Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer.
Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer.
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DOI：
10.1158/0008-5472.can-12-2202
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发表时间：
2013-01-15
期刊：
影响因子：
11.2
通讯作者：
Ponnazhagan S
中科院分区：
文献类型：
--
作者：
Sawant A;Deshane J;Jules J;Lee CM;Harris BA;Feng X;Ponnazhagan S
骨破坏增强是各种癌症的标志，如乳腺癌，溶骨性骨转移与发病率和死亡率的增加有关。免疫细胞有助于癌症生长中的骨溶解，但导致侵袭性骨破坏的因素尚不清楚。在这项研究中，我们证明了髓系来源的抑制细胞(MDSC)在骨转移部位的这一过程中的重要性。由于MDSC与作为破骨细胞前体的巨噬细胞起源于同一髓系，我们推测MDSC可能经历了破骨细胞分化，并有助于促进骨破坏和肿瘤生长。利用免疫活性的小鼠乳腺癌骨转移模型，我们证实了从肿瘤-骨微环境中分离出来的MDSC在体外和体内都分化为具有功能的破骨细胞。机制研究表明，一氧化氮信号转导通路在MDSC向破骨细胞分化过程中起关键作用。值得注意的是，从无骨转移的对照组或荷瘤小鼠分离的MDSC没有发生破骨细胞分化，这表明肿瘤细胞和髓系祖细胞在骨微环境中的基本串扰是MDSC破骨细胞分化的必要条件。总体而言，我们的结果确定了MDSC在驱动肿瘤进展中的多功能的一个全新方面，在这种情况下，MDSC是一种新的破骨细胞前体，在癌症进展过程中特异性地驱动骨转移。
Enhanced bone destruction is a hallmark of various carcinomas such as breast cancer, where osteolytic bone metastasis is associated with increased morbidity and mortality. Immune cells contribute to osteolysis in cancer growth but the factors contributing to aggressive bone destruction are not well understood. In this study, we demonstrate the importance of myeloid-derived suppressor cells (MDSC) in this process at bone metastatic sites. Since MDSC originate from the same myeloid lineage as macrophages, which are osteoclast precursors, we hypothesized that MDSC may undergo osteoclast differentiation and contribute to enhanced bone destruction and tumor growth. Using an immunocompetent mouse model of breast cancer bone metastasis, we confirmed that MDSC isolated from the tumor-bone microenvironment differentiated into functional osteoclasts both in vitro and in vivo. Mechanistic investigations revealed that nitric oxide signaling was critical for differentiation of MDSC into osteoclasts. Remarkably, osteoclast differentiation did not occur in MDSC isolated from control or tumor-bearing mice that lacked bone metastasis, signifying the essential cross-talk between tumor cells and myeloid progenitors in the bone microenvironment as a requirement for osteoclast differentiation of MDSC. Overall, our results identify a wholly new facet to the multifunctionality of MDSC in driving tumor progression, in this case as a novel osteoclast progenitor that specifically drives bone metastasis during cancer progression.