Abstract
BackgroundMechanisms driving the progression of castration-resistant prostate cancer are believed to relate substantially to the tumor microenvironment. However, the cross-talks between tumor epithelial cell, stromal cells, and immune cells are yet to be fully elucidated. The present study aims to determine the role of chemokine and neutrophil derived cytokine paracrine axis in mediating the interaction between tumor cells, stromal myofibroblasts, and neutrophils in the tumor microenvironment of prostate cancer.MethodsTo identify myofibroblasts and neutrophil derived specific proteins affecting progression of prostate cancer, bioinformatics analyses were firstly performed in independent human prostate cancer gene expression data sets from the GEO data bank. Expression of stromal myofibroblasts secretory chemokine CXCL1 and neutrophil derived cytokine LCN2 was evaluated in prostate tissues via immunohistochemistry assay. We further investigated the effect of CXCL1 and LCN2 on prostate cancer using in vivo and in vitro models, and explored the underlying signal transduction pathways.ResultsA CXCL1-LCN2 paracrine network was confirmed in prostate cancer tissue samples, which was correlated with the biochemical recurrence of prostate cancer. Of note, CXCL1-LCN2 axis activates Src signaling, triggers the epithelial-mesenchymal transition (EMT), consequently promotes the migration of prostate cancer cells, leading to enhanced tumor metastasis.ConclusionsOur findings may provide enhanced insight into the interactions of carcinoma-stromal cells and immune cells linked to prostate cancer progression, wherein CXCL1-LCN2 axis is a key contributor to prostate cancer cells migration. These data indicate tumor microenvironment and Src signaling pathway may be potential therapeutic targets of prostate cancer treatment.
Highlights
Mechanisms driving the progression of castration-resistant prostate cancer are believed to relate substantially to the tumor microenvironment
Neutrophil-derived LCN2 is a highly related factor coexpressed with Chemokine ligand 1 (CXCL1) in prostate cancer To identify molecules presumably involved in mediating the impact of CXCL1 and neutrophils, we first analyzed the published human Prostate cancer (PCa) gene expression data sets, with a focus on neutrophil-derived genes encoding secreted proteins
A list of CXCL1-associated candidates was stratified from 18 independent human PCa gene expression data sets from the Gene Expression Omnibus (GEO) data bank (Additional file 1: Table S1), which highlighted IL8/ CXCL8 and LCN2 as neutrophil-derived cytokines that were closely associated with CXCL1
Summary
Mechanisms driving the progression of castration-resistant prostate cancer are believed to relate substantially to the tumor microenvironment. The present study aims to determine the role of chemokine and neutrophil derived cytokine paracrine axis in mediating the interaction between tumor cells, stromal myofibroblasts, and neutrophils in the tumor microenvironment of prostate cancer. Growth factors, as well as matrix metalloproteinases secreted by stromal fibroblasts and myofibroblasts, are believed to support carcinoma cell survival even under low androgen conditions and promote both local tumor growth and distant metastasis [5, 6]. Chemokines (i.e., CXCL8/IL-8, CXCL12) overexpressed in prostate carcinoma activate proliferation-related pathways and stimulate angiogenesis, recruit immune cells infiltrating into cancerous foci, and trigger tumor-associated inflammation [7, 8]
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