A combined microfluidic-transcriptomic approach to characterize the extravasation potential of cancer cells.
A combined microfluidic-transcriptomic approach to characterize the extravasation potential of cancer cells.
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DOI：
10.18632/oncotarget.26306
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发表时间：
2018-11-16
期刊：
影响因子：
--
通讯作者：
Adriani, Giulia
中科院分区：
文献类型：
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作者：
Bersini, Simone;Miermont, Agnes;Adriani, Giulia
循环中的肿瘤细胞(CTCs)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)之间的复杂相互作用。然而，大多数体外研究只关注一种异型细胞与细胞之间的相互作用，往往缺乏生理相关性。在这个项目中，我们研究了癌细胞渗出过程中CTC-内皮和CTC-次级部位的相互作用。我们首先对渗出的MDA-MB-231乳腺癌细胞进行微阵列分析，以确定与渗出有关的关键标志物。然后，我们开发了一个结合了癌细胞、内皮和类骨(BMI)微环境的三培养微流控平台，以评估器官趋向性如何影响不同组织中癌细胞的外渗能力。通过对外渗癌细胞的基因芯片分析，我们发现外渗与晚期转移标志物以及特定的蛋白水解酶的表达上调有关，如基质金属蛋白酶(MMPs)、α-去整合素和金属蛋白水解酶(ADAM)、α-去整合素和带有血栓反应蛋白基序的金属蛋白酶(ADAMTS)家族成员，这些都与内皮糖萼脱落有关。通过微流控外渗实验，我们发现骨样微环境增加了乳腺、膀胱和卵巢癌细胞(MDA-MB-231、T24和OVCAR-3)的侵袭力和运动能力。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，从而概括了它们在体内观察到的不同程度的趋骨性。综上所述，我们的结果阐明了CTCs和其他非肿瘤细胞之间的细胞间通讯的重要性，这些细胞通讯对于促进癌细胞外渗是必不可少的。
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.