三叶青多糖调控Hedgehog信号通路逆转TAMs-M2极化的抗乳腺癌机制研究

乳腺癌的发病率逐年攀升，免疫治疗相较传统治疗方案明显提高中晚期患者生存期，具有较好的临床应用前景。中医药在肿瘤免疫治疗中有独特优势。三叶青是著名的畲族民间中药，因其显著的抗肿瘤活性而备受关注，但迄今对其抗肿瘤作用机制所知甚少。申请人前期研究表明：三叶青多糖能够抑制小鼠乳腺癌的生长与转移，逆转肿瘤相关巨噬细胞（TAMs）M2型极化，改善肿瘤微环境；筛选显示其能调控Hedgehog（Hh）信号通路相关基因表达。已有研究表明，M2型TAMs是形成肿瘤免疫抑制微环境的主要原因，而Hh信号通路通过促进M2型TAMs极化而促肿瘤发展。因此我们提出假说三叶青多糖通过调控Hh信号通路逆转TAMs M2极化而抑制乳腺癌发展。本项目拟采用细胞及转基因小鼠模型，结合分子生物学技术，阐明三叶青多糖通过逆转TAMs M2极化而抗乳腺癌的作用机制，为扩大三叶青临床应用提供理论基础，并为乳腺癌的免疫治疗提供新思路。

The global incidence rate of breast cancer is increasing every year, immunotherapy could improve the lifetime of patients with advanced stage compared with the traditional treatment, and has a good prospect of clinical application. Traditional Chinese medicine has unique advantages in tumor immunotherapy. Tetrastigma hemsleyanum Diels et Gilg, a rare herbal plant native of She minority, developing to a promising Chinese herbal medicine based on the high antitumor activity. However, the mechanism is still essentially unknown. Our previous research showed that tetrastigma hemsleyanum tubers polysaccharide inhibited the growth and metastasis of breast cancer in mice, reversing M2-like polarization of tumor-associated macrophage (TAMs) and improve the tumor microenvironment. Screening studies showed that it could regulate the expression of Hedgehog (Hh) signaling pathway. Studies have showed that M2-like polarization of TAMs is one of the main causes of the immunosuppressive tumor microenvironment, and Hh signaling pathway promotes the M2-like polarization of TAMs, thereby promoting tumor development. Therefore, we hypothesized that Tetrastigma hemsleyanum tubers polysaccharide could inhibit breast cancer by reversing M2-like polarization of TAMs via Hh signaling pathway. In this study, we aim to clarify the mechanism in this process by cell lines and transgenic mouse models with modern molecular biological methods. The results of this study will provide theoretical basis for the application of Tetrastigma hemsleyanum, and provide the novel therapy for the immunotherapy of breast cancer.