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(xué)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(guān)性，不過具體機(jī)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(xué)華西口腔醫(yī)院、美國西達(dá)賽奈醫(yī)療中心、美國退伍軍人事務(wù)部大洛杉磯地區(qū)醫(yī)療中心的研究報(bào)告，探討了牙周炎癥對(duì)乳腺腫瘤進(jìn)展轉(zhuǎn)移的影響及其可能機(jī)制。
該研究表明，發(fā)生于小鼠的牙周炎癥實(shí)驗(yàn)?zāi)Ｐ涂梢源龠M(jìn)4T1乳腺癌細(xì)胞的淋巴結(jié)微轉(zhuǎn)移以及頭頸部轉(zhuǎn)移，無論癌癥進(jìn)展的早期還是晚期。頸部淋巴結(jié)與其他部位的淋巴結(jié)相比，腫瘤細(xì)胞的數(shù)量、骨髓來源抑制細(xì)胞和抑制炎癥的Ⅱ型巨噬細(xì)胞浸潤顯著較多。對(duì)于牙周炎癥患者和小鼠模型，可以檢測(cè)到比細(xì)胞凋亡發(fā)生更快的細(xì)胞焦亡以及由此產(chǎn)生的白細(xì)胞介素1β。白細(xì)胞介素1受體拮抗劑阿那白滯素雖然可以限制腫瘤進(jìn)展早期階段的轉(zhuǎn)移、骨髓來源抑制細(xì)胞聚集，但是無法逆轉(zhuǎn)已經(jīng)形成的腫瘤轉(zhuǎn)移。牙周炎癥以及由此產(chǎn)生的白細(xì)胞介素1β，可以促進(jìn)趨化因子配體CCL5、CXCL12、CCL2、CXCL5表達(dá)。這些趨化因子可以吸引骨髓來源抑制細(xì)胞和抑制炎癥的Ⅱ型巨噬細(xì)胞，最終在炎癥部位產(chǎn)生轉(zhuǎn)移前微環(huán)境，為腫瘤細(xì)胞轉(zhuǎn)移提供溫床。
因此，該研究結(jié)果表明，牙周炎癥通過細(xì)胞焦亡誘導(dǎo)產(chǎn)生白細(xì)胞介素1β，繼而促進(jìn)CCL2、CCL5、CXCL5等趨化因子信號(hào)轉(zhuǎn)導(dǎo)，從而吸引骨髓來源抑制細(xì)胞和抑制炎癥的Ⅱ型巨噬細(xì)胞，可以促進(jìn)乳腺癌早期轉(zhuǎn)移。該研究確定了白細(xì)胞介素1β對(duì)乳腺癌進(jìn)展轉(zhuǎn)移的作用，并且強(qiáng)調(diào)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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