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Modelling the impact of liver regeneration on hepatoblastoma patient-derived-xenograft tumor growth

Pediatric Research (2024)Cite this article

Abstract

Background

Twenty percent of children with hepatoblastoma (HB) have lung metastasis at diagnosis. Treatment protocols recommend surgical removal of chemotherapy-refractory lung nodules, however no chronological order is established. As hepatectomy is followed by release of growth factors, it has been proposed that partial hepatectomy (PH) could boost local or distant residual tumor growth.

Methods

To evaluate the impact of PH on distant tumor growth, PH was performed in mice subcutaneously implanted with a HB patient-derived xenograft (PDX). The influence of PH on tumor growth at primary site was assessed by performing PH concomitantly to HB PDXs orthotopic implantation.

Results

Subcutaneously implanted HB PDX failed to show any influence of hepatectomy on tumor growth. Instead, intrahepatic tumor growth of one of the 4 HB PDXs implanted orthotopically was clearly enhanced. Cells derived from the hepatectomy-sensitive HB PDX exposed to hepatic growth factor (HGF) showed increased proliferation rate compared to cells derived from a hepatectomy-insensitive model, suggesting that the HGF/MET pathway could be one of the effectors of the crosstalk between liver regeneration and HB growth.

Conclusion

These results suggest that hepatectomy can contribute to HB growth in some patients, further studies will be necessary to identify biomarkers predictive of patient risk of PH-induced HB recurrence.

Impact

  • Key message: Cytokines and growth factors secreted following partial hepatectomy can contribute to intrahepatic tumor growth in some hepatoblastoma models.

  • What does it add to the existing literature: It is the first article about the impact of liver regeneration induced by partial hepatectomy on hepatoblastoma local or distant tumoral growth in nude mice.

  • What is the impact: It is important to identify the secreted factors that enhance tumor growth and to define biomarkers predictive of patient risk of partial hepatectomy-induced hepatoblastoma recurrence.

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Fig. 1: Impact of hepatectomy on HB-217 PDX extrahepatic growth.
Fig. 2: Impact of hepatectomy on HB-217 PDX extrahepatic tumor growth following chemotherapy.
Fig. 3: Orthotopic and subcutaneous HB PDXs retain histological features of their parental tumors.
Fig. 4: Impact of liver regeneration on HB-217 and HB-284 PDX intrahepatic tumor growth.
Fig. 5: Impact of liver regeneration on HB-214 and HB-243 PDXs intrahepatic tumor growth.
Fig. 6: Evaluation of HGF impact on cell growth from a PH-sensitive vs PH-insensitive tumor cells.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful to all the technicians from XenTech’s in vivo facility for their contribution in the study.

Funding

The study was supported and financed by XenTech; M.C. received a fellowship from SFCP (Societé Française de Chirurgie Pédiatrique).

Author information

Author notes

  1. These authors contributed equally: Sophie Branchereau, Stefano Cairo.

Authors and Affiliations

  1. Department of Paediatric Surgery, Paris-Saclay University, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin Bicêtre, France

    Marianna Cornet & Sophie Branchereau

  2. XenTech, Evry-Courcouronnes, France

    Marianna Cornet, Laura Brulle-Soumare, Olivier Deas, Jean-Gabriel Judde & Stefano Cairo

  3. Institut de Recherche Saint Louis, Inserm U1160, Saint Louis Hospital, Paris, France

    Valeria Bisio

  4. Onco-Hematology Clinic and Lab, Women’s and Children’s Health department, University-Hospital of Padova, Padova, Italy

    Valeria Bisio & Martina Pigazzi

  5. Department of Pathology, Paris-Saclay University, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin Bicêtre, France

    Charlotte Mussini & Catherine Guettier

  6. Department of Pathology, Paris Cité University, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France

    Monique Fabre

  7. Fondazione Istituto di Ricerca Pediatrica (IRP), Padova, Italy

    Martina Pigazzi & Stefano Cairo

  8. Université Paris Saclay, Faculté des Sciences d’Orsay, INSERM U.1193, Orsay, France

    Thierry Tordjmann

  9. Champions Oncology, Hackensack, NJ, USA

    Stefano Cairo

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Contributions

Conception and design: M.C., S.C. and S.B. Acquisition of data: M.C., L.B.S., V.B., C.M., C.G. Analysis and interpretation of data: M.C., L.B.S., O.D., C.M., C.G., M.F. Revising the article: T.T., M.P., J.G.J. Final approval of the version to be published: M.C., S.C. and S.B. All authors have read and agreed to the published version of the manuscript.”

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Correspondence to Marianna Cornet or Stefano Cairo.

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Cornet, M., Brulle-Soumare, L., Bisio, V. et al. Modelling the impact of liver regeneration on hepatoblastoma patient-derived-xenograft tumor growth. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03020-x

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