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The status of donor cancer tissues affects the fate of patient-derived colorectal cancer xenografts in NOG mice.

ABSTRACT: Patient-derived xenografts (PDXs) of tumors are increasingly becoming important tools for translational research in oncology. The NOD.Cg-Prkdc(scid) Il2rg(tm1Sug)/Jic (NOG) mouse is an efficient host for PDXs. Thus as a basis for future development of methods to obtain PDXs from various disease types, we have studied the factors that affect the outcome of transplantation of human colorectal cancer in NOG mice. Of the original donor cases examined, 73% had successful engraftment. The outcome of donor-matched tissues was consistent in most cases, and was thought to show that the condition of the host did not affect engraftment. Next we analyzed the tumor aggressiveness in terms of histology grade of the original tumor and found that they were related to engraftment. Detailed histopathological examination of the transplanted tissues strongly indicated that lymphocytes engrafted with the tumor cells affect engraftment. As a factor related to transplantation of lymphocytes, we studied the human IgG concentration in the serum of tumor-bearing mice, but there was no tendency for higher concentrations to result in unsuccessful engraftment. Finally, we studied the type, density and location of T cells in the original donor tissue to determine the immune contexture and found that the unsuccessful engraftment cases tended to have an adequate or coordinated immune contexture compared to successful engraftment cases. From these results, we concluded that the aggressiveness and the T cell infiltration of the original tumor affect the outcome of transplantation in the NOG mouse.

SUBMITTER: Fujii E

PROVIDER: S-EPMC4427733 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The status of donor cancer tissues affects the fate of patient-derived colorectal cancer xenografts in NOG mice.

Fujii Etsuko E Kato Atsuhiko A Chen Yu Jau YJ Matsubara Koichi K Ohnishi Yasuyuki Y Suzuki Masami M

Experimental animals 20150126 2

Patient-derived xenografts (PDXs) of tumors are increasingly becoming important tools for translational research in oncology. The NOD.Cg-Prkdc(scid) Il2rg(tm1Sug)/Jic (NOG) mouse is an efficient host for PDXs. Thus as a basis for future development of methods to obtain PDXs from various disease types, we have studied the factors that affect the outcome of transplantation of human colorectal cancer in NOG mice. Of the original donor cases examined, 73% had successful engraftment. The outcome of d ...[more]

PMID: 25740629

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Project description:Endogenous retroviruses are remnants of retroviral infections. In contrast to their human counterparts, murine endogenous retroviruses (mERV) still can synthesize infectious particles and retrotranspose. Xenotransplanted human cells have occasionally been described to be mERV infected. With genetic engineered mice and patient-derived xenografts (PDXs) on the rise as eminent research tools, we here systematically investigated, if different tumor models harbor mERV infections. Relevant mERV candidates were first preselected by next generation sequencing (NGS) analysis of spontaneous lymphomas triggered by colorectal cancer (CRC) PDX tissue. Two primer systems were designed for each of these candidates (AblMLV, EcoMLV, EndoPP, MLV, and preXMRV) and implemented in an quantitative real-time (RT-qPCR) screen using murine tissues (n = 11), PDX-tissues (n = 22), PDX-derived cell lines (n = 13), and patient-derived tumor cell lines (n = 14). The expression levels of mERV varied largely both in the PDX samples and in the mouse tissues. No mERV signal was, however, obtained from cDNA or genomic DNA of CRC cell lines. Expression of EcoMLV was higher in PDX than in murine tissues; for EndoPP it was the opposite. These two were thus further investigated in 40 additional PDX. In addition, four patient-derived cell lines free of any mERV expression were subcutaneously injected into immunodeficient mice. Outgrowing cell-derived xenografts barely expressed EndoPP. In contrast, the expression of EcoMLV was even higher than in surrounding mouse tissues. This expression gradually vanished within few passages of re-cultivated cells. In summary, these results strongly imply that: (i) PDX and murine tissues in general are likely to be contaminated by mERV, (ii) mERV are expressed transiently and at low level in fresh PDX-derived cell cultures, and (iii) mERV integration into the genome of human cells is unlikely or at least a very rare event. Thus, mERVs are stowaways present in murine cells, in PDX tissues and early thereof-derived cell cultures. We conclude that further analysis is needed concerning their impact on results obtained from studies performed with PDX but also with murine tumor models.

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The status of donor cancer tissues affects the fate of patient-derived colorectal cancer xenografts in NOG mice.

Publications

The status of donor cancer tissues affects the fate of patient-derived colorectal cancer xenografts in NOG mice.

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