炎症因子IL-6、TNF-α调控cell-in-cell增强结肠癌细胞免疫反击的分子机制

Cell-in-cell means living cells go inside another cell. We have published that lymphocytes could go into a broad-spectrum of tumor cell lines and die inside. Cell-in-cell was also revealed to occur in tumor and inflammatory tissues in vivo. Recently, during the screening of large numbers of pathological specimens, we found cell-in-cell significantly in colon cancer. And the rate is associated with inflammation of tumor tissue. We also have found the inflammatory cytokines IL-6, TNF- α can reduce the cell death ratio of external tumor cells / internal cell death ratio. To sum up, we speculate that the inflammatory cytokines IL-6, TNF- α can promote lymphocyte into tumor cells and increase the colon cancer development. It may be a new way of colon cancer immune escape induced by inflammation. We will carry out work from analysis of in vivo samples, experiment in vitro and animal model. We expect to confirm the functions of inflammatory cytokines in cell-in-cell formation and clarify the molecular mechanism of IL-6/TNF-α to cell-in-cell from affecting cytotoxicity, adhesion proteins expression, cell signal pathways. We will also explore the mechanism of outer tumor cells’ autophagy and vesicle expansion for defensing inner lymphocytes which can be enhanced by inflammatory cytokines. Through the above experiments, we will elucidate how the inflammatory cytokines can enhance colon cancer cells’ resistance to lymphocytes through cell-in-cell way. Analysis of this mechanism will provide new evidence for the theory of inflammation promoting cancer.

cell-in-cell是指活细胞进入另一个细胞内，我们已揭示淋巴细胞可钻入广谱肿瘤细胞系与广泛体内肿瘤及炎症组织细胞中，并发生胞内死亡，最近大量病理标本筛查又发现结肠癌中淋巴细胞钻入肿瘤细胞显著，并与组织内炎症相关，且炎症因子IL-6、TNF-α可降低cell-in-cell中外部肿瘤细胞/内部淋巴细胞死亡比率。综上推测结肠癌组织中炎症因子IL-6、TNF-α可促进淋巴细胞钻入肿瘤细胞并加剧其胞内死亡，可能是炎症调控结肠癌免疫逃逸的新途径。本课题拟从体内标本分析、体外细胞实验、动物模型方面，分析结肠癌中cell-in-cell规律性，明确IL-6、TNF-α对cell-in-cell相关的细胞杀伤、粘附蛋白表达、细胞信号通路的调控，以及强化肿瘤自噬与囊泡扩张等防御反击能力的作用机制，以期阐明炎症因子增强结肠癌细胞经cell-in-cell清除淋巴细胞的分子机制，为炎症促癌理论提供新佐证。

Cell-in-cell指的是一个或多个同质或异质细胞主动“钻”入另一个细胞的胞浆内，形成细胞套叠结构的现象。其中免疫细胞与肿瘤细胞发生的该结构广泛出现于各类肿瘤组织中，我们在病理标本观察中发现结直肠癌中cell-in-cell结构出现的频率要高于正常组织中，特别伴有炎症的肿瘤组织中频率更高，结合炎症是癌症发生发展的重要因素的结论，我们推测免疫细胞与肿瘤细胞的额cell-in-cell在结直肠癌的炎癌关系中具有重要意义。我们通过大量结直肠癌术后标本的切片观察、统计与患者随访发现结直肠癌组织内cell-in-cell的发生频率与组织炎症/术后生存期具有相关性。体外细胞实验与动物模型标本进一步证实了炎症因子IL-6、TNF-α可以促进肿瘤细胞黏附分子以及细胞动力从而显著提高cell-in-cell比率。此外炎症因子还通过调控肿瘤细胞的自噬以及抗凋亡信号通路，改变cell-in-cell后肿瘤细胞和淋巴细胞的命运，导致进入肿瘤内部的淋巴细胞死亡增多，而被淋巴细胞从内部杀伤的肿瘤细胞减少。因此我们认为结直肠癌组织中淋巴细胞与肿瘤细胞的 cell-in-cell 结构及淋巴细胞的胞内死亡是炎症促进肿瘤细胞免疫反击的特殊方式，是炎症促进肿瘤细胞逃避免疫杀伤并对淋巴细胞进行免疫反击的新途径，在细胞生物学方面为 cell-in-cell 的发生提供新思路，同时为炎症促癌理论提供新证据，也为结肠癌的恶化发展及免疫调变、干预提供新的思路。