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Predictive Value of CD44 in Muscle-Invasive Bladder Cancer and Its Relationship with IL-6 Signaling

Annals of Surgical Oncology volume 25, pages 3518–3526 (2018)Cite this article

Abstract

Background

CD44, a cancer stem cell surface marker, is associated with treatment resistance and prognosis in some cancers. In the present study, we examined the predictive value of CD44 in muscle-invasive bladder cancer (MIBC).

Methods

We retrospectively analyzed the clinical outcomes of 105 MIBC patients and correlated these outcomes with the expression of CD44. Furthermore, the bladder cancer cell lines HT1197 and MB49 were selected for cellular and animal experiments to investigate the correlation between CD44 and tumor aggressiveness.

Results

Analysis of clinical specimens indicated that CD44 staining was significantly associated with a higher clinical stage, higher locoregional failure rate, and lower disease-specific survival rate for MIBC patients. Using cellular experiments and orthotopic tumor models, we showed that CD44+ bladder cancer cells had a higher invasion ability and augmented epithelial-mesenchymal transition (EMT) compared with CD44 cells. There was a significant correlation between interleukin (IL)-6 and CD44 levels noted by in vitro testing, and clinical samples. Blockade of IL-6 attenuated the expression of CD44, cancer stem-cell-like properties, and aggressive tumor behavior in vitro and in vivo. The related changes included the attenuated STAT3 activation and EMT, and decreased programmed death ligand 1-mediated T-cell suppression.

Conclusion

Our findings suggest that CD44 expression is positively associated with tumor aggressiveness in bladder cancer, and activated IL-6 signaling provides a suitable microenvironment for the induction of CD44 expression.

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Funding

This work was support by Chang Gung Memorial Hospital, Taiwan (Grant Number OMRPG6C0011 and CMRPG6D0323, to M-F Chen), and the National Science Council, Taiwan (Grant Number NMRPG2E6031, to C-T Wu).

Author information

Affiliations

  1. Department of Urology, Chang Gung Memorial Hospital at Keelung, Keelung City, Taiwan

    Chun-Te Wu MD, PhD

  2. College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Chun-Te Wu MD, PhD, Wei-Yu Lin MD, Wen-Cheng Chen MD & Miao-Fen Chen MD, PhD

  3. Department of Urology, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan

    Wei-Yu Lin MD

  4. Department of Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, Putz City, Chia-Yi Hsien, Taiwan

    Wen-Cheng Chen MD & Miao-Fen Chen MD, PhD

Authors
  1. Chun-Te Wu MD, PhD
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  2. Wei-Yu Lin MD
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  3. Wen-Cheng Chen MD
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  4. Miao-Fen Chen MD, PhD
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Corresponding author

Correspondence to Miao-Fen Chen MD, PhD.

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Conflicts of interest

Chun-Te Wu, Wei-Yu Lin, Wen-Cheng Chen, and Miao-Fen Chen confirm they have no conflicts of interest.

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Wu, CT., Lin, WY., Chen, WC. et al. Predictive Value of CD44 in Muscle-Invasive Bladder Cancer and Its Relationship with IL-6 Signaling. Ann Surg Oncol 25, 3518–3526 (2018). https://doi.org/10.1245/s10434-018-6706-0

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  • DOI: https://doi.org/10.1245/s10434-018-6706-0

Keywords

  • Bladder Cancer Cells
  • MIBC Patients
  • Orthotopic Tumor Model
  • Lower Disease-specific Survival Rate
  • Higher Locoregional Failure Rates