Live Multicellular Tumor Spheroid Models For High-Content Imaging and Screening In Cancer Drug Discovery

Reid, Brian G.; Jerjian, Taleen; Patel, Purvi; Zhou, Qiong; Kabos, Peter; Sartorius, Carol A.; LaBarbera, Daniel V.

doi:10.2174/2213988501408010027

Cited by 36 publications

(32 citation statements)

References 38 publications

(34 reference statements)

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“…Using a GFP reporter driven by the human CK5 promoter and time-lapse microscopy, we showed that previously CK5− cells become CK5+ upon progesterone treatment [125]. This argues against expansion of pre-existing CK5+ cells through cell division and suggests that progesterone directly stimulates reprogramming from a CK5− to CK5+ state.…”

Section: Intrinsic Vs Extrinsic Signaling In Progesterone-mediated Exmentioning

confidence: 99%

Steroid Hormones, Steroid Receptors, and Breast Cancer Stem Cells

Finlay-Schultz

Sartorius

2015

J Mammary Gland Biol Neoplasia

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The ovarian hormones progesterone and estrogen play important roles in breast cancer etiology, proliferation, and treatment. Androgens may also contribute to breast cancer risk and progression. In recent years, significant advances have been made in defining the roles of these steroid hormones in stem cell homeostasis in the breast. Stem cells are potential origins of breast cancer and may dictate tumor phenotype. At least a portion of breast cancers are proposed to be driven by cancer stem cells (CSCs), cells that mimic the self-renewing and repopulating properties of normal stem cells, and can confer drug resistance. Progesterone has been identified as the critical hormone regulating normal murine mammary stem cell (MaSC) populations and normal human breast stem cells. Synthetic progestins increase human breast cancer risk; one theory speculates that this occurs through increased stem cells. Progesterone treatment also increases breast CSCs in established breast cancer cell lines. This is mediated in part through progesterone regulation of transcription factors, signal transduction pathways, and microRNAs. There is also emerging evidence that estrogens and androgens can regulate breast CSC numbers. The evolving concept that a breast CSC phenotype is dynamic and can be influenced by cell signaling and external cues emphasizes that steroid hormones could be crucial players in controlling CSC number and function. Here we review recent studies on steroid hormone regulation of breast CSCs, and discuss mechanisms by which this occurs.

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Section: Intrinsic Vs Extrinsic Signaling In Progesterone-mediated Exmentioning

confidence: 99%

Steroid Hormones, Steroid Receptors, and Breast Cancer Stem Cells

Finlay-Schultz

Sartorius

2015

J Mammary Gland Biol Neoplasia

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“…To circumvent these technical issues, 3D cultures are being formed and analyzed in a variety of interesting formats [7], [8], [9], and co-cultures are being recognized as valuable systems for predicting drug responses in vivo for a number of different diseases [10], [11], [12]. A call for complex 3D culture models specifically for breast cancer [13] highlights the importance of the work by Reid et al to measure transcriptional changes in 3D monotypic cultures using high content imaging [14], as well as of our study here where we measure cell viability in high-throughput (HT) amenable 3D co-cultures that demonstrate the usefulness of 3D co-cultures for identifying anti-tumor agents with robust selectivity for tumor cells over normal cells.…”

Section: Introductionmentioning

confidence: 99%

3-Dimensional Culture Systems for Anti-Cancer Compound Profiling and High-Throughput Screening Reveal Increases in EGFR Inhibitor-Mediated Cytotoxicity Compared to Monolayer Culture Systems

et al. 2014

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3-dimensional (3D) culture models have the potential to bridge the gap between monolayer cell culture and in vivo studies. To benefit anti-cancer drug discovery from 3D models, new techniques are needed that enable their use in high-throughput (HT) screening amenable formats. We have established miniaturized 3D culture methods robust enough for automated HT screens. We have applied these methods to evaluate the sensitivity of normal and tumorigenic breast epithelial cell lines against a panel of oncology drugs when cultured as monolayers (2D) and spheroids (3D). We have identified two classes of compounds that exhibit preferential cytotoxicity against cancer cells over normal cells when cultured as 3D spheroids: microtubule-targeting agents and epidermal growth factor receptor (EGFR) inhibitors. Further improving upon our 3D model, superior differentiation of EC50 values in the proof-of-concept screens was obtained by co-culturing the breast cancer cells with normal human fibroblasts and endothelial cells. Further, the selective sensitivity of the cancer cells towards chemotherapeutics was observed in 3D co-culture conditions, rather than as 2D co-culture monolayers, highlighting the importance of 3D cultures. Finally, we examined the putative mechanisms that drive the differing potency displayed by EGFR inhibitors. In summary, our studies establish robust 3D culture models of human cells for HT assessment of tumor cell-selective agents. This methodology is anticipated to provide a useful tool for the study of biological differences within 2D and 3D culture conditions in HT format, and an important platform for novel anti-cancer drug discovery.

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“…extracellular matrix, ECM) [6]. Also like organoids, MCTS can self assemble, contain more than one cell type, and harbor subpopulations of cancer stem cells (CSC) [7, 8]. MCTS display in vivo tumor function with zones of proliferation, quiescence and hypoxia, and gradients of oxygen and nutrients [9, 10].…”

Section: Introductionmentioning

confidence: 99%

High-throughput imaging: Focusing in on drug discovery in 3D

Zhou

Voss

et al. 2016

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3D organotypic culture models such as organoids and multicellular tumor spheroids (MCTS) are becoming more widely used for drug discovery and toxicology screening. As a result, 3D culture technologies adapted for high-throughput screening formats are prevalent. While a multitude of assays have been reported and validated for high-throughput imaging (HTI) and high-content screening (HCS) for novel drug discovery and toxicology, limited HTI/HCS with large compound libraries have been reported. Nonetheless, 3D HTI instrumentation technology is advancing and this technology is now on the verge of allowing for 3D HCS of thousands of samples. This review focuses on the state-of-the-art high-throughput imaging systems, including hardware and software, and recent literature examples of 3D organotypic culture models employing this technology for drug discovery and toxicology screening.

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Live Multicellular Tumor Spheroid Models For High-Content Imaging and Screening In Cancer Drug Discovery

Cited by 36 publications

References 38 publications

Steroid Hormones, Steroid Receptors, and Breast Cancer Stem Cells

Steroid Hormones, Steroid Receptors, and Breast Cancer Stem Cells

3-Dimensional Culture Systems for Anti-Cancer Compound Profiling and High-Throughput Screening Reveal Increases in EGFR Inhibitor-Mediated Cytotoxicity Compared to Monolayer Culture Systems

High-throughput imaging: Focusing in on drug discovery in 3D

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