Decorin gene transfer-mediated suppression of TGF-β synthesis abrogates experimental malignant glioma growth in vivo

Ständer, Marko; Naumann, Ulrike; Dumitrescu, Logan; Heneka, Michael T.; Löschmann, P.-A.; Gulbins, Erich; Dichgans, J.; Weller, Michael

doi:10.1038/sj.gt.3300709

Cited by 118 publications

(96 citation statements)

References 24 publications

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“…The improved survival in Lewis rats that received decorin-transfected CNS-1 cells, is similar to results obtained in tumor xenografts and in the C6 glioma model using C6 cells expressing decorin. 11,13 However, in the C6 glioma model decorin expression resulted in tumor regression in 100% of experimental Sprague-Dawley (SD) rats. One of the possible explanations for the increased tumor regression is that because C6 cells are not syngeneic in SD rats, tumor regression by decorin could be enhanced by host versus graft rejection.…”

Section: Discussionmentioning

confidence: 99%

“…4,31,32 Additionally, it has also been shown that decorin inhibits TGF-b mRNA transcription and TGF-b protein synthesis. 13,33 However, these functions appear to be highly cell-type specific. In certain cellular systems, decorin blocks the activity of TGF-b, whereas in others its binding augments the bioactivity of the cytokine.…”

Section: Discussionmentioning

confidence: 99%

“…3 Finally, it has been shown that ectopic expression of decorin in C6 rat glioma cells resulted in the inhibition of tumor formation in vivo. 13 These unique features make decorin a very good candidate gene for many experimental cancer gene therapy applications. Malignant gliomas frequently secrete TGF-b which creates a state of immunosuppression in the glioma microenvironment, and due to the invasive nature of glioma, throughout the surrounding brain parenchyma.…”

Section: Ecorin Plays Different Roles In Regulating Matrixmentioning

confidence: 99%

“…26 BCMGS/neo/decorin or BCMGS/neo without insert, as a control, was then transfected into CNS-1 glioma cells by electroporation. 13 PCR was used to confirm the presence of human decorin sequences in genomic DNA extracted from decorin stably transfected CNS-1 cells. A 944 bp decorin-specific PCR product was amplified using the primers decorin-fwd (5 0 -CCCA GAAGTTCCTGATGAC-3 0 ) and decorin-rev (5 0 -CA GAGCGCACGTAGACAC-3 0 ).…”

Section: Cell Culturementioning

confidence: 99%

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Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

et al. 2004

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Given the failure of conventional treatments for glioblastoma, gene therapy has gained interest considerable in recent years. Gliomas are associated with a state of immunosuppression, which appears to be partially mediated by an increase in secretion of transforming growth factor-b (TGF-b) from glioma cells. Decorin, a small proteoglycan which can bind to and inactivate TGF-b, has been successfully used as an antitumor strategy on stably transfected tumor cells and has been shown to cause growth suppression in neoplastic cells of various histological origins. In this paper, we investigated the use of gene therapy to deliver the decorin transgene in a site-specific manner in an experimental model of intracranial gliomas. Our aim was to inhibit the glioma-associated immunosuppressive state, and prolong the survival of tumor-bearing rats.We studied the effects of decorin gene transfer in the rat CNS-1 glioma model. To assess the effect of ectopic expression of decorin on glioma progression in vivo, stably transfected CNS-1 cells expressing decorin were implanted into the brain parenchyma of syngeneic Lewis rats. The rats implanted with CNS-1 cells expressing decorin survived significantly longer than those in the control groups which received CNS-1 cells that did not express decorin (Po.0001). We then investigated whether the survival observed with decorin expressing cells could be mimicked in vivo, using recombinant adenoviruses (RAds) expressing the decorin gene under the control of two different promoters: the human immediate-early cytomegalovirus (h-IE-CMV) and the glial fibrillary acidic protein (GFAP). In vivo results showed that administration of RAd expressing the human decorin under the control of h-IE-CMV promoter has a small, but significant effect in prolonging the survival of experimental tumor bearing rats (Po.0001). Our data indicate that ectopic decorin expression has the potential to slow glioma progression in vivo. Our results also indicate that expression of decorin has to be present in all cells which constitute the intracranial tumor mass for the inhibition of tumor growth and prolongation of the life expectancy of tumor-bearing rats to be effective.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ecorin Plays Different Roles In Regulating Matrixmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

See 2 more Smart Citations

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

et al. 2004

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“…De modo adicional, el TGF-β2 está implicado en la angiogénesis y en la estimulación del crecimiento tumoral 43 . Apoyando estos datos, existen experimentos con un inhibidor de este factor, la decorina, que han demostrado una supresión del crecimiento tumoral con efecto inmunoestimulador en diferentes estudios in vivo e in vitro 72,95 .…”

Section: Inmunología De Los Astrocitomasunclassified

Inmunoterapia en astrocitomas de alto grado: principios y estado actual

et al. 2005

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TGF-β-independent induction of immunogenicity by decorin gene transfer in human malignant glioma cells

et al. 1999

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Ectopic expression of the proteoglycan, decorin, abrogates the growth of experimental C6 gliomas in the rat. Since gliomas release large amounts of transforming growth factor-beta (TGF-beta) and since decorin is a TGF-beta antagonist, decorin gene transfer-mediated abrogation of glioma growth in vivo may involve enhanced immunogenicity of the tumor cells. Here, we report that human glioma cells stimulate alloreactive immune responses when engineered to express decorin whereas parental glioma cells are non-immunogenic in vitro. The alloreactive immune response is mediated by CD8+ and CD4+ T cells as well as by NK cells. The immunosuppression exerted by parental or mock-transfected glioma cells is mediated by soluble factors and can in part be mimicked by exogenous TGF-beta. However, neutralizing anti-TGF-beta antibodies do not reverse glioma-mediated immunosuppression, suggesting that decorin abrogates glioma-induced immune cell inhibition by interfering with the activity of other, so far unidentified glioma-secreted mediators. We conclude that enhanced immunogenicity may mediate the antineoplastic effects of decorin gene therapy for malignant glioma but that factors other than TGF-beta may be responsible for glioma-induced immunosuppression.

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Decorin gene transfer-mediated suppression of TGF-β synthesis abrogates experimental malignant glioma growth in vivo

Cited by 118 publications

References 24 publications

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

Inmunoterapia en astrocitomas de alto grado: principios y estado actual

TGF-β-independent induction of immunogenicity by decorin gene transfer in human malignant glioma cells

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