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In vitro throughput screening of anticancer drugs by patient-derived cell lines cultured　on vascularized three-dimensional stromal tissues

ABSTRACT: The development of high-throughput anticancer drug screening using patient-derived cancer cell lines (PDCs) that maintain their original characteristics in an in vitro three-dimensional (3D) culture system poses a significant challenge for achieving personalized cancer medicine. Because stromal tissue plays a critical role in the composition and maintenance of the cancer microenvironment, in vitro 3D-culture using reconstructed stromal tissues has attracted much attention. Here, a simple and unique in vitro 3D-culture method using heparin and collagen together with fibroblast and endothelial cells to fabricate vascularized 3D-stromal tissues for in vitro culture of PDCs is reported. While co-treatment with bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, and 5-fluorouracil (5-FU) significantly reduced the survival rate of the 3D-cultured PDCs to 30%, separate addition of each drug did not induce such strong cytotoxicity, suggesting the possibility of evaluating the combined effect of anticancer drug and an angiogenesis inhibitor. Surprisingly, drug evaluation using eight PDCs with the 3D-culture method resulted in a drug efficacy concordance rate of 75% with clinical history. The model is expected to be applied to in vitro throughput drug screening for the development of personalized cancer medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248026 | GEO | 2023/12/01

REPOSITORIES: GEO

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Project description:The traditional method for studying cancer in vitro is to grow immortalized cancer cells in two-dimensional (2D) monolayers on plastic. However, many cellular features are impaired in these unnatural conditions and big alterations in gene expression in comparison to tumors have been reported. Three-dimensional (3D) cell culture models have become increasingly popular and are suggested to be better models than 2D monolayers due to improved cell-to-cell contacts and structures that resemble in vivo architecture. The aim of this study was to develop a simple high-throughput 3D drug screening method and to compare drug responses in JIMT1 breast cancer cells when grown in 2D, in polyHEMA coated anchorage independent 3D models and in Matrigel on-top 3D cell culture models. We screened 102 compounds with multiple concentrations and biological replicates for their effects on cell proliferation. The cells were either treated immediately upon plating or they were allowed to grow in 3D for four days prior to the drug treatment. Big variations in drug responses were observed between the models indicating that comparisons of culture model influenced drug sensitivities cannot be made based on effects of a single drug. However, we show with the 63 most prominent drugs that, in general, JIMT1 cells grown on Matrigel were significantly more sensitive to drugs than cells grown in 2D cultures, while responses of cells grown in polyHEMA resembled those of 2D. Furthermore, comparison of gene expression profiles of the cell culture models to xenograft tumors indicated that cells cultured in Matrigel and as xenografts most closely resembled each other. In this study we also suggest that 3D cultures can provide a platform for systematic experimentation of larger compound collections in a high-throughput mode and be used as alternatives for traditional 2D screens towards better comparability to in vivo state. Gene expression analysis of JIMT1 breast cancer cells cultured as xenografts for 43 days, in two dimensional cultures for seven days (2D7d), in polyHEMA three dimensional cell culture models for four and seven days (PH7d and PH7d), and in Matrigel three dimensional cultures for four and seven days (MG4d and MG7d). Two biological replicates was included for each sample.

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In vitro throughput screening of anticancer drugs by patient-derived cell lines cultured on vascularized three-dimensional stromal tissues

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In vitro throughput screening of anticancer drugs by patient-derived cell lines cultured　on vascularized three-dimensional stromal tissues