Abstract
Tumor microenvironment is enriched in plasma membrane microvesicles (MV) shed from all cell types that constitute the tumor mass, reflecting the antigenic profile of the cells they originate from. Fibroblasts and tumor cells mutually communicate within tumor microenvironment. Recent evidences suggest that tumor-derived MVs (TMV) exert a broad array of biological functions in cell-to-cell communication. To elucidate their role in cancer-to-fibroblast cell communication, TMV obtained from two prostate carcinoma cell lines with high and weak metastatic potential (PC3 and LnCaP, respectively) have been characterized. TMV exhibit matrix metalloproteinases (MMP) and extracellular MMP inducer at their surface, suggesting a role in extracellular matrix degradation. Moreover, TMV not only induce the activation of fibroblasts assessed through extracellular signal-regulated kinase 1/2 phosphorylation and MMP-9 up-regulation, increase motility and resistance to apoptosis but also promote MV shedding from activated fibroblasts able in turn to increase migration and invasion of highly metastatic PC3 cells but not LnCaP cells. PC3 cell chemotaxis seems, at least partially, dependent on membrane-bound CX3CL1/fractalkine ligand for chemokine receptor CX3CR1. The present results highlight a mechanism of mutual communication attributable not only to soluble factors but also to determinants harbored by MV, possibly contributing to the constitution of a favorable niche for cancer development.
Highlights
After cellular stimulation in the broad sense of the term, including initiation of a death program by apoptosis, the asymmetric distribution of membrane phospholipids is no longer maintained and the cell releases submicrometric membrane fragments (0.1–1 Am), termed microvesicles (MV), into its environment
Other cell culture reagents were from Cambrex, actinomycin D (Act.D), staurosporine (St), etoposide (VP-16), 4¶,6-diamidino-2-phenylindole (DAPI), propidium iodide (PI), PKH-26 and antibody (Ab) to h-actin, neutralizing goat Ab antiCX3CL1, and control goat IgG were from Sigma. z-Val-Ala-Asp.fluoromethyl ketone (z-VAD.fmk) and U1026 ([1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene]) were from Calbiochem
Polyclonal Ab to phosphorylated ERK1/2, Ab anti-EMMPRIN, Ab anti-CX3CR1, and donkey peroxidase-conjugated anti-goat IgG were from SantaCruz, polyclonal Ab against ERK1/2 from CellSignaling, goat peroxidase–conjugated anti-rabbit IgG purchased from Bio-Rad, sheep peroxidase–conjugated anti-mouse IgG from AmershamBiosciences, and streptavidine-FITC conjugate from Rockland
Summary
After cellular stimulation in the broad sense of the term, including initiation of a death program by apoptosis, the asymmetric distribution of membrane phospholipids is no longer maintained and the cell releases submicrometric membrane fragments (0.1–1 Am), termed microvesicles (MV), into its environment. It has been shown that the quantity of generated MV is directly proportional to the degree of cellular activation including apoptosis in vitro, and that it is a quasi-universal feature of eukaryotic cells [2, 3]. MV may be considered multifunctional bioeffectors in intercellular communication, and their roles have been investigated in hemostasis, inflammation, immunity, and angiogenesis [1], but only scarce information is available in cancer
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