Three‐dimensional models of cancer for pharmacology and cancer cell biology: Capturing tumor complexity in vitro/ex vivo

Abstract

Cancers are complex and heterogeneous pathological "organs" in a dynamic interplay with their host. Models of human cancer in vitro, used in cancer biology and drug discovery, are generally highly reductionist. These cancer models do not incorporate complexity or heterogeneity. This raises the question as to whether the cancer models' biochemical circuitry (not their genome) represents, with sufficient fidelity, a tumor in situ. Around 95% of new anticancer drugs eventually fail in clinical trial, despite robust indications of activity in existing in vitro pre-clinical models. Innovative models are required that better capture tumor biology. An important feature of all tissues, and tumors, is that cells grow in three dimensions. Advances in generating and characterizing simple and complex (with added stromal components) three-dimensional in vitro models (3D models) are reviewed in this article. The application of stirred bioreactors to permit both scale-up/scale-down of these cancer models and, importantly, methods to permit controlled changes in environment (pH, nutrients, and oxygen) are also described. The challenges of generating thin tumor slices, their utility, and potential advantages and disadvantages are discussed. These in vitro/ex vivo models represent a distinct move to capture the realities of tumor biology in situ, but significant characterization work still remains to be done in order to show that their biochemical circuitry accurately reflects that of a tumor.

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

“…3E). We observed dose-dependent reduction in the number of PS in the presence of EC-70124 compared with control cells (IC 50 ¼ 139 nmol/L). Thus, treatment with EC-70124 impaired the ability of the CSC subpopulation to expand and generate single-cell-derived PS.…”

“…To calculate IC 50 values, means and standard deviations were plotted using GraphPad Prism Version 6. A sigmoidal 4PL model was used to interpolate the data and calculate IC 50 . Each interpolation with R 2 !…”

“…Using a similar approach, we examined the effects of EC-70124 on the NF-kB/STAT3 axis in the bulk and CSC-enriched cell subpopulation derived from human prostate cancer cell lines. PS formed in vitro by single cells grown in nonadherent and serum-free culture conditions are enriched of prostate CSCs and represent an elective model to study the biology of CSCs and their response to drugs (42,50). Notably, PS derived from human prostate cancer cell lines, like DU145 cells, exhibited hyperactivity of NF-kB and STAT3 and overexpression of numerous target genes compared with the bulk cancer cells, despite the enhanced activity of these pathways in the bulk tumor cell population.…”

Spheroids Formation on Non‐Adhesive Surfaces by Liquid Overlay Technique: Considerations and Practical Approaches

“…[1,2] These type of cultures are simple, cheap, and compatible with the different equipment used for high-throughput screening (HTS). [3] In the last few decades, with the development of 2D cells co-cultures, these models gained the ability to better represent the cellular heterogeneity found in different human tissues.…”

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

“…21 Among them, multicellular tumor spheroids (MCTSs) are of great interest in cancer research since some of their physiological features are close to those of avascular cancer metastases. 22,23 MCTS models have been recognized suitable for studies of cell survival, cell proliferation, resistance to drug therapy, cell migration and hypoxia phenomena. 24 MCTS models are also appropriate to estimate the ability of nanotherapeutics to penetrate and distribute inside tumor tissues.…”