Three-dimensional spheroid cultures of human prostate cancer cell lines

Hedlund, Tammy E.; Duke, Richard C.; Miller, Gary J.

doi:10.1002/(sici)1097-0045(19991101)41:3<154::aid-pros2>3.0.co;2-m

Cited by 23 publications

(9 citation statements)

References 36 publications

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“…1B), the difference in their sizes is not likely to be due to an increase in cell number. Instead, overexpression of CCN3 presumably enhances the intercellular adhesion because a compact spheroid morphology is often due to an increased number of cell-cell contacts (36,37). However, addition of recombinant CCN3 minimally affected the ability of control MDA-231 cells to form three-dimensional spheroids (Fig.…”

Section: Methodsmentioning

confidence: 99%

Matricellular Protein CCN3 (NOV) Regulates Actin Cytoskeleton Reorganization

Sin

Tse

Planque

et al. 2009

Journal of Biological Chemistry

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CCN3 (NOV), a putative ligand for integrin receptors, is tightly associated with the extracellular matrix and mediates diverse cellular functions, including cell adhesion and proliferation. CCN3 has been shown to negatively regulate growth although it promotes migration in a cell type-specific manner. In this study, overexpression of CCN3 reduces growth and increases intercellular adhesion of breast cancer cells. Interestingly, CCN3 overexpression also led to the formation of multiple pseudopodia that are enriched in actin, CCN3, and vinculin. Breast cancer cells preincubated with exogenous CCN3 protein also induced the same phenotype, indicating that secreted CCN3 is sufficient to induce changes in cell morphology. Surprisingly, extracellular CCN3 is internalized to the early endosomes but not to the membrane protrusions, suggesting pseudopodia-enriched CCN3 may derive from a different source. The presence of an intracellular variant of CCN3 will be consistent with our finding that the cytoplasmic tail of the gap junction protein connexin43 (Cx43) associates with CCN3. Cx43 is a channel protein permitting intercellular communication to occur. However, neither the channel properties nor the protein levels of Cx43 are affected by the CCN3 protein. In contrast, CCN3 proteins are down-regulated in the absence of Cx43. Finally, we showed that overexpression of CCN3 increases the activity of the small GTPase Rac1, thereby revealing a pathway that links Cx43 directly to actin reorganization.

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Section: Methodsmentioning

confidence: 99%

Matricellular Protein CCN3 (NOV) Regulates Actin Cytoskeleton Reorganization

Sin

Tse

Planque

et al. 2009

Journal of Biological Chemistry

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“…In particular, tumor cells in MCTS restore a differentiation pattern similar to that observed in vivo, which is maintained for several weeks of culture. 16,55,56,[77][78][79] These features are initiated and maintained by the tumor cell-derived extracellular matrix (ECM) assembly and a complex 3-D network of cell-to-cell and cell-to-matrix interactions, which are largely absent from monolayer cultures. In addition, the 3-D spheroid structure is relevant for both the modeling of distribution and function of (patho)physiologically occurring factors in tissues, as well as the penetration, binding, and bioactivity of drugs.…”

Section: Multicellular Tumor Spheroidsmentioning

confidence: 99%

The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model

et al. 2004

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Over the past few years, establishment and adaptation of cell-based assays for drug development and testing has become an important topic in high-throughput screening (HTS). Most new assays are designed to rapidly detect specific cellular effects reflecting action at various targets. However, although more complex than cell-free biochemical test systems, HTS assays using monolayer or suspension cultures still reflect a highly artificial cellular environment and may thus have limited predictive value for the clinical efficacy of a compound. Today's strategies for drug discovery and development, be they hypothesis free or mechanism based, require facile, HTS-amenable test systems that mimic the human tissue environment with increasing accuracy in order to optimize preclinical and preanimal selection of the most active molecules from a large pool of potential effectors, for example, against solid tumors. Indeed, it is recognized that 3-dimensional cell culture systems better reflect the in vivo behavior of most cell types. However, these 3-D test systems have not yet been incorporated into mainstream drug development operations. This article addresses the relevance and potential of 3-D in vitro systems for drug development, with a focus on screening for novel antitumor drugs. Examples of 3-D cell models used in cancer research are given, and the advantages and limitations of these systems of intermediate complexity are discussed in comparison with both 2-D culture and in vivo models. The most commonly used 3-D cell culture systems, multicellular spheroids, are emphasized due to their advantages and potential for rapid development as HTS systems. Thus, multicellular tumor spheroids are an ideal basis for the next step in creating HTS assays, which are predictive of in vivo antitumor efficacy. (Journal of Biomolecular Screening 2004:273-285)

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“…21). Spheroid cultures have been classified into three general shapes, ''fused cell mass, '' ''tight aggregate, '' and ''loose aggregate'' (23). Previous attempts to quantify tumor morphology include using the fractal dimension of the tumor periphery to characterize degree of tumor aggression focusing on the existence and stability of asymmetric solutions to a mathematical model of solid tumor growth (22).…”

Section: Introductionmentioning

confidence: 99%

An Integrated Computational/Experimental Model of Tumor Invasion

Frieboes¹,

Zheng²,

et al. 2006

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The intracellular and extracellular dynamics that govern tumor growth and invasiveness in vivo remain poorly understood. Cell genotype and phenotype, and nutrient, oxygen, and growth factor concentrations are key variables. In previous work, using a reaction-diffusion mathematical model based on variables that directly describe tumor cell cycle and biology, we formulated the hypothesis that tumor morphology is determined by the competition between heterogeneous cell proliferation caused by spatial diffusion gradients, e.g., of cell nutrients, driving shape instability and invasive tumor morphologies, and stabilizing mechanical forces, e.g., cell-to-cell and cell-to-matrix adhesion. To test this hypothesis, we here obtain variable-based statistics for input to the mathematical model from in vitro human and rat glioblastoma cultures. A linear stability analysis of the model predicts that glioma spheroid morphology is marginally stable. In agreement with this prediction, for a range of variable values, unbounded growth of the tumor mass and invasion of the environment are observed in vitro. The mechanism of invasion is recursive subspheroid component development at the tumor viable rim and separation from the parent spheroid. Results of computer simulations of the mathematical model closely resemble the morphologies and spatial arrangement of tumor cells from the in vitro model. We propose that tumor morphogenesis in vivo may be a function of marginally stable environmental conditions caused by spatial variations in cell nutrients, oxygen, and growth factors, and that controlling these conditions by decreasing spatial gradients could benefit treatment outcomes, whereas current treatment, and especially antiangiogenic therapy, may trigger spatial heterogeneity (e.g., local hypoxia), thus causing invasive instability. (Cancer Res 2006; 66(3): 1597-604)

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Three-dimensional spheroid cultures of human prostate cancer cell lines

Cited by 23 publications

References 36 publications

Matricellular Protein CCN3 (NOV) Regulates Actin Cytoskeleton Reorganization

Matricellular Protein CCN3 (NOV) Regulates Actin Cytoskeleton Reorganization

The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model

An Integrated Computational/Experimental Model of Tumor Invasion

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