Targeting Rat Brainstem Glioma Using Human Neural Stem Cells and Human Mesenchymal Stem Cells

Abstract

Purpose: Brainstem gliomas are usually inoperable and have a dismal prognosis.Based on the robust tropisms of neural stem cells (NSC) and mesenchymal stem cells (MSC) to brain tumors, we compared the tumor-tropic migratory capacities of these stem cells and evaluated the therapeutic potential of genetically engineered human NSCs encoding cytosine deaminase (CD) and IFNβ against brainstem gliomas. Experimental Design: The directed migratory capacities of NSCs and MSCs to brainstem glioma (F98) were evaluated both in vitro and in vivo. The human NSCs (HB1. F3) and various human MSCs, such as bone marrow-derived MSCs (HM3.B10), adipose tissue-derived MSCs, and umbilical cord blood-derived MSCs, were tested. Human fibroblast cells (HFF-1) were used as the negative control. As a proof of concept, the bioactivity of HB1.F3-CD-IFNβ was analyzed with a cell viability assay, and animals with brainstem gliomas were injected with HB1.F3-CD-IFNβ cells followed by systemic 5-fluorocytosine treatment.Results: In an in vitro modified Transwell migration assay and in vivo stem cell injection into established brainstem gliomas in rats, all the stem cells showed a significant migratory capacity compared with that of the control (P < 0.01). Histologic analysis showed a 59% reduction in tumor volume in the HB1.F3-CD-IFNβ-treated group (P < 0.05). Apoptotic cells were increased 2.33-fold in animals treated with HB1.F3-CD-IFNβ compared with the respective control groups (P < 0.01). Conclusion: The brainstem glioma-tropic migratory capacities of MSCs from various sources were similar to those of NSCs. Genetically engineered NSCs show therapeutic efficacy against brainstem gliomas.

Migration of mouse-induced pluripotent stem cells to glioma-conditioned medium is mediated by tumor-associated specific growth factors

“…For iPS cells to function appropriately, the migratory activity of iPS cells to the appropriate regions is crucial. Although numerous studies have shown the in vitro and in vivo tumortropic migratory ability of NSCs and MSCs to malignant gliomas (6,7,9,11,12,15,30,31), studies of migratory activity of iPS cells have yet to be performed.…”

“…Accumulating evidences of tropism of stem cells for malignant glioma (6) show that gene therapies, using stem cells as the vehicles for therapeutic agents, have emerged as a promising treatment modality for malignant glioma. Furthermore, a number of preclinical trials of stem cell-based gene therapies have shown that neural stem cells (NSCs) are effective tumor-specific delivery vehicles for transgenes to malignant glioma (7)(8)(9)(10)(11)(12). Similarly, evidence indicated that bone marrow-derived mesenchymal stem cells (MSCs) are effective vehicles for the delivery of gene therapies to malignant glioma (5,13).…”

Advances in the research of basic study and clinical application of adipose-derived mesenchymal stem cells

“…[47] Based on this characteristic, ADSC can be genetically modified to carry specific genes into the target tissue for expression, so as to play a therapeutic role. This method has become a research hotspot, for example, combined use of stem cells and precursor drugs for cancer treatment.…”

Stem cell technology and engineering for cancer treatment

“…Active drugs are able to attack neighboring cancer cells via the gap junction, intracellular communication, and connexins; this process is known as bystander effect (Kandouz and Batist, 2010). 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).…”