title: Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors.
abstract: Glioblastomas are the most aggressive of the brain tumors occurring in adults and children. Currently available chemotherapy prolongs the median survival time of patients by only 4 months. The low efficiency of current treatments is partly owing to the blood-brain barrier, which restricts the penetration of most drugs into the central nervous system. Locoregional treatment strategies thus become mandatory. In this context, viral tools are of great interest for the selective delivery of genes into tumoral cells. Gliomas express high levels of type 2 somatostatin receptors (sstr2A), pinpointing them as suitable targets for the improvement of transduction efficiency in these tumors. We designed a new adenoviral vector based on the introduction of the full-length somatostatin (SRIF (somatotropin release-inhibiting factor)) sequence into the HI loop of the HAdV fiber protein. We demonstrate that (i) HAdV-5-SRIF uptake into cells is mediated by sstr2A, (ii) our vector drives high levels of gene expression in cells expressing endogenous sstr2A, with up to 65-fold enhancement and (iii) low doses of HAdV-5-SRIF are sufficient to infect high-grade human primary glioblastoma cells. Adenoviral vectors targeting SRIF receptors might thus represent a promising therapeutic approach to brain tumors.
authors.affiliation: Inserm, UMR837, rue Polonovski, Lille, France.
authors.forename: K
authors.initials: K
authors.lastname: Lécolle
authors.forename: S
authors.initials: S
authors.lastname: Bégard
authors.forename: R
authors.initials: R
authors.lastname: Caillierez
authors.forename: D
authors.initials: D
authors.lastname: Demeyer
authors.forename: E
authors.initials: E
authors.lastname: Grellier
authors.forename: A
authors.initials: A
authors.lastname: Loyens
authors.forename: Z
authors.initials: Z
authors.lastname: Csaba
authors.forename: J C
authors.initials: JC
authors.lastname: Beauvillain
authors.forename: J C
authors.initials: JC
authors.lastname: D'Halluin
authors.forename: M
authors.initials: M
authors.lastname: Baroncini
authors.forename: J P
authors.initials: JP
authors.lastname: Lejeune
authors.forename: A
authors.initials: A
authors.lastname: Sharif
authors.forename: V
authors.initials: V
authors.lastname: Prévot
authors.forename: P
authors.initials: P
authors.lastname: Dournaud
authors.forename: L
authors.initials: L
authors.lastname: Buée
authors.forename: M
authors.initials: M
authors.lastname: Colin
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016466:CHO Cells; D036022:Capsid Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000493:pharmacokinetics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D016023:Integrins / Q000378:metabolism; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods*; D014407:Tumor Cells, Cultured
chemical_list: D036022:Capsid Proteins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016023:Integrins; D017481:Receptors, Somatostatin; C018315:hexon capsid protein, Adenovirus; D013004:Somatostatin; C093733:somatostatin receptor 2