从调控炎性微环境抑制肿瘤对骨髓来源细胞的募集和修饰探讨肺瘤平膏对肺癌的作用及机制

Inflammation is one of two core features of tumor microenvironment, and tumor can recruit and modify various kinds of tisuse cells to serve itself and creat a suitable microenviroment for its development through secreting many kinds of inflammatory factors. These cells include not only cells in tumor itself but also cells in distant sites of body especially bone marrow derived cells.With these cell's help, tumor cell's invasiveness is enhanced,antitumor immunity is restrained,new blood vessels emerges and tumor makes progress and metastasis. Our previous study also finds that the level of inflammatory factors in cultural supernatant is elevated after the lung cancer cells is co-cultured with macrophages.At the same time,lung cancer cells show higher Epithelial-mesenchymal transition propensity and it can be reversed partly by Feiliuping Extractum. Therefore, we speculate that the therapeutic principle of Fuzhengjiedu play their effects throuth regulating the inflammation environments and inhibiting recruitment and modification by tumor cells. We are to set up lung cancer models in mice with bone marrow GFP(+) and cancer cells Luc(+) and cell co-culture system in vitro,choose bone marrow derived cells as breakthrough points and use technology like living imaging,cDNA arrays,Elisa,western blot,flow cytometry to test and verify our hypothesis,further explore the anti-metastasis mechanisms of Feiliuping Extractum and provide new ideas for Chinese herbs' antitumor mechanism .

炎症是肿瘤微环境的两个核心特征之一，肿瘤可通过分泌多种炎性因子来招募、修饰机体的各种细胞为自己服务，形成并维持适宜肿瘤发展的微环境。这些细胞不仅包括肿瘤局部的细胞，机体远端特别是骨髓来源细胞也是肿瘤相关细胞的重要来源。正是在这些细胞的帮助下，肿瘤细胞侵袭性增强，抗肿瘤免疫受到抑制，新生血管形成，肿瘤得以进展转移。我们前期的研究也发现，肺癌细胞与巨噬细胞共培养后，培养上清中炎性因子水平升高，肺癌细胞上皮间质转化的倾向增强，而肺瘤平膏可部分逆转这种现象。因此，我们推测"扶正解毒治法通过调控炎性微环境抑制肿瘤细胞对机体细胞的招募和修饰来发挥抗癌作用"。我们拟通过骨髓GFP（+）肿瘤细胞Luc(+)的肺癌小鼠模型和体外细胞共培养体系，以骨髓来源细胞为切入点，采用活体成像、cDNA arrays、Elisa等技术验证我们的假说，进一步探索肺瘤平膏的抗癌机制，并为中药的抗肿瘤作用机制提供新的思路。

炎症是肿瘤微环境的两个核心特征之一，肿瘤可通过分泌多种炎性因子来招募、修饰机体的各种细胞为自己服务，形成并维持适宜肿瘤发展的微环境。这些细胞不仅包括肿瘤局部的细胞，机体远端特别是骨髓来源细胞也是肿瘤相关细胞的重要来源。正是在这些细胞的帮助下，肿瘤细胞侵袭性增强，抗肿瘤免疫受到抑制，新生血管形成，肿瘤得以进展转移。我们前期的研究也发现，肺癌细胞与巨噬细胞共培养后，培养上清中炎性因子水平升高，肺癌细胞上皮间质转化的倾向增强，而肺瘤平膏可部分逆转这种现象。因此，我们推测“扶正解毒治法通过调控炎性微环境抑制肿瘤细胞对机体细胞的招募和修饰来发挥抗癌作用”。本研究通过绿色荧光蛋白(GFP)/荧光素酶（Luc）双标记肿瘤细胞所建立的肺癌小鼠模型和肺癌细胞与骨髓来源细胞的共培养体系，观察炎症介导的骨髓来源细胞募集在肺瘤平抗肺癌效果中的作用，并以TNF-α/IL-1-NF-κB/STAT3炎症通路为靶点探究其调控机制。体内研究发现，肺瘤平+环磷酰胺组小鼠的肿瘤体积最小，瘤块增值率最低，食料消耗量最大，同时该组小鼠血液、瘤组织、脾中的髓源抑制性细胞的比例在各组中最低。进一步的检测发现，肺瘤平+环磷酰胺组的TNF-α/IL-1-NF-κB/STAT3炎症通路的表达较其他组显著降低，其下游的EMT指标、血管生成和趋化因子的表达亦显著下降。此外该组肿瘤组织的乳酸浓度最低，糖酵解和微环境酸碱度相关指标的表达也显著下降。我们认为化疗与肺瘤平膏在抑制肺癌生长上具有协同作用，而这种作用部分是因为二者联用可以抑制TNF-α/IL-1- STAT3炎症通路、影响肿瘤细胞与骨髓细胞的相互作用，进而干预肿瘤局部微环境实现的。提示在肿瘤治疗中，化疗药和扶正解毒中药应联用，做到直接杀伤肿瘤细胞和调控肿瘤微环境并重，才能最大限度的提高抗肿瘤效果。