Abstract
The mechanical homeostasis of tissues can be altered in response to trauma or disease, such as cancer, resulting in altered mechanotransduction pathways that have been shown to impact tumor development, progression, and the efficacy of therapeutic approaches. Specifically, ovarian cancer progression is parallel to an increase in tissue stiffness and fibrosis. With in vivo models proving difficult to study, tying tissue mechanics to altered cellular and molecular properties necessitate advanced, tunable, in vitro 3D models able to mimic normal and tumor mechanic features. First, we characterized normal human ovary and high-grade serous (HGSC) ovarian cancer tissue stiffness to precisely mimic their mechanical features on collagen I-based sponge scaffolds, soft (NS) and stiff (MS), respectively. We utilized three ovarian cancer cell lines (OVCAR-3, Caov-3, and SKOV3) to evaluate changes in viability, morphology, proliferation, and sensitivity to doxorubicin and liposomal doxorubicin treatment in response to a mechanically different microenvironment. High substrate stiffness promoted the proliferation of Caov-3 and SKOV3 cells without changing their morphology, and upregulated mechanosensors YAP/TAZ only in SKOV3 cells. After 7 days in culture, both OVCAR3 and SKOV3 decreased the MS scaffold storage modulus (stiffness), suggesting a link between cell proliferation and the softening of the matrix. Finally, high matrix stiffness resulted in higher OVCAR-3 and SKOV3 cell cytotoxicity in response to doxorubicin. This study demonstrates the promise of biomimetic porous scaffolds for effective inclusion of mechanical parameters in 3D cancer modeling. Furthermore, this work establishes the use of porous scaffolds for studying ovarian cancer cells response to mechanical changes in the microenvironment and as a meaningful platform from which to investigate chemoresistance and drug response.
Highlights
The microenvironment surrounding cancer cells has been shown to contribute to tumor progression at both biological and physical levels [1,2]
The role of mechanical constrains in tumorigenesis has been well-studied in breast cancer, for example, where the stiffening and remodeling of the extracellular matrix (ECM) accompany the promotion of breast carcinoma cell proliferation, and local tumor cell invasion and progression [17,18]
Using a sponge scaffold 3D collagen-based culture system, we investigate the role of substrate stiffness in affecting epithelial ovarian cancer (EOC) cell behavior and chemoresistance in vitro
Summary
The microenvironment surrounding cancer cells has been shown to contribute to tumor progression at both biological and physical levels [1,2]. Alterations in extracellular matrix (ECM) composition and organization, as well as crosstalk with the surrounding physical and biochemical niche microenvironment, has been shown to drive cancer cell responses, such as proliferation, cytoskeleton distribution, migration, gene expression, and signal transduction [6–12]. Mounting evidence suggest that the composition of the ECM, and its stiffness, can significantly affect cancer cell responses to treatment and chemoresistance [13–15]. Increased density and reorganization of collagen fibrils around malignant breast tumors appears to facilitate local tumor cell invasion [19,20]. Nonlinear optical imaging methods, such as multiphoton microscopy (MPM) and second harmonic generation (SHG) imaging, have been used to visualize local changes in collagen fibril density around invasive breast tumors [21]
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