Women's Cancer Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
J Ovarian Res. 2010 Oct 19;3:24. doi: 10.1186/1757-2215-3-24.
Most cases of ovarian cancer are epithelial in origin and diagnosed at advanced stage when the cancer is widely disseminated in the peritoneal cavity. The objective of this study was to establish an immunocompetent syngeneic mouse model of disseminated epithelial ovarian cancer (EOC) to facilitate laboratory-based studies of ovarian tumor biology and preclinical therapeutic strategies.
Individual lines of TgMISIIR-TAg transgenic mice were phenotypically characterized and backcrossed to inbred C57BL/6 mice. In addition to a previously described line of EOC-prone mice, two lines (TgMISIIR-TAg-Low) were isolated that express the oncogenic transgene, but have little or no susceptibility to tumor development. Independent murine ovarian carcinoma (MOVCAR) cell lines were established from the ascites of tumor-bearing C57BL/6 TgMISIIR-TAg transgenic mice, characterized and tested for engraftment in the following recipient mice: 1) severe immunocompromised immunodeficient (SCID), 2) wild type C57BL/6, 3) oophorectomized tumor-prone C57BL/6 TgMISIIR-TAg transgenic and 4) non-tumor prone C57BL/6 TgMISIIR-TAg-Low transgenic. Lastly, MOVCAR cells transduced with a luciferase reporter were implanted in TgMISIIR-TAg-Low mice and in vivo tumor growth monitored by non-invasive optical imaging.
Engraftment of MOVCAR cells by i.p. injection resulted in the development of disseminated peritoneal carcinomatosis in SCID, but not wild type C57BL/6 mice. Oophorectomized tumor-prone TgMISIIR-TAg mice developed peritoneal carcinomas with high frequency, rendering them unsuitable as allograft recipients. Orthotopic or pseudo-orthotopic implantation of MOVCAR cells in TgMISIIR-TAg-Low mice resulted in the development of disseminated peritoneal tumors, frequently accompanied by the production of malignant ascites. Tumors arising in the engrafted mice bore histopathological resemblance to human high-grade serous EOC and exhibited a similar pattern of peritoneal disease spread.
A syngeneic mouse model of human EOC was created by pseudo-orthotopic and orthotopic implantation of MOVCAR cells in a susceptible inbred transgenic host. This immunocompetent syngeneic mouse model presents a flexible system that can be used to study the consequences of altered gene expression (e.g., by ectopic expression or RNA interference strategies) in an established MOVCAR tumor cell line within the ovarian tumor microenvironment and for the development and analysis of preclinical therapeutic agents including EOC vaccines and immunotherapeutic agents.
大多数卵巢癌为上皮来源，在癌症广泛播散于腹腔时被诊断为晚期。本研究旨在建立一种免疫活性同基因小鼠模型，以促进卵巢肿瘤生物学和临床前治疗策略的实验室研究。
单独的 TgMISIIR-TAg 转基因小鼠品系在表型上进行了特征描述，并与近交 C57BL/6 小鼠进行了回交。除了之前描述的易患卵巢癌的小鼠品系外，还分离出两条表达致癌转基因但几乎没有或没有肿瘤易感性的品系（TgMISIIR-TAg-Low）。从携带肿瘤的 C57BL/6 TgMISIIR-TAg 转基因小鼠的腹水建立了独立的小鼠卵巢癌（MOVCAR）细胞系，对其进行了特征描述，并在以下受体小鼠中进行了移植实验：1）严重免疫缺陷免疫缺陷（SCID），2）野生型 C57BL/6，3）卵巢切除易患卵巢癌的 C57BL/6 TgMISIIR-TAg 转基因，4）非易患卵巢癌的 C57BL/6 TgMISIIR-TAg-Low 转基因。最后，将携带荧光素酶报告基因的 MOVCAR 细胞植入 TgMISIIR-TAg-Low 小鼠体内，并通过非侵入性光学成像监测体内肿瘤生长情况。
MOVCAR 细胞通过腹腔内注射移植导致 SCID 而不是野生型 C57BL/6 小鼠发生播散性腹膜癌。卵巢切除易患卵巢癌的 TgMISIIR-TAg 小鼠高频发生腹膜癌，使其不适合作为同种异体移植物受体。MOVCAR 细胞在 TgMISIIR-TAg-Low 小鼠中的原位或假原位植入导致播散性腹膜肿瘤的发生，常伴有恶性腹水的产生。在植入小鼠中发生的肿瘤在组织病理学上与人类高级别浆液性卵巢癌相似，并表现出类似的腹膜疾病扩散模式。
通过将 MOVCAR 细胞在易感近交转基因宿主中进行假原位和原位植入，创建了一种人类卵巢癌的同基因小鼠模型。这种免疫活性同基因小鼠模型提供了一个灵活的系统，可用于在卵巢肿瘤微环境中研究改变基因表达（例如通过异位表达或 RNA 干扰策略）的后果，并开发和分析临床前治疗剂，包括卵巢癌疫苗和免疫治疗剂。
