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Fibrinogen promotes gallbladder cancer cell metastasis and extravasation by inducing ICAM1 expression

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Abstract

Fibrinogen plays an important role in tumor progression. Here, we explored the role of fibrinogen in gallbladder cancer (GBC) metastasis. The plasma fibrinogen level in M1 GBC patients was higher than in M0 GBC patients, indicating that fibrinogen may participate in GBC metastasis. Treatment of GBC cell lines with fibrinogen promoted metastasis and induced the expression of intercellular adhesion molecule 1 (ICAM1). ICAM1 overexpression promoted metastasis and knockdown inhibited it. The cell adhesion and transendothelial migration of GBC cells were enhanced by fibrinogen treatment and ICAM1 overexpression. In addition, the medium of fibrinogen-treated and overexpression-ICAM1 NOZ cells exhibited enhanced macrophages recruitment. This may work in concert to promote angiogenesis. Immunohistochemistry results on clinical specimens showed that higher fibrinogen levels, higher ICAM1 expression, higher blood vessel density, and higher macrophage levels were present simultaneously. Collectively, this study indicates fibrinogen promotes metastasis and extravasation by inducing ICAM1 expression to enhance tumor cell migration, cell adhesion, transendothelial migration and promote angiogenesis and increase vascular endothelial permeability.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank the following individuals for their significant contributions to the Chinese Research Group of Gallbladder Cancer study, as following: Dr. Tai Ren, Dr. Yang Yang, Dr. Xiaoling Song, Dr. Liguo Liu, Dr. Rui Bian, Dr. Huijie Miao, Dr. Guoqiang Li, Dr. Ruiyan Yuan, Dr. Ziyi Wang, Dr. Siyuan Yan, Dr. Xuechuan Li, Dr. Lu Zou, Dr. Ke Liu, Dr. Lingxiao Zhang, Dr. Yiming Li, Dr. Wei Dang, Dr. Zexu Chen, Dr. Letai Liao, and Dr. Junjie Li at Shanghai Key Laboratory of Biliary Tract Disease Research. We thank our collaborators for their dedications in the CRGGC, as following: Dr. Kai Qu at The First Affiliated Hospital of Xi'an Jiaotong University, Prof. Rongsheng Zhang and, Prof. Ling Zhang at Shanxi Provincial Cancer Hospital, Prof. Fubao Liu at The First Affiliated Hospital of Anhui Medical University, Prof. Lei Zou at The First Affiliated Hospital of Kunming Medical University, Dr. Lei Wang at Wuxi Second People's Hospital, and Dr. Jie Zhang at Xinhua (Chongming) Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. We thank Prof. Jian Hou and Prof. Lan Zhang for gifting HUVEC cell lines.

Funding

This study was supported by the National Natural Science Foundation of China (81874181, 31701108, and 81701749), the National Science and Technology Major Projects for "Major New Drugs Innovation and Development" (2019ZX09301158), the Emerging Frontier Program of Hospital Development Center (SHDC12018107), the General Surgery Construction Program of Shanghai Municipal Health Commission (2017ZZ02011), the Clinical Research Program of Xinhua Hospital (19XHCR3D), the Shanghai Artificial Intelligence Innovation and Development Project (2019-RGZN-01096), the Shanghai “Rising Stars of Medical Talent” Youth Development Program, and the Shanghai Key Laboratory of Biliary Tract Disease Research Foundation (17DZ2260200).

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Authors and Affiliations

  1. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Chengkai Jiang, Yang Li, Yongsheng Li, Liguo Liu, Xu-an Wang, Wenguang Wu, Maolan Li, Yajun Geng & Yingbin Liu

  2. State Key Laboratory for Oncogenes and Related Genes, Shanghai, 200127, China

    Chengkai Jiang, Yang Li, Yongsheng Li, Liguo Liu, Xu-an Wang, Wenguang Wu, Maolan Li, Yajun Geng & Yingbin Liu

  3. Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, 200092, China

    Chengkai Jiang, Yang Li, Yongsheng Li, Liguo Liu, Xu-an Wang, Wenguang Wu, Runfa Bao, Hao Weng, Maolan Li, Yajun Geng, Yijun Shu & Yingbin Liu

  4. Shanghai Research Center of Biliary Tract Disease, Shanghai, 200092, China

    Chengkai Jiang, Yang Li, Yongsheng Li, Liguo Liu, Xu-an Wang, Wenguang Wu, Runfa Bao, Hao Weng, Maolan Li, Yajun Geng, Yijun Shu & Yingbin Liu

  5. Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Runfa Bao, Hao Weng & Yijun Shu

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  1. Chengkai Jiang
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  10. Yajun Geng
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Contributions

CJ: Data curation; Formal analysis; Investigation; Methodology; Project administration; Software; Validation; Visualization; Writing—original draft; Writing—review & editing. YL (Yang Li): Data curation; Formal analysis; Validation; Visualization; Writing—review & editing. YL (Yongsheng Li): Data curation; Resources; Writing—original draft. LL: Resources; Supervision. XW: Resources; Supervision. WW: Resources; Supervision. RB: Methodology; Supervision. HW: Methodology; Resources; Supervision. ML: Methodology; Supervision. YG: Writing—review & editing. YS: Conceptualization; Funding acquisition; Investigation; Methodology; Supervision; Validation; Writing—review & editing. YL (Yingbin Liu): Conceptualization; Funding acquisition; Project administration; Resources; Supervision; Writing—review & editing.

Corresponding authors

Correspondence to Yajun Geng, Yijun Shu or Yingbin Liu.

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The authors declare no competing interest.

Ethical approval

The human study was approved by the Institutional Ethical Board of Xinhua Hospital and informed consent was obtained from all patients with GBC prior to enrollment of the study. All of the animal studies were approved by the Institutional Animal Care and Use Committee of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. All the animal experiments were performed according to our institution's guidelines for the use of laboratory animals.

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Jiang, C., Li, Y., Li, Y. et al. Fibrinogen promotes gallbladder cancer cell metastasis and extravasation by inducing ICAM1 expression. Med Oncol 40, 10 (2023). https://doi.org/10.1007/s12032-022-01874-x

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