Effects of urinary extracellular vesicles from prostate cancer patients on the transcriptomes of cancer-associated and normal fibroblasts

Abstract

Background Increasing evidence suggests that cancer-derived extracellular vesicles (EVs) alter the phenotype and functions of fibroblasts and trigger the reprogramming of normal fibroblasts into cancer-associated fibroblasts (CAFs). Here, we for the first time studied the effects of urinary EVs from PC patients and healthy males on the transcriptional landscape of prostate CAFs and normal foreskin fibroblasts. Methods Patient-derived prostate fibroblast primary cultures PCF-54 and PCF-55 were established from two specimens of PC tissues. EVs were isolated from urine samples of 3 patients with PC and 2 healthy males and used for the treatment of prostate fibroblast primary cultures and normal foreskin fibroblasts. The EV-treated fibroblasts were subjected to RNA sequencing analysis. Results RNA sequencing analysis showed that the fibroblast cultures differed significantly in their response to urinary EVs. The transcriptional response of foreskin fibroblasts to the urinary EVs isolated from PC patients and healthy controls was very similar and mostly related to the normal functions of fibroblasts. On the contrary, PCF-54 cells responded very differently - EVs from PC patients elicited transcriptional changes related to the regulation of the cell division and chromosome segregation, whereas EVs from healthy males affected mitochondrial respiration. In PCF-55 cells, EVs from both, PC-patients and controls induced the expression of a number of chemokines such as CCL2, CCL13, CXCL1, CXCL8, whereas pathways related to regulation of apoptotic signaling and production of cell adhesion molecules were triggered specifically by EVs from PC patients. Conclusion This study demonstrates that urinary EVs from PC patients and healthy controls elicit distinct transcriptional responses in prostate CAFs and supports the idea that EVs contribute to the generation of functional heterogeneity of CAFs. Moreover, this study suggests that the changes in the gene expression pattern in EV recipient cells might serve as a novel type of functional cancer biomarkers.

Prostate cancer-derived small extracellular vesicle proteins: the hope in diagnosis, prognosis, and therapeutics

“…Furthermore, treatment of prostate fibroblasts with sEVs isolated from urine samples of PCa patients and healthy individuals elicits distinct transcriptional responses, whereas the transcriptional response in foreskin fibroblasts exhibits remarkable similarity. These findings provide further evidence that sEV derived from PCa patients exert a profound influence on the phenotypic and functional changes of fibroblasts [ 103 ]. There are reasons to speculate that sEV proteins of PCa cells play a significant role in this process.…”

The role of proinflammatory cytokines and CXC chemokines (CXCL1–CXCL16) in the progression of prostate cancer: insights on their therapeutic management

“…CXC chemokines and CXCRs expression patterns varied between PCa patients depending on the metastatic site, indicating that these molecules may be involved in organ-specific PCa metastasis [ 153 ]. Both PC-EVs and HC-EVs stimulated the expression of the chemokine CXCL1 in PCF-55 cells [ 154 ]. It is also demonstrated that CXCL1 promotes angiogenesis, motility, epithelial–mesenchymal transition, adhesion, and metastasis in PCa cells [ 25 ].…”

sRNAflow: A Tool for the Analysis of Small RNA-Seq Data

“…Classical methods are not tailored for analysing unannotated expressed regions. Despite employing repositioning algorithms [ 22 ], up to 80% of mapped reads in certain analysed datasets [ 23 ] remained unannotated. Consequently, exploring these unannotated data can offer complementary insights to traditional biomarkers or refine biological signatures in machine learning by incorporating unknown regions.…”