From competency to dormancy: a 3D model to study cancer cells and drug responsiveness

Fang, Josephine Y.; Tan, ShihJye; Wu, Yichen; Yang, Zhi; Hoang, Ba X.; Han, Bo

doi:10.1186/s12967-016-0798-8

Cited by 42 publications

(37 citation statements)

References 47 publications

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“…Additionally, HCT116 cells suspended in a 3D matrix have doubling times of approximately 74 hours, which means that cells will likely experience the full SN-38 concentration before completing a division. 50 …”

Section: Resultsmentioning

confidence: 99%

Assessing chemotherapeutic effectiveness using a paper-based tumor model

Boyce

LaBonia

Hummon

et al. 2017

Analyst

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In vitro models for screening new cancer chemotherapeutics often rely on two-dimensional cultures to predict therapeutic potential. Unfortunately, the predictive power of these models is limited, as they fail to recapitulate the complex three-dimensional environments in tumors that promote the development of a chemoresistant phenotype. In this study, we describe the preparation and characterization of paper-based cultures (PBC) engineered to assess chemotherapeutic effectiveness in three dimensional, diffusion-limited environments. Similar environments are found within poorly vascularized tumors. These cultures, which are assembled by stacking together cell-laden paper scaffolds to yield thick tissue-like structures, generate monotonic gradients vertically through the culture and provide distinct chemical environments for each scaffold. After prolonged incubation, the scaffolds can simply be peeled apart and analyzed to relate cellular responses to the chemical environment experienced at that scaffold. Through fluorescence imaging, viable and proliferative cell populations were mapped within a stacked culture and found to be most abundant in scaffolds close to the nutrient-rich medium. By adjusting the cell density, we modulated the spatiotemporal evolution of oxygen gradients across the cultures and correlated these environmental changes with cellular sensitivity to SN-38 exposure. From these results, we showed that differences in the oxygen gradients produced cellular populations with significantly different chemosensitivities. Through this work, we highlight PBCs ability to serve as an analytical model capable of determining chemotherapeutic effectiveness under a range of chemical environments.

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Section: Resultsmentioning

confidence: 99%

Assessing chemotherapeutic effectiveness using a paper-based tumor model

Boyce

LaBonia

Hummon

et al. 2017

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“…Further methods to externally increase MMP activity include mechanical induction to replicate a more rigid ECM[224], injection of MMP regulators[225], gene delivery[226], or oxidative stress[227]. Curiously, mechanical induction of MMP overexpression in MDA-MB-231 cells was correlated with advanced resistance to free drug chemotherapeutics, but was not tested against MMP-induced controlled release systems[224]. This enhanced chemoresistance has been observed in various other studies evaluating high expression of MMPs (not externally induced) as well[228–232].…”

Section: Strategies For Targetingmentioning

confidence: 99%

Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression

Isaacson

Jensen

Subrahmanyam

et al. 2017

Journal of Controlled Release

115

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While commonly known for degradation of the extracellular matrix, matrix metalloproteinases (MMPs) exhibit broad potential for use in targeting of bioactive and imaging agents in cancer treatment. MMPs are upregulated at all stages of expression in cancers. A comprehensive analysis of published literature on expression of all MMP subtypes at the genetic, protein, and activity levels in normal and diseased tissues indicate targeting applicability in a variety of cancers. This expression significantly increases at advanced cancer stages, providing an improved opportunity for controlled release in higher-stage patients. Since MMPs are integral at every stage of metastasis, MMP roles in cancer are discussed with a focus on MMP distribution and mobility within cells and tumors for cancer targeting applications. Several strategies for MMP utilization in targeting – such as matrix degradation, MMP cleavage, MMP binding, and MMP-induced environmental changes – are addressed.

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“…Further interrogation indicated that the differences in basal metabolic levels induced by scaffold composition were significant enough to influence how the cells responded to xenobiotic challenges [42,65], demonstrating that these emerging methods of 3D culture and adequate tools for evaluating cellular health are essential to modern drug discovery models. These results were not limited to only a single cell type, as breast, pancreatic and colon cancer cellular models all showed alterations to their proliferation and metabolic rates in the presence of stiffer 3D matrices, and were consequently found to be less sensitive to paclitaxel and gemcitabine treatment [62]. This was corroborated through a direct interrogation of collagenencapsulated autobioluminescent HEK293 cells, which were observed to be more resistant to treatment with a metabolic inhibitor relative to their monolayer-grown counterparts.…”

Section: Using Autobioluminescent Cellular Models To Elucidate Metabomentioning

confidence: 72%

“…This growth format is more representative of the cells' natural state, as their proliferation rates, morphology, and gene expression more closely resemble their in vivo states [41][42][43]60]. However, the use of a 3D culture system does not guarantee faithful replication of in vivo-like conditions, as the 3D scaffold itself, through traits such as matrix stiffness or construct dimensions, can induce hypoxia at levels that differ significantly from those observed in vivo [61,62]. These cases often better model tumor biology than healthy tissues, with the 3D construct mimicking a necrotic center with a proliferative exterior and a range of metabolic states in between [63].…”

Section: Using Autobioluminescent Cellular Models To Elucidate Metabomentioning

confidence: 99%

Autobioluminescent Cellular Models for Enhanced Drug Discovery

Xu¹,

Conway²,

Frank³

et al. 2016

Special Topics in Drug Discovery

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Autobioluminescent cellular models are emerging tools for drug discovery that rely on the expression of a synthetic, eukaryotic-optimized luciferase that does not require an exogenous chemical substrate to produce its resultant output signal. These models can therefore self-modulate their output signals in response to metabolic activity dynamics and avoid the sample destruction and intermittent data acquisition limitations of traditional fluorescent or chemically stimulated bioluminescent approaches. While promising for reducing drug discovery costs and increasing data acquisition relative to alternative approaches, these models have remained relatively untested for drug discovery applications due to their recent emergence within the field. This chapter presents a history and background of these autobioluminescent cellular models to offer investigators a generalized point of reference for understanding their capabilities and limitations and provides side-by-side comparisons between autobioluminescent and traditional, substrate-requiring toxicology screening platforms for pharmaceutically relevant three-dimensional and high-throughput screening applications to introduce investigators to autobioluminescence as a potential new drug discovery toolset.

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From competency to dormancy: a 3D model to study cancer cells and drug responsiveness

Cited by 42 publications

References 47 publications

Assessing chemotherapeutic effectiveness using a paper-based tumor model

Assessing chemotherapeutic effectiveness using a paper-based tumor model

Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression

Autobioluminescent Cellular Models for Enhanced Drug Discovery

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