Abstract
Multicellular tumor spheroid (MCTS) systems provide an in vitro cell culture model system which mimics many of the complexities of an in vivo solid tumor and tumor microenvironment, and are often used to study cancer cell growth and drug efficacy. Here, we present a coupled experimental-computational framework to estimate phenotypic growth and biophysical tumor microenvironment properties. This novel framework utilizes standard microscopy imaging of MCTS systems to drive a biophysical mathematical model of MCTS growth and mechanical interactions. By extending our previous in vivo mechanically-coupled reaction–diffusion modeling framework we developed a microscopy image processing framework capable of mechanistic characterization of MCTS systems. Using MDA-MB-231 breast cancer MCTS, we estimated biophysical parameters of cellular diffusion, rate of cellular proliferation, and cellular tractions forces. We found significant differences in these model-based biophysical parameters throughout the treatment time course between untreated and treated MCTS systems, whereas traditional size-based morphometric parameters were inconclusive. The proposed experimental-computational framework estimates mechanistic MCTS growth and invasion parameters with significant potential to assist in better and more precise assessment of in vitro drug efficacy through the development of computational analysis methodologies for three-dimensional cell culture systems to improve the development and evaluation of antineoplastic drugs.
Highlights
Multicellular tumor spheroid (MCTS) systems provide an in vitro cell culture model system which mimics many of the complexities of an in vivo solid tumor and tumor microenvironment, and are often used to study cancer cell growth and drug efficacy
One example is through the use of three-dimensional (3D) multicellular tumor spheroids (MCTS) as they more closely resemble in vivo solid tumors compared to the much more simplified 2D culture systems, and bridge the gap between conventional monolayer cell culture methods and animal studies10,11. 3D MCTS invasion culture systems, consisting of a MCTS embedded within an extracellular matrix (ECM), provide a further enhanced biological model system which recapitulates several architectural and
A highly studied mechanical interaction is the forces exerted by cancer cells on their surrounding environment, known as cellular traction forces, which has gained its popularity in cancer research as it has shown to be a potential biomarker for metastasis[16,29,30]
Summary
Multicellular tumor spheroid (MCTS) systems provide an in vitro cell culture model system which mimics many of the complexities of an in vivo solid tumor and tumor microenvironment, and are often used to study cancer cell growth and drug efficacy. Quantifying the growth and response to treatment of MCTS is typically through the use of conventional morphometric analysis techniques using measurements of MCTS length and area to determine growth, shrinkage, or stasis in the presence of drug t reatment[17] These common in vitro analysis techniques are analogous to standard in vivo measurements of the response to therapy performed in the clinic that utilize the response evaluation criteria in solid tumors (RECIST), which is based on measurements of the longest dimension of the tumor from noninvasive patient imaging d ata[18,19]. It has been shown that these tensile forces originated from the cancer cells facilitates tumor invasion[31,33] Characterization of these mechanical interactions in MCTS model systems in combination with cellular growth parameters could serve as additional biomarkers of drug responsiveness, which could provide a more complete biophysical characterization of mechanistic changes in drug response assays
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