芳香烃受体AhR对于肿瘤微环境间充质干细胞的调控作用及机制研究

High incidence of cancer is closely related to environment pollution. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is best known for mediating the environment toxicity the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as ‘dioxin’. It has been reported that AhR influences the major stages of tumorigenesis — initiation, promotion, progression and metastasis. However, the underlying mechanism still remains unclear. We found that mesenchymal stem cells (MSCs) derived from mice lymphoma expressed higher levels of AhR compared to the cells from the bone marrow of wild type mice. Meanwhile, we found that AhR deficiency in MSCs significantly impaired MSC-mediated promotion of melanoma metastasis in mice models. Moreover, we found that AhR deficiency resulted in lower expression levels of chemokines and metalloprotease in MSCs. To investigate the mechanism underlying the regulatory effects of AhR on MSCs and delineate the effects of AhR regulation of MSCs on tumor pathogenesis and metastasis, we will determine: 1) the effects of AhR in MSCs on tumorigenesis and metastasis; 2) the regulatory role of AhR in the biology properties and functions of MSCs; 3) the target molecule of AhR in MSCs and MSC-mediated function in tumor; 4) the molecular mechanism underlying the regulatory effects of AhR on its target molecule in MSCs. We believe that the completion of this study will provide not only the critical information for understanding of AhR-mediated regulation on MSCs and tumor pathogenesis,but also for designing new anti-cancer strategies.

恶性肿瘤的高发与环境污染关系紧密。作为多环芳烃类环境污染物的受体——芳香烃受体AhR在肿瘤致病中的作用及机制还不清楚。我们研究发现，小鼠淋巴瘤的肿瘤微环境内的间充质干细胞（MSCs）表达高水平的AhR分子，AhR的缺失将极大削弱MSCs原本促进黑色素瘤转移的能力。同时发现，AhR缺失导致MSCs表达的趋化因子和金属蛋白酶水平显著下降。为深入研究AhR调控肿瘤微环境MSCs进而干扰肿瘤发生与转移的分子机制，我们将研究以下内容：明确MSCs表达的AhR分子对于肿瘤发生和转移的影响；阐明AhR对于MSCs生物学特性及功能的影响；揭示AhR调控MSCs进而干预肿瘤进程的靶标分子；阐明AhR调控MSCs内靶标分子的分子机制。本研究不仅拓展关于AhR在肿瘤致病中作用的认识，也将加深MSCs参与肿瘤微环境构建以及发挥肿瘤免疫反应调控作用的了解，为以MSCs为靶向的肿瘤防治提供可能的干预靶标和治疗新策略。

肿瘤免疫微环境在肿瘤发生发展中起到决定性作用，MSCs作为肿瘤微环境中重要的基质细胞，参与肿瘤免疫微环境的构建。对MSCs通过调控免疫参与肿瘤发生发展的机制目前已有了大量研究，然而，肿瘤微环境中MSCs免疫调控功能的上游控制因子尚无定论。本项目系统阐述了AhR对MSCs多种免疫调控机制的影响，明确了MSCs在炎症环境中通过高表达免疫趋化因子与免疫抑制分子塑造抑制性免疫微环境的功能依赖于AhR信号；以AhR信号为切入点，揭示了MSCs促肿瘤转移作用的新机制；明晰炎症刺激的MSCs通过调控适应性免疫细胞促进肿瘤转移需要AhR信号的激活；并发现AhR信号可能通过调控MSCs Vegf表达进而影响CD8+ T细胞的激活与增殖。研究成果不仅拓展了我们对MSCs塑造肿瘤免疫微环境的认识，同时也为靶向MSCs治疗肿瘤提供了新思路。