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Abstract：
The reciprocal interaction between circulating tumor cells (CTCs) and tissue-specific cells is influential for the progression of metastases. In particular, the process of extravasation relies on the complex cross-talk between cancer cells and other cellular players such as the endothelium and the secondary tissue. However, most in vitro studies only focus on one heterotypic cell-cell interaction and often lack of physiological relevance. In this project, we investigated both CTC-endothelium and CTC-secondary site interactions during cancer cell extravasation. We first used a microarray analysis of extravasated MDA-MB-231 breast cancer cells to identify key markers involved in extravasation. Then, we developed a tri-culture microfluidic platform combining cancer cells, endothelium and a bone-mimicking (BMi) microenvironment to assess how organ tropism influences the extravasation potential of cancer cells from different tissues. Through the microarray analyses of extravasated cancer cells we found that extravasation is associated with upregulation of late-metastatic markers along with specific proteases, such as matrix metalloprotease (MMP), a-disintegrin and metalloprotease (ADAM) and a-disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family members, which are all involved in endothelium glycocalyx shedding. Through the microfluidic extravasation assay, we found that the bone-like microenvironment increased invasion and motility of breast, bladder and ovarian cancer cell (MDA-MB-231, T24 and OVCAR-3). Among the three cell types, ovarian cancer cells presented the lowest migration rate and bladder cancer cells the highest, hence recapitulating their different level of bone tropism observed in vivo. Taken together, our results shed light on the importance of intercellular communication between CTCs and other non-tumor cells essential for promoting cancer cell extravasation.
摘要：
循环肿瘤细胞（CTC）和组织特异性细胞之间的相互作用对转移的进展有影响。特别是,外渗过程依赖于癌细胞和其他细胞参与者如内皮和次级组织之间复杂的串扰。然而,大多数体外研究只关注一种异型细胞间的相互作用，往往缺乏生理相关性。在这个项目中,我们研究了癌细胞外渗过程中CTC-内皮和CTC-次级位点的相互作用.我们首先使用外渗MDA-MB-231乳腺癌细胞的微阵列分析来鉴定与外渗有关的关键标志物。然后，我们开发了一个结合癌细胞的三培养微流控平台，内皮和骨模拟（BMi）微环境，以评估器官嗜性如何影响来自不同组织的癌细胞的外渗潜力。通过对外渗癌细胞的微阵列分析，我们发现外渗与晚期转移标志物以及特定蛋白酶的上调有关。如基质金属蛋白酶(MMP)，a-去整合素和金属蛋白酶（ADAM）和a-去整合素和金属蛋白酶与血小板反应蛋白基序（ADAMTS）家族成员，这些都与内皮糖萼脱落有关。通过微流控外渗分析，我们发现类骨微环境增加了乳房的侵袭和运动，膀胱癌和卵巢癌细胞（MDA-MB-231，T24和OVCAR-3）。在三种细胞类型中，卵巢癌细胞的迁移率最低，膀胱癌细胞的迁移率最高，因此，概括了他们在体内观察到的不同水平的骨嗜性。一起来看,我们的研究结果揭示了CTC和其他非肿瘤细胞间通讯对促进癌细胞外渗至关重要的重要性.
