3D Models for Ovarian Cancer

Transcriptome profiling of 3D models compared to 2D models in various cancer cell lines shows differential expression of TGF-β-mediated and cell adhesion pathways. Presence of TGF-β in these cell lines shows an increased invasion potential which is specific to cell type. In the present study, we identified exogenous addition of TGF-β can induce Epithelial to Mesenchymal Transition (EMT) in a few cancer cell lines. RNA sequencing and real time PCR were carried out in different ovarian cancer cell lines to identify molecular profiling and metabolic profiling. Since EMT induction by TGF-β is cell-type specific, we decided to select two promising ovarian cancer cell lines as model systems to study EMT. TGF-β modulation in EMT and cancer invasion were successfully depicted in both 2D and 3D models of SKOV3 and CAOV3 cell lines. Functional evaluation in 3D and 2D models demonstrates that the addition of the exogenous TGF-β can induce EMT and invasion in cancer cells by turning them into aggressive phenotypes. TGF-β receptor kinase I inhibitor (LY364947) can revert the TGF-β effect in these cells. In a nutshell, TGF-β can induce EMT and migration, increase aggressiveness, increase cell survival, alter cell characteristics, remodel the Extracellular Matrix (ECM) and increase cell metabolism favorable for tumor invasion and metastasis. We concluded that transcriptomic and phenotypic effect of TGF-β and its inhibitor is cell-type specific and not cancer specific.

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Modeling the Tumor Microenvironment of Ovarian Cancer: The Application of Self-Assembling Biomaterials

Cancers ◽

10.3390/cancers13225745 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5745

Author(s):

Ana Karen Mendoza-Martinez ◽

Daniela Loessner ◽

Alvaro Mata ◽

Helena S. Azevedo

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Materials Science ◽

Treatment Options ◽

Tumor Biology ◽

3D Models ◽

Gynecologic Malignancies ◽

Cell Behaviors ◽

Self Assembling ◽

Key Driver

Ovarian cancer (OvCa) is one of the leading causes of gynecologic malignancies. Despite treatment with surgery and chemotherapy, OvCa disseminates and recurs frequently, reducing the survival rate for patients. There is an urgent need to develop more effective treatment options for women diagnosed with OvCa. The tumor microenvironment (TME) is a key driver of disease progression, metastasis and resistance to treatment. For this reason, 3D models have been designed to represent this specific niche and allow more realistic cell behaviors compared to conventional 2D approaches. In particular, self-assembling peptides represent a promising biomaterial platform to study tumor biology. They form nanofiber networks that resemble the architecture of the extracellular matrix and can be designed to display mechanical properties and biochemical motifs representative of the TME. In this review, we highlight the properties and benefits of emerging 3D platforms used to model the ovarian TME. We also outline the challenges associated with using these 3D systems and provide suggestions for future studies and developments. We conclude that our understanding of OvCa and advances in materials science will progress the engineering of novel 3D approaches, which will enable the development of more effective therapies.

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Carboplatin sensitivity in epithelial ovarian cancer cell lines: The impact of model systems

PLoS ONE ◽

10.1371/journal.pone.0244549 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244549

Author(s):

Bishnubrata Patra ◽

Muhammad Abdul Lateef ◽

Melica Nourmoussavi Brodeur ◽

Hubert Fleury ◽

Euridice Carmona ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cell Line ◽

Cell Lines ◽

Drug Testing ◽

3D Models ◽

Model Systems ◽

Microfluidic Chips ◽

The Impact

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in North America, underscoring the need for the development of new therapeutic strategies for the management of this disease. Although many drugs are pre-clinically tested every year, only a few are selected to be evaluated in clinical trials, and only a small number of these are successfully incorporated into standard care. Inaccuracies with the initial in vitro drug testing may be responsible for some of these failures. Drug testing is often performed using 2D monolayer cultures or 3D spheroid models. Here, we investigate the impact that these different in vitro models have on the carboplatin response of four EOC cell lines, and in particular how different 3D models (polydimethylsiloxane-based microfluidic chips and ultra low attachment plates) influence drug sensitivity within the same cell line. Our results show that carboplatin responses were observed in both the 3D spheroid models tested using apoptosis/cell death markers by flow cytometry. Contrary to previously reported observations, these were not associated with a significant decrease in spheroid size. For the majority of the EOC cell lines (3 out of 4) a similar carboplatin response was observed when comparing both spheroid methods. Interestingly, two cell lines classified as resistant to carboplatin in 2D cultures became sensitive in the 3D models, and one sensitive cell line in 2D culture showed resistance in 3D spheroids. Our results highlight the challenges of choosing the appropriate pre-clinical models for drug testing.

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Peptide-protein coassembling matrices as a biomimetic 3D model of ovarian cancer

Science Advances ◽

10.1126/sciadv.abb3298 ◽

2020 ◽

Vol 6 (40) ◽

pp. eabb3298 ◽

Cited By ~ 1

Author(s):

Clara Louise Hedegaard ◽

Carlos Redondo-Gómez ◽

Bee Yi Tan ◽

Kee Woei Ng ◽

Daniela Loessner ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Three Dimensional ◽

3D Culture ◽

Cell Communication ◽

3D Models ◽

Biologically Relevant ◽

Actin Networks ◽

The Matrix ◽

Cell Matrix Interactions

Bioengineered three-dimensional (3D) matrices expand our experimental repertoire to study tumor growth and progression in a biologically relevant, yet controlled, manner. Here, we used peptide amphiphiles (PAs) to coassemble with and organize extracellular matrix (ECM) proteins producing tunable 3D models of the tumor microenvironment. The matrix was designed to mimic physical and biomolecular features of tumors present in patients. We included specific epitopes, PA nanofibers, and ECM macromolecules for the 3D culture of human ovarian cancer, endothelial, and mesenchymal stem cells. The multicellular constructs supported the formation of tumor spheroids with extensive F-actin networks surrounding the spheroids, enabling cell-cell communication, and comparative cell-matrix interactions and encapsulation response to those observed in Matrigel. We conducted a proof-of-concept study with clinically used chemotherapeutics to validate the functionality of the multicellular constructs. Our study demonstrates that peptide-protein coassembling matrices serve as a defined model of the multicellular tumor microenvironment of primary ovarian tumors.

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Organotypic 3D Models of the Ovarian Cancer Tumor Microenvironment

Cancers ◽

10.3390/cancers10080265 ◽

2018 ◽

Vol 10 (8) ◽

pp. 265 ◽

Cited By ~ 15

Author(s):

Karen M. Watters ◽

Preety Bajwa ◽

Hilary A. Kenny

Keyword(s):

Ovarian Cancer ◽

Cell Lines ◽

Cancer Progression ◽

Stromal Cells ◽

Stromal Cell ◽

Single Cells ◽

Fibroblast Cell ◽

3D Models ◽

Ovarian Cancer Cells ◽

Functional Assays

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.

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TGF-β Mediated Cell Adhesion Dynamics and Epithelial to Mesenchymal Transition in 3D and 2D Ovarian Cancer Models

10.1101/465617 ◽

2018 ◽

Cited By ~ 1

Author(s):

Wafa Al Ameri ◽

Ikhlak Ahmed ◽

Fatima M. Al-Dasim ◽

Yasmin Ali Mohamoud ◽

Iman K. AlAzwani ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Adhesion ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Epithelial To Mesenchymal Transition ◽

3D Models ◽

Cancer Invasion ◽

Mesenchymal Transition ◽

Cancer Models

AbstractBackgroundThree-dimensional (3D) tumor cultures in vitro have recently regained attention as they have been acclaimed to have higher similarity to in vivo tumors than cells grown in conventional monolayers (2D). Cancer cells in 2D monolayers fail to mimic the exact tumor microenvironment existing in the real clinical samples. The 3D anchorage-independent cancer models can better explain the cell adhesion properties in ovarian cancer cells.ResultsTranscriptome profiling of 3D models compared to 2D models in various cancer cell lines shows differential expression of TGF-β-mediated and cell adhesion pathways. Presence of TGF-β in these cell lines shows an increased invasion potential which is specific to cell type. We decided to choose two ovarian cancer cell lines as model systems to study Epithelial to Mesenchymal Transition (EMT) and cancer invasion based on their invasion potential and ability to switch the cadherins expression. TGF-β modulation in EMT and cancer invasion was successfully depicted in both 2D and 3D models of SKOV3 and CAOV3 cell lines. Functional evaluations in 3D and 2D models demonstrate that the addition of the exogenous TGF-β can induce EMT and invasion in cancer cells by turning them into aggressive phenotypes. TGF-β receptor kinase I inhibitor (LY364947) can revert TGF-β effect in these cells.ConclusionsIn a nutshell, TGF-β can induce EMT and migration, increase aggressiveness, increase cell survival, alter cell characteristics, remodel the Extracellular Matrix (ECM) and increase cell metabolism favorable for tumor invasion and metastasis.

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