Primary gene-engineered neural stem/progenitor cells demonstrate tumor-selective migration and antitumor effects in glioma.
The prognosis of patients with glioblastoma multiforme (GBM) is generally poor after surgical tumor resection. With the aim of developing new adjuvant therapeutic strategies, we have investigated primary neural stem/progenitor cells (NSPC) in co-cultures with glioma cells, and in a model of gene therapy on aggressively growing malignant glioma. NSPC exhibited tropism towards medium conditioned by glioma cells, and in adherent low-cell density co-culture, were attracted to, and fused with, tumor cells. Similarly, within 24-48 hr of co-culture in suspension, NSPC-tumor hybrids were observed, representing 2-3% of the total cell population. NSPC were then coinjected into mouse brain with GBM cells, employing NSPC expressing cyclophosphamide (CPA)-activating enzyme cytochrome p450 2B6 (CYP2B6), which catalyzes CPA prodrug transformation into membrane diffusible DNA-alkylating metabolites. Upon CPA administration, NSPC containing CYP2B6 elicited substantial impairment of tumor growth. When implanted intracerebrally at a distant site from the tumor, gene-engineered NSPC specifically targeted GBM grafts, after traveling through brain parenchyma, and hindered tumor growth through local activation of CPA. Directed migration of primary NSPC corresponded closely with intracerebral and tumoral pattern of expression of vascular endothelial growth factor, which is a motility factor for NSPC. Overall, these findings indicate that therapeutic gene delivery mediated by primary NSPC is a potentially valid strategy for treatment of high-grade gliomas.
Mercapide
Javier
J
Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
Rappa
Germana
G
Anzanello
Fabio
F
King
Judy
J
Fodstad
Oystein
O
Lorico
Aurelio
A
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001932:Brain Neoplasms / Q000628:therapy*; D002454:Cell Differentiation; D002465:Cell Movement; D018920:Coculture Techniques; D003520:Cyclophosphamide / Q000494:pharmacology; D065702:Cytochrome P-450 CYP2B6; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000628:therapy*; D006822:Hybrid Cells / Q000637:transplantation*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D013234:Stem Cells / Q000166:cytology*; D014161:Transduction, Genetic
D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating