PyMT-Maclow: A novel, inducible, murine model for determining the role of CD68 positive cells in breast tumor development.
PyMT-Maclow: A novel, inducible, murine model for determining the role of CD68 positive cells in breast tumor development.
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DOI：
10.1371/journal.pone.0188591
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Miller G
中科院分区：
文献类型：
--
作者：
Rumney RMH;Coffelt SB;Neale TA;Dhayade S;Tozer GM;Miller G
CD 68+肿瘤相关巨噬细胞（TAM）是促肿瘤发生、促血管生成的，与癌症（包括乳腺癌）患者的生存率降低相关。巨噬细胞消融的非特异性模型减少了TAM的数量并限制了乳腺肿瘤的发展。然而，缺乏特异性和与这些模型相关的副作用损害了它们的可靠性。我们假设特异性和受控的巨噬细胞耗竭将提供关于减少TAM数量对肿瘤发展的影响的精确数据。在这项研究中，多西环素诱导和选择性CD 68+巨噬细胞耗竭的MacLow小鼠模型与自发性导管乳腺癌的小鼠乳腺肿瘤病毒（MMTV）-多瘤病毒中T抗原（PyMT）小鼠模型杂交，以产生PyMT-MacLow系。在多西环素治疗的PyMT-MacLow小鼠中，肿瘤周围区域的巨噬细胞数量减少了43%。将巨噬细胞的数量减少到这个水平延迟了肿瘤的进展，产生了较少的增殖性肿瘤，减少了癌的血管形成，并下调了许多促血管生成基因的表达。这些结果表明，以可诱导和选择性的方式消耗CD 68+巨噬细胞延迟了乳腺肿瘤的发展，并且PyMT-MacLow模型是研究TAM在乳腺癌中的作用的有用且独特的工具。
CD68+ tumor-associated macrophages (TAMs) are pro-tumorigenic, pro-angiogenic and are associated with decreased survival rates in patients with cancer, including breast cancer. Non-specific models of macrophage ablation reduce the number of TAMs and limit the development of mammary tumors. However, the lack of specificity and side effects associated with these models compromise their reliability. We hypothesized that specific and controlled macrophage depletion would provide precise data on the effects of reducing TAM numbers on tumor development. In this study, the MacLow mouse model of doxycycline-inducible and selective CD68+ macrophage depletion was crossed with the murine mammary tumor virus (MMTV)-Polyoma virus middle T antigen (PyMT) mouse model of spontaneous ductal breast adenocarcinoma to generate the PyMT-MacLow line. In doxycycline-treated PyMT-MacLow mice, macrophage numbers were decreased in areas surrounding tumors by 43%. Reducing the number of macrophages by this level delayed tumor progression, generated less proliferative tumors, decreased the vascularization of carcinomas and down-regulated the expression of many pro-angiogenic genes. These results demonstrate that depleting CD68+ macrophages in an inducible and selective manner delays the development of mammary tumors and that the PyMT-MacLow model is a useful and unique tool for studying the role of TAMs in breast cancer.
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