Patient-Derived Tumor Xenografts Are Susceptible to Formation of Human Lymphocytic Tumors

Abstract

Patient-derived xenograft (PDX) tumor models have emerged as a new approach to evaluate the effects of cancer drugs on patients’ personalized tumor grafts enabling to select the best treatment for the cancer patient and providing a new tool for oncology drug developers. Here, we report that human tumors engrafted in immunodeficient mice are susceptible to formation of B-and T-cell PDX tumors. We xenografted human primary and metastatic tumor samples into immunodeficient mice and found that a fraction of PDX tumors generated from patients’ samples of breast, colon, pancreatic, bladder and renal cancer were histologically similar to lymphocytic neoplasms. Moreover, we found that the first passage of breast and pancreatic cancer PDX tumors after initial transplantation of the tumor pieces from the same human tumor graft could grow as a lymphocytic tumor in one mouse and as an adenocarcinoma in another mouse. Whereas subcutaneous PDX tumors resembling human adenocarcinoma histology were slow growing and non-metastatic, we found that subcutaneous PDX lymphocytic tumors were fast growing and formed large metastatic lesions in mouse lymph nodes, liver, lungs, and spleen. PDX lymphocytic tumors were comprised of B-cells which were Epstein-Barr virus positive and expressed CD45 and CD20. Because B-cells are typically present in malignant solid tumors, formation of B-cell tumor may evolve in a wide range of PDX tumor models. Although PDX tumor models show great promise in the development of personalized therapy for cancer patients, our results suggest that confidence in any given PDX tumor model requires careful screening of lymphocytic markers.

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

“…Recently, the PDX mouse model has been used to identify personalized therapy for cancer patients [44]. In our study, a subcutaneously transplanted tumor model of ICC and two PDX mouse models demonstrated the anti-tumor effects of RA190 in vivo.…”

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

“…And DLBCL PDXs tend to form large metastases and grow faster than CRC PDXs which basically do not metastasize when grown subcutaneously in immunocompromised mice [9, 16]. As shown in Table 1, the days for growth tended to be shorter in DLBCL PDX than in CRC PDX.…”

“…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.…”

“…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]. 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].…”

PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models

“…Validation is required to confirm the PDX tumor is of the appropriate patient, and not of murine origin nor consisting primarily of Epstein-Barr virus (EBV) Human B lymphocytic cells as both are frequently observed in PDX model creation(9). Other “desirable” quality assurance methods vary with tumor types and can include histopathology, assessment of human cancer biomarkers by immunohistochemistry, in situ hybridization, and assessment of gene mutations and rearrangements, DNA methylation or gene expression profiling.…”