Development of human hepatocellular carcinoma in X-linked severe combined immunodeficient pigs: An orthotopic xenograft model

PLoS One. 2021 Mar 22;16(3):e0248352. doi: 10.1371/journal.pone.0248352. eCollection 2021.

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common primary tumor and the third leading cause of cancer-related deaths worldwide. Rodent models of HCC have contributed to the advancement of studies investigating liver carcinogenesis, tumor-host interactions, and drug screening. However, their small size renders them unsuitable for surgical or clinical imaging studies, necessitating the development of larger-size HCC models. Here, we developed a xenograft model of human HCC in X-linked interleukin-2 receptor gamma chain gene (Il2rg)-targeted severe combined immunodeficient (SCID) pigs. HepG2 cell suspension in serum-free medium containing 50% membrane matrix was directly injected into the liver parenchyma of eight X-linked Il2rg-targeted SCID pigs (6.6-15.6 kg) via ultrasonography-guided percutaneous puncture. Tumor engraftment was evaluated weekly using ultrasonography, and cone-beam computed tomography was performed during arterial portography (CTAP) and hepatic arteriography (CTHA) to evaluate the hemodynamics of engrafted tumors. The engrafted tumors were histologically analyzed following necropsy and assessed for pathological similarities to human HCCs. Macroscopic tumor formation was observed in seven of the eight pigs (simple nodular tumors in three and multinodular tumors in four). Engrafted tumors were identified as low-echoic upon ultrasonography and as perfusion-defect nodules on the CTAP images. Meanwhile, CTHA showed that the tumors were hyperattenuating. Further, histopathological findings of the engrafted tumors were consistent with those of human HCC. In conclusion, the porcine model of human HCC, successfully generated herein, might help develop more effective therapeutic strategies for HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / diagnostic imaging
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Contrast Media / pharmacology
  • Disease Models, Animal
  • Hep G2 Cells
  • Heterografts
  • Humans
  • Interleukin Receptor Common gamma Subunit / genetics*
  • Liver / diagnostic imaging
  • Liver / pathology
  • Liver Neoplasms / diagnostic imaging
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Swine / genetics
  • Tomography, X-Ray Computed
  • X-Linked Combined Immunodeficiency Diseases / diagnostic imaging
  • X-Linked Combined Immunodeficiency Diseases / genetics*
  • X-Linked Combined Immunodeficiency Diseases / pathology

Substances

  • Contrast Media
  • IL2RG protein, human
  • Interleukin Receptor Common gamma Subunit

Grant support

This work was supported by JSPS KAKENHI Grant Number JP15K06809. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.