胃癌细胞可塑性调控影响靶器官内“定植前壁龛”形成及其分子机制

Malignant cells spread from the tumor of origin to colonize distant organs is an ominous feature of most malignant tumors, which has the greatest impact on clinical progression. Although the natural history of this process varies in different cancers, such metastatic “colonization” reflects the ability of disseminated tumor cells to adapt to a foreign tissue microenvironment.Specialized tumor microenvironments called metastatic niches are thought to be responsible for nurturing disseminated cancer cells from micrometastases to full macrometastases. Recently increasing evident indicated that there may be a direct link between cancer stem cells (CSCs) and their metastatic niches. Identifying the limiting factors that regulate the properties of CSCs and their colonization of metastatic niches is therefore important for developing strategies to treat patients with gastric metastatic tumors. The importance of CSCs in tumor-initiation has been firmly established in a variety of tumors. However, the role of CSCs in multistage cancer progression, particularly with respect to metastasis, has not been well-defined. Especially, the applicable non-CSC-to-CSC cell plasticity suggests that tumors as a whole need to be viewed as adaptable and evolving tissues, which shed new insights into the biology of gastric cancers’ growth, recurrence, and progression to metastatic disease. In our previous study,beta2-AR (β2-AR) mediated signaling has been proved to upregulate expression levels of “stem”-related proteins in gastric cancer cells and modulate the phenotypic switching between gastric CSCs and non-CSCs. Although our data further demonstrated that β2-AR signaling contributed to the initiation of EMT and led to an increased expression of mesenchymal proteins at both mRNA and protein levels in gastric cancer cells, there is little research on the signaling mechanism downstream of β2-AR activation which is responsible for the organ-specific metastasis, especially the formation of metastatic niche, in gastric cancers.In present study, we used CD44 as a CSC-related marker to identify the ability of different populations of gastric cancer cells in developing liver metastases. We aimed to explore the limiting niche components that are critical for initiating metastatic colonization during gastric cancer progression. Given that β2-AR signaling was a upstream regulatory in regulating gastric cancer cells’ plasticity, we tried to elucidate the roles of CSC plasticity involved in the formation of tumor-promoting pre-metastatic niche during gastric metastases by interfering β2-AR-mediated signaling pathway. Our study is likely to build up a cross-talk between cancer cell plasticity and organ-specific colonization, and further understanding of the mechanisms driving pre-metastatic niche formation will aid in the discovery of novel targets for better personalized therapy and may finally provide the elusive cure for patients with metastatic gastric cancer.

肿瘤细胞诱导靶器官内“定植前壁龛”形成是肿瘤转移的重要环节，其诱导能力与肿瘤细胞的干性密切相关。前期工作中我们发现β2-AR/STAT3/miR-373/CD44信号通路能够调控胃癌细胞的干性并影响其可塑性。由此提出科学问题“β2-AR及其下游信号通路可能是调控定植前壁龛形成的因素之一。”本研究拟采用CD44为标记分选胃癌组织内的肿瘤干样细胞和已分化肿瘤细胞亚群，（1）研究转移发生时胃癌干样细胞对靶器官内定植前壁龛形成的诱导作用；（2）锁定关键的定植前壁龛形成诱导分子，并探讨这些分子在指引胃癌干样细胞定植、维持其生物学性状中的作用；（3）以β2-AR信号通路为介入点，阐述胃癌细胞可塑性调控定植前壁龛形成及影响胃癌细胞靶向定植的相关分子机制。本工作有助于我们进一步揭示肿瘤细胞可塑性与定植前壁龛形成之间的分子联系；同时为临床通过β2-AR及其下游信号通路干预胃癌细胞的转移定植提供理论依据。

肿瘤细胞诱导靶器官内“定植前壁龛”形成是肿瘤转移的重要环节，而诱导能力与肿瘤细胞的干性有关。本研究中我们发现（1）β2-AR/STAT3/microRNA373信号通路不但能够调控胃癌细胞的可塑性还可以上调EMT相关蛋白在胃癌细胞中的表达，并影响胃癌细胞的侵袭和迁移能力；（2）发现β2-AR信号通路能从转录及翻译水平促进肿瘤微环境关键组成分子periostin在胃癌细胞内的表达，并借此增强胃癌细胞对周围微环境的诱导驯化能力；（3）借助高通量 lncRNA 芯片技术，筛选并构建了基于血液lncRNA（TINCR、 CCAT2、AOC4P、 BANCR 和 LINC008570）的分子诊断组。发现CCAT2不但与患者临床病理特征紧密相关，而且可能通过调控miR-20a作用于periostin 的 3’UTR 区域并影响其功能。本研究为解决和突破胃癌基础研究的瓶颈，探寻和阐明胃癌侵袭转移的分子机制，预防和阻断胃癌细胞远处转移奠定夯实的理论基础。同时，也为针对定植壁龛设计个性化的治疗方案，提高靶向药物的特异性和有效性带来新的契机。