Surrounding matrix and stroma influence normal epithelial and prostate cancer cell behavior in vivo, regulating many aspects of cellular development and differentiation by providing structural support and soluble factors. Alteration of the surrounding environment modifies epithelial cell behavior and involves modifications to stiffness, tissue density, fat and lipid content, and vascularity. As the cellular microenvironment is a dynamic contributor to prostate cancer progression, there is a need to understand individual and collective cell-cell interactions and discover the underlying mechanisms to target them therapeutically.
In order to mimic the complex multi-cellular 3D microenvironment seen in vivo, we generated a novel 3D tissue engineered construct of human PCa that incorporates relevant primary human cells from patients with and without PCa. We designed, fabricated and validated the model using individualised fiber-based self-reporting scaffolds to support the growth of individual cell types and corresponding extracellular matrix found in prostatic tumors. Using layers of primary human cell cultures on the scaffolds we defined multi-cell interactions. We show how tumour stroma drives epithelial transformation particularly involving CAFs & mast cells through specific cytokine and chemokine signalling pathways that are co-ordinated by estrogen hormone action. We show the influence of the tumour microenvironment on neoangiogenesis in PCa, with CAFs and mast cells.Our approachhighlights the potential importance of the tumour microenvironment in PCa, with specific mechanisms coordinated by estrogen hormone action. By defining the roles, interactions and contributions of these components, new therapeutic targets could be identified and rapidly bought to the clinic for PCa (compounds targeting estrogen or mast cell action (as used in this study) are already approved and in clinical use for the treatment of other diseases.