Integrative metabolic and transcriptomic profiling of prostate cancer tissue containing reactive stroma

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.

Identification of potential key genes in gastric cancer using bioinformatics analysis

“…KEGG pathway analysis showed that the DEGs were primarily enriched in ECM-receptor interaction, protein digestion and absorption, and focal adhesion. ECM-receptor interaction serves a vital role in several types of cancer (36)(37)(38). The interaction between membrane receptors of tumor cells and ECM proteins serve an important role in tumor invasion and metastasis (39), and ECM-receptor interaction serve a crucial role in the process of tumor shedding, adhesion, degradation, movement and hyperplasia (38).…”

The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

“…Whole genome and whole exome sequencing analysis on PCa patient-derived xenografts has identified a 93-gene stroma-derived metastatic signature that can independently predict metastatic progression even in intermediate-risk primary PCa patients [109]. A combination of metabolic and transcriptomic profiling was performed in histologically defined PCa tissues with low versus high reactive stroma content [110]. High reactive stroma tissues were enriched in metabolites and transcript expression was linked to ECM and immune pathways, and there was also a significant association with BCR progression [110].…”

“…A combination of metabolic and transcriptomic profiling was performed in histologically defined PCa tissues with low versus high reactive stroma content [110]. High reactive stroma tissues were enriched in metabolites and transcript expression was linked to ECM and immune pathways, and there was also a significant association with BCR progression [110]. Finally, analysis of the amount of reactive stroma fraction together with PCa cells DNA ploidy represents a prognostic tool to predict disease recurrence [111].…”

Metabolomics Contributions to the Discovery of Prostate Cancer Biomarkers

“…Moreover, additional clinically robust biomarkers able to differentiate between indolent and aggressive PCa are urgently needed. In this context, several metabolomics studies have been carried out to attempt the characterization of a specific PCa metabolic profile, with the ultimate goal of identifying potential metabolic biomarkers that could improve the clinical management of PCa patients [16,17,18,19].…”