Mechanomimetic 3D Scaffolds as a Humanized In Vitro Model for Ovarian Cancer

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.

Decellularization Techniques to Manufacture Ovary Cancer Niche Scaffold as Prototype for 3D Cancer Cell Culture

“…SKOV-3 ovary cancer cell line can be cultured with the decellularized scaffold with very low toxicity than reported previously by Paradiso et al [17]. This study showed cytotoxicity at a level of up to 7.4% while Paradiso et al study indicated up to 14% of cell death with the synthetic scaffold.…”

Bioelectricity in dental medicine: a narrative review

“…Abundance studies demonstrated that mechanical stimulation plays an essential role in wide biological processes [ 107 – 111 ]. A variety of mechanical stimulation, fluid shear stress, tension, and (hydrostatic) compression, and matrix stiffness can modulate differentiation of stem cell [ 112 ], immune response [ 113 ], cellular apoptosis [ 114 ], tumor development [ 115 ] and bone remodeling [ 116 ]. An intimate connection between bioelectricity and mechanical forces has been acknowledged, wherein intracellular bioelectric signals and mechanical signals can reciprocally transfer.…”

Matrix‐based molecular mechanisms, targeting and diagnostics in oral squamous cell carcinoma

“…Both the ECM itself and the mechanical stimuli is triggered by ECM stiffening and can activate cell membrane receptors and several mechanosensors, thereby modulating the malignant phenotype of tumor and stromal cells. 13,16 By directly stimulating cell survival, migration, proliferation and differentiation, the abnormal ECM influences the development of cancer. 15,17 By deregulating stromal cell behavior and modulating signaling cascades mediated by interactions with cell surface receptors, the remodeled ECM and its degradation fragments may promote the emergence of an oncogenic microenvironment.…”

“…To understand the specific features of the ECM in solid tumors is necessary to develop approaches to influence its negative effects. Both the ECM itself and the mechanical stimuli is triggered by ECM stiffening and can activate cell membrane receptors and several mechanosensors, thereby modulating the malignant phenotype of tumor and stromal cells 13,16 . By directly stimulating cell survival, migration, proliferation and differentiation, the abnormal ECM influences the development of cancer 15,17 .…”