Organotypic 3D Models of the Ovarian Cancer Tumor Microenvironment

Abstract

Ovarian cancer progression involves multifaceted and variable tumor microenvironments (TMEs), from the in situ carcinoma in the fallopian tube or ovary to dissemination into the peritoneal cavity as single cells or spheroids and attachment to the mesothelial-lined surfaces of the omentum, bowel, and abdominal wall. The TME comprises the tumor vasculature and lymphatics (including endothelial cells and pericytes), in addition to mesothelial cells, fibroblasts, immune cells, adipocytes and extracellular matrix (ECM) proteins. When generating 3D models of the ovarian cancer TME, researchers must incorporate the most relevant stromal components depending on the TME in question (e.g., early or late disease). Such complexity cannot be captured by monolayer 2D culture systems. Moreover, immortalized stromal cell lines, such as mesothelial or fibroblast cell lines, do not always behave the same as primary cells whose response in functional assays may vary from donor to donor; 3D models with primary stromal cells may have more physiological relevance than those using stromal cell lines. In the current review, we discuss the latest developments in organotypic 3D models of the ovarian cancer early metastatic microenvironment. Organotypic culture models comprise two or more interacting cell types from a particular tissue. We focus on organotypic 3D models that include at least one type of primary stromal cell type in an ECM background, such as collagen or fibronectin, plus ovarian cancer cells. We provide an overview of the two most comprehensive current models—a 3D model of the omental mesothelium and a microfluidic model. We describe the cellular and non-cellular components of the models, the incorporation of mechanical forces, and how the models have been adapted and utilized in functional assays. Finally, we review a number of 3D models that do not incorporate primary stromal cells and summarize how integration of current models may be the next essential step in tackling the complexity of the different ovarian cancer TMEs.

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

“…To faithfully reproduce human ovarian cancer in vivo, in 3D organotypic cell culture models, cell–ECM interactions may recreate tumor progression step by step in vitro. [ 196 ] By the different ECM components in vitro, the inherent role of cell–ECM interactions are identified in the transformation of the initiating cancer cells into inert, metastatic, and resistant cancer cells. However, synthetic ECM components available restrain the organotypic models to achieve the primary tissue constructs, including access to tissue heterogeneity and the lifespan of the 3D cultures.…”

“…C) A546 lung cancer cells; when seeded on different EFK8 hydrogels, tumor spheroidal colony growth pattern is formed in 1.25 mg mL −1 EFK8 peptide hydrogel, 5.0 mg mL −1 EFK8 peptide hydrogel, and 1.25 mg mL −1 EFK8‐SWNT hybrid hydrogel (adapted with permission. [ 196 ] Copyright 2018, Elsevier Ltd).…”

Bioengineering models of female reproduction

“…Results indicated that the created 3D in vitro cervical cancer model showed stratified epithelial layers and expressed the same types and patterns of differentiation marker proteins as seen in corresponding in vivo tissue in either normal cervical or cervical cancerous tissues. Additionally, other 3D microfluidic systems have been investigated to mimic ovarian cancer environments [58,83,85]. For example, a microfluidic platform of the peritoneum was constructed to mimic ovarian cancer spheroids in the peritoneal cavity with mesothelial cells under hydrodynamic conditions.…”

Regulation of Female Folliculogenesis by Tsp1a in Nile Tilapia (Oreochromis niloticus)

“…Factors within the extracellular matrix (ECM) have also been reported to offer the complex milieu that facilitates the necessary interaction between ovarian follicles and their surroundings to ensure follicles growth and development. Members of the thrombospondin (TSP) family also belong to this group of ECM proteins [5][6][7][8][9][10].…”