肾上腺素能信号在乳腺癌肿瘤微环境重塑中的作用及机制

A solid tumor, which is composed of tumor cells, various infiltrating immune cells, blood vessels, and nerve fibers, behaves like an integrated organ. Recent studies demonstrated that biobehaviours of tumor were affected by the activity of nervous system like other human organs. However, the related mechanisms remain unclear. Our previous studies revealed that the adrenergic signaling not only promoted proliferation, metastasis and drug resistance of tumor, but also affected the biobehaviours of non-tumor cells in tumor microenvironment. Our data in the recent studies demonstrated that adrenergic signaling manipulated the crosstalk between tumor cells and macrophage, inducing infiltration of macrophage to tumor tissues. Crosstalk between tumor cells and endothelial cells was also regulated by adrenergic signaling. Activation of adrenergic signaling promoted tumor angiogenesis by triggering hypoxia-like effects in tumor microenvironment and activating the Jagged-1/Notch intercellular signaling in a tumor and endothelial cell contact-dependent manner. These data strongly imply that sympathetic nerve signaling may regulate the tumor microenvironment remodeling and the malignant progression of cancer by manipulating the crosstalk of tumor/non-tumor cells in tumor microenvironment. In this study, we will further explore the molecular mechanisms, by which the adrenergic signaling regulates the crosstalk between breast cancer cells and macrophage; the adrenergic signaling promotes tumor angiogenesis in both intercellular interaction-dependent manner and paracrine manner; sympathetic nerve activities and adrenergic signaling regulate tumor microenvironment remodeling. We will evaluate the possibility of manipulating adrenergic signaling as one of the potential intervention strategies in breast cancer. The studies will shed some new light on the development of new adjuvant therapies and novel drugs for cancer.

肿瘤是由多种细胞、细胞外基质、血管和神经等构成的“类器官”。肿瘤的生物学行为亦可能像其它器官一样受神经信号的调控，但相关机制尚不清楚。我们发现，肾上腺素能信号不仅可促进肿瘤细胞增殖、侵袭、转移，而且还可对间质细胞产生重要的影响。肾上腺素能信号可调控肿瘤细胞与巨噬细胞互作，促进巨噬细胞在肿瘤组织中的浸润；肾上腺素能信号可诱导“类缺氧”效应，调控肿瘤细胞与血管内皮细胞互作并激活Jagged-1/Notch信号通路，促进肿瘤血管生成，提示肾上腺素能信号可能通过调控肿瘤细胞与非肿瘤细胞相互作用，诱导肿瘤微环境重塑。本课题拟通过临床和体内外实验研究，探索肾上腺素能信号：1) 调控乳腺癌细胞与巨噬细胞相互作用的分子机制；2) 激活旁分泌及肿瘤/内皮细胞接触依赖性信号、诱导血管新生的分子机制；3) 调变肿瘤微环境的生物学意义；4)探索干预肾上腺素能信号作为肿瘤辅助治疗的可行性，并为新药研发提供理论依据。

本课题主要围绕“心理应激相关的肾上腺素能信号对肿瘤微环境中巨噬细胞和血管内皮细胞生物学行为的影响及相关机制”开展研究工作。相关研究结果发表SCI收录论文5篇，影响因子合计31.46。肿瘤是由多种细胞、细胞外基质、血管和神经等构成的“类器官”。肿瘤的生物学行为亦可能像其它器官一样受神经信号的调控，但相关机制尚不清楚。本课题通过多种动物模型从整体水平探索肾上腺素能神经及其信号在乳腺癌炎细胞浸润、血管生成及肿瘤转移中的作用；通过体内外实验探索肾上腺素能信号调控肿瘤细胞与巨噬细胞间相互作用的精确分子机制并鉴定关键节点分子；应用体内实验及体外3D培养等多种实验模型，研究肾上腺素能信号通过影响接触依赖及旁分泌途径调控肿瘤细胞、巨噬细胞及血管内皮细胞相互作用的分子机制；研究操控肾上腺素能信号作为肿瘤辅助治疗候选方案的可行性。. 我们发现，肾上腺素能信号不仅可促进肿瘤细胞增殖、侵袭、转移，而且还可对间质细胞产生重要的影响。肾上腺素能信号可调控肿瘤细胞与巨噬细胞互作，促进巨噬细胞在肿瘤组织中的浸润。肾上腺素刺激肿瘤细胞，通过增强肿瘤细胞透明质酸合成酶2的表达，促进透明质酸分泌。肿瘤细胞分泌的透明质酸可诱导巨噬细胞向M2型分化；肾上腺素能信号可诱导“类缺氧”效应，调控肿瘤细胞与血管内皮细胞发生接触非依赖和接触依赖的相互作用，促进肿瘤新生血管生成。肾上腺素能信号活化诱导肿瘤细胞高表达Jagged-1，后者与表达于血管内皮细胞的Notch1相互作用，诱导血管内皮细胞中的Notch信号活化，促进肿瘤血管生成。以上研究结果说明肾上腺素能信号可能通过调控肿瘤细胞与非肿瘤细胞相互作用，诱导肿瘤微环境重塑，为建立以肾上腺素能信号为靶点的新型肿瘤治疗策略奠定了理论基础。