title: Induced transgene expression for the treatment of solid tumors by hematopoietic stem cell-based gene therapy.
abstract: Tumor microenvironment is composed of different cell types including immune cells. Far from acting to eradicate cancer cells, these bone marrow-derived components could be involved in carcinogenesis and/or tumor invasion and metastasis. Here, we describe an alternative approach to treat solid tumors based on the genetic modification of hematopoietic stem and progenitor cells with lentiviral vectors. To achieve transgene expression in derivative tumor infiltrating leukocytes and to try to decrease systemic toxicity, we used the stress inducible human HSP70B promoter. Functionality of the promoter was characterized in vitro using hyperthermia. Antitumor efficacy was assessed by ex vivo genetic modification of lineage-negative cells with lentiviral vectors encoding the dominant-negative mutant of the human transforming growth factor-β receptor II (TβRIIDN) driven by the HSP70B promoter, and reinfusion of cells into recipient mice. Subsequently, syngeneic GL261 glioma cells were subcutaneously injected into bone marrow-transplanted mice. As a result, a massive antitumor response was observed in mice harboring TβRIIDN under the HSP70B promoter, without the need of any external source of stress. In summary, this study shows that stem cell-based gene therapy in combination with spatial and temporal control of transgene expression in derivative tumor-infiltrating cells represents an alternative strategy for the development of novel antitumor therapies.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Noyan
authors.forename: I Avedillo
authors.initials: IA
authors.lastname: Díez
authors.forename: M
authors.initials: M
authors.lastname: Hapke
authors.forename: C
authors.initials: C
authors.lastname: Klein
authors.forename: R A
authors.initials: RA
authors.lastname: Dewey
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000601:surgery / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics / Q000601:surgery / Q000628:therapy*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000601:surgery / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D019076:Transgenes
chemical_list: D018840:HSP70 Heat-Shock Proteins; C491129:HSPA7 protein, human; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II