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Cellular and Molecular Biology

High expression of the cachexia-related protein Fn14 in esophageal squamous cell carcinoma correlates with poor chemotherapy response and anti-Fn14 therapy decreases chemotherapeutic resistance

British Journal of Cancer volume 133, pages 771–783 (2025)Cite this article

Subjects

Abstract

Background

In cancer cachexia, cytokine release by tumours causes weight loss, decreased therapeutic efficacy, and worsened prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast inducible factor 14 (Fn14) are cancer cachexia-related proteins; however, their expression in oesophageal squamous cell carcinoma (ESCC) and association with therapeutic resistance remain unclear.

Methods

We evaluated how Fn14 knockdown and overexpression in ESCC lines (TE6 and TE10) contributed to proliferation, migration, and chemotherapy resistance in vitro and in vivo. In 135 ESCC patients who underwent esophagectomy after neoadjuvant chemotherapy, tumour expression of TWEAK and Fn14 was evaluated immunohistochemically to assess the association with clinicopathological factors and prognosis, including chemotherapeutic efficacy.

Results

Proliferation, migration, and chemotherapy resistance of ESCC cell lines were decreased by Fn14 knockdown but increased by Fn14 overexpression. Patients with Fn14-overexpressing ESCC had a decreased response rate to neoadjuvant chemotherapy and significantly lower rates of overall and recurrence-free survival, while concurrent expression of TWEAK and Fn14 was associated with further reductions in the response rate to chemotherapy and the rates of overall and recurrence-free survival.

Conclusions

TWEAK and Fn14 expression was associated with treatment resistance and prognosis in ESCC. Inhibiting the TWEAK/Fn14 axis may reduce treatment resistance and improve prognosis.

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Fig. 1: Effects of Fn14 knockdown on proliferation, migration, and chemosensitivity.
Fig. 2: Effect of Fn14 overexpression on proliferation, migration, and chemosensitivity.
Fig. 3: Proliferation and chemoresistance of a Fn14-overexpressing ESCC cell line (TE6) in vivo, and inhibition of tumour growth and chemosensitivity by anti-Fn14 antibodies.
Fig. 4: Proliferation and chemoresistance of a Fn14-positive ESCC cell line (TE10) in vivo, and inhibition of tumour growth and chemosensitivity by anti-Fn14 antibodies.
Fig. 5: Association of TWEAK and Fn14 expression with chemoresistance and prognosis in ESCC patients.

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Data availability

The datasets generated and analyzed during the current study are not publicly available because they contain private information pertaining to the research participants but are available on request from the corresponding author.

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Acknowledgements

We would like to thank Zenis (https://www.zenis.co.jp) for English language editing.

Funding

This research was partially supported by Japan society for the promotion of science (JSPS) (#. 22K08771).

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Authors and Affiliations

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

    Kei Adachi, Kotaro Yamashita, Yu Kamakura, Kota Momose, Takuro Saito, Koji Tanaka, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Kiyokazu Nakajima, Hidetoshi Eguchi & Yuichiro Doki

  2. Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan

    Kazuyoshi Yamamoto

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Contributions

Conceptualization and design– KY, TT, YK. Sample and data collection– KA, YK, KM. Data curation and statistical analyses –KA, TS, KT, TM. Supervision– KN, HE, YD. Writing-Original draft– KA. Writing-review and editing– KY, KY.

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Correspondence to Kotaro Yamashita.

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This study had a retrospective design and was approved by the Institutional Ethics Review Committee of Certificate Number 08226-10. All the procedures were performed in accordance with the principles of the Declaration of Helsinki and its amendments.

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Adachi, K., Yamashita, K., Kamakura, Y. et al. High expression of the cachexia-related protein Fn14 in esophageal squamous cell carcinoma correlates with poor chemotherapy response and anti-Fn14 therapy decreases chemotherapeutic resistance. Br J Cancer 133, 771–783 (2025). https://doi.org/10.1038/s41416-025-03087-1

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