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

• Published in: Clinical cancer research 2009-08, Vol.15 (15), p.4925-4934
• Main Authors: LEE, Do-Hun, AHN, Yong, KIM, Seung-Ki, KIM, Seung U, WANG, Kyu-Chang, CHO, Byung-Kyu, JI HOON PHI, IN HO PARK, BLACK, Peter M, CARROLL, Rona S, LEE, Joonyub
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antitumor effect; Biological and medical sciences; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Brainstem glioma; Cell Line, Tumor; Cell Movement - physiology; Cytosine Deaminase - metabolism; Female; Genetic Therapy - methods; Glioma - pathology; Glioma - therapy; Humans; Interferon-beta - metabolism; Medical sciences; Mesenchymal stem cell; Mesenchymal Stromal Cells - physiology; Migration; Neural stem cell; Neurology; Neurons - physiology; Pharmacology. Drug treatments; Rats; Stem Cells - physiology; Tumor tropism; Tumors of the nervous system. Phacomatoses
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-3076

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.