Abstract
While patient-derived xenograft (PDX) models of hepatocellular carcinoma (HCC) have been successfully generated from resected tissues, no reliable methods have been reported for the generation of PDXs from patients who are not candidates for resection and represent the vast majority of patients with HCC. Here we compare two methods for the creation of PDXs from HCC biopsies and find that implantation of whole biopsy samples without the addition of basement membrane matrix favors the formation of PDX tumors that resemble Epstein-Barr virus (EBV)-driven B-cell lymphomas rather than HCC tumors. In contrast, implantation with Matrigel supports growth of HCC cells and leads to a high rate of HCC tumor formation from these biopsies. We validate the resulting PDXs, confirm their fidelity to the patients’ disease and conclude that minimally invasive percutaneous liver biopsies can be used with relatively high efficiency to generate PDXs of HCC.
Highlights
The high failure rate of clinical trials is a costly feature of cancer drug development and can be largely attributed to limited drug efficacy in patients[1]
In light of previous studies showing that patient-derived xenograft (PDX) in immunodeficient mice are vulnerable to Epstein-Barr virus (EBV)-driven B-cell lymphomas arising from the parent tissue of origin[10,14], we evaluated the expression of leukocyte markers in our xenograft tissues by immunohistochemistry (IHC, Supplementary Table 1)
We evaluated our xenografts for evidence of EBV infection by in situ hybridization (ISH) or polymerase chain reaction (PCR) for EBV-encoded RNA (EBER1) and found that the human-derived lymphoid tumors were EBER1 positive; no signal could be detected in the CD45− xenografts (Fig. 2A,B)
Summary
The high failure rate of clinical trials is a costly feature of cancer drug development and can be largely attributed to limited drug efficacy in patients[1]. Human samples from a variety of cancer types were found to yield Epstein-Barr virus (EBV) associated lymphomas when implanted into NOD scid gamma (NSG) mice These lymphomas are known to occur after implantation of HCC samples[10] and thought to originate from intra-tumoral B lymphocytes that have reactivated a latent EBV infection. The susceptibility of immunocompromised mice to engraftment of EBV-transformed cells, the high rate of EBV infection in humans (>90%) and the presence of B lymphocytes in HCC samples[10] necessitate the development of appropriate methodologies that identify the formation of lymphoid PDXs. We endeavored to derive PDX models from biopsies of intermediate and advanced stage HCC (Barcelona Clinic Liver Cancer Staging System B and C) patients who are not candidates for resection. Our primary objective was to demonstrate that PDXs can be derived from percutaneous biopsies of HCC and that methodological improvements can increase the rate of success
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