Human neural stem cells transduced with IFN-β and cytosine deaminase genes intensify bystander effect in experimental glioma

Abstract

Previously, we have shown that the genetically modified human neural stem cells (NSCs) show remarkable migratory and tumortropic capability to track down brain tumor cells and deliver therapeutic agents with significant therapeutic benefit. Human NSCs that were retrovirally transduced with cytosine deaminase (CD) gene showed remarkable 'bystander killer effect' on the glioma cells after application of the prodrug, 5-fluorocytosine (5-FC). Interferon-b (IFN-b) is known for its antiproliferative effects in a variety of cancers. In our pilot clinical trial in glioma, the IFN-b gene has shown potent antitumor activity in patients with malignant glioma. In the present study, we sought to examine whether human NSCs genetically modified to express both CD and IFN-b genes intensified antitumor effect on experimental glioma. In vitro studies showed that CD/IFN-b-expressing NSCs exerted a remarkable bystander effect on human glioma cells after the application of 5-FC, as compared with parental NSCs and CD-expressing NSCs. In animal models with human glioma orthotopic xenograft, intravenously infused CD/IFN-b-expressing NSCs produced striking antitumor effect after administration of the prodrug 5-FC. Furthermore, the same gene therapy regimen prolonged survival periods significantly in the experimental animals. The results of the present study indicate that the multimodal NSC-based treatment strategy might have therapeutic potential against gliomas.

Induction of Apoptosis in Glioma Cells and Upregulation of Fas Expression Using the Human Interferon-β Gene

“…Despite the clinical activity of IFN-β on malignant gliomas (Lin et al, 2004;Yoshida et al, 2004;Ito et al, 2010), its antitumor mechanism in vivo remains unclear.…”

Development of Anti-Cancer Stem Cells as Theranostic Agents in the Treatment of Different Cancer Types: An Update

“…An example the appearance of organic agents that attach to epidermal growth factor receptor (EGFR) or with tumor specific variant EGFRvIII [158,159] and cytokines like interferon-β (IFNβ) and IFNα41, it controls the tumor growth in a negative way but in different preclinical cancer models [160][161][162][163][164]. Some of the effectors involving that agents restrain the development of tumor-associated vasculature, for instance antangiogenic thrombospondin 1 (TSP also called as THBS1) [165] and PEX which is a part of MMP2, successfully restrict the development of tumor accumulation due to having a nonpermissive microenvironment [166].…”

Stem cell technology and engineering for cancer treatment

“…MSCs-based gene therapy has been used to treat several diseases in animal models including glioblastoma (Altaner et al, 2014;Altanerova et al, 2012;Fei et al, 2012;Lee et al, 2009), prostate cancer (Cavarretta et al, 2010), melanoma (Kucerova et al, 2008), gastrointestinal cancer (You et al, 2009), and other malignancies. Along with MSCs, neural stem cells (NSCs) carrying suicide enzyme have shown to reduce tumor volume and to increase survival in mouse model of malignant disease including medulloblastoma (Kim et al, 2006), melanoma brain metastases (Aboody et al, 2006), glioblastoma (Barresi et al, 2003;Ito et al, 2010), breast cancer brain metastases (Joo et al, 2009), prostate cancer , and breast cancer (Yi et al, 2014).…”