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-beta (
TGF-beta) from
glioma cells.
Decorin, a small
proteoglycan which can bind to and inactivate
TGF-beta, 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 (P < .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 (P < .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.