Co-culture of 3D tumor spheroids with fibroblasts as a model for epithelial–mesenchymal transition in vitro

Kim, Sunah; Lee, Eun Kyung; Kuh, Hyo-Jeong

doi:10.1016/j.yexcr.2015.05.016

Cited by 94 publications

(83 citation statements)

References 41 publications

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“…A key step in EMT noted in various types of cancer of epithelial origin is the loss of E-cadherin expression (21). This has been demonstrated in previous studies of CRC (22–24). Therefore, in order to identify novel biomarkers of CRC, an miRNA microarray assay was used to investigate differentially expressed miRNAs between E-cadherin-positive and -negative CRC tissues.…”

Section: Discussionsupporting

confidence: 83%

Decreased expression of miR-193a-3p is associated with poor prognosis in colorectal cancer

Lin

Duan

et al. 2017

Oncology Letters

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Epithelial-mesenchymal transition (EMT) is an early and key process in the metastatic cascade during the progression of colorectal cancer (CRC). The aim of the present study was to identify deregulated EMT-related microRNAs (miRNAs/miRs) of CRC and assess the effect of differentially expressed miRNAs on the prognosis of patients with CRC. Genome-wide expression profiling of miRNAs was assessed in 3 EMT-negative and 3 EMT-positive CRC tissues. Differentially expressed miRNA was further validated in 90 pairs of CRC and corresponding paracarcinoma tissues using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A total of 6 miRNAs (miR-10a-5p miR-204-3p, miR-1224-3p, miR-193a-3p, miR-365a-3p and miR-3678-3p) were identified to be differentially expressed between different EMT statuses of CRC tissues. Following validation using RT-qPCR, 3 miRNAs (miR-10a-5p, miR-365a-3p and miR-193a-3p) were selected for subsequent studies. The expression levels of miR-10a-5p, miR-193a-3p and miR-365a-3p were markedly increased compared with levels in corresponding paracarcinoma tissues. Survival analyses revealed that down-regulation of miR-193a-3p was associated with worse prognosis of patients with CRC, particularly in female and older patients. The results of the present study indicate that miR-193a-3p may be an EMT-related biomarker and serve as a novel prognostic factor for CRC.

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Section: Discussionsupporting

confidence: 83%

Decreased expression of miR-193a-3p is associated with poor prognosis in colorectal cancer

Lin

Duan

et al. 2017

Oncology Letters

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“…CAFs are a major component of cancer stroma and contribute to disease progression by secreting growth factors, cytokines, and chemokines, as well as modulating angiogenesis. Various research groups use co‐cultures of tumor spheroids with CAFs to examine the effect of CAFs on breast and (CRC) progression (Jaganathan et al, ; Jeong, Lee, Shin, Chung, & Kuh, ; Kim, Lee, & Kuh, ; Li & Lu, ). Li and Lu () demonstrated that CAFs strongly influence spheroid morphology in breast cancer cells.…”

Section: Merits and Demerits Of 3d Cell Culturementioning

confidence: 99%

Three‐dimensional cell culture models for anticancer drug screening: Worth the effort?

Verjans

Doijen

Luyten

et al. 2017

Journal Cellular Physiology

166

185

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High attrition of new oncology drug candidates in clinical trials is partially caused by the poor predictive capacity of artificial monolayer cell culture assays early in drug discovery. Monolayer assays do not take the natural three-dimensional (3D) microenvironment of cells into account. As a result, false positive compounds often enter clinical trials, leading to high dropout rates and a waste of time and money. Over the past 2 decades, tissue engineers and cell biologists have developed a broad range of 3D in vitro culturing tools that better represent in vivo cell biology. These tools preserve the 3D architecture of cells and can be used to predict toxicity of and resistance against antitumor agents. Recent progress in tissue engineering further improves 3D models by taking into account the tumor microenvironment, which is important for metastatic progression and vascularization. However, the widespread implementation of 3D cell cultures into cell-based research programs has been limited by various factors, including their cost and reproducibility. In addition, different 3D cell culture techniques often produce spheroids of different size and shape, which can strongly influence drug efficacy and toxicity. Hence, it is imperative to morphometrically characterize multicellular spheroids to avoid generalizations among different spheroid types. Standardized 3D culturing procedures could further reduce data variability and enhance biological relevance. Here, we critically evaluate the benefits and challenges inherent to growing cells in 3D, along with an overview of the techniques used to form spheroids. This is done with a specific focus on antitumor drug screening.

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“…Many ECM proteins (fibronectin, laminin, collagen and GAGs) can be found in MCTS in similar proportions to those expressed in tumor in vivo. 33 As a matter of fact, numerous studies reported the utility of MCTS taking into consideration the mechanisms of tumor cells' migration and invasiveness as well as the treatments applied to prevent them. 26,34 MCTS production techniques MCTS is the 3D in vitro model that is most widely used for different purposes, such as cell proliferation, tumor growth, immune interactions, drug screening and in the case of the ECM-embedded MCTS, for cell invasion and matrix remodeling.…”

Section: Characteristics Of Mcts Modelmentioning

confidence: 99%

“…19,36 To be more representative of tumor complexity, coculture of tumor cells with immune, endothelial cells or fibroblasts helps to better understand a crosstalk between cancer and stromal cells as well as the mechanisms of metastatic invasiveness. 19,33,37 For example, the migration of endothelial cells into MCTS or the formation of vascular networks within spheroids is often used to assess the potential of tumor vascularization. Thus, by means of this spheroid coculture technique, factors that induce or inhibit angiogenesis can be studied.…”

Section: Characteristics Of Mcts Modelmentioning

confidence: 99%

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

Millard¹,

Yakavets²,

Zorin³

et al. 2017

IJN

108

107

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The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS) model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM) components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs) play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a better comprehension of the interactions between NPs and tumor components that affect tumor drug delivery. MCTS is particularly suitable for the high-throughput screening of new nanodrugs.

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Co-culture of 3D tumor spheroids with fibroblasts as a model for epithelial–mesenchymal transition in vitro

Cited by 94 publications

References 41 publications

Decreased expression of miR-193a-3p is associated with poor prognosis in colorectal cancer

Decreased expression of miR-193a-3p is associated with poor prognosis in colorectal cancer

Three‐dimensional cell culture models for anticancer drug screening: Worth the effort?

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

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