title: Systemic delivery of fusogenic membrane glycoprotein-expressing neural stem cells to selectively kill tumor cells.
abstract: Intravenously injected neural stem cells (NSCs) can infiltrate both primary and metastatic tumor sites; thus, they are attractive tumor-targeting vehicles for delivering anticancer agents. However, because the systemic distribution of the injected NSCs involves normal organs and might induce off-target actions leading to unintended side effects, clinical applications of this approach is impeded. Given that the vesicular stomatitis virus glycoprotein (VSV-G) can promote the formation of multinucleated syncytia to kill cells in a pH-dependent manner, we engineered a pH sensor of VSV-G and generated a novel VSV-G mutant that efficiently promotes syncytium formation at the tumor extracellular pH (pHe) but not at pH 7.4. Using transduced NSCs derived from induced pluripotent stem cells (iPSCs), the VSV-G mutant was delivered into mice with metastatic breast cancers in the lung through tail vein injection. Compared with the conventional stem cell-based gene therapy that uses the herpes simplex virus thymidine kinase (HSVtk) suicide gene, this treatment did not display toxicity to normal non-targeted organs while retaining therapeutic effects in tumor-bearing organs. Our findings demonstrate the effectiveness of a new approach for achieving tumor-selective killing effects following systemic stem cell administration. Its potential in stem cell-based gene therapy for metastatic cancer is worthy of further exploration.
authors.affiliation: Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
authors.forename: Detu
authors.initials: D
authors.lastname: Zhu
authors.forename: Dang Hoang
authors.initials: DH
authors.lastname: Lam
authors.forename: Yovita Ida
authors.initials: YI
authors.lastname: Purwanti
authors.forename: Sal Lee
authors.initials: SL
authors.lastname: Goh
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Wu
authors.forename: Jieming
authors.initials: J
authors.lastname: Zeng
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D016923:Cell Death; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D005260:Female; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D015726:Giant Cells / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D058953:Neural Stem Cells / Q000378:metabolism* / Q000637:transplantation*; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins