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李佳, 卫韡, 汤博钰, 等. 牙周炎诱导巨噬细胞M2极化促进口腔鳞状细胞癌进展[J]. 四川大学学报(医学版), 2023, 54(1): 83-90. DOI: 10.12182/20230160108
引用本文: 李佳, 卫韡, 汤博钰, 等. 牙周炎诱导巨噬细胞M2极化促进口腔鳞状细胞癌进展[J]. 四川大学学报(医学版), 2023, 54(1): 83-90. DOI: 10.12182/20230160108
LI Jia, WEI Wei, TANG Bo-yu, et al. Periodontitis Promotes the Progression of Oral Squamous Cell Carcinoma by Inducing Macrophage M2 Polarization[J]. Journal of Sichuan University (Medical Sciences), 2023, 54(1): 83-90. DOI: 10.12182/20230160108
Citation: LI Jia, WEI Wei, TANG Bo-yu, et al. Periodontitis Promotes the Progression of Oral Squamous Cell Carcinoma by Inducing Macrophage M2 Polarization[J]. Journal of Sichuan University (Medical Sciences), 2023, 54(1): 83-90. DOI: 10.12182/20230160108

牙周炎诱导巨噬细胞M2极化促进口腔鳞状细胞癌进展

Periodontitis Promotes the Progression of Oral Squamous Cell Carcinoma by Inducing Macrophage M2 Polarization

  • 摘要:
      目的  探讨牙周炎对口腔鳞状细胞癌(oral squamous cell carcinoma, OSCC)发展的作用,明确牙周炎微生物是否诱导M2巨噬细胞极化并促进肿瘤进展。
      方法  通过收集有无牙周炎的OSCC患者肿瘤组织,免疫组化验证M2巨噬细胞变化趋势;将连续3 d用含四联抗生素饮用水处理后的小鼠,每隔1 d涂牙周炎患者唾液集合菌5次,颊黏膜注射小鼠口腔鳞状细胞癌细胞(SCC7)建立伴牙周炎OSCC小鼠模型,观察牙周炎对OSCC发展的影响,分析肿瘤组织M2巨噬细胞含量,检测小鼠唾液菌群结构、脾脏和结肠组织的病理变化;最后,将收集的来自牙周炎患者的唾液,与小鼠外周血单个核细胞(PBMC)和SCC7细胞共同培养,流式细胞术检测M2巨噬细胞含量。
      结果  临床样本的免疫组化结果显示,伴牙周炎OSCC患者(27.01%±2.12%)比不伴牙周炎OSCC患者(17.00%±3.66%)肿瘤组织中M2极化巨噬细胞增多(P<0.05)。伴牙周炎OSCC小鼠(PO组)肿瘤体积更大,生存率更低,Ki67阳性细胞表达率(35.49%±5.00%)高于OSCC组(O组)(23.89%±4.13%)(P<0.05);流式细胞术结果表明,PO组小鼠肿瘤组织中M2巨噬细胞含量(24.97%±4.41%)高于O组(5.75%±0.52%)(P<0.05),同时qPCR结果显示M2巨噬细胞相关因子Arg1、IL-10、CD206的表达总体呈现上升趋势;免疫组化结果表明PO组小鼠肿瘤组织中M2巨噬细胞阳性表达(21.82%±4.16%)相对O组(9.64%±0.60%)增加(P<0.05);PO组小鼠口腔菌群结构改变,条带增多,多样性增加,脾脏组织白髓减少,红髓分界不明,出血严重,结肠组织腺体形态异常,隐窝结构破坏较严重。细胞实验结果表明,PBMC与SCC7细胞共培时,牙周炎微生物的存在增加了M2巨噬细胞极化(71.00%±0.66%)。
      结论  牙周炎促进了OSCC的发展,诱导肿瘤相关巨噬细胞向M2极化,牙周炎症治疗对OSCC患者具有重要价值。

     

    Abstract:
      Objective  To investigate the role of periodontitis in the development of oral squamous cell carcinoma (OSCC) and to determine whether periodontitis microorganisms induce M2 macrophage (M2) polarization and promote tumor progression.
      Methods  The tumor tissues of OSCC patients with periodontitis and those without periodontitis were collected and immunohistochemistry tests were done to validate the trend of changes in M2 macrophages. A mouse model of OSCC accompanied by periodontitis was established by treating mice with drinking water containing four antibiotics for three consecutive days, applying in the mouths of the mice a coat of bacteria collected from the saliva of patients with periodontitis once every other day for five times, and injecting in their buccal mucosa OSCC cells (SCC7). We observed the effect of periodontitis on the development of OSCC, analyzed the M2 macrophage content in the tumor tissues, and analyzed salivary microbiota structure, and examined the pathological changes in the spleen and colon tissues of the mice. Finally, we collected saliva from patients with periodontitis, co-cultured it with mice peripheral blood mononuclear cells (PBMC) and SCC7 cells, and examined M2 macrophage percentage by flow cytometry.
      Results  Immunohistochemical findings from the clinical samples showed that M2-polarized macrophages in OSCC patients with periodontitis were more enriched (27.01%±2.12%) compared with those of OSCC patients without periodontitis (17.00%±3.66%). The OSCC mice with periodontitis (PO group) had tumors of larger size and lower survival rate than OSCC mice (O group) did. Furthermore, the expression rate of Ki67-positive cells (35.49%±5.00%) was significantly higher than that of O group (23.89%±4.13%) (P<0.05). According to the results of flow cytometry, M2 macrophage expression (24.97%±4.41%) in PO group was higher than that of O group (5.75%±0.52%) (P<0.05). In addition, qPCR results showed that gene expression of M2 macrophage-related factors, Arg1, IL-10, and CD206, showed an overall upward trend. Immunohistochemistry results showed that the positive expression of M2 macrophages was significantly increased in the PO group (21.82%±4.16%) compared to that of the O group (9.64%±0.60%) (P<0.05). Mice in the PO group showed changes in their oral flora structure, exhibiting increased bands and diversity. The white pulp in their spleen tissue decreased and the boundary of the red pulp became indistinct with severe bleeding. The morphology of the colon glands was abnormal and the U-shaped crypt was damaged rather seriously. According to the results of cell experiment, when co-culturing PBMC with SCC7 cells, the presence of periodontitis microorganisms increased the polarization of M2 macrophages (71.00%±0.66%).
      Conclusion  Periodontitis promotes the development of OSCC by inducing M2 polarization in tumor-associated macrophages. Hence, periodontitis treatment holds important values for OSCC patients.

     

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