The extent of inflammatory infiltration in primary cancer tissues is associated with lymphomagenesis in immunodeficient mice

Abstract

Xenotransplantation of human cancers into immunodeficient mice is a very useful approach for studying human tumor biology. However, the occasional occurrence of lymphomagenesis in some mice can spoil the model and must be investigated in detail. We found that a high percentage (32.5%, 26/80) of cancer patient-derived xenografts (PDXs) resembled lymphoma in NOD/SCID mice. Of the 26 xenografts, 23 were human-derived expressing human CD45 (hCD45+) and proved to be of the B-cell subtype (CD3-/CD20+), and they were all positive for Epstein - Barr virus (EBV). The remaining 3 xenografts proved to be mouse-derived for both hCD45- and negative amplification of a human gene. The most interesting finding is that gastric cancer had much higher rates (24/126, 19.0%) of lymphoma formation in the PDX model than did colorectal cancer (1/43, 2.3%). Statistical analysis revealed that cancer type and inflammation in the parent tumor are significantly associated with lymphomagenesis. Further validation discovered lymphomagenesis by inoculating only gastritis mucosa. Therefore, our findings suggest that it is necessary to take precautions when directly xenografting cancer tissues with remarkable baseline inflammation, such as gastric cancer into immunodeficient NOD/SCID strains. Further, the established xenograft models should be validated by both leukocyte markers and human gene signatures.

Evaluation of the risk of lymphomagenesis in xenografts by the PCR-based detection of EBV BamHI W region in patient cancer specimens

“…In this study, 2 out of 9 PDXs showed morphological characteristics of lymphoma (22.2%). Although the number of the reports on the lymphomagenesis in PDXs are still limited, other two reports present that the incidence of lymphomagenesis in the PDX transplanted with human CRC tissues was 3.3% (1/30) and 28.6% (2/7) [8, 9], suggesting that it is important to consider a possibilities of the lymphomagenesis when establishing PDX using the patient CRC tissues.…”

“…For example, the frequency of lymphomagenesis is up to 80% in the prostate cancer PDX which will be attributed to the low tumorigenicity of the androgen-sensitive prostate cancer [10]. Zhang et al suggested that cancer type, preoperative chemotherapy and inflammation in patient primary cancer were associated with high risk of lymphomagenesis in PDX [8]. They suggested that gastric cancer specimens are more likely form DLBCL PDX than CRC ones, because of chronic mucosal inflammation caused by Helicobacter pylori.…”

“…The incidence of lymphomagenesis among the established PDXs differ widely depending on the cancer types; for example, 1/30 PDXs (3.3 %) in colorectal cancer (CRC), 11/21 (56%) PDXs derived from 16 patients in liver cancer, and 8/10 PDXs (80%) in prostate cancer [7, 8, 10]. In addition, transplantation of the same cancer specimen resulted in the formation of a lymphoma PDX in one mouse and a cancer PDX in another mouse [9].…”

“…In addition, transplantation of the same cancer specimen resulted in the formation of a lymphoma PDX in one mouse and a cancer PDX in another mouse [9]. Pathological analyses of 26 lymphoma PDXs revealed that 23 PDXs were Epstein-Barr virus (EBV)-associated human B cell lymphoma, and the remaining 3 PDXs were lymphoma of mouse origin [8]. …”

Gastric Cancer in the Era of Precision Medicine

“…In PDX models with transferred peripheral blood mononuclear cells from the same patient, combination therapy with anti-hCD137 and anti-hPD1 antibodies (urelumab and nivolumab, respectively) significantly slowed tumor growth 115 . Although these data are promising, practical challenges remain to improving use of PDX models in cancer research, including delay between murine engraftment time and patient treatment schedule, lymphomagenesis of human tumors in mice, and cost 16, 116. In one large breast cancer PDX model study, even within the first murine passage, all models showed moderate drift to dramatic clonal selection during tumor growth 117 …”