Gene therapy of experimental brain tumors using neural progenitor cells

Benedetti, Sara; Pirola, Barbara; Pollo, Bianca; Magrassi, Lorenzo; Bruzzone, Maria Grazia; Rigamonti, Dorotea; Galli, Rossella; Selleri, Silvia; Meco, Francesco Di; Fraja, Claudio De; Vescovi, Angelo L.; Cattaneo, Elena; Finocchiaro, Gaetano

doi:10.1038/74710

Cited by 424 publications

(316 citation statements)

References 18 publications

Supporting

Mentioning

308

Contrasting

Unclassified

Order By: Relevance

“…Benedetti and Staflin et al described the ability of nonengineered rat neural progenitors to inhibit glioma growth in vivo. 25,26 The exact mechanism underlying the observations remains unclear, although they have reported that NSCs may elaborate a secretory agent that could inhibit tumor cell growth. For verifying this demonstration, we co-cultured BMSCs and C6 at the ratio of 1:1.…”

Section: Discussionmentioning

confidence: 99%

The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells

Huang

Xz²,

et al. 2009

Cancer Gene Ther

View full text Add to dashboard Cite

The disseminated neoplastic foci of malignant gliomas are essentially responsible for the limited efficacy of current available therapeutic modalities. Bone marrow-derived stem cells (BMSCs) have the ability to migrate into these tumors and even track infiltrating tumor cells, making them to be promising cellular vehicles for delivering therapeutic agents to glioma cells. The herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) suicide gene therapy with a potent bystander effect has been considered as one of the most promising therapeutic strategies for malignant gliomas. In this study, we evaluate the anti-glioma effect of suicide gene therapy using BMSCs expressing HSV-TK combined with overexpression of connexin 43 (Cx43), which can restore the gap junction of intercellular communication and may enhance the bystander effect of suicide gene therapy. To assess the potential of BMSCs to track glioma cells, a spheroid co-culture system in matrigel was used to show that some BMSCs migrated to C6 glioma cell microspheres. Transwell assay showed the tumor tropic property of BMSCs. In addition, BrdU-labeled BMSCs injected directly into the cerebral hemisphere opposite to the established C6 rat gliomas were capable of migrating into the xenograft gliomas. C6 cell growth was more intensively inhibited by HSV-TK/GCV treatment mediated by BMSCs, and could be further enhanced by combination with Cx43 transfection into glioma cells. The same result was observed in vivo by the growth of C6 gliomas and the survival analysis of rats bearing C6 glioma. In conclusion, Cx43 combined with HSV-TK/GCV gene therapy using BMSCs as vehicles was highly effective in a rat glioma model and therefore hold great potential as a novel approach for the gene therapy of human malignant gliomas.

show abstract

Section: Discussionmentioning

confidence: 99%

The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells

Huang

Xz²,

et al. 2009

Cancer Gene Ther

View full text Add to dashboard Cite

show abstract

“…DC injection induced specific T-cell reactivity against 9L, the level of response was rather modest. 26 Cytokine gene therapy for gliomas appears to have a promising future, based on encouraging results in murine models, 19,27 although the efficacy in orthotopic i.c. models remains inferior to that observed in systemic tumor models.…”

Section: Glioma Gene Therapy With Ifn-a and Dcsmentioning

confidence: 99%

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

et al. 2004

View full text Add to dashboard Cite

Effective presentation of tumor antigens by dendritic cells (DCs) is considered to be essential for the induction of antitumor T-cell responses. Apoptotic and necrotic tumors have been noted to be a robust antigen source for DCs. Because glioma cells undergo apoptosis after transfection with the type I interferon (IFN) gene and type I IFNs promote the stimulatory activity of DCs, we hypothesized that transfection of glioma cells with type I IFN genes and provision of DCs would promote particularly effective antitumor activity by both facilitating apoptosis of glioma cells and the presentation of the glioma antigens, thereby inducing specific immune responses against glioma cells. We have previously reported the proof of this hypothesis in vitro and in a subcutaneous tumor model. Here we report an extension of this approach in intracranial (i.c.) gliomas using adenoviral IFN-a (Ad-IFN-a) vector. Mice bearing day-5 i.c. GL261 glioma received sequential intratumoral (i.t.) delivery of Ad-IFN-a and bone marrow-derived syngeneic DCs. This treatment prolonged survival in that nine of 17 animals survived long term (460 days versus 0 of 10 control animals). Specific CTL activity was demonstrated following this regimen in the cervical lymph nodes, and the therapeutic efficacy was dependent upon CD8+ cells. Furthermore, these animals were protected against subsequent rechallenge with GL261 gliomas. DCs injected i.t. survived in the tumor and migrated into cervical lymph node. In vitro migration assays revealed the ability of DCs to migrate toward the tumor, suggesting that i.t. injected DCs migrate through the glioma. Taken together, this combination of gene therapy and cellular immunotherapy may be an effective future strategy for treating human gliomas.

show abstract

“…This gene therapy approach was based on the grafting of neural stem cells (NSC) producing therapeutic molecules. 77 Well-characterized NSC lines (lacZ and/or CD-positive) injected into the tail vein of adult nude mice with established experimental intracranial and/or subcutaneous flank tumors of neural and non-neural origin were localized to various tumor sites with little accumulation in normal tissues. These findings suggested that intravascularly administered NSCs may be an effective delivery vehicle to target invasive tumors of neural and non-neural origin, both within and outside the brain.…”

Section: Stem Cellsmentioning

confidence: 99%