Prostate cancer arises in the epithelium, but there is increasing evidence that surrounding stromal fibroblast cells play an active role in tumour initiation, progression and metastases. Fibroblast cells from prostate tumour stroma (Cancer Associated Fibroblasts - CAFs) are molecularly and functionally distinct from fibroblasts from non-malignant prostate stroma (Normal Prostate Fibroblasts - NPFs). In fact, CAFs can promote cancer in benign prostate epithelial cells using in vivo and in vitro mouse models. The molecular basis of this difference is controversial, with some studies reporting a high frequency of genetic aberrations in CAFs and others finding negligible mutation rates. An alternative explanation is that prostate CAFs have a normal genotype but undergo aberrant epigenetic changes.
Our aim is to investigate the epigenetic changes underlying the permanent expression and functional differences between CAFs and NPFs. We used cutting-edge microarray and sequencing techniques to investigate genome-wide differences in genotype, expression, DNA methylation and histone modification between pair-matched CAF and NPF cells from prostate cancer patients (n=8 patients). From our initial results we have identified 294 regions showing differential DNA methylation between CAFs and NPFs. Notably, we find that DNA methylation changes correlate precisely with changes in gene expression.
Our ongoing study represents the most in-depth epigenetic analysis of stromal changes in any tumour type to date. Our initial results pinpoint consistent epigenetic differences between NPFs and CAFs in genes previously identified as having a functional role in tumour progression. We plan to demonstrate the functional role of these epigenetically-regulated genes using in vivo tissue recombination assays. We anticipate that our findings will provide an increased understanding of the aetiology of cancer progression and provide evidence that the CAF epigenome could be an important therapeutic target in prostate cancer.