牙周疾病可以引起慢性炎症，影响牙齿支撑组织的完整性。近年来，科学家们发现了牙周疾病与原发癌症之间存在惊人的相关性，不过具体机制尚不明确。

　　2019年11月4日，英国《自然》旗下《肿瘤基因》在线发表中国四川大学华西口腔医院、美国西达赛奈医疗中心、美国退伍军人事务部大洛杉矶地区医疗中心的研究报告，探讨了牙周炎症对乳腺肿瘤进展转移的影响及其可能机制。

　　该研究表明，发生于小鼠的牙周炎症实验模型可以促进4T1乳腺癌细胞的淋巴结微转移以及头颈部转移，无论癌症进展的早期还是晚期。颈部淋巴结与其他部位的淋巴结相比，肿瘤细胞的数量、骨髓来源抑制细胞和抑制炎症的Ⅱ型巨噬细胞浸润显著较多。对于牙周炎症患者和小鼠模型，可以检测到比细胞凋亡发生更快的细胞焦亡以及由此产生的白细胞介素1β。白细胞介素1受体拮抗剂阿那白滞素虽然可以限制肿瘤进展早期阶段的转移、骨髓来源抑制细胞聚集，但是无法逆转已经形成的肿瘤转移。牙周炎症以及由此产生的白细胞介素1β，可以促进趋化因子配体CCL5、CXCL12、CCL2、CXCL5表达。这些趋化因子可以吸引骨髓来源抑制细胞和抑制炎症的Ⅱ型巨噬细胞，最终在炎症部位产生转移前微环境，为肿瘤细胞转移提供温床。

　　因此，该研究结果表明，牙周炎症通过细胞焦亡诱导产生白细胞介素1β，继而促进CCL2、CCL5、CXCL5等趋化因子信号转导，从而吸引骨髓来源抑制细胞和抑制炎症的Ⅱ型巨噬细胞，可以促进乳腺癌早期转移。该研究确定了白细胞介素1β对乳腺癌进展转移的作用，并且强调了控制牙周炎症的必要性。

Oncogene. 2019 Nov 4. [Epub ahead of print]

Periodontal inflammation recruits distant metastatic breast cancer cells by increasing myeloid-derived suppressor cells.

Ran Cheng, Sandrine Billet, Chuanxia Liu, Subhash Haldar, Diptiman Choudhury, Manisha Tripathi, Monirath Hav, Akil Merchant, Tao Hu, Haiyun Huang, Hongmei Zhou, Neil A. Bhowmick.

West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; Cedars-Sinai Medical Center, Los Angeles, CA, USA; Greater Los Angeles Veterans Administration, Los Angeles, CA, USA.

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.

DOI: 10.1038/s41388-019-1084-z

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