Grun, B; (2013) Stroma and epithelial interactions in three dimensional cell biology models of ovarian cancer. Doctoral thesis , UCL (University College London).

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Abstract

Over the past years it has become increasingly apparent that the tumour microenvironment plays a crucial role in tumour initiation/development/metastasis. The interactions of the tumour microenvironment and the malignant epithelial cells in epithelial ovarian cancer (EOC) biology remain poorly understood. This is in part due to the lack of representative in vitro models of disease that closely resemble the in vivo situation. A tumour exhibits a three-dimensional (3D) architecture comprising the malignant epithelial cells surrounded by the tumour stroma, which predominately contains the so-called cancer associated fibroblasts (CAFs). In vitro 3D models using primary epithelial cancer cell lines showed striking morphological similarities with the primary tumours. Immunohistochemistry and proteomic profiling further revealed that 3D models more closely resemble the primary tumour compared to traditional 2D culture methods. To further develop these 3D models and to recreate the interactions of epithelial cells with the microenvironment in vitro, heterotypic 3D models were established. Mesenchymal stem cells (MSCs) and immortalized normal ovarian fibroblasts (INOFs) were used to represent the tumour stroma and co-cultured with malignant and non-malignant epithelial ovarian cells. These 3D models proved an improvement to the previously established homotypic 3D models and offered a very good representation of the in vivo tumour. Finally, the recruitment of CAFs into the tumour stroma by EOC cell lines was investigated. Both MSCs and INOFs showed the ability to transdifferentiate into CAFs upon treatment with conditioned medium from an EOC cell line. Transdifferentiation was assessed by the expression of a-smooth muscle actin (aSMA), Vimentin and fibroblast specific protein (FSP). Both differentiated cell lines were also able to induce increased proliferation and invasion rates in a transformed ovarian surface epithelial cell line. These results provide in vitro evidence that both MSCs and INOFs can serve as precursor cell types of CAFs in EOC.

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