Cho Hyeon-Yeol, Choi Jin-Ha, Kim Kyeong-Jun, Shin Minkyu, Choi Jeong-Woo
Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul, South Korea.
Interdisciplinary Program for Bio-Health Convergence, Kookmin University, Seoul, South Korea.
Front Bioeng Biotechnol. 2021 Feb 15;8:611802. doi: 10.3389/fbioe.2020.611802. eCollection 2020.
Metastasis is the primary cause of a large number of cancer-associated deaths. By portraying the precise environment of the metastasis process , the microfluidic system provides useful insights on the mechanisms underlying cancer cell migration, invasion, colonization, and the procurement of supplemental nutrients. However, current metastasis models are biased in studying blood vessel-based metastasis pathways and thus the understanding of lymphatic metastasis is limited which is also closely related to the inflammatory system. To understand the effects of inflammatory cytokines in lymphatic metastasis, we developed a three-channel microfluidic system by mimicking the lymph vessel-tissue-blood vessel (LTB) structure. Based on the LTB chip, we successfully confirmed the inflammatory cytokine, interleukin 6 (IL-6), -mediated intercellular communication in the tumor microenvironment during lymphatic metastasis. The IL-6 exposure to different subtypes of breast cancer cells was induced epithelial-mesenchymal transition (EMT) and improved tissue invasion property (8-fold). And the growth of human vein endothelial cells toward the lymph vessel channel was observed by VEGF secretion from human lymphatic endothelial cells with IL-6 treatment. The proposed LTB chip can be applied to analyze the intercellular communication during the lymphatic metastasis process and be a unique tool to understand the intercellular communication in the cancer microenvironment under various extracellular stimuli such as inflammatory cytokines, stromal reactions, hypoxia, and nutrient deficiency.
转移是大量癌症相关死亡的主要原因。通过描绘转移过程的精确环境，微流控系统为癌细胞迁移、侵袭、定植以及获取补充营养的潜在机制提供了有用的见解。然而，目前的转移模型在研究基于血管的转移途径时存在偏差，因此对与炎症系统也密切相关的淋巴转移的理解有限。为了了解炎性细胞因子在淋巴转移中的作用，我们通过模拟淋巴管-组织-血管（LTB）结构开发了一种三通道微流控系统。基于LTB芯片，我们成功证实了炎性细胞因子白细胞介素6（IL-6）在淋巴转移过程中肿瘤微环境中介导的细胞间通讯。IL-6作用于不同亚型的乳腺癌细胞可诱导上皮-间质转化（EMT）并提高组织侵袭能力（提高8倍）。通过用IL-6处理人淋巴管内皮细胞分泌VEGF，观察到了人静脉内皮细胞向淋巴管通道的生长。所提出的LTB芯片可用于分析淋巴转移过程中的细胞间通讯，并且是理解在诸如炎性细胞因子、基质反应、缺氧和营养缺乏等各种细胞外刺激下癌症微环境中细胞间通讯的独特工具。
