Abstract
Gastric cancer (GC) is a common aggressive malignant tumor with high incidence and mortality worldwide. GC is classified into intestinal and diffuse types according to the histo-morphological features. Because of distinctly different clinico-pathological features, new cancer therapy strategies and in vitro preclinical models for the two pathological variants of GC is necessary. Since extracellular matrix (ECM) influence the biological behavior of tumor cells, we hypothesized that GC might be more similarly modeled in 3D with matrix rather than in 2D. Herein, we developed a microfluidic-based a three-dimensional (3D) in vitro gastric cancer model, with subsequent drug resistance assay. AGS (intestinal type) and Hs746T (diffuse type) gastric cancer cell lines were encapsulated in collagen beads with high cellular viability. AGS exhibited an aggregation pattern with expansive growth, whereas Hs746T showed single-cell-level infiltration. Importantly, in microtumor models, epithelial-mesenchymal transition (EMT) and metastatic genes were upregulated, whereas E-cadherin was downregulated. Expression of ß-catenin was decreased in drug-resistant cells, and chemosensitivity toward the anticancer drug (5-FU) was observed in microtumors. These results suggest that in vitro microtumor models may represent a biologically relevant platform for studying gastric cancer cell biology and tumorigenesis, and for accelerating the development of novel therapeutic targets.
Highlights
Many researchers are promoting 3D platforms for studying the interactions of tumor cells with the microenvironment and identifying the key factors that regulate the mode of migration and epithelial-mesenchymal transition (EMT) responses[25,26]
The polydimethylsiloxane (PDMS)-based microfluidic device is functionally composed of an aqueous channel with gastric cancer cells, collagen solution and oil
4 mg/ml collagen type 1 with Gastric cancer (GC) cells and oil were injected into the device
Summary
Many researchers are promoting 3D platforms for studying the interactions of tumor cells with the microenvironment and identifying the key factors that regulate the mode of migration and EMT responses[25,26]. We demonstrated a droplet-based microtumor model to assess cell-ECM interactions and drug resistances of different types of gastric cancer, using the AGS (intestinal type) and Hs746T (diffuse type) cell lines. With this model, we performed a systematic comparison between 2D and 3D system in cultured cell characteristics and functional assessment. By using a microfluidic-based droplet formation, we obtained well-controlled cell-encapsulated ECM microbeads. In both cell types, the expression of pro-metastatic genes, such as those involved with EMT, were upregulated in our model compared with 2D monolayer culture. We confirmed that the drug resistance-related molecules were significantly up-regulated in 3D microtumor model of both cancer types; the chemosensitivity against the anticancer drug, 5-fluorouracil (5-FU) is correlated with the expression of drug-resistance genes and proteins
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