Patient-derived xenograft mouse models of pseudomyxoma peritonei recapitulate the human inflammatory tumor microenvironment.
Patient-derived xenograft mouse models of pseudomyxoma peritonei recapitulate the human inflammatory tumor microenvironment.
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DOI：
10.1002/cam4.640
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发表时间：
2016-04
期刊：
影响因子：
4
通讯作者：
Govindarajan V
中科院分区：
文献类型：
--
作者：
Kuracha MR;Thomas P;Loggie BW;Govindarajan V
腹膜假粘液瘤 (PMP) 是一种肿瘤综合征，其特征是腹膜肿瘤植入并伴有大量粘液性腹水。 PMP 患者的护理标准是积极的细胞减灭手术与加热腹腔化疗相结合。并非所有患者都适合这些手术，大多数患者都会出现复发性疾病。除了分泌的粘蛋白外，炎症和纤维化是 PMP 发病机制的核心，但调节腹膜肿瘤微环境内肿瘤间质相互作用的分子过程仍然很大程度上未知。这些知识不仅对于阐明 PMP 病理学至关重要，而且对于确定新的治疗靶点也至关重要。在这里，我们报告了 PMP 患者来源的异种移植 (PDX) 小鼠模型的生成，并评估了这些模型复制人类 PMP 患者炎症性腹膜微环境的能力。生成了低级别和高级别 PMP 的 PDX 小鼠模型，其组织病理学与人类 PMP 相似。先前显示在人 PMP 中升高的细胞因子在 PDX 腹水中也升高。人和 PDX 腹水中的 IL-6 和 IL-8/KC/MIP2 存在显着差异。有趣的是，这些细胞因子主要是由小鼠来源的肿瘤相关基质细胞而不是人源的 PMP 肿瘤细胞分泌的。我们的数据表明，PMP PDX 小鼠模型特别适合研究调节 PMP 中腹膜炎症环境的肿瘤基质相互作用，因为这些小鼠模型中的肿瘤和基质细胞分别源自人类和小鼠。因此，这些小鼠模型可能可作为体内替代品，用于测试和开发 PMP 的新型治疗干预措施。
Pseudomyxoma peritonei (PMP) is a neoplastic syndrome characterized by peritoneal tumor implants with copious mucinous ascites. The standard of care for PMP patients is aggressive cytoreductive surgery performed in conjunction with heated intraperitoneal chemotherapy. Not all patients are candidates for these procedures and a majority of the patients will have recurrent disease. In addition to secreted mucin, inflammation and fibrosis are central to PMP pathogenesis but the molecular processes that regulate tumor‐stromal interactions within the peritoneal tumor microenvironment remain largely unknown. This knowledge is critical not only to elucidate PMP pathobiology but also to identify novel targets for therapy. Here, we report the generation of patient‐derived xenograft (PDX) mouse models for PMP and assess the ability of these models to replicate the inflammatory peritoneal microenvironment of human PMP patients. PDX mouse models of low‐ and high‐grade PMP were generated and were of a similar histopathology as human PMP. Cytokines previously shown to be elevated in human PMP were also elevated in PDX ascites. Significant differences in IL‐6 and IL‐8/KC/MIP2 were seen between human and PDX ascites. Interestingly, these cytokines were mostly secreted by mouse‐derived, tumor‐associated stromal cells rather than by human‐derived PMP tumor cells. Our data suggest that the PMP PDX mouse models are especially suited to the study of tumor‐stromal interactions that regulate the peritoneal inflammatory environment in PMP as the tumor and stromal cells in these mouse models are of human and murine origins, respectively. These mouse models are therefore, likely to be useful in vivo surrogates for testing and developing novel therapeutic treatment interventions for PMP.