Open AccessEctopic matrix metalloproteinase-9 expression in human brain tumor cells enhances oncolytic HSV vector infection
Author(s) -
ChangSook Hong,
Wendy Fellows,
Ajay Niranjan,
Sean Alber,
Simon C. Watkins,
Justus B. Cohen,
Joseph C. Glorioso,
Paola Grandi
Publication year - 2010
Publication title -
gene therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.332
H-Index - 159
eISSN - 1476-5462
pISSN - 0969-7128
DOI - 10.1038/gt.2010.66
Subject(s) - oncolytic virus , mmp9 , extracellular matrix , in vivo , biology , matrix metalloproteinase , herpes simplex virus , cancer research , viral vector , glioma , brain tumor , genetic enhancement , vector (molecular biology) , gene delivery , in vitro , cell culture , virus , immunology , pathology , transfection , microbiology and biotechnology , medicine , downregulation and upregulation , tumor cells , gene , recombinant dna , biochemistry , genetics
Oncolytic herpes simplex virus (oHSV) vectors have shown promise in the treatment of patients with recurrent brain tumors although few complete responses have accrued. Impediments to effective therapy include limited vector distribution on delivery, a consequence of injected virion particle trapping in the tumor extracellular matrix (ECM). To enhance virus delivery and spread, we investigated the use of the matrix metalloproteinase-9 (MMP-9) as a means to degrade collagen type IV, a major component of the ECM and basement membranes of gliomas that is absent in normal brain tissue. SK-N-AS neuroblastoma cells were transduced for constitutive, elevated expression of MMP-9, which did not enhance tumor cell migration in vitro or tumor progression in a murine xenograft brain tumor model. MMP-9 expression improved the distribution and infection of oHSV vectors in spheroid model in vitro. Furthermore, MMP9 induced a vector infection over larger areas of brain tumors in vivo. These results suggest that vector delivery and distribution in vivo can be improved by compromising the ECM, potentially enhancing oncolytic efficacy.