Butler Kristina A, Hou Xiaonan, Becker Marc A, Zanfagnin Valentina, Enderica-Gonzalez Sergio, Visscher Daniel, Kalli Kimberly R, Tienchaianada Piyawan, Haluska Paul, Weroha S John
Department of Gynecologic Surgery, Mayo Clinic, Rochester, MN, 55905.
Department of Medical Oncology, Mayo Clinic, Rochester, MN, 55905.
Neoplasia. 2017 Aug;19(8):628-636. doi: 10.1016/j.neo.2017.04.007. Epub 2017 Jun 26.
Interest in preclinical drug development for ovarian cancer has stimulated development of patient-derived xenograft (PDX) or tumorgraft models. However, the unintended formation of human lymphoma in severe combined immunodeficiency (SCID) mice from Epstein-Barr virus (EBV)-infected human lymphocytes can be problematic. In this study, we have characterized ovarian cancer PDXs which developed human lymphomas and explore methods to suppress lymphoproliferative growth. Fresh human ovarian tumors from 568 patients were transplanted intraperitoneally in SCID mice. A subset of PDX models demonstrated atypical patterns of dissemination with mediastinal masses, hepatosplenomegaly, and CD45-positive lymphoblastic atypia without ovarian tumor engraftment. Expression of human CD20 but not CD3 supported a B-cell lineage, and EBV genomes were detected in all lymphoproliferative tumors. Immunophenotyping confirmed monoclonal gene rearrangements consistent with B-cell lymphoma, and global gene expression patterns correlated well with other human lymphomas. The ability of rituximab, an anti-CD20 antibody, to suppress human lymphoproliferation from a patient's ovarian tumor in SCID mice and prevent growth of an established lymphoma led to a practice change with a goal to reduce the incidence of lymphomas. A single dose of rituximab during the primary tumor heterotransplantation process reduced the incidence of CD45-positive cells in subsequent PDX lines from 86.3% (n = 117 without rituximab) to 5.6% (n = 160 with rituximab), and the lymphoma rate declined from 11.1% to 1.88%. Taken together, investigators utilizing PDX models for research should routinely monitor for lymphoproliferative tumors and consider implementing methods to suppress their growth.
对卵巢癌临床前药物开发的兴趣推动了患者来源异种移植（PDX）或肿瘤移植模型的发展。然而，来自感染爱泼斯坦-巴尔病毒（EBV）的人类淋巴细胞的严重联合免疫缺陷（SCID）小鼠中意外形成人类淋巴瘤可能会带来问题。在本研究中，我们对发生人类淋巴瘤的卵巢癌PDX进行了特征描述，并探索抑制淋巴细胞增殖性生长的方法。将来自568例患者的新鲜人类卵巢肿瘤腹腔内移植到SCID小鼠中。一部分PDX模型表现出非典型的播散模式，伴有纵隔肿块、肝脾肿大以及CD45阳性淋巴细胞异型性，而无卵巢肿瘤植入。人类CD20而非CD3的表达支持B细胞谱系，并且在所有淋巴细胞增殖性肿瘤中均检测到EBV基因组。免疫表型分析证实了与B细胞淋巴瘤一致的单克隆基因重排，并且整体基因表达模式与其他人类淋巴瘤密切相关。抗CD20抗体利妥昔单抗抑制SCID小鼠中患者卵巢肿瘤的人类淋巴细胞增殖并阻止已建立淋巴瘤生长的能力导致了实践改变，目标是降低淋巴瘤的发生率。在原发性肿瘤异种移植过程中单次给予利妥昔单抗可使后续PDX系中CD45阳性细胞的发生率从86.3%（n = 117，未使用利妥昔单抗）降至5.6%（n = 160，使用利妥昔单抗），淋巴瘤发生率从11.1%降至1.88%。综上所述，利用PDX模型进行研究的研究者应常规监测淋巴细胞增殖性肿瘤，并考虑采用方法抑制其生长。
