Abstract
Reactive stroma is a tissue feature commonly observed in the tumor microenvironment of prostate cancer and has previously been associated with more aggressive tumors. The aim of this study was to detect differentially expressed genes and metabolites according to reactive stroma content measured on the exact same prostate cancer tissue sample. Reactive stroma was evaluated using histopathology from 108 fresh frozen prostate cancer samples gathered from 43 patients after prostatectomy (Biobank1). A subset of the samples was analyzed both for metabolic (n = 85) and transcriptomic alterations (n = 78) using high resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) and RNA microarray, respectively. Recurrence-free survival was assessed in patients with clinical follow-up of minimum five years (n = 38) using biochemical recurrence (BCR) as endpoint. Multivariate metabolomics and gene expression analysis compared low (≤15%) against high reactive stroma content (≥16%). High reactive stroma content was associated with BCR in prostate cancer patients even when accounting for the influence of Grade Group (Cox hazard proportional analysis, p = 0.013). In samples with high reactive stroma content, metabolites and genes linked to immune functions and extracellular matrix (ECM) remodeling were significantly upregulated. Future validation of these findings is important to reveal novel biomarkers and drug targets connected to immune mechanisms and ECM in prostate cancer. The fact that high reactive stroma grading is connected to BCR adds further support for the clinical integration of this histopathological evaluation.
Highlights
The tumor microenvironment (TME) has in recent years gained attention for its role in cancer cell and tumor development
Before consensus between pathologists was reached on tumor containing samples (n = 108), the original evaluations gave a kappa score of 0.64 and 0.30 for Grade Group and reactive stromal grading (RSG), respectively
In this study we have demonstrated that reactive stroma content in human prostate cancer tissue is associated with metabolic and transcriptomic alteration, and significantly influence biochemical recurrence
Summary
The tumor microenvironment (TME) has in recent years gained attention for its role in cancer cell and tumor development. TME include activated fibroblasts called cancer associated fibroblasts (CAFs), immune cells and vasculature cells It is often the site of chronic inflammation and extracellular matrix (ECM) remodeling, similar to what occurs during wound-healing with an increase of activated fibroblasts[2,3]. The current gold standard for predicting clinical outcome is histopathological evaluation through the Grade Group system[4]. This system sets a grade based on the morphological appearance of prostate glands and cancerous epithelial cells. Dakova et al.[16] performed global gene expression on laser dissected prostate tissue samples, identifying several differentially expressed genes between reactive and normal stroma These included genes related to functions such as neurogenesis and DNA repair[16]. Further we investigated how the expression of significant genes and metabolites of reactive stroma are correlated, and investigated biochemical recurrence of patients with high reactive stroma content
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