基于量子点标记分子探针的胃癌微环境特征识别及其演化机制研究

The comprehensive overview of gastric cancer (GC) progression suggests that the process is influenced by intrinsic properties of the tumor cells, as well as by tumor microenvironmental factors. The co-evolution effects between cancer cells and tumor microenvironment determine the process of invasion and metastasis, which are the basic biological behaviors of gastric cancer. Recognizing and identifing the features of tumor microenvironment would pave the way to illustrate the co-evolution mechanisms. In addition, such results would be useful to demonstrate the reciprocal interactions and the mechanisms by which tumor microenvironment influence the cancer biological behaviors. Our previous studies showed that quantum dots (QDs) based molecular probes have striking technical advantages in terms of qualitative and quantitative detection and dynamic monitoring of the complexed components, which is very suitable for the study of tumor microenvironment. According to these findings, this program would develop a new platform with multiplexed molecular imaging and spectrum analysis technology, and cellular tracing method based on quantum dots labeled molecular probe to reveal multiple components simultaneously in the complexed tumor microenvironment with highly sensitivity and specificity. We will focus on the dynamic evolution process, i.e., normal stromal-activated stromal- promote progression stromal. Extensive study would be performed to effectively recognize the tumor microenvironment features, including organizational structural features and molecular features, by the new platform abovementioned. Then, this enhanced understanding presents the opportunity to explore the relationship between tumor microenvironment features and gastric cancer biological behaviors. In addition, visualized animal model would be established to monitor the dynamic evolution process and investigate the evolution mechanisms of tumor micoenvironment. Further more, a new prediction model for the risk of gastric cancer would be developed based on the tumor microenvironment features identifed in this study, which may indicate the important role of tumor microenvironment in cancer biology, and opened a new field to predict clinical outcome in gastric cancer from the perspectives of tumor microenvironment.

侵袭转移是胃癌最本质的生物学行为特征，是胃癌细胞与肿瘤微环境相互作用的结果。识别并鉴定胃癌微环境特征，明确其演化规律，有助于阐明肿瘤微环境与癌细胞相互作用影响胃癌生物学行为的机制。我们的前期研究提示，基于量子点标记分子探针可发展针对肿瘤微环境复杂特点的创新性纳米肿瘤学技术体系，促进肿瘤微环境特征研究。本项目拟在前期研究基础上，进一步发挥多学科交叉优势，发展基于量子点标记分子探针的多分子光谱成像分析技术和细胞示踪技术，原位、实时显示胃癌肿瘤微环境演化过程中的关键组织形态变化和微环境稳态异常分子表达变化，有效识别具有代表性的胃癌微环境特征（组织形态特征和分子特征）；分析其与胃癌生物学行为的关系及演化规律，建立胃癌预警模型；在动物模型中动态观察肿瘤微环境特征演化过程并探索其机制，在临床样本中评价预警模型效能；以期在促进量子点标记分子探针生物学应用的同时，为发展胃癌创新诊疗策略提供参考。

侵袭转移是胃癌最本质的生物学行为特征，是胃癌细胞与肿瘤微环境相互作用的结果。识别并鉴定胃癌微环境特征，明确其演化规律，有助于阐明肿瘤微环境与癌细胞相互作用影响胃癌生物学行为的机制。我们的前期研究提示，基于量子点标记分子探针可发展针对肿瘤微环境复杂特点的创新性纳米肿瘤学技术体系，促进肿瘤微环境特征研究。本项目首先建立了胃癌临床标本库和信息库（16张组织芯片，包含494例胃癌组织和237例癌旁组织），为本项目和后续研究奠定了基础。其次，建立了基于量子点标记分子探针的多分子光谱成像分析技术，提出了胃癌间质活化概念，为胃癌间质微环境研究提供了更多证据。第三，分析了胃癌预后分期系统，建立综合考虑胃癌间质微环境整体效应的TSNM（tumor-stromal-node-metastasis）预后分期系统。第四，探讨了独特间质细胞（成纤维细胞，巨噬细胞，肿瘤浸润淋巴细胞）作为胃癌间质微环境标志物的可行性，根据癌细胞-间质交互作用理念创造性的提出了根据分布区域分析间质细胞功能的假说，突破了分子表型的局限性。第五，分别分析了间质重塑、关键分子特征（缺氧、血管生成）在胃癌侵袭转移过程中的作用。目前已经发表SCI收录论文4篇，1篇已经接收，尚有2篇待投稿，另有综合研究胃癌间质微环境标志物的论文尚待总结。利用建立了量子点标记分子探针的多分子光谱成像分析技术和细胞示踪技术，可以原位、实时显示胃癌肿瘤微环境演化过程中的关键组织形态变化和微环境稳态异常分子表达变化，有效识别具有代表性的胃癌微环境特征（组织形态特征和分子特征）；分析其与胃癌生物学行为的关系及演化规律，以期在促进量子点标记分子探针生物学应用的同时，为发展胃癌创新诊疗策略提供参考。