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  • br Statement of Significance br


    Statement of Significance
    Brain metastasis (BM) of non-small cell lung cancer (NSCLC) is a complex cascade, and in particular, the process of lung cancer cells penetrating the blood–brain barrier (BBB) is very unique. However, due to the lack of reliable models that can faithfully mimic the dynamic process of BBB breaking, its molecular mechanisms have not well elucidated so far. In addition, although Aldo-keto reductase family 1 B10 (AKR1B10) has been implicated to the tumor development of liver cancer and many other cancers, little is known on its roles in the BM. Here, we established a multi-organ microfluidic bionic chip platform to recapitulate the entire BM process, and applied it to the BM pathology research, especially BBB extrava-sation. By using the chip and traditional models synergistically, we first demonstrated that AKR1B10 was significantly elevated in lung cancer BM, and defined the value of AKR1B10 as a diagnostic serum biomar-ker for lung cancer patients suffering from BM. Further, we investigated the role and mechanisms of AKR1B10 in BM that it promotes the extravasation of cancer cells through the BBB.
    2019 Acta Materialia Inc. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (
    ⇑ Corresponding authors.
    E-mail addresses: [email protected] (W. Wang), [email protected] (H. Shi), [email protected] (Q. Wang). 1 These authors contributed equally to this work.
    This is an open access article under the CC BY-NC-ND license (
    1. Introduction
    Non-small cell lung cancer (NSCLC) is characterized by a high incidence of distant metastases, and Doxorubicin metastasis (BM) occurs in approximately 40% of patients with NSCLC [1,2]. The prognosis of patients with BM is particularly poor, and these patients have a median survival of only 4–6 months [3]. A better understanding of the mechanisms underlying BM of NSCLC is critical for exploring new diagnostic and therapeutic approaches.
    BM refers to the spread of cancer cells from other organs to the brain, which consists of a series of pathophysiological processes [4–6], such as proliferation of primary cancer cells, migration of cancer cells, and metastatic tumor growth in the brain. Although the steps of BM are similar to that of metastasis to other distant organs, the mechanisms differ because of the blood–brain barrier (BBB). The BBB is a selective dynamic barrier between the circula-tory system and the central nervous system (CNS), and is charac-terized by the presence of continuous tight junctions (TJs) formed by cerebral microvascular endothelial cells (BMVECs) and the perivascular end-feet of astrocytes [7]. Previous studies have shown that tumor cells infiltrate the BBB in a trans-endothelial migration model by disrupting the TJs [8,9], suggesting that ‘open-ing’ TJs at the BBB is a key event in BM. However, the underlying mechanisms remain largely unknown.
    To better understand BM pathology, especially BBB extravasa-tion, a reliable and efficient model that faithfully mimics the in vivo microenvironment is needed. Even though several experi-mental models of BM, including conventional in vitro models and in vivo animal models [10–12], have been established, the lack of reliable, accurate models that mimic the dynamic process of BM has diminished our understanding of the underlying mechanism of BBB penetration. Conventional in vitro models that use incuba-tion chambers (Transwell) separated by a filter coated with matrix to represent and study the metastatic extravasation process [13,14], have limited functionality and relevance to disease pro-cesses because of their static and two-dimensional nature. In addi-tion, animal models are costly and present possible ethical problems. Particularly, it is difficult to visually monitor the dynamic process of BM in real-time.