Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis

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. [Cancer Res 2009;69(3):785-93]

Microvesicles: mediators of extracellular communication during cancer progression

“…In this study, microvesicles released by PC3 cells, an invasive prostate cancer cell line, triggered ERK phosphorylation, MMP9 upregulation, increased motility and resistance to apoptosis in fibroblasts in the surrounding microenvironment. In turn, the activated fibroblasts shed microvesicles to facilitate the migration and invasion of the prostate cancer line (Castellana et al, 2009). A similar feedback phenomenon was reported in yet another study, confirming the role of prostate-tumor-derived microvesicles in the 'activation' of stromal cells in the tumor microenvironment (Di Vizio et al, 2009).…”

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

“…The supernatant was centrifuged at 4000×g for 1 h to remove the cellular debris, and the resulting supernatant was then distributed into EP tubes for an additional centrifugation at 16 000×g for 1 h. The supernatant was discarded to remove the exosomes, and the MV pellet was washed and resuspended in PBS, followed by another centrifugation at 16 000×g for 1 h to remove the remaining exosomes. The protein content of the MV preparation was quantified using the Bradford method (Bio-Rad, Hercules, CA, USA) as previously reported [24] . All of the centrifugations were performed at 4 °C, and the isolated MVs were stored in PBS at 4 °C until use.…”

Microvesicles containing miRNAs promote muscle cell death in cancer cachexia viaTLR7

“…MVs and exosomes are secreted from various cell types (9), and their miRNA content is associated with regulating cellular processes involved in cell communication, angiogenesis, and extracellular matrix remodeling (9)(10)(11). Recently, we revealed that tumor-secreted miRNAs contributed to tumorigenesis by acting in a paracrine manner to signal to target cells.…”