牙周疾病可以引起慢性炎癥，影響牙齒支撐組織的完整性。近年來，科學家們發(fā)現(xiàn)了牙周疾病與原發(fā)癌癥之間存在驚人的相關性，不過具體機制尚不明確。
2019年11月4日，英國《自然》旗下《腫瘤基因》在線發(fā)表中國四川大學華西口腔醫(yī)院、美國西達賽奈醫(yī)療中心、美國退伍軍人事務部大洛杉磯地區(qū)醫(yī)療中心的研究報告，探討了牙周炎癥對乳腺腫瘤進展轉移的影響及其可能機制。
該研究表明，發(fā)生于小鼠的牙周炎癥實驗模型可以促進4T1乳腺癌細胞的淋巴結微轉移以及頭頸部轉移，無論癌癥進展的早期還是晚期。頸部淋巴結與其他部位的淋巴結相比，腫瘤細胞的數(shù)量、骨髓來源抑制細胞和抑制炎癥的Ⅱ型巨噬細胞浸潤顯著較多。對于牙周炎癥患者和小鼠模型，可以檢測到比細胞凋亡發(fā)生更快的細胞焦亡以及由此產(chǎn)生的白細胞介素1β。白細胞介素1受體拮抗劑阿那白滯素雖然可以限制腫瘤進展早期階段的轉移、骨髓來源抑制細胞聚集，但是無法逆轉已經(jīng)形成的腫瘤轉移。牙周炎癥以及由此產(chǎn)生的白細胞介素1β，可以促進趨化因子配體CCL5、CXCL12、CCL2、CXCL5表達。這些趨化因子可以吸引骨髓來源抑制細胞和抑制炎癥的Ⅱ型巨噬細胞，最終在炎癥部位產(chǎn)生轉移前微環(huán)境，為腫瘤細胞轉移提供溫床。
因此，該研究結果表明，牙周炎癥通過細胞焦亡誘導產(chǎn)生白細胞介素1β，繼而促進CCL2、CCL5、CXCL5等趨化因子信號轉導，從而吸引骨髓來源抑制細胞和抑制炎癥的Ⅱ型巨噬細胞，可以促進乳腺癌早期轉移。該研究確定了白細胞介素1β對乳腺癌進展轉移的作用，并且強調了控制牙周炎癥的必要性。
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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