Hepatocyte Growth Factor/Scatter Factor Released during Peritonitis Is Active on Mesothelial Cells

Rampino, Teresa; Cancarini, Giovanni; Gregorini, Marilena; Guallini, Paola; Maggio, Milena; Ranghino, Andrea; Soccio, Grazia; Canton, Antonio Dal

doi:10.1016/s0002-9440(10)62514-x

Cited by 44 publications

(37 citation statements)

References 38 publications

(39 reference statements)

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“…MeT-5A is an untransformed MC line, which is increasingly used in peritoneal MC research; data obtained with this cell line have shown concordance with data obtained with primary cells (Rampino et al, 2001;Bidmon et al, 2004).…”

Section: Isolation and Culture Of Mcssupporting

confidence: 58%

Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway

Strippoli¹,

Benedicto²,

Pérez-Lozano³

et al. 2008

Disease Models &Amp; Mechanisms

104

116

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SUMMARYEpithelial-to-mesenchymal transition (EMT) occurs in fibrotic diseases affecting the kidney, liver and lung, and in the peritoneum of patients undergoing peritoneal dialysis. EMT in the peritoneum is linked to peritoneal membrane dysfunction, and its establishment limits the effectiveness of peritoneal dialysis. The molecular regulation of EMT in the peritoneum is thus of interest from basic and clinical perspectives. Treatment of primary human mesothelial cells (MCs) with effluent from patients undergoing peritoneal dialysis induced a genuine EMT, characterized by downregulated E-cadherin and cytokeratin expression, cell scattering, and spindle-like morphology. This EMT was replicated by co-stimulation with transforming growth factor (TGF)-β1 and interleukin (IL)-1β. Retroviral overexpression of a mutant inhibitor of kappaB (IκB) demonstrated that NF-κB activation is required for E-cadherin and cytokeratin downregulation during EMT. Pre-treatment with the MAP kinase kinase (MEK)-1/2 inhibitor U0126 showed that cytokinetriggered NF-κB nuclear translocation and transcriptional activity are mediated by activation of extracellular regulated kinase (ERK). Cytokine-mediated induction of mRNA expression of the transcription factor Snail1, a repressor of E-cadherin expression and a potent inducer of EMT, was prevented by blockade of ERK or NF-κB. Finally, blockade of ERK/NF-κB signaling in ex vivo MCs that were cultured from peritoneal dialysis effluents reverted cells to an epithelioid morphology, upregulated E-cadherin and cytokeratin expression, and downregulated Snail1 expression. Modulation of the ERK/NF-κB/Snail1 pathway may provide a means of counteracting the progressive structural and functional deterioration of the peritoneal membrane during peritoneal dialysis.

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Section: Isolation and Culture Of Mcssupporting

confidence: 58%

Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway

Strippoli¹,

Benedicto²,

Pérez-Lozano³

et al. 2008

Disease Models &Amp; Mechanisms

104

116

View full text Add to dashboard Cite

show abstract

“…In experimental renal disease, the therapeutic value of HGF was established at a relatively high dosage of 500 g/kg per d to 5 mg/kg per d 38,39 ; however, HGF prevented the histologic changes in peritoneum of an animal model of PD at a lower dosage of 4 g/kg per d, which might be due to direct administration of HGF on targeting tissue by adding to peritoneal dialysate in a rat model of PD. 25 An article by Rampino et al 40 showed that a high concentration of HGF (50 ng/ml) caused a fibroblast-like change and a detachment of cells from peritoneal membrane. These findings suggest that an antifibrotic effect of HGF may be dosage dependent with variable therapeutic dosages that depend on experimental conditions, types of animal model, and route of administration.…”

Section: Discussionmentioning

confidence: 99%

HGF and BMP-7 Ameliorate High Glucose–Induced Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelium

Shin

Kim

et al. 2009

Journal of the American Society of Nephrology

117

130

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Over time, peritoneal dialysis results in functional and structural alterations of the peritoneal membrane, but the underlying mechanisms and whether these changes are reversible are not completely understood. Here, we studied the effects of high levels of glucose, which are found in the dialysate, on human peritoneal mesothelial cells (HPMCs). We found that high concentrations of glucose induced epithelialto-mesenchymal transition (EMT) of HPMC, suggested by decreased expression of E-cadherin and increased expression of ␣-smooth muscle actin, fibronectin, and type I collagen and by increased cell migration. Normalization of glucose concentration on day 2 reversed the phenotypic transformation, but the changes were irreversible after 7 d of stimulation with high glucose. In addition, exposure of HPMC to high glucose resulted in a decreased expression of the antifibrotic cytokines, hepatocyte growth factor (HGF) and bone morphogenic protein 7 (BMP-7). Exogenous treatment with HGF resulted in a dosage-dependent prevention of high glucose-induced EMT. Both BMP-7 peptide and gene transfection with an adenoviral vector of BMP-7 also protected HPMCs from EMT. Furthermore, adenoviral BMP-7 transfection decreased peritoneal EMT and ameliorated peritoneal thickening in an animal model of peritoneal dialysis. In summary, high concentrations of glucose induce a reversible EMT of HPMCs, associated with decreased production of HGF and BMP-7. Treatment of HPMCs with HGF or BMP-7 blocks high glucose-induced EMT, and BMP-7 ameliorates peritoneal fibrosis in an animal model of peritoneal dialysis.

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“…Mesothelial and fibroblast cells at early passages (1-3) were used for the experiments to minimize dedifferentiation and modification of the original phenotype as described. [16][17][18] Mesothelial or fibroblast cells were incubated in serum-free media for 24 hr and conditioned media collected.…”

Section: Isolation and Culture Of Primary Human Mesothelial Fibroblamentioning

confidence: 99%

Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extra‐cellular matrices on adhesion and invasion of ovarian cancer cells to the omentum

Kenny

Krausz

Yamada

et al. 2007

Intl Journal of Cancer

221

267

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The omentum is a major site of ovarian cancer metastasis. Our goal was to establish a three-dimensional (3D) model of the key components of the omental microenvironment (mesothelial cells, fibroblasts and extracellular matrices) to study ovarian cancer cell adhesion and invasion. The 3D model comprised of primary human fibroblasts extracted from normal human omentum, mixed with ECM and covered by a layer of primary human mesothelial cells, also from normal human omentum. After addition of ovarian cancer cells, the histological appearance of the 3D culture mimicked microscopic metastases to the omentum from patients with ovarian cancer. When ovarian cancer cells, SKOV3ip.1 and HeyA8, were applied to the 3D omental culture, 60% and 68% of all cells attached, respectively, but only 18% and 25% were able to invade. Ovarian cancer cells preferentially adhered to and invaded collagen I, followed by binding to collagen IV, fibronectin, vitronectin, laminin 10 and 1. Omental mesothelial cells significantly inhibited ovarian cancer cell adhesion and invasion, while omental fibroblasts induced adhesion and invasion. This effect is clearly mediated by direct cell-cell contact, since conditioned medium from mesothelial cells or fibroblasts has a minimal, or no, effect on ovarian cancer cell adhesion and invasion. In summary, we have established a 3D model to study the early steps of ovarian cancer metastasis to the human omentum, and found that omental mesothelial cells inhibit, while omental fibroblasts and the ECM enhance, the attachment and invasion of ovarian cancer cells. ' 2007 Wiley-Liss, Inc.Key words: 3-dimensional culture; 3D; tumor-stroma interaction; metastasis; ovarian cancer Ovarian cancer is typically diagnosed at an advanced stage, because most patients develop clinical symptoms late in the course of the disease, after the tumor has metastasized.1 The most common sites of metastasis from the primary ovarian tumor are the abdominal peritoneum and the omentum. Often the pliable, semitransparent omental tissue is transformed into a dense omental ''cake'' that impinges on the stomach and the transverse colon, causing a bowel obstruction. Even after infragastric removal of the omentum, which is regularly performed for ovarian cancer staging or debulking at the time of surgery, recurrent tumor cells home to residual areas of the omentum at the splenic hilum, the stomach and the transverse colon causing the reappearance of significant clinical symptoms.The majority of ovarian cancers are of epithelial origin, arising from the single layer of cells that covers the ovary, which is separated by a basement membrane from the underlying ovarian stroma.2,3 There are features unique to ovarian cancer that might facilitate its intraperitonel (ip) spread. The ovarian epithelium can adopt a mesenchymal phenotype characterized by cells that lack tight junctions, which makes them prone to exfoliation. 4 Once an ovarian epithelial cell undergoes transformation it is free to disseminate throughout the peritoneal cavity, carried b...

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Hepatocyte Growth Factor/Scatter Factor Released during Peritonitis Is Active on Mesothelial Cells

Cited by 44 publications

References 38 publications

Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway

Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway

HGF and BMP-7 Ameliorate High Glucose–Induced Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelium

Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extra‐cellular matrices on adhesion and invasion of ovarian cancer cells to the omentum

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