
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Reactive oxygen species (ROS) generated by chemoradiotherapy lead to cancer cell death. Although ROS regulation mechanisms play important roles in chemoradioresistance, few markers exist that indicated intracellular ROS status. This study aimed to identify novel cell surface markers that represented intracellular ROS status to characterize cells with low ROS (ROSlow) in colorectal cancer (CRC).

Methods

We used ROS indicators and an antibody array with 242 cell surface antibodies to identify markers of ROSlow cells. After validation, we performed immunohistochemical analyses and chemosensitivity assays. We used small interfering RNA to assess the effect of silencing the identified markers. We tested cell differentiation assays with spheroid cell assays.

Results

CD107a was identified as a common marker of ROSlow cells in several CRC cell lines and clinical specimens. CD107a+/ROSlow cells were enriched in HT29 and DLD1 cultures after treatments with oxaliplatin, 5-fluorouracil, and the irinotecan metabolite SN38. CD107a silencing improved chemosensitivity by increasing ROS production. Immunohistochemistry showed enhanced CD107a surface expression on cells that formed immature cell clusters and on cells located in the invasive fronts of cancer foci. CD107a expression was also enhanced on specimens from patients with poorly differentiated adenocarcinoma who had received neoadjuvant chemotherapy. Cell surface CD107a expression was enhanced on cells that formed colonospheres, but expression diminished during cell differentiation.

Conclusions

CD107a was identified as a novel marker of ROSlow cells in CRC. CD107a expression was closely related to chemoresistance and the immature cell phenotype. Anti-CD107a treatments represent a novel approach for targeting chemoresistant cells in CRC.

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Acknowledgement

Supported in part by the Foundation of the Pharma-Link between Academia and Shionogi (FLASH), an initiative between Osaka University and Shionogi & Co. Ltd.

Disclosure

The authors declare no conflict of interest.

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Author notes

    Authors and Affiliations

    1. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan

      Tomohiro Kitahara MD, Naotsugu Haraguchi MD, PhD, Hidekazu Takahashi MD, PhD, Junichi Nishimura MD, PhD, Taishi Hata MD, PhD, Ichiro Takemasa MD, PhD, Tsunekazu Mizushima MD, PhD, Hirofumi Yamamoto MD, PhD, Yuichiro Doki MD, PhD & Masaki Mori MD, PhD

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    1. Tomohiro Kitahara MD
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    2. Naotsugu Haraguchi MD, PhD
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    3. Hidekazu Takahashi MD, PhD
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    Correspondence to Naotsugu Haraguchi MD, PhD.

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    Tomohiro Kitahara and Naotsugu Haraguchi contributed equally to this work.

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    Kitahara, T., Haraguchi, N., Takahashi, H. et al. Identification and Characterization of CD107a as a Marker of Low Reactive Oxygen Species in Chemoresistant Cells in Colorectal Cancer. Ann Surg Oncol 24, 1110–1119 (2017). https://doi.org/10.1245/s10434-016-5671-8

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    • DOI: https://doi.org/10.1245/s10434-016-5671-8

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