A tumor-microvessel on-a-chip reveals a mechanism for cancer cell cluster intravasation

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-04-24 DOI:10.1016/j.isci.2025.112517

Yukinori Ikeda , Makoto Kondo , Jun-ichi Suehiro , Hiroko Oshima , Sau Yee Kok , Kazuki Takahashi , Joris Pauty , Dong Wang , Hiroyuki Sakurai , Tetsuro Watabe , Masanobu Oshima , Yukiko T. Matsunaga

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引用次数: 0

Abstract

Circulating tumor cell (CTC) clusters are often detected in blood samples of patients with high-grade tumor and are associated with tumor metastasis and poor prognosis. However, the underlying mechanisms by which cancer cell clusters are released from primary tumors beyond blood vessel barriers remain unclear. In this study, a three-dimensional (3D) in vitro culture system was developed to visualize tumor intravasation by positioning tumor organoids with distinct genetic backgrounds to surround microvessels. We visualized tumor intravasation in a cluster unit, including collective migration toward microvessels, vessel co-option, and the release of CTC clusters—an invasion mechanism not previously reported. Furthermore, elevated levels of transforming growth factor β (TGF-β) and activin expression in endothelial cells within the coculture microenvironment were pivotal for facilitating tumor cell intravasation, which was associated with endothelial-to-mesenchymal transition (EndoMT) in microvessels. Our 3D in vitro system can be used to develop therapeutic strategies for tumor metastasis by targeting the release of CTC clusters.

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肿瘤微血管芯片揭示了癌细胞簇内渗的机制

循环肿瘤细胞（CTC）簇经常在高级别肿瘤患者的血液样本中检测到，并与肿瘤转移和预后不良有关。然而，癌细胞簇从原发肿瘤中释放出血管屏障之外的潜在机制尚不清楚。在这项研究中，我们开发了一个三维（3D）体外培养系统，通过定位具有不同遗传背景的肿瘤类器官来观察肿瘤在微血管周围的内渗。我们可视化了肿瘤在集群单元中的内渗，包括向微血管的集体迁移、血管的选择和CTC集群的释放——这是一种以前未报道的侵袭机制。此外，在共培养微环境中，内皮细胞中转化生长因子β (TGF-β)和激活素表达水平的升高是促进肿瘤细胞内渗的关键，这与微血管中内皮到间充质转化（EndoMT）有关。我们的3D体外系统可以通过靶向CTC簇的释放来开发肿瘤转移的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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