Shedding of Membrane Vesicles Mediates Fibroblast Growth Factor-2 Release from Cells

Taverna, Simona; Ghersi, Giulio; Ginestra, A; Rigogliuso, Salvatrice; Pecorella, S.; Alaimo, G; Saladino, Francesca; Dolo, Vincenza; Dell’Era, Patrizia; Pavan, Antonio; Pizzolanti, Giuseppe; Mignatti, Paolo; Presta, Marco; Vittorelli, Maria Letizia

doi:10.1074/jbc.m304192200

Cited by 103 publications

(136 citation statements)

References 55 publications

(82 reference statements)

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“…FGF2 lacks signal peptide but yet could be exported to the extracellular space, and, accordingly, it is considered as an unconventionally secreted protein. Recent reports provide experimental evidence for FGF2 release through vesicle shedding (Taverna et al, 2003) or direct translocation across the plasma membrane (Schafer et al, 2004) and work is in progress to identify the mechanism utilized by OSE/IOSE cells for FGF2 export.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

et al. 2004

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Epithelial ovarian cancer (EOC) is the gynecological disease with the highest death rate. We applied an automatic class discovery procedure based on gene expression profiling to stages III-IV tumors to search for molecular signatures associated with the biological properties and progression of EOC. Using a complementary DNA microarray containing 4451 cancer-related, sequence-verified features, we identified a subset of EOC characterized by the expression of numerous genes related to the extracellular matrix (ECM) and its remodeling, along with elements of the fibroblast growth factor 2 (FGF2) signaling pathway. A total of 10 genes were validated by quantitative real-time polymerase chain reaction, and coexpression of FGF2 and fibroblast growth factor receptor 4 in tumor cells was revealed by immunohistochemistry, confirming the reliability of gene expression by cDNA microarray. Since the functional relationships among these genes clearly suggested involvement of the identified molecular signature in processes related to epithelial-stromal interactions and/or epithelial-mesenchymal cellular plasticity, we applied supervised learning analysis on ovarian-derived cell lines showing distinct cellular phenotypes in culture. This procedure enabled construction of a gene classifier able to discriminate mesenchymal-like from epithelial-like cells. Genes overexpressed in mesenchymal-like cells proved to match the FGF2 signaling and ECM molecular signature, as identified by unsupervised class discovery on advanced tumor samples. In vitro functional analysis of the cell plasticity classifier was carried out using two isogenic and immortalized cell lines derived from ovarian surface epithelium and displaying mesenchymal and epithelial morphology, respectively. The results indicated the autocrine, but not intracrine stimulation of mesenchymal conversion and cohort/scatter migration of cells by FGF2, suggesting a central role for FGF2 signaling in the maintenance of cellular plasticity of ovary-derived cells throughout the carcinogenesis process. These findings raise mechanistic hypotheses on EOC pathogenesis and progression that might provide a rational underpinning for new therapeutic modalities.

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Section: Discussionmentioning

confidence: 99%

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

et al. 2004

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“…Both low and high molecular weight FGF2 isoforms show angiogenic activity [63]. At variance with other FGFs, FGF2 isoforms lack a leader sequence for secretion and are released in limited amounts by an alternative secretion pathway [64] or via membrane vesicle shedding [65]. Experimental evidences point to different functions of FGF2 isoforms in transfected endothelial cells [66], possibly related to differences in their subcellular localization and release.…”

Section: Autocrine Intracrine Paracrine Mechanisms Of Action Of Fgfmentioning

confidence: 99%

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Presta

Dell’Era

Mitola

et al. 2005

Cytokine & Growth Factor Reviews

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Fibroblast growth factors (FGFs) are a family of heparin-binding growth factors. FGFs exert their pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. Their activity is modulated by a variety of free and extracellular matrix-associated molecules. Also, the cross-talk among FGFs, vascular endothelial growth factors (VEGFs), and inflammatory cytokines/chemokines may play a role in the modulation of blood vessel growth in different pathological conditions, including cancer. Indeed, several experimental evidences point to a role for FGFs in tumor growth and angiogenesis. This review will focus on the relevance of the FGF/FGF receptor system in adult angiogenesis and its contribution to tumor vascularization. #

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“…Previous reports have demonstrated the presence of these molecules in shed membrane vesicles. The mechanism of vesicle formation remains unclear; however, this process has been associated with the release of growth factors, dissemination of tumor antigens, increased cellular invasiveness, metastasis, and suppression of immune surveillance (17)(18)(19)(20)(21)(22)(23). In this report we investigated the potential role of proteinase-rich vesicles on cellular invasion and describe a novel function of ascites that may account for the extremely aggressive metastatic behavior exhibited by epithelial ovarian carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

Proinvasive Properties of Ovarian Cancer Ascites-Derived Membrane Vesicles

et al. 2004

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Malignant ovarian ascites are rich in cellular components, membranebound vesicles, and soluble proteins. This study focused on the structure of membrane-bound vesicles and their ability to promote invasion in cultured malignant ovarian epithelium. Membrane vesicles were derived from women with stage I-IV malignant ovarian ascites and from nonmalignant gynecologic ascites. Isolated vesicles were characterized by immunofluorescence and Western blot analysis. Using gel zymography for matrix metalloproteinase (MMP) detection and a colorimetric assay for urokinase-type plasminogen activator (uPA) analysis, we analyzed the proteinase activities of MMP-2, MMP-9, and uPA from the prepared vesicles, whole cells isolated from ascites, and the cell-free ultracentrifuged supernatant. The invasiveness of established cultured malignant ovarian epithelium on addition of ascites-derived vesicles was tested using a Matrigel-based invasion assay. Fractionation of malignant ascites revealed that extracellular matrix-degrading proteinases including MMPs and uPA are localized preferentially in membrane vesicles. All malignant vesicles tested, regardless of cancer stage, stimulated invasion. Furthermore, the combination of ovarian cancer cells and membrane vesicles resulted in greater uPA activation than that of cells or vesicles alone. Membrane vesicles from malignant ascites were also found to contain activated MMP-2, MMP-9, and uPA. Our data suggest that vesiclestimulated proteinase activation leads to increased extracellular matrix degradation, which may facilitate tumor cell invasion and metastasis.

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Shedding of Membrane Vesicles Mediates Fibroblast Growth Factor-2 Release from Cells

Cited by 103 publications

References 55 publications

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Proinvasive Properties of Ovarian Cancer Ascites-Derived Membrane Vesicles

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