Abstract
Metastasis is the primary cause of a large number of cancer-associated deaths. By portraying the precise environment of the metastasis process in vitro, the microfluidic system provides useful insights on the mechanisms underlying cancer cell migration, invasion, colonization, and the procurement of supplemental nutrients. However, current in vitro 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.
Highlights
Cancer metastasis is a phenomenon involving the spread and proliferation of the primary cancer cells into secondary sites through the circulatory system, including lymph and blood vessels (Gupta and Massague, 2006)
Prior to the fabrication of the microfluidic chip, epithelial-mesenchymal transition (EMT) was induced to the breast cancer cells by treating various kinds of cytokines and microRNAs that generally exist in the cancer environment and induce the EMT process
After the generation of two endothelial cell layers with the hydrogel, the interleukin 6 (IL-6)-treated breast cancer cells were injected into the lymphatic channel to emulate the cancer metastasis process in the microfluidic system
Summary
Cancer metastasis is a phenomenon involving the spread and proliferation of the primary cancer cells into secondary sites through the circulatory system, including lymph and blood vessels (Gupta and Massague, 2006). Epithelial cells undergo a change in their cell polarities, cytoskeletal systems, and cell-cell adhesion properties, and transition to mesenchymal cells with migratory and invasive properties (Yilmaz and Christofori, 2009) These cells present as circulating tumor cells (CTC), circulate the blood vessels and lymph nodes, and metastasize to other organs by the mesenchymal-epithelial transition (MET), which is the opposite of the EMT process (Banyard and Bielenberg, 2015). New blood vessels are generated in the anchored cancer cells by a process called angiogenesis, and the nutrients and oxygen necessary for their maintenance and proliferation are supplied to these cells (Folkman, 2002). This is one of the primary reasons why cancer is a very serious disease and difficult to treat. This study is necessary to identify effective cancer therapies involving the prevention and elimination of metastasis
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