Abstract
Cancer-associated fibroblasts (CAFs) in the cancer microenvironment play an essential role in metastasis. Differentiation of endothelial cells into CAFs is induced by cancer cell-derived exosomes secreted from cancer cells that transfer molecular signals to surrounding cells. Differentiated CAFs facilitate migration of cancer cells to different regions through promoting extracellular matrix (ECM) modifications. However, in vitro models in which endothelial cells exposed to cancer cell-derived exosomes secreted from various cancer cell types differentiate into CAFs or a microenvironmentally controlled model for investigating cancer cell invasion by CAFs have not yet been studied. In this study, we propose a three-dimensional in vitro cancer cell invasion model for real-time monitoring of the process of forming a cancer invasion site through CAFs induced by exosomes isolated from three types of cancer cell lines. The invasiveness of cancer cells with CAFs induced by cancer cell-derived exosomes (eCAFs) was significantly higher than that of CAFs induced by cancer cells (cCAFs) through physiological and genetic manner. In addition, different genetic tendencies of the invasion process were observed in the process of invading cancer cells according to CAFs. Our 3D microfluidic platform helps to identify specific interactions among multiple factors within the cancer microenvironment and provides a model for cancer drug development.
Highlights
High mortality associated with cancer is attributable to metastasis and uncontrolled spread of cancer cells across the body [1]
cancer-associated fibroblasts (CAFs) contribute to extracellular matrix (ECM) degradation and destruction of the endothelial barrier, and they play a role in metastatic growth and progression of cancer cells [30,31]
To investigate whether exosomes derived from cancer cells are more effective in generating CAFs from HUVECs than cancer cells themselves, (1) HUVECs were cultured in the central channel of the 3D microfluidic device, (2) exosomes derived from cancer cells were injected into the endothelialized central channel for the differentiation of HUVECs into CAFs and (3) after CAFs were generated, cancer cells were injected into the central channel to investigate cancer cell invasion (Figure 6a)
Summary
High mortality associated with cancer is attributable to metastasis and uncontrolled spread of cancer cells across the body [1]. Recent studies have reported that exosomes act as communication signals between primary and secondary cancer invasion sites [29] It is not known whether progress of EndMT by exosomes derived from different cancer cells has a common gene and whether specific physiological phenomena occur through such a common gene. We further investigated the differences in CAFs induced by various cancer cell-derived exosomes and their potential involvement in development of secondary cancer invasion sites within a 3D microfluidic cancer microenvironment in physiological and genetic manner. Our data from this 3D microfluidic platform showed that CAF-mediated guidance of cancer cell invasion in the extracellular matrix was dependent on physiological factors. Sci. 2020, 21, 8153 contribute significantly to cancer research programs and accelerate drug development efforts for personalized therapy
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