Interleukin-3 Stimulates Migration and Proliferation of Vascular Smooth Muscle Cells

Brizzi, Maria Felice; Formato, L.; Dentelli, Patrizia; Rosso, Arturo; Pavan, Marzia; Garbarino, Giovanni; Pegoraro, Mattia; Camussi, Giovanni; Pegoraro, Luigi

doi:10.1161/01.cir.103.4.549

Cited by 64 publications

(63 citation statements)

References 37 publications

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“…Informed consent was provided according to the Declaration of Helsinki. M07e cells (Avanzi et al, 1990) and IL-3 releasing gibbon MLA cell line (Brizzi et al, 2001) were used as positive control for c-Kit or IL-3 expression, respectively. Primary renal carcinoma cells were obtained from an informed patient (cells derived from a man 50 years old: T3bG2N0M0) who underwent clinical surgery.…”

Section: Cell Culturesmentioning

confidence: 99%

IL-3 is a novel target to interfere with tumor vasculature

et al. 2011

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Angiogenesis inhibiting agents are currently integral component of anticancer therapy. However, tumors, initially responsive to anti-angiogenic drugs or vascular targeting agents, can acquire resistance. The limited clinical efficacy might result from the heterogeneous nature of tumors or alternatively from the unique phenotype of tumor vascular cells, widely diverse from so-called 'normal' endothelium. Hence, defining the molecular mechanisms driving this diversity might provide a rational basis to design combinatory therapies that should be more effective in avoiding resistance. Herein, we demonstrated that tumor-derived endothelial cells (TECs) isolated from breast and kidney carcinomas retained an endothelial phenotype, but outspread independently of growth factors. Applying small interfering RNA approach, we demonstrated that interleukin (IL)-3, but not vascular endothelial growth factor, released by TECs, supports their autocrine growth and promotes in vivo vessel formation and tumor angiogenesis. Meanwhile, we found that the expression of the membrane-bound kit ligand (mbKitL) depends on IL-3, and it is crucial for adhesion of endothelial progenitor cells (EPCs) and inflammatory cells to TECs. These events required Akt activation. Finally, the finding that depletion of the mbKitL prevented EPC and inflammatory cell trafficking into vascular microenvironment, indicates that, as in bone marrow, the mbKitL can act as a membrane/adhesion molecule for c-Kit-expressing cells. These data provide evidences that an IL-3 autocrine loop can drive a tumor endothelial switch and that targeting IL-3 might confer a significant therapeutic advantage to hamper tumor angiogenesis.

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Section: Cell Culturesmentioning

confidence: 99%

IL-3 is a novel target to interfere with tumor vasculature

et al. 2011

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“…19,30 Nuclear localization of PCNA was analyzed by confocal microscopy. Confocal microscopy was performed on a Leica TCS SP2 model confocal microscope (Heidelberg, Germany) using a ϫ63 magnification lens and 488-nm argon laser.…”

Section: Immunofluorescencementioning

confidence: 99%

Angiopoietin 2 Induces Cell Cycle Arrest in Endothelial Cells: A Possible Mechanism Involved in Advanced Plaque Neovascularization

Calvi

Dentelli

Pagano

et al. 2004

ATVB

Self Cite

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Objective-To characterize the molecules and the mechanisms regulating the neoangiogenetic process in advanced atherosclerotic plaques. Methods and Results-Western blot and immunofluorescence analysis of atherosclerotic specimens demonstrated that unlike neovessels from early lesions that expressed vascular endothelial growth factor (VEGF) and angiopoietin1 (Angio1), vessels from advanced lesions expressed VEGF and angiopoietin 2 (Angio2). Moreover, only few neovessels from advanced lesions showed a positive immunostaining for proliferating cell nuclear antigen. Angio1-elicited and Angio2-elicited intracellular events in endothelial cells (EC) demonstrated that while Angio1 triggered Erk1/Erk2 mitogen activated protein kinases (MAPK) and Akt activation, Angio2 (50 ng/mL) induced STAT5 activation and p21 waf expression and increased the fraction of cells in G1. Both Angio2-mediated events were abrogated by expressing a dominant negative STAT5 construct (⌬STAT5). Consistent with the expression of Angio2 in neovessels of advanced lesions a transcriptionally active STAT5 was detected. Moreover, co-immunoprecipitation experiments revealed the presence of a STAT5/Tie2 molecular complex in neointima vessels from advanced, but not from early, lesions. 3 Consistently, in vivo developing primary lesions might be considered as underperfused and dependent on neovessel formation for continued growth. 4 Angiogenesis in mature tissues is composed of a series of cellular responses including activation of EC proliferation by angiogenic factors, such as VEGF, fibroblast growth factor (FGF), and angiopoietins (Angio) and formation of tube-like structures and vessel stabilization. 5 Compared with the developmental angiogenesis, the role of angiopoietins in pathological angiogenesis is less understood. The angiopoietin family consists of four members, Angio1 to 4. 6 -8 Angio1 and 4 stimulate their receptor tyrosine kinase Tie2, whereas Angio2 and 3 by binding to Tie2 antagonize Angio1 signaling. 6 -8 Signal transduction pathways via Tie2 and VEGF receptors (VEGFR) have been extensively examined. 9,10 In particular, Korpelainem et al showed that Tie2 and VEGFR1 overexpression triggers the phosphorylation of the signal transducer and activator of transcription (STAT) 3 and STAT5. 11 STAT5 belongs to the family of transcriptional factors, which, on activation, binds to the receptor via their src homology 2 domain (SH2). 12 Recruited STATs, dimerize, translocate to the nucleus, and activate transcription of target genes mainly involved in regulation of cell cycle progression. 12,13 Cell cycle phases are coordinated by regulatory proteins denoted as cyclins and cyclin-dependent kinases (CDKs). 14 Phase-specific cyclin/CDK complexes confer specificity and orderly progression through the cell cycle. Initially, cyclin D/CDK4 or cyclin E/CDK2 complexes, in cooperation with proliferating cell nuclear antigen (PCNA), coordinate DNA duplication by regulating the transition through the G1 and S phase. 15 Furthermore, cell cycle progression is ...

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“…Hematopoietic cytokines affect cardiomyogenic differentiation. In murine embryos, EPO triggers cardiomyocyte proliferation [62]; its receptor is detected by E10.5 until day E14.5 [62,63], and IL-3 can induce endothelial cell formation as well as stimulate and chemo-attract smooth muscle cell proliferation and migration [64]. The formation of mixed lineage hematopoietic cells in the same cultures as CFU-Beats suggests that this may be a good system for future studies on common progenitor cells involved in cardiomyocyte and hematopoietic development in the early embryo, the role of the hemangioblast, the interaction of different cytokines and morphogens at specific timepoints, and the influence of the 3D microenvironment and metabolism.…”

Section: Discussionmentioning

confidence: 99%

Early Exposure of Murine Embryonic Stem Cells to Hematopoietic Cytokines Differentially Directs Definitive Erythropoiesis and Cardiomyogenesis in Alginate Hydrogel Three-Dimensional Cultures

Fauzi

Panoskaltsis

Mantalaris

2014

Stem Cells and Development

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HepG2-conditioned medium (CM) facilitates early differentiation of murine embryonic stem cells (mESCs) into hematopoietic cells in two-dimensional cultures through formation of embryoid-like colonies (ELCs), bypassing embryoid body (EB) formation. We now demonstrate that three-dimensional (3D) cultures of alginateencapsulated mESCs cultured in a rotating wall vessel bioreactor can be differentially driven toward definitive erythropoiesis and cardiomyogenesis in the absence of ELC formation. Three groups were evaluated: mESCs in maintenance medium with leukemia inhibitory factor (LIF, control) and mESCs cultured with HepG2 CM (CM1 and CM2). Control and CM1 groups were cultivated for 8 days in early differentiation medium with murine stem cell factor (mSCF) followed by 10 days in hematopoietic differentiation medium (HDM) containing human erythropoietin, m-interleukin (mIL)-3, and mSCF. CM2 cells were cultured for 18 days in HDM, bypassing early differentiation. In CM1, a fivefold expansion of hematopoietic colonies was observed at day 14, with enhancement of erythroid progenitors, hematopoietic genes (Gata-2 and SCL), erythroid genes (EKLF and b-major globin), and proteins (Gata-1 and b-globin), although z-globin was not expressed. In contrast, CM2 primarily produced beating colonies in standard hematopoietic colony assay and expressed early cardiomyogenic markers, anti-sarcomeric a-actinin and Gata-4. In conclusion, a scalable, automatable, integrated, 3D bioprocess for the differentiation of mESC toward definitive erythroblasts has been established. Interestingly, cardiomyogenesis was also directed in a specific protocol with HepG2 CM and hematopoietic cytokines making this platform a useful tool for the study of erythroid and cardiomyogenic development.

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Interleukin-3 Stimulates Migration and Proliferation of Vascular Smooth Muscle Cells

Abstract: IL-3, expressed by activated T lymphocytes infiltrating early and advanced atherosclerotic plaques, may sustain the atherosclerotic process either directly, by activating SMC migration and proliferation, or indirectly, via VEGF production.

Cited by 64 publications

References 37 publications

IL-3 is a novel target to interfere with tumor vasculature

IL-3 is a novel target to interfere with tumor vasculature

Angiopoietin 2 Induces Cell Cycle Arrest in Endothelial Cells: A Possible Mechanism Involved in Advanced Plaque Neovascularization

Early Exposure of Murine Embryonic Stem Cells to Hematopoietic Cytokines Differentially Directs Definitive Erythropoiesis and Cardiomyogenesis in Alginate Hydrogel Three-Dimensional Cultures

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