Three-Dimensional Modelling of Ovarian Cancer: From Cell Lines to Organoids for Discovery and Personalized Medicine

Abstract

Ovarian cancer has the highest mortality of all of the gynecological malignancies. There are several distinct histotypes of this malignancy characterized by specific molecular events and clinical behavior. These histotypes have differing responses to platinum-based drugs that have been the mainstay of therapy for ovarian cancer for decades. For histotypes that initially respond to a chemotherapeutic regime of carboplatin and paclitaxel such as high-grade serous ovarian cancer, the development of chemoresistance is common and underpins incurable disease. Recent discoveries have led to the clinical use of PARP (poly ADP ribose polymerase) inhibitors for ovarian cancers defective in homologous recombination repair, as well as the anti-angiogenic bevacizumab. While predictive molecular testing involving identification of a genomic scar and/or the presence of germline or somatic BRCA1 or BRCA2 mutation are in clinical use to inform the likely success of a PARP inhibitor, no similar tests are available to identify women likely to respond to bevacizumab. Functional tests to predict patient response to any drug are, in fact, essentially absent from clinical care. New drugs are needed to treat ovarian cancer. In this review, we discuss applications to address the currently unmet need of developing physiologically relevant in vitro and ex vivo models of ovarian cancer for fundamental discovery science, and personalized medicine approaches. Traditional two-dimensional (2D) in vitro cell culture of ovarian cancer lacks critical cell-to-cell interactions afforded by culture in three-dimensions. Additionally, modelling interactions with the tumor microenvironment, including the surface of organs in the peritoneal cavity that support metastatic growth of ovarian cancer, will improve the power of these models. Being able to reliably grow primary tumoroid cultures of ovarian cancer will improve the ability to recapitulate tumor heterogeneity. Three-dimensional (3D) modelling systems, from cell lines to organoid or tumoroid cultures, represent enhanced starting points from which improved translational outcomes for women with ovarian cancer will emerge.

Cancer Three-Dimensional Spheroids Mimic In Vivo Tumor Features, Displaying “Inner” Extracellular Vesicles and Vasculogenic Mimicry

“…Ovarian cancer (OC) is one of the most frequently diagnosed tumors and a leading cause of tumor death in women [ 24 , 33 ]; since specific symptoms are lacking and effective early screening is not available, the diagnosis is often late and most commonly occurs when most women already are in an advanced stage and have abdominal metastases and ascites [ 34 , 35 , 36 ]. This lowers the 5-years survival rate, and most of the deaths occur within 2 years from diagnosis [ 35 ].…”

“…This is the reason why, in recent years, alternative 3D culture models are being developed. In cancer research, 3D models are considered as an intermediate model between 2D cultures and in vivo experiments, being able to represent more truthfully some characteristics of in vivo tumors, in terms of cell-to-cell and cell-to-extracellular matrix (ECM) contacts, cellular layered assembling, hypoxia, and gradients of nutrient, oxygen, and pH [ 22 , 23 , 24 ].…”

“…Several 3D models are currently available; in some of them cells are grown on exogenous 3D structures (scaffold-based models) and in some others they are not (scaffold-free models) [ 24 , 25 ]. In the scaffold-free cultures, cells produce and deposit their own ECM similarly to what happens in vivo and grow as aggregates named “multicellular tumor spheroids” or, simply, “spheroids”.…”

“…Along with several advantages of this method (adjustable size of a spheroid modifying the cell number, no requirement of professional expensive equipment, possibility to generate a huge number of homogeneous spheroids, reproducible size) [ 23 , 27 ], some issues have also been reported with this method, such as difficulty in drug addition or media replacement [ 24 ].…”

“…Since it has been observed in vivo that ovarian cancers often tend to grow in ascites as cell clusters (spheroids) having the potential to metastasize [ 29 , 30 , 31 ], the spheroid model could be particularly relevant to study, in vitro, the ovarian cancer biology and how EVs contribute to cancer progression, taking advantage of an approach that is more consistent with in vivo situation. Indeed, several studies on ovarian cancer have already suggested that the culture model choice can impact, for example, sensitivity to chemotherapeutic agents [ 24 , 32 ].…”