Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma
Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma
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DOI：
10.1158/1535-7163.mct-07-0579
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发表时间：
2008-04-01
影响因子：
5.7
通讯作者：
Kane, Agnes B.
中科院分区：
文献类型：
--
作者：
Miselis, Nathan R.;Wu, Zhijin J.;Kane, Agnes B.
肿瘤是肿瘤细胞和宿主基质细胞的混合物，其建立了有助于肿瘤进展的微环境。在这项研究中，肿瘤相关的巨噬细胞（TAMs）的肿瘤生长和转移的贡献进行了检查，使用原位，免疫活性的小鼠模型弥漫性恶性腹膜间皮瘤。实体瘤中细胞因子和趋化因子的表达谱与M2极化、TAM介导的免疫抑制微环境一致。使用脂质体包封的氯膦酸盐（CLIP）靶向TAM。肿瘤球状体原位暴露于CM-Dil标记的CLIP证实了巨噬细胞而不是间皮瘤细胞的靶向。腹膜内（i. p.）与脂质体包封的PBS或PBS的递送相反，CLIP的递送在肿瘤球状体和实体瘤中产生细胞凋亡。小鼠接受间皮瘤细胞的腹膜内注射，每5天腹膜内递送CLIP。与暴露于脂质体包封的PBS或PBS的小鼠相比，该治疗方案产生肿瘤数量减少4倍，相对肿瘤负荷减少17倍，侵袭和转移减少5倍。在移植肿瘤球状体并用CLIP治疗后，小鼠显示肿瘤数量减少4倍，相对肿瘤负荷减少15倍。当暴露于通过重复腹膜内注射递送的先前剂量的一半的CLIP时，具有已建立肿瘤的小鼠显示肿瘤数量和相对肿瘤负荷减少2倍。这些肿瘤负荷的降低具有统计学显著性，并将TAM确定为有助于弥漫性恶性腹膜间皮瘤生长、侵袭和转移的重要宿主来源细胞。
Tumors are a mixture of neoplastic and host stromal cells, which establish a microenvironment that contributes to tumor progression. In this study, the contribution of tumor-associated macrophages (TAMs) to tumor growth and metastasis was examined using an orthotopic, immunocompetent murine model of diffuse malignant peritoneal mesothelioma. The expression profile of cytokines and chemokines in solid tumors was consistent with a M2-polarized, TAM-mediated immunosuppressive microenvironment. TAMs were targeted using liposome-encapsulated clodronate (CLIP). Exposure of tumor spheroids to CM-Dil-labeled CLIP in situ confirms targeting of macrophages and not mesothelioma cells. Intraperitoneal (i.p.) delivery of CLIP produced apoptosis in tumor spheroids and solid tumors in contrast to delivery of liposome-encapsulated PBS or PBS. Mice received an i.p. injection of mesothelioma cells with CLIP delivered i.p. every 5 days. This treatment protocol produces a 4-fold reduction in the number of tumors, a 17-fold reduction in the relative tumor burden, and a 5-fold reduction in invasion and metastasis when compared with mice exposed to liposome-encapsulated PBS or PBS. Following transplantation of tumor spheroids and treatment with CLIP, mice showed a 4-fold reduction in the number of tumors and a 15-fold reduction in relative tumor burden. Mice bearing established tumors showed a 2-fold reduction in the number of tumors and relative tumor burden when exposed to half the previous dose of CLIP delivered by repeated i.p. injection. These reductions in tumor burden are statistically significant and identify TAMs as an important host-derived cell that contributes to growth, invasion, and metastasis in diffuse malignant peritoneal mesothelioma.