癌症长期监测对于精准医学的临床实践至关重要，发现早期癌症或癌症早期复发是取得最佳临床结局的关键，因为对已经转移的晚期癌症进行根治要困难得多。可惜，目前的癌症检测技术缺点较多：标准的组织活检为创伤性且难以反复进行，放射成像技术无法捕捉到乳腺癌生长过程的重要变化。液体活检是一种通过简单采血检测癌症的方法，可以克服上述问题；不过，经过多年研究，仍然没有一种液体活检方法进入临床被广泛应用。
越来越多的证据表明，在细胞之间进行分子转运的细胞外囊泡对于肿瘤生长和转移具有重要作用，包括通过转运基质金属蛋白酶MMP对基质进行重塑，参与细胞表面受体分解、释放细胞凋亡配体以及趋化因子和细胞因子的去活化，在许多细胞行为中扮演重要角色，例如细胞增殖、细胞迁移、细胞黏附、细胞分散、细胞分化、血管新生、细胞凋亡、细胞免疫。然而，细胞外囊泡的临床意义尚不明确，部分由于细胞外囊泡分析存在困难。
2020年6月10日，美国科学促进会《科学》旗下《转化医学》以封面和头版发表堪萨斯大学、堪萨斯大学医疗中心、堪萨斯大学癌症中心、佛罗里达大学曾勇等学者的研究报告，发现利用纳米微型芯片对细胞外囊泡进行分子和功能分析，可以微创监测乳腺肿瘤的生长和转移。
与现有技术主要仅对细胞外囊泡分子组成进行分析不同的是，该研究通过纳米工程微细加工技术，将多种功能像集成电路一样全部集成于一块微型芯片，如同一个实验室，能够自动完成肿瘤相关细胞外囊泡功能和分子表现型的整合分析。该研究还开发了一种通用的高分辨率胶体喷墨打印方法，能够可靠且可扩展地制造三维纳米图案化设备。
利用该纳米芯片平台，该研究对癌细胞株和小鼠模型的细胞外囊泡基质金属蛋白酶MMP14表达水平和蛋白水解活性进行整合分析，可以检测体外细胞浸润和监测体内肿瘤转移。
临床血液标本分析表明，该技术可被用于癌症检测，包括对年龄匹配对照者和乳腺导管原位癌、乳腺导管浸润癌或乳腺局部转移癌患者进行精准区分，对于30例训练队列和70例独立验证队列的准确率分别达96.7%和92.9%。
因此，该研究结果表明，该技术可以提供实用的微创液体活检工具，有助于改善癌症诊断和患者肿瘤生长转移的实时监控，从而为个体化治疗提供依据，对癌症的微创诊断和监测具有重要意义。
Lab-on-a-chip: catching molecular messages sent by tumors | Yong Zeng | TEDxLawrence
Sci Transl Med. 2020 Jun 10;12(547):eaaz2878.
Molecular and functional extracellular vesicle analysis using nanopatterned microchips monitors tumor progression and metastasis.
Peng Zhang, Xiaoqing Wu, Gulhumay Gardashova, Yang Yang, Yaohua Zhang, Liang Xu, Yong Zeng.
University of Kansas, Lawrence, KS, USA; University of Kansas Medical Center, Kansas City, KS, USA; University of Kansas Cancer Center, Kansas City, KS, USA; University of Florida, Gainesville, FL, USA.
PROBING PLASMA WITH PATTERNED CHIPS
Liquid biopsy of blood or other biofluids has shown promise for cancer detection and monitoring response to treatment. Zhang et al. used colloidal inkjet printing to create nanopatterned polydimethylsiloxane/glass microfluidic chips to analyze extracellular vesicles (EVs) in plasma. The chips captured EVs expressing different surface markers of interest and measured the expression and activity of EV-bound MMP14. EVs derived from cancer cell lines in vitro and breast cancer tumors in mouse models and patients analyzed using chips revealed differential expression and activity of EV-bound MMP14 with metastasis or cancer stage. These chips provide a useful platform for characterizing EVs with implications for noninvasive cancer diagnosis and surveillance.
Longitudinal cancer monitoring is crucial to clinical implementation of precision medicine. There is growing evidence indicating important functions of extracellular vesicles (EVs) in tumor progression and metastasis, including matrix remodeling via transporting matrix metalloproteases (MMPs). However, the clinical relevance of EVs remains largely undetermined, partially owing to challenges in EV analysis. Distinct from existing technologies mostly focused on characterizing molecular constituents of EVs, here we report a nanoengineered lab-on-a-chip system that enables integrative functional and molecular phenotyping of tumor-associated EVs. A generalized, high-resolution colloidal inkjet printing method was developed to allow robust and scalable manufacturing of three-dimensional (3D) nanopatterned devices. With this nanochip platform, we demonstrated integrative analysis of the expression and proteolytic activity of MMP14 on EVs to detect in vitro cell invasiveness and monitor in vivo tumor metastasis, using cancer cell lines and mouse models. Analysis of clinical plasma specimen showed that our technology could be used for cancer detection including accurate classification of age-matched controls and patients with ductal carcinoma in situ, invasive ductal carcinoma, or locally metastatic breast cancer in a training cohort (n = 30, 96.7% accuracy) and an independent validation cohort (n = 70, 92.9% accuracy). With clinical validation, our technology could provide a useful liquid biopsy tool to improve cancer diagnostics and real-time surveillance of tumor evolution in patients to inform personalized therapy.
DOI: 10.1126/scitranslmed.aaz2878
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