Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells.

Letizia Mezzasoma,Vincenzo Nicola Talesa,Ilaria Bellezza,Paolo Scarpelli,Egidia Costanzi

doi:10.3390/cancers11091276

Abstract

Prostate cancer (PCa) progression is strictly associated with microenvironmental conditions, which can be modified by cancer-released extracellular vesicles (EVs), important mediators of cell-cell communication. However, the role of EVs in the inflammatory cross-talk between cancer cells and microenvironment-residing cells remains largely unknown. To evaluate the role of EVs in the tumour microenvironment, we treated the non-cancerous prostate cell line PNT2 with EVs isolated from advanced-stage prostate cancer PC3 (PC3-EVs). Caspase-1-mediated IL-1β maturation was evaluated after 24 h incubation with EVs. Moreover, the effect of PC3-EVs on differentiated macrophagic THP-1 cells was assessed by analyzing cytokine expression and PC3 cells migration and proliferation profiles. We illustrated that PC3 cells contain active NLRP3-inflammasome cascade and secrete IL-1β. PC3-EVs affect the PNT2 inflammatory response, inducing caspase-1-mediated IL-1β maturation via ERK1/2-mediated lysosomal destabilization and cathepsin B activation. We also verified that PC3-EVs induce a functional TAM-like polarization in differentiated THP-1 cells. Our results demonstrated that cancer-derived EVs induce an inflammatory response in non-cancerous prostate cells, while inducing an immunomodulatory phenotype in immune cells. These apparently contradictory effects are both committed to strengthening the tumour-promoting microenvironment

Highlights

Prostate cancer (PCa) is the leading cause of cancer-related death in men in Western countries.Several pathogenic factors have an implication in PCa, including age, diet, hereditary status, and inflammation [1]
It has already been established that prostate cancer cell lines secrete extracellular vesicles (EVs), known as prostasomes, similar to that produced by the prostate gland [29,31]
THP1 cells were differentiated in M0 macrophages by a 300 nM TPA 3-day exposure and treated for another 6 h with 100 μg/mL PC3-derived EVs (PC3-EVs) (Figure 1A)

Summary

Introduction

Prostate cancer (PCa) is the leading cause of cancer-related death in men in Western countries.Several pathogenic factors have an implication in PCa, including age, diet, hereditary status, and inflammation [1]. The progression of all tumours, including prostate cancer, depends on cell-cell communication between cancer cells and the surrounding microenvironment, which drives cancer progression, immune modulation and the metastatic process. Both cancer and non-cancerous cells cooperate to determine the features of the tumour microenvironment. The extracellular matrix is assembled as a three-dimensional supramolecular structure which supplies an active support to both cancer and stromal cells. These latter cells include fibroblasts, mesenchymal cells and immune cells [2,3]. Tumour cells themselves secrete several pro-inflammatory cytokines, including interleukin (IL)-6 and IL-1β, strongly

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