Prostate cancer is hormone dependent and is regulated by a balance of androgens as well as estrogens. Local estrogen synthesis and the activation of estrogen receptors, particularly ERα, drive disease through reciprocal stromal-epithelial cell interactions. In the tumour microenvironment (TME), cancer associated fibroblasts (CAFs) promote tumour progression and have an estrogenic gene expression signature with increased ERa expression. Estrogen driven cytokine production promotes recruitment and expansion of mast cells (MCs), a resident prostate stromal immune population. MC numbers are specifically increased in estrogen driven inflammation and malignancy, with the tryptase-only MC sub-population being the most significantly increased. Tryptase is a preformed heparin-stabilised serine protease that is contained within MC cytoplasmic granules and is released upon cell activation. The enzyme affects multiple mechanisms within the TME, including extracellular matrix remodelling, activation of matrix-metalloproteinases, promoting angiogenesis, and activation of PAR receptors. To date, the specific role of tryptase in the prostate and its contribution to prostate cancer remains unknown.
To identify the contribution and role of MCs and tryptase in prostate cancer initiation and progression we have utilised a multicellular 3D microtissue TME model, developed in collaboration with bioengineers. Our data reveal that MCs cooperate with CAFs, potentiating CAF mediated tumourigenic effects. Increasing numbers of MC in the TME, mimicking the in vivo situation, accelerate epithelial transformation and tumour progression. These effects are mediated by MC secreted factors, specifically tryptase. Tryptase inhibition completely abrogates the effects of MCs, reducing transformation and disease progression, thus highlighting the contribution of this protease to prostate tumourigenesis.
Overall, these data highlight the cascade of multicellular interactions in the TME that include MCs and CAFs, which, when perturbed, drive epithelial transformation and disease progression. Our data also highlight tryptase as a key mediator of these effects, which may be a novel therapeutic target to slow disease progression.