ADAM17 in tumor associated leukocytes regulates inflammatory mediators and promotes mammary tumor formation.
ADAM17 in tumor associated leukocytes regulates inflammatory mediators and promotes mammary tumor formation.
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DOI：
10.18632/genesandcancer.115
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Schwertfeger KL
中科院分区：
文献类型：
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作者：
Bohrer LR;Chaffee TS;Chuntova P;Brady NJ;Witschen PM;Kemp SE;Nelson AC;Walcheck B;Schwertfeger KL
肿瘤微环境中炎性细胞的存在与乳腺肿瘤的形成和进展密切相关。具体而言，肿瘤细胞和浸润性巨噬细胞之间的相互作用可以有助于促肿瘤发生微环境的产生。了解驱动肿瘤细胞-巨噬细胞串扰的复杂机制将最终导致预防或治疗早期乳腺癌的方法的发展。如本文所述，我们证明了细胞表面蛋白酶解整合素和金属蛋白酶17（ADAM 17）由乳腺肿瘤中的巨噬细胞表达，并有助于调节促炎介质的表达，包括炎性细胞因子和炎性介质环氧合酶-2（考克斯-2）。此外，我们证明，ADAM 17表达的白细胞，包括巨噬细胞，多瘤中T（PyMT）衍生的乳腺肿瘤。白细胞中ADAM 17的基因缺失导致乳腺肿瘤生长的开始减少，这与肿瘤内考克斯-2的表达减少有关。这些发现表明，ADAM17调节巨噬细胞中的关键炎症介质，白细胞特异性ADAM17是乳腺肿瘤发生的重要促进剂。了解与早期肿瘤发生相关的机制对早期乳腺癌的预防和/或治疗策略的发展具有重要意义。
The presence of inflammatory cells within the tumor microenvironment has been tightly linked to mammary tumor formation and progression. Specifically, interactions between tumor cells and infiltrating macrophages can contribute to the generation of a pro-tumorigenic microenvironment. Understanding the complex mechanisms that drive tumor cell-macrophage cross-talk will ultimately lead to the development of approaches to prevent or treat early stage breast cancers. As described here, we demonstrate that the cell surface protease a disintegrin and metalloproteinase 17 (ADAM17) is expressed by macrophages in mammary tumors and contributes to regulating the expression of pro-inflammatory mediators, including inflammatory cytokines and the inflammatory mediator cyclooxygenase-2 (Cox-2). Furthermore, we demonstrate that ADAM17 is expressed on leukocytes, including macrophages, within polyoma middle T (PyMT)-derived mammary tumors. Genetic deletion of ADAM17 in leukocytes resulted in decreased onset of mammary tumor growth, which was associated with reduced expression of the Cox-2 within the tumor. These findings demonstrate that ADAM17 regulates key inflammatory mediators in macrophages and that leukocyte-specific ADAM17 is an important promoter of mammary tumor initiation. Understanding the mechanisms associated with early stage tumorigenesis has implications for the development of preventive and/or treatment strategies for early stage breast cancers.