Stromal Gene Signatures as Source of Targets for Drug-Repositioning and Prognostic Biomarkers in Prostate Cancer

Doldi, Valentina (2020). Stromal Gene Signatures as Source of Targets for Drug-Repositioning and Prognostic Biomarkers in Prostate Cancer. PhD thesis The Open University.



The interplay between cancer cells and adjacent stroma is fundamental for the development and progression of tumours. In fact, this crosstalk sustains carcinogenesis and promotes the acquisition of additional malignant features. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) have been shown to fuel tumour development and metastasis by mutually interacting with tumour cells. In this regard, defining stromal gene signatures relevant for cancer progression could be a successful strategy to identify novel therapeutic targets and prognostic biomarkers for PCa. Recently, we have performed a gene expression profiling analysis comparing CAFs and fibroblasts stimulated with IL-6 or TGF-β, to examine the molecular signatures involved in fibroblast activation. The gene set enriched analysis revealed that CAFs are characterized by positive enrichment of genes coding for calcium, sodium, and potassium cation channels and genes related to extracellular matrix (ECM) remodelling. This evidence suggests a crucial role of characteristic stromal-related pathways in fibroblast conversion to a phenotype able to sustain PCa progression. In addition, the definition of reactive stroma players that are crucial for cancer progression could be a strategy to identify novel therapeutic targets and biomarkers for the early detection of aggressive PCa.

To better understand the involvement of cation channels in CAFs activation and potentially revert such activated phenotype, in this work we treated CAFs with specific cation channel inhibitors, such as antiarrhythmics. Interestingly, we found that antiarrhythmics are able to interfere with crucial features of prostate CAFs, as indicated by the modulation of specific activation markers and reduction of contraction and migration capabilities. Moreover, co-culture experiments indicate that antiarrhythmics are able to impair CAF-induced proliferative spur and EMT in PCa cells, and ultimately induce tumour growth delay in vivo.

Given the ability of a reactive stroma to support cancer progression, the prognostic relevance of selected genes found up-regulated in activated fibroblasts was tested in relation to clinical-pathological characteristics and patient outcome.

Among crucial factors found up-regulated in prostate CAFs compared to normal fibroblasts we identified a set o ECM-remodelling protein, including periostin. Interestingly, the immunostaining analysis we performed in a series of prostatectomies from PCa patients confirmed that periostin is mainly expressed in the stroma components surrounding tumour foci, and that its staining correlates with tumour grade and cribriform gland morphology, which is indicative of adverse outcome. Most importantly, high levels of stromal periostin expression were associated with a significantly increased probability to experience biochemical recurrence after prostatectomy. In light of the positive correlation observed between periostin stromal staining and aggressive disease, we also investigated the prognostic potential of circulating periostin in patients with potentially indolent tumours followed in the context of an active surveillance protocol. However, results from the study indicated that baseline plasma levels of periostin displayed a moderate capability to identify patients with aggressive disease.

Overall these studies may open new opportunities for the translation of drugs already used in different fields into the targeting of tumour-associated fibroblasts with the aim to interrupt their tumour-supportive spur. Finally, the characterisation of relevant stromal gene signatures may improve diagnostic tools for an early identification of high-risk PCa.

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