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Establishment of childhood hepatoblastoma xenografts and evaluation of the anti-tumour effects of anlotinib, oxaliplatin and sorafenib

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Abstract

Background

Hepatoblastoma (HB) is a common primary malignant liver tumour in children, mainly treated by means of traditional chemotherapy using platinum and doxorubicin (ADM). There has been limited progress in the research and development of new drugs for treating HB.

Methods

A tumour biopsy from a child with HB was implanted into immunodeficient mice. The primary tumour and patient-derived xenograft (PDX) tumour were extensively characterised by histology, immunohistochemistry (IHC), and humanisation identification. We used the PDX model to evaluate the anti-tumour effects of anlotinib oxaliplatin (L-OHP) and sorafenib on childhood HB.

Results

The established PDX model maintained the histological characteristics of the primary tumour. Anlotinib, L-OHP, and sorafenib can significantly inhibit the tumour growth in the PDX model. There was no obvious damage of the drugs to the heart, liver and kidney of the mice, and the side effects observed were light.

Conclusion

We have successfully established a PDX model of childhood HB. The model retains important molecular characteristics of human primary tumours. Using the model, it was found that anlotinib, L-OHP, and sorafenib have a good inhibitory effect on the growth of childhood HB. This provides a preliminary research basis for the clinical application of the drugs.

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References

  1. Hiyama E et al (2015) Mortality and morbidity in primarily resected hepatoblastomas in Japan: experience of the JPLT (Japanese Study Group for Pediatric Liver Tumor) trials. J Pediatr Surg 50(12):2098–2101. https://doi.org/10.1016/j.jpedsurg.2015.08.035

    Article  PubMed  Google Scholar 

  2. Czauderna P et al (2016) The children’s hepatic tumors international collaboration (CHIC): novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer 52:92–101. https://doi.org/10.1016/j.ejca.2015.09.023

    Article  PubMed  Google Scholar 

  3. DeBord LC et al (2018) The chick chorioallantoic membrane (CAM) as a versatile patient-derived xenograft (PDX) platform for precision medicine and preclinical research. Am J Cancer Res 8(8):1642–1660

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Fujii E, Kato A, Suzuki M (2020) Patient-derived xenograft (PDX) models: characteristics and points to consider for the process of establishment. J Toxicol Pathol 33(3):153–160. https://doi.org/10.1293/tox.2020-0007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xin Y et al (2020) Establishment of a jaw fibrosarcoma patient-derived xenograft and evaluation of the tumor suppression efficacy of plumbagin against jaw fibrosarcoma. Front Oncol 10:1479. https://doi.org/10.3389/fonc.2020.01479

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rivankar S (2014) An overview of doxorubicin formulations in cancer therapy. J Cancer Res Ther 10:853–858. https://doi.org/10.4103/0973-1482.139267

    Article  PubMed  Google Scholar 

  7. Carvalho FS et al (2014) Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med Res Rev 34(1):106–135. https://doi.org/10.1002/med.21280

    Article  CAS  PubMed  Google Scholar 

  8. Limsuwan T, Castells MC (2010) Outcomes and safety of rapid desensitization for chemotherapy hypersensitivity. Expert Opin Drug Saf 9(1):39–53. https://doi.org/10.1517/14740330903446936

    Article  CAS  PubMed  Google Scholar 

  9. Han B et al (2018) Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase II trial (ALTER0302). Br J Cancer 118(5):654–661. https://doi.org/10.1038/bjc.2017.478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ruan X et al (2019) Antitumor effects of anlotinib in thyroid cancer. Endocr Relat Cancer 26(1):153–164. https://doi.org/10.1530/ERC-17-0558

    Article  CAS  PubMed  Google Scholar 

  11. Zhou A-P et al (2019) Anlotinib versus sunitinib as first-line treatment for metastatic renal cell carcinoma: a randomized phase II clinical trial. Oncologist 24(8):e702–e708. https://doi.org/10.1634/theoncologist.2018-0839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Song F et al (2020) Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma. Cell Death Dis 11(7):573. https://doi.org/10.1038/s41419-020-02749-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Noda S et al (2020) Sorafenib exposure and its correlation with response and safety in advanced hepatocellular carcinoma: results from an observational retrospective study. Cancer Chemother Pharmacol 86(1):129–139. https://doi.org/10.1007/s00280-020-04105-0

    Article  CAS  PubMed  Google Scholar 

  14. Chollet P et al (1996) Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer. Ann Oncol 7(10):1065–1070. https://doi.org/10.1093/oxfordjournals.annonc.a010500

    Article  CAS  PubMed  Google Scholar 

  15. Esim O et al (2020) Development, optimization and in vitro evaluation of oxaliplatin loaded nanoparticles in non-small cell lung cancer. DARU J Pharm Sci 28(2):673–684. https://doi.org/10.1007/s40199-020-00374-5

    Article  CAS  Google Scholar 

  16. Tanaka R et al (2020) Reactive fibrosis precedes doxorubicin-induced heart failure through sterile inflammation. ESC Heart Fail 7(2):588–603. https://doi.org/10.1002/ehf2.12616

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kimura G et al (2017) Sorafenib as a potential strategy for refractory pulmonary arterial hypertension. Pulm Pharmacol Ther 44:46–49. https://doi.org/10.1016/j.pupt.2017.03.009

    Article  CAS  PubMed  Google Scholar 

  18. Cividalli A et al (2002) Radiosensitization by oxaliplatin in a mouse adenocarcinoma: influence of treatment schedule. Int J Radiat Oncol*Biol*Phys 52(4):1092–1098. https://doi.org/10.1016/S0360-3016(01)02792-4

    Article  CAS  PubMed  Google Scholar 

  19. Bondoc A et al (2021) Identification of distinct tumor cell populations and key genetic mechanisms through single cell sequencing in hepatoblastoma. Commun Biol 4(1):1049–1049. https://doi.org/10.1038/s42003-021-02562-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Johnston Ii ME et al (2021) Olaparib inhibits tumor growth of hepatoblastoma in patient-derived xenograft models. Hepatology 74(4):2201–2215. https://doi.org/10.1002/hep.31919

    Article  CAS  Google Scholar 

  21. Xu R et al (2019) Clinical value of spectral CT imaging combined with AFP in identifying liver cancer and hepatic focal nodular hyperplasia. J B.U.ON: Off J Balkan Union Oncol 24(4):1429–1434

    Google Scholar 

  22. Marcu L, Bezak E (2010) Modelling of tumour repopulation after chemotherapy. Australas Phys Eng Sci Med 33(3):265–270. https://doi.org/10.1007/s13246-010-0026-4

    Article  PubMed  Google Scholar 

  23. Senan S, Smit EF (2007) Design of clinical trials of radiation combined with antiangiogenic therapy. Oncologist 12(4):465–477. https://doi.org/10.1634/theoncologist.12-4-465

    Article  CAS  PubMed  Google Scholar 

  24. Jain RK et al (2006) Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3(1):24–40. https://doi.org/10.1038/ncponc0403

    Article  CAS  PubMed  Google Scholar 

  25. Lin B et al (2018) Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRβ and FGFR1. Gene 654:77–86. https://doi.org/10.1016/j.gene.2018.02.026

    Article  CAS  PubMed  Google Scholar 

  26. Rini BI et al (2020) Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol 21(1):95–104. https://doi.org/10.1016/S1470-2045(19)30735-1

    Article  CAS  PubMed  Google Scholar 

  27. Falcon BL et al (2011) Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Can Res 71(5):1573. https://doi.org/10.1158/0008-5472.CAN-10-3126

    Article  CAS  Google Scholar 

  28. Yang C et al (2018) Ki67 targeted strategies for cancer therapy. Clin Transl Oncol 20(5):570–575. https://doi.org/10.1007/s12094-017-1774-3

    Article  CAS  PubMed  Google Scholar 

  29. Li LT et al (2015) Ki67 is a promising molecular target in the diagnosis of cancer (review). Mol Med Rep 11(3):1566–1572. https://doi.org/10.3892/mmr.2014.2914

    Article  CAS  PubMed  Google Scholar 

  30. Hsieh MJ et al (2020) Inactivation of APC induces CD34 upregulation to promote epithelial-mesenchymal transition and cancer stem cell traits in pancreatic cancer. Int J Mol Sci. https://doi.org/10.3390/ijms21124473

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was funded by the Futang Children Health Development Planning Foundation (FTCSF-2018-03), the National Natural Science Foundation of China (No: 81960101; 81960443), Science Technology Foundation of Jiangxi Province (20212BAG70003), and Jiangxi Province Health Committee Research Project (20203689; 202110098).

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Correspondence to Jinlong Yan or Shouhua Zhang.

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The authors declare there is no interest conflict.

Ethical approval

All experiments using immunodeficient mice were performed in accordance with guidelines approved by the Institutional Animal Care and Use Committee of Nanchang University. The study was approved by the Ethics Committee of Affiliated Children’s Hospital of Nanchang University. Informed consent was obtained from the patient’s guardian.

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Yang, D., Chen, F., Gong, D. et al. Establishment of childhood hepatoblastoma xenografts and evaluation of the anti-tumour effects of anlotinib, oxaliplatin and sorafenib. Pediatr Surg Int 38, 465–472 (2022). https://doi.org/10.1007/s00383-021-05043-5

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