Stromal hedgehog signalling in prostate epithelial cell transformation

The stromal microenvironment plays a key role in the normal development of the prostate and in the development of epithelial derived prostate cancer (PCa). A better understanding of how the stroma directs the correct differentiation of prostatic epithelium during development is therefore not only of interest to the developmental biologist, but vital in determining how the microenvironment may be effecting epithelium in diseases such as cancer. PCa can be treated in its early stages, however, many patients regress after treatment, and there is currently no cure for late stage disease. The aim of this thesis was to study the mechanisms of stromal mediated epithelial transformation in both development and disease, with the goal of informing better treatment options for PCa. The Hedgehog (Hh) signalling pathway is active during prostate development, and this thesis shows it is also involved in prostatic stromal mediated lineage transformation of adult epithelial stem cells. The Hh signalling pathway has also been implicated in PCa, however, the mechanisms of its involvement in this disease are still unclear. For this reason, subsequent studies in this thesis focused on the mechanisms of Hh signalling between the stromal and epithelial cellular compartments of the prostate and other tissues during non-malignant epithelial transformations, as well as in carcinogenesis. During epithelial transformation across a developmental germ layer boundary, paracrine Hh signalling occurs with increased downstream target gene expression in adjacent epithelium. On the other hand, Hh downstream target expression was found to be highly active in the PCa stroma, and may therefore be involved in the ability of PCa associated fibroblasts (known as CAFs) to promote epithelial tumours. This suggests a role for paracrine/stromal-epithelial Hh signalling in an opposite direction to that observed during epithelial transformation, but similar to the activity of Hh signalling in the developing prostate. Current PCa treatments are focused on removing and/or targeting the carcinogenic epithelial tissue in PCa. This thesis highlights the importance of the stroma and its paracrine signals in transforming adjacent epithelium and therefore adds impetus to notion that to treat and prevent recurrence and cancer we cannot just target the cancer itself, but must also target the microenvironment surrounding it. This thesis demonstrates that this microenvironment and its paracrine signals can both initiate epithelial transformations and also be conducive, if not instructive, to epithelial changes associated with malignancy. Implications of this work on PCa treatment may involve blocking stromal Hh signals after radical prostatectomy and/or chemotherapeutic adjuvant therapy of blocking stromal Hh may improve the prognosis of PCa sufferers. Future studies will need to test the efficacy of these approaches in the clinic.