TGF-β1 Overexpression in Murine Pancreas Induces Chronic Pancreatitis and Together with TNF-α, Triggers Insulin-Dependent Diabetes

Sanvito, Francesca; Nichols, Andrew J.; Herrera, Pedro Luis; Huarte, Joachim; Wohlwend, Annelise Isabelle; Vassalli, Jean‐Dominique; Orci, Lelio

doi:10.1006/bbrc.1995.2906

Cited by 121 publications

(75 citation statements)

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“…pancreatic cancer and chronic pancreatitis, which are characterized by a strong accumulation of ®brotic tissue. The role of TGFb for the development of pancreatic ®brosis has been well documented in human diseases (Friess et al, 1993; Van Laethem et al, 1995) and in animal models of pancreatic ®brosis (Sanvito et al, 1995;Menke et al, 1997). Our in vitro results suggested that in pancreatic cancer tissues CTGF produced by pancreatic cancer cells may contribute to the development of the desmoplastic reaction.…”

Section: Discussionsupporting

confidence: 58%

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Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells

et al. 1999

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Section: Discussionsupporting

confidence: 58%

“…As both, EGF/TGFa and TGFb have been shown to induce ®brosis in the pancreas (Bockman and Merlino, 1992;Sanvito et al, 1995;Menke et al, 1997) it is feasible to assume that CTGF plays an important role in the development of ®brosis in pancreatic diseases as e.g. in pancreatic cancer and chronic pancreatitis.…”

Section: Introductionmentioning

confidence: 99%

Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells

et al. 1999

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“…After 3 -9 months animals were sacrificed, the pancreas was removed and tissues were snap frozen in liquid nitrogen. In all transgenic mice the pancreas exhibited massive fibrosis, as previously described (Sanvito et al, 1995).…”

Section: Transgenic Micementioning

confidence: 60%

“…The fusion fragment was inserted in the EcoRI site of pBS containing the human growth hormone (Sanvito et al, 1995). Seven transgenic animals were used for this study; control animals were of the BL6 strain.…”

Section: Transgenic Micementioning

confidence: 99%

Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

et al. 2002

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PTEN is a candidate tumour suppressor gene and frequently mutated in multiple cancers, however, not in pancreatic cancer.Recently, it has been demonstrated that PTEN expression is regulated by TGF-b1. Using TGF-b1 transgenic mice (n=7) and wildtype littermates (n=6), as well as pancreatic tissues obtained from organ donors (n=10) and patients with pancreatic cancer (n=10), we assessed the expression of PTEN by means of immunohistochemistry and semiquantitative PCR analysis. In addition, PANC-1 cells were treated with TGF-b1 in vitro and the levels of PTEN mRNA were determined in these cells. In human pancreatic cancers PTEN mRNA levels were significantly decreased (P50.05). In addition, in the pancreas of TGF-b1 transgenic mice the expression of PTEN was significantly reduced (P50.01), as compared to wildtype littermates and incubation of PANC-1 cells with TGF-b1 decreased PTEN mRNA levels after 24 h. Inasmuch as TGF-b1 decreases PTEN expression in human pancreatic cancer cells and human pancreatic cancers overexpress TGF-b1, the reduced expression of PTEN in pancreatic cancer may be mediated by TGF-b1 overexpression. Thus, although PTEN is not mutated in pancreatic cancers, the reduction of its expression may give pancreatic cancer cells an additional growth advantage.

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“…A new lentiviral vector, pTRIP ΔU3.RIP405-eGFP, was constructed with the Rat insulin II gene promoter (RIP) in order to restrict the expression of eGFP to insulin-producing cells. A 405-bp fragment of RIP was amplified from the PBS-RIP-beta globin plasmid (kindly provided by P. Herrera, University of Geneva, Switzerland) [21] using the PCR expand system (Roche Diagnostic, Meylan, France) with the following primers: MluI RIP405 sense 5′cgacgcgtGGAC ACAGCTATCAGTGGGA3′ and BamHI RIP antisense 5′cgggatccTAGGGCTGGGGGTTACT3′.…”

Section: Dna Constructs and Recombinant Lentiviral Productionmentioning

confidence: 99%

Efficient restricted gene expression in beta cells by lentivirus-mediated gene transfer into pancreatic stem/progenitor cells

et al. 2005

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Aims/hypothesis: Gene transfer into pancreatic beta cells, which produce and secrete insulin, is a promising strategy to protect such cells against autoimmune destruction and also to generate beta cells in mass, thereby providing a novel therapeutic approach to treat diabetic patients. Until recently, exogenous DNA has been directly transferred into mature beta cells with various levels of success. We investigated whether exogenous DNA could be stably transferred into pancreatic stem/progenitor cells, which would subsequently differentiate into mature beta cells expressing the transgene. Methods: We designed transplantation and tissue culture procedures to obtain ex vivo models of pancreatic development. We next constructed recombinant lentiviruses expressing enhanced green fluorescent protein (eGFP) under the control of either the rat insulin promoter or a ubiquitous promoter, and performed viral infection of rat embryonic pancreatic tissue. Results: Embryonic pancreas infected with recombinant lentiviruses resulted in endocrine cell differentiation and restricted cell type expression of the transgene according to the specificity of the promoter used in the viral construct. We next demonstrated that the efficiency of infection could be further improved upon infection of embryonic pancreatic epithelia, followed by their in vitro culture, using conditions that favour endocrine cell differentiation. Under these conditions, endocrine stem/progenitor cells expressing neurogenin 3 are efficiently transduced by recombinant lentiviral vectors.Moreover, when eGFP was placed under the control of the insulin promoter, 70.4% of the developed beta cells were eGFP-expressing cells. All of the eGFP-positive cells were insulin-producing cells. Conclusions/interpretation: We have demonstrated that mature rat pancreatic beta cells can be stably modified by infecting pancreatic stem/progenitor cells that undergo endocrine differentiation.

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TGF-β1 Overexpression in Murine Pancreas Induces Chronic Pancreatitis and Together with TNF-α, Triggers Insulin-Dependent Diabetes

Cited by 121 publications

References 0 publications

Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells

Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells

Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

Efficient restricted gene expression in beta cells by lentivirus-mediated gene transfer into pancreatic stem/progenitor cells

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