Reactive oxygen species–mediated switching expression of MMP-3 in stromal fibroblasts and cancer cells during prostate cancer progression

Abstract

Studies on the aberrant control of extracellular matrices (ECMs) have mainly focused on the role of malignant cells but less on that of stromal fibroblasts during cancer development. Herein, by using paired normal and prostate cancer-associated stromal fibroblasts (CAFs) derived from a coculture cell model and clinical patient samples, we demonstrated that although CAFs promoted prostate cancer growth, matrix metalloproteinase-3 (MMP-3) was lower in CAFs but elevated in prostate cancer cells relative to their normal counterparts. Furthermore, hydrogen peroxide was characterized as the central modulator for altered MMP-3 expression in prostate cancer cells and CAFs, but through different regulatory mechanisms. Treatment of CAFs but not prostate cancer cells with hydrogen peroxide directly inhibited mmp-3 promoter activity with concomitant nuclear translocation of nuclear factor-κB (NF-κB), indicating that NF-κB is the downstream pathway for the transcriptional repression of MMP-3 in CAFs. Hydrogen peroxide reduced thrombospondin 2 (an MMP-3 suppressor) expression in prostate cancer cells by upregulating microRNA-128. To the best of our knowledge, this is the first study to demonstrate the crucial role of reactive oxygen species in the switching expression of MMP-3 in stromal fibroblasts and prostate cancer cells during tumor progression, clarifying how the tumor microenvironment modulates ECM homeostasis control.

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

“…Moreover, it has been shown that cancer exosomes could trigger MSC differentiation into pro-angiogenic and pro-invasive myofibroblasts, secreting high levels of matrix-regulating factors (MMP-1, -3, and -13), VEGF-A, and HGF [49]. A recent study reported MMP3 to be up-regulated in both stromal fibroblasts and cancer cells by oxidative stress [50]. Moreover, CCN2/CTGF can be produced from both tumor and stromal cells.…”

Extracellular Oncosomes Rich in Moonlighting Metalloproteinase (MMP3) Are Transmissive, Pro-Tumorigenic, and Induces Cellular Communication Network Factor 2 (CCN2/CTGF): CRISPR against Cancer

“…Moreover, cancer exosomes triggered MSC differentiation into pro-angiogenic and pro-invasive myofibroblasts secreting high levels of matrix regulating factors (MMP-1, -3 and -13), VEGF-A, and HGF [43]. A recent study reported MMP3 to be up-regulated in both stromal fibroblasts and cancer cells by oxidative stress [44].…”

Exosome Release of Drugs: Coupling with Epithelial-Mesenchymal Transition

“…Tumor cells are surrounded by tumor stroma composed of various types of cells including cancer-associated fibroblasts (CAFs) with properties of mesenchymal stem cells (MSCs), tumorassociated immune cells including tumor-associated macrophages (TAMs), T cells, B cells, and dendritic cells (DCs), tumor endothelial cells (TECs), adipocytes, and normal epithelial cells. These stromal cells communicate with each other using cytokines, growth factors, MMPs [53], ECM, microRNAs, and EVs [54,55]. Earlier studies suggested that tumor stroma was tumor-suppressing, although recent studies have unveiled that stroma signals often drive tumor progression.…”

“…CAFs control ECM deposition and remodeling by producing fibronectin, collagen 1A1, tenascin C, osteopontin, and MMPs [62]. It has been shown that these secretory phenotypes of CAFs were often carried by EVs, including TGFβ, MMPs, microRNA, and ECMs, which alter epithelial cells, tumor cells, and tumor milieu [53,55,[62][63][64]. Proteomics of stroma-derived EVs is important to elucidate the mechanism of tumor progression.…”