Stromal and epithelial transcriptional map of initiation progression and metastatic potential of human prostate cancer

Abstract

While progression from normal prostatic epithelium to invasive cancer is driven by molecular alterations, tumor cells and cells in the cancer microenvironment are co-dependent and co-evolve. Few human studies to date have focused on stroma. Here, we performed gene expression profiling of laser capture microdissected normal non-neoplastic prostate epithelial tissue and compared it to non-transformed and neoplastic low-grade and high-grade prostate epithelial tissue from radical prostatectomies, each with its immediately surrounding stroma. Whereas benign epithelium in prostates with and without tumor were similar in gene expression space, stroma away from tumor was significantly different from that in prostates without cancer. A stromal gene signature reflecting bone remodeling and immune-related pathways was upregulated in high compared to low-Gleason grade cases. In validation data, the signature discriminated cases that developed metastasis from those that did not. These data suggest that the microenvironment may influence prostate cancer initiation, maintenance, and metastatic progression.

Targeting the tumour stroma to improve cancer therapy

“…These data indicate that mutations might occur in stromal cells before they affect the cancer cells, subsequently driving tumorigenesis. Further efforts to determine the molecular underpinnings on the conversion of non-activated fibroblasts to CAFs in both patient-derived tumour samples and mouse models have revealed several signalling mechanisms, including activation of the Hippo pathway (reference is Calvo 2013), loss of p53 (reference is Procopio 2015), or activation of heat shock factor 1 (HSF1) (reference is Scherz-Shouval 2014), that enhance tumour-promoting properties of CAFs in several tumour types (Tyekucheva 2017 is a general reference to the molecular undrpinnings of stromal-epitehlial interactions) 192–195 .…”

Fibroblast as a critical stromal cell type determining prognosis in prostate cancer

“…Recently, stroma has been shown to have both tumor‐suppressing and tumor‐promoting effects in many solid tumors . Olumi et al described a dramatic tumor‐promoting effect of carcinoma‐associated fibroblasts in PCa, and tumor stroma has been shown to be associated with aggressive disease features and shorter time to biochemical recurrence using needle biopsy as well as prostatectomy samples . Moreover, stromal gene expression analysis in prostatectomy samples revealed signatures specific for metastatic potential of PCa …”

Genomic and clinical characterization of stromal infiltration markers in prostate cancer

“…As such, genomics is increasingly being incorporated into prognostication, treatment decisions, and targeted therapy design for prostate cancer. Still, the clinical significance and implications of stromal infiltration in primary prostate cancer are not well‐defined or understood …”