Periodontal inflammation recruits distant metastatic breast cancer cells by increasing myeloid-derived suppressor cells
Periodontal inflammation recruits distant metastatic breast cancer cells by increasing myeloid-derived suppressor cells
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牙周炎症通过增加骨髓源性抑制细胞来招募远处转移性乳腺癌细胞
DOI：
10.1038/s41388-019-1084-z
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发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Bhowmick, Neil A.
中科院分区：
文献类型：
--
作者：
Cheng, Ran;Billet, Sandrine;Bhowmick, Neil A.
牙周病可导致慢性炎症，影响牙齿支持组织的完整性。最近，一个惊人的关联已经取得了牙周病和原发性癌症之间的机制的理解。在这里，我们解决牙周炎（PI）对肿瘤进展，转移的影响，并可能强调机制。我们发现，PI在小鼠中的实验模型可以促进淋巴结（LN）微转移，以及4 T1乳腺癌细胞的头颈部转移，无论是在癌症进展的早期和晚期阶段。与其他部位的淋巴结相比，颈部淋巴结的肿瘤负荷和MDSC和M2巨噬细胞浸润更大。在PI患者中检测到焦亡和由此产生的IL-1β产生，反映在小鼠模型中。阿那白滞素、IL-1受体拮抗剂、有限转移和肿瘤进展早期MDSC募集，但未能逆转已建立的转移性肿瘤。发现PI和由此产生的IL-1β的产生促进CCL 5、CXCL 12、CCL 2和CXCL 5的表达。这些趋化因子募集MDSC和巨噬细胞，最终使得能够在炎症部位产生转移前小生境。这些发现支持了牙周炎促进乳腺癌转移的观点，即在转移的早期阶段，部分通过热解诱导的IL-1β产生和下游CCL 2、CCL 5和CXCL 5信号传导招募MDSC。这些研究定义了IL-1β在乳腺癌转移进展中的作用，并强调了控制PI（老年患者中普遍存在的炎症性疾病）的必要性。
Periodontal diseases can lead to chronic inflammation affecting the integrity of the tooth supporting tissues. Recently, a striking association has been made between periodontal diseases and primary cancers in the absence of a mechanistic understanding. Here we address the effect of periodontal inflammation (PI) on tumor progression, metastasis, and possible underlining mechanisms. We show that an experimental model of PI in mice can promote lymph node (LN) micrometastasis, as well as head and neck metastasis of 4T1 breast cancer cells, both in early and late stages of cancer progression. The cervical LNs had a greater tumor burden and infiltration of MDSC and M2 macrophages compared with LNs at other sites. Pyroptosis and the resultant IL-1β production were detected in patients with PI, mirrored in mouse models. Anakinra, IL-1 receptor antagonist, limited metastasis, and MDSC recruitment at early stages of tumor progression, but failed to reverse established metastatic tumors. PI and the resulting production of IL-1β was found to promote CCL5, CXCL12, CCL2, and CXCL5 expression. These chemokines recruit MDSC and macrophages, finally enabling the generation of a premetastatic niche in the inflammatory site. These findings support the idea that periodontal inflammation promotes metastasis of breast cancer by recruiting MDSC in part by pyroptosis-induced IL-1β generation and downstream CCL2, CCL5, and CXCL5 signaling in the early steps of metastasis. These studies define the role for IL-1β in the metastatic progression of breast cancer and highlight the need to control PI, a pervasive inflammatory condition in older patients.