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Translational Therapeutics

Serum thrombospondin-1 serves as a novel biomarker and agonist of gemcitabine-based chemotherapy in intrahepatic cholangiocarcinoma

British Journal of Cancer volume 128, pages 907–917 (2023)Cite this article

Subjects

Abstract

Background

At present, the first-line treatment for advanced intrahepatic cholangiocarcinoma (ICC) is gemcitabine combined with cisplatin, but a considerable portion of ICC patients exhibit resistance to gemcitabine. Therefore, finding sensitisers for gemcitabine chemotherapy in ICC patients and predicting molecular markers for chemotherapy efficacy have become urgent needs.

Methods

In this study, PDX models were established to conduct gemcitabine susceptibility tests. The selected PDX tissues of the chemotherapy-sensitive group and drug-resistant group were subjected to transcriptome sequencing and protein chip technology to identify the key genes. Sixty-one ICC patients treated with gemcitabine chemotherapy were recruited for clinical follow-up validation.

Results

We found that thrombospondin-1 (TSP1) can predict gemcitabine chemosensitivity in ICC patients. The expression level of TSP1 could reflect the sensitivity of ICC patients to gemcitabine chemotherapy. Functional experiments further confirmed that TSP1 can increase the efficacy of gemcitabine chemotherapy for ICC. A mechanism study showed that TSP1 may affect the intake of oleic acid by binding to the CD36 receptor.

Conclusions

In summary, we found a key molecule—TSP1—that can predict and improve the sensitivity of ICC patients to gemcitabine chemotherapy, which is of great significance for the treatment of advanced cholangiocarcinoma.

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Fig. 1: Preclinical models of PDX preserved the patients’ pathological characteristics.
Fig. 2: Thrombospondin-1 (TSP1) is significantly abundant in PDXs sensitive to gemcitabine.
Fig. 3: High serum TSP1 levels correlate with better efficacy of gemcitabine-based chemotherapy for ICC.
Fig. 4: Serum TSP1 levels could predict the prognosis of patients with unresectable ICC.
Fig. 5: Thrombospondin-1 (TSP1) enhances the effect of gemcitabine chemotherapy on intrahepatic cholangiocarcinoma.
Fig. 6: TSP1 inhibits the uptake of oleic acid by intrahepatic cholangiocarcinoma cells, thereby increasing the therapeutic effect of gemcitabine.

Data availability

All presented data are available from the corresponding author upon reasonable request.

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Acknowledgements

Thank all participants for their support and help.

Funding

This study was supported by the National Natural Science Foundation of China (81972575,81903059, 81802983), the San Hang Program of the Second Military Medical University, and Shanghai Municipal Commission of Health and Family Planning Program (20174Y0085).

Author information

Author notes

  1. These authors contributed equally: Dong-yang Ding, Xiao-jie Gan, Jia-ning Zhang, Guo-jun Hou.

Authors and Affiliations

  1. The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China

    Dong-yang Ding, Xiao-jie Gan, Jia-ning Zhang, Guo-jun Hou, Qi-fei Tao, Da-peng Sun, Wen Li, Yuan Yang, Wen-bin Ding, Lei Liu, Wei-ping Zhou & Sheng-xian Yuan

  2. Department of General Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 200438, Shanghai, China

    Jian Yu

  3. The Department of Medical Genetics, Naval Medical University, 200438, Shanghai, China

    Fu Yang

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Contributions

D-yD: Data curation, Writing-Original draft preparation; J-nZ and X-jG: Visualisation, Investigation; G-jH and Q-fT: Software; D-pS, WL and JY: Writing-Reviewing and Editing; YY, W-bD and LL: Software, Validation; S-XY and FY: Conceptualisation, Methodology; W-pZ: Supervision.

Corresponding authors

Correspondence to Lei Liu, Fu Yang, Wei-ping Zhou or Sheng-xian Yuan.

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This study was performed with the approval of the Ethics Committee of the Third Affiliated Hospital of Navy Medical University (ethical authorisation protocol numbers: EHBHKY201802012).

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Ding, Dy., Gan, Xj., Zhang, Jn. et al. Serum thrombospondin-1 serves as a novel biomarker and agonist of gemcitabine-based chemotherapy in intrahepatic cholangiocarcinoma. Br J Cancer 128, 907–917 (2023). https://doi.org/10.1038/s41416-022-02101-0

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