title: Controlled Secretion of the Anticancer Protein MDA-7 from Engineered Mesenchymal Stem Cells.
abstract: Mesenchymal stem cells (MSCs) have been explored as a "live" carrier of cytokines for targeted cancer therapy, but, in earlier reports in the literature, the secretion process of therapeutic cytokines was not regulated. The purpose of this study was to generate MSCs to conditionally secrete the melanoma differentiation-associated gene-7 (MDA-7) tumor-suppressor protein. To control the secretion of MDA-7 from MSCs, a well-established tetracycline-controlled transcriptional activation system was incorporated into MDA-7 plasmid. MDA-7 gene expression was induced in the engineered MSCs only in the presence of doxycycline, as characterized by quantitative reverse transcription (qRT)-PCR. Enzyme-linked immunosorbent assay (ELISA) also revealed that the MDA-7 protein was secreted from the engineered MSCs only after the cells had been exposed to doxycycline. Both recombinant human MDA-7 protein and the conditioned medium from the engineered MSCs in the presence of doxycycline significantly inhibited tube formation of human umbilical vascular endothelial cells (HUVECs), indicating that our system could be used for targeted, antiangiogenic therapy. Overall, this study provides useful information on the potential use of engineered MSCs for the controlled secretion of therapeutic proteins, in this case MDA-7, for targeted cancer therapy.
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences.
authors.forename: Atsunobu
authors.initials: A
authors.lastname: Sagara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Karasawa
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Igarashi
authors.forename: Maky
authors.initials: M
authors.lastname: Otsuka
authors.forename: Rei
authors.initials: R
authors.lastname: Sugiura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kodama
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Yamashita
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kato
mesh_terms: D000818:Animals; D004318:Doxycycline / Q000494:pharmacology*; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000099180:Interleukin-24
chemical_list: D004318:Doxycycline; D007378:Interleukins; D011994:Recombinant Proteins; D000099180:Interleukin-24