基于MDSCs干扰转移前微环境形成研究活血化瘀法抗乳腺癌转移机制

Patients with malignant tumors often have blood stasis syndrome. Similar to pre-metastatic niche, cancer patients often have microcirculatory disorders, tissue hypoxia, angiogenesis, inflammatory cell infiltration, angiogenesis and tumor matrix remodeling. This may suggest that blood stasis syndrome is closely related to the formation of pre-metastatic niche. MDSCs plays a central role in the formation of pre-metastatic niche. Tumor cells can promote the recruitment of MDSCs through ERα, enhance their activity, and promote the formation of pre-metastatic niche. Our previous research found that Blood-activating and Stasis-resolving herbs are the main drugs for the anti-breast cancer of Xi Huang formula. Its main target is ERα, and it can inhibit the lung metastasis of breast cancer, decrease the expression of IL-6, IL-10, TGF-β and increase the level of IFN-γ in vivo. Based on this, this study intends to explore the relationship between blood stasis syndrome and the formation of pre-metastatic niche by establishing a C57/BL6 mouse model with lung pre-metastatic niche, confirming that Blood-activating and Stasis-resolving therapy can inhibit breast cancer metastasis by suppressing pre-metastatic niche formation via MDSCs by inhibiting the expression of ERα.

肿瘤患者普遍存在血瘀证，同“转移前微环境”病理改变相似，肿瘤血瘀证患者也存在微循环障碍、组织缺氧、免疫细胞浸润、细胞因子过表达、免疫抑制、高通透性血管生成、基质重塑等病理改变，提示血瘀证与肿瘤转移前微环境关系密切；MDSCs在转移前微环境形成中发挥核心作用，肿瘤细胞可通过ERα招募MDSCs，促进转移前微环境形成。因此，通过ERα抑制MDSCs，干扰转移前微环境形成，能够抑制肿瘤转移。前期发现，活血化瘀药乳香、没药为西黄丸抗乳腺癌主要作用药物，其靶点为ERα；同时，西黄丸可抑制乳腺癌荷瘤小鼠肺转移，降低体内MDSCs，IL-6、IL-10、TGF-β，增加IFN-γ表达。据此提出：血瘀证可能是肿瘤转移前微环境形成的一种标志，活血化瘀法可通过ERα抑制MDSCs干扰转移前微环境形成。本项目拟通过乳腺癌肺转移前微环境小鼠模型，验证此假说，为活血化瘀法抗肿瘤转移提供新思路。

血瘀证与肿瘤转移前微环境关系密切；MDSCs在转移前微环境形成中发挥核心作用。本研究首先探讨了血瘀证与乳腺癌肺转移微环境形成的关系，分析了改善血瘀证对4T1荷瘤小鼠荷瘤量及肺转移抑制作用，证实活血化瘀药物乳香、没药及西黄丸可以抑制乳腺癌增殖及肺转移。通过对肺转移微环境内MMP9、S100A8/9表达及微环境内免疫抑制细胞MDSCs检测，证实乳香、没药及西黄丸能够抑制乳腺癌肺转移前微环境基质形成及抑制微环境内免疫抑制细胞MDSCs聚集，干扰转移前微环境形成。该研究还进一步证实了活血化瘀单体丹参酮IIa对转移前微环境基质形成及MDSCs的抑制作用，证实了丹参酮IIa对血瘀证及乳腺癌肺转移抑制作用。同时，分析了西黄丸对乳腺癌患者MDSCs及相关炎症因子的影响，基于临床研究证实了西黄丸对MDSCs的作用。综上，本研究立足于血瘀证，结合转移前微环境及MDSCs在转移前微环境所发挥的核心作用，揭示乳腺癌血瘀证的病理机制，为活血化瘀抗肿瘤转移机制提供了新思路。