Establishment of a Patient‐Derived Xenograft Tumor From Hepatitis C–Associated Liver Cancer and Evaluation of Imatinib Treatment Efficacy

Abstract

Background and Aims Chronic hepatitis C virus (HCV) infection is one of the major causal factors for hepatocellular carcinoma (HCC). The treatment options for HCC are limited for lack of a convenient animal model for study in HCV infection and liver pathogenesis. This study aimed to develop a patient‐derived xenograft (PDX) tumor in mice by using a tumor from a patient with HCV‐associated HCC and evaluating this model’s therapeutic potential. Approach and Results After resection of the primary tumor from the patient liver, excess viable tumor was implanted into highly immunodeficient mice. A mouse xenograft tumor line was developed, and the tumor was successfully passaged for at least three rounds in immunodeficient mice. The patient’s primary tumor and the mouse xenografts were histologically similar. Genetic profiling by short‐tandem‐repeat analysis verified that the HCC‐PDX model was derived from the HCC clinical specimen. HCV RNA present in the patient liver specimen was undetectable after passage as xenograft tumors in mice. Human albumin, α1‐antitrypsin, glypican‐3, α–smooth muscle actin, and collagen type 1A2 markers were detected in human original tumor tissues and xenograft tumors. Both the patient primary tumor and the xenograft tumors had a significantly higher level of receptor tyrosine kinase (c‐Kit) mRNA. Treatment of HCC‐PDX xenograft tumor–bearing mice with the c‐Kit inhibitor imatinib significantly reduced tumor growth and phospho‐Akt and cyclin D1 expression, as compared with untreated control tumors. Conclusions Our results demonstrated establishment of an HCV‐associated HCC‐PDX model as a powerful tool for evaluating candidate drugs. Information on molecular changes in cancer‐specific gene expression facilitates efficient targeted therapies and treatment strategies.

Sulfarotene, a synthetic retinoid, overcomes stemness and sorafenib resistance of hepatocellular carcinoma via suppressing SOS2-RAS pathway

“…In a sterile environment, NOG mice were anesthetized and the HCC tissue blocks were implanted subcutaneously into the top right flank of the mice. About two months later, after reaching 1 cm in diameter, the subcutaneous PDX tumor nodes were removed, dissected into approximately 2 × 2 × 2 mm 3 pieces, and re-transplanted into the flanks of nude mice for 30 days to permit growth as previously described [ 10 , 11 ].…”

C-Kit, a Double-Edged Sword in Liver Regeneration and Diseases

“…PreS1 protein of HBV stimulates the appearance and self-renewal of LCSCs by activating the expression of c-kit and is confirmed in human hepatoma cells and HCC tissues ( Liu et al, 2017 ). And in HCV infection patients, c-kit overexpression is observed ( Kwon et al, 2015 ; Nazzal et al, 2020 ). Data shows that HCV core protein upregulates the expression of c-kit in hepatocytes, inducing the epithelial-mesenchymal transition, and extends the life span of cells ( Kwon et al, 2015 ).…”

“…The roles of c-kit + cells in chronic hepatitis B and C have been described in HCC ( Kara et al, 2008 ; Kwon et al, 2015 ; Liu et al, 2017 ; Nazzal et al, 2020 ). Also, it is reported that there is an increase of mast cells in alcoholic hepatitis, but reports on the relationship between c-kit and alcoholic hepatitis are insufficient ( Farrell et al, 1995 ).…”

“…Furthermore, Nazzal et al recently showed that HCC-patient-derived xenograft (PDX) tumors respond well following imatinib treatment. Treatment of HCC-PDX xenograft tumor-bearing mice with imatinib significantly reduced tumor growth and c-kit downstream molecules expression ( Nazzal et al, 2020 ). In clinical, Becker et al (2007) discovered that the positive rate of c-kit is 2.3% and that there was no role for imatinib.…”

Imatinib and GNF-5 Exhibit an Inhibitory Effect on Growth of Hepatocellar Carcinoma Cells by Downregulating S-phase Kinase-associated Protein 2

“…Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor of the breakpoint cluster region-Abelson murine leukemia (Bcr-Abl) fusion gene and is used in the treatment of chronic myeloid leukemia (CML) [ 12 ]. Imatinib has also been used to treat gastrointestinal stromal tumors and various other malignancies [ 13 - 15 ]. GNF-5 is a selective, non-ATP-competitive inhibitor of Bcr-Abl and is used in combination with an ATP-competitive inhibitor, such as imatinib or nilotinib, to enhance antitumor effects in vitro [ 16 ].…”