表达组氨酸脱羧酶的髓系来源抑制细胞促进肠道菌群失调小鼠发生乳腺癌的机制研究

Although intestinal dysbiosis (ID) contributes to gastrointestinal diseases including tumor, direct evidence for ID involving the tumorigenesis of non-intestinal organs is lacking. The innate immunity in response to ID can recruit tumor-associated neutrophils (TANs) to promote mammary cancer process. However, whether its progenitors, granulocytic myeloid-derived suppressor cells (PMN-MDSCs), serve as essential component during this process is largely unknown. Our preliminary results indicated that, in the setting of ID, bacterium can translocate to mammary cancer tissue and increase the frequency of PMN-MDSCs, which express high level of histidine decarboxylase (Hdc). Thus, we propose that ID promotes the translocation of intestinal bacterium to mammary gland and recruits Hdc+ PMN-MDSCs, which in turn secret Wnts to activate Wnt/β-catenin and finally result in the malignant transformation of mammary tubular epithelium. To test this, we will mainly conduct fluorescence in situ hybridization (FISH), RNA-seq, and adoptive transfer to explore the exact pathway of bacterial translocation and the underlying molecular mechanisms by which Hdc+ PMN-MDSCs exert effects on mammary cancerogenesis, providing mechanistic insights into treating ID-associated tumors.

肠道菌群失调（Intestinal Dysbiosis，ID）可引发胃肠道疾病包括肿瘤，但是否与胃肠道外器官恶性病变有关，却鲜有明确证据。ID的先天性免疫应答可募集肿瘤相关嗜中性粒细胞促发乳腺癌。而其前体细胞——粒细胞性髓系来源抑制细胞（PMN-MDSCs）是否参与其中尚不清楚。课题组前期研究表明ID小鼠会发生乳腺癌，癌组织内存在转移的细菌，且表达组氨酸脱羧酶（Hdc）的PMN-MDSCs比例显著升高。由此我们提出假说：ID可致细菌转移至乳腺，并募集Hdc+ PMN-MDSCs，后者通过高表达Wnts激活乳腺导管上皮内Wnt/β-catenin信号通路并出现恶变。本研究拟在Hdc和Apcmin/+ ID小鼠模型中，用RNA-seq、荧光原位杂交、双光子显微镜和过继移植等方法，进一步探索细菌转移途径和Hdc+ PMN-MDSCs调控乳腺癌发生的分子机制，为临床防治ID相关肿瘤提供理论基础。

微生物失调在肠道疾病的发展中起着重要作用。最近的研究表明肠道细菌与乳腺癌之间存在联系。在本研究中我们的研究结果表明：与未感染的同窝小鼠相比，感染肝螺杆菌（H.hepaticus）的雌性 ApcMin/+小鼠表现出增加的乳腺和小肠/大肠肿瘤负荷。在小肠/大肠、乳腺肿瘤和邻近淋巴结中检测到H.hepaticus DNA，表明存在迁移途径。 CD11b+Gr1+髓源性抑制细胞 (MDSCs) 浸润并表达高水平的Wnt，可能通过激活Wnt/β-catenin通路增强肿瘤发生。我们之前的研究表明，组氨酸脱羧酶 (Hdc) 标记了一群骨髓偏向的造血干细胞和粒细胞MDSC。由表达IL-17的肥大细胞和肿瘤组织分泌的细胞因子/趋化因子促进 Hdc+ MDSCs扩张和向乳腺肿瘤的运输。从H. hepaticus感染的小鼠中分离出的MDSCs的过继转移增加了受体ApcMin/+小鼠外周血、肠系膜淋巴结、乳腺和淋巴结中MDSCs的频率。H. hepaticus引发的MDSCs的过继转移也增加了乳腺肿瘤的大小和数量。我们的结果表明H. hepaticus可以从肠道转移到乳腺组织，以促进 MDSC的乳腺肿瘤发生。靶向细菌和MDSCs可能有助于预防和治疗肠外癌症。