Heme oxygenase-1 in macrophages controls prostate cancer progression.
Heme oxygenase-1 in macrophages controls prostate cancer progression.
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DOI：
10.18632/oncotarget.5284
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Wegiel B
中科院分区：
文献类型：
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作者：
Nemeth Z;Li M;Csizmadia E;Döme B;Johansson M;Persson JL;Seth P;Otterbein L;Wegiel B
先天免疫细胞通过多种机制强烈影响癌症的生长和进展，包括调节上皮细胞向间质细胞转化（EMT）。在这项研究中，我们研究了代谢基因血红素加氧酶-1（HO-1）在肿瘤微环境中的表达是否对前列腺癌的进展产生显著影响。我们发现HO-1在前列腺癌（PCa）异种移植物和人前列腺癌的MARCO阳性巨噬细胞中表达。我们证明了HO-1的巨噬细胞特异性（LyzM-Cre）条件性缺失抑制了体内PC 3异种移植物的生长，并延迟了TRAMP小鼠中前列腺上皮内瘤变（PIN）的进展。然而，在缺乏HO-1的巨噬细胞存在的情况下，癌症异种移植物的起始和进展导致E-钙粘蛋白的丢失，E-钙粘蛋白是预后不良以及EMT的已知标志物。HO-1催化的产物CO的应用增加了癌细胞之间粘附连接处的E-钙粘蛋白水平。我们进一步表明，在巨噬细胞存在下培养的癌细胞中，HO-1驱动的E-钙粘蛋白表达依赖于癌细胞的线粒体活性。总之，这些数据表明，HO-1衍生的CO从肿瘤相关的巨噬细胞的影响，在一定程度上，E-钙粘蛋白的表达，从而肿瘤的发生和发展。
Innate immune cells strongly influence cancer growth and progression via multiple mechanisms including regulation of epithelial to mesenchymal transition (EMT). In this study, we investigated whether expression of the metabolic gene, heme oxygenase-1 (HO-1) in tumor microenvironment imparts significant effects on prostate cancer progression. We showed that HO-1 is expressed in MARCO-positive macrophages in prostate cancer (PCa) xenografts and human prostate cancers. We demonstrated that macrophage specific (LyzM-Cre) conditional deletion of HO-1 suppressed growth of PC3 xenografts in vivo and delayed progression of prostate intraepithelial neoplasia (PIN) in TRAMP mice. However, initiation and progression of cancer xenografts in the presence of macrophages lacking HO-1 resulted in loss of E-cadherin, a known marker of poor prognosis as well as EMT. Application of CO, a product of HO-1 catalysis, increased levels of E-cadherin in the adherens junctions between cancer cells. We further showed that HO-1-driven expression of E-cadherin in cancer cells cultured in the presence of macrophages is dependent on mitochondrial activity of cancer cells. In summary, these data suggest that HO-1-derived CO from tumor-associated macrophages influences, in part, E-cadherin expression and thus tumor initiation and progression.