Induced apoptosis supports spread of adenovirus vectors in tumors.
Selectively replicating viruses hold promise as anticancer agents. To eliminate the tumor, these viruses must efficiently spread throughout the tumor and induce oncolysis. We hypothesized that viral release and spread could be supported by apoptosis induced after assembly of de novo-produced virions in tumor cells. As a model to test this, we employed an adenovirus vector that replicated in human tumor cell lines. Expression of a dominant-negative I-kappaB from this vector sensitized tumor cells to recombinant human tumor necrosis factor alpha (TNF-alpha)-mediated apoptosis. We found that apoptosis induced during viral DNA replication compromised virus production, whereas apoptosis induced after virion assembly enhanced viral release from infected cells and dissemination. Electron microscopy demonstrated that viral particles were associated with or included in apoptotic bodies whose phagocytosis by neighboring cells provides a potential means for viral spread. Apoptosis induced after viral replication also supported spread in vivo, in subcutaneous tumors or liver metastases, resulting in a delay of tumor growth. Our findings could be applicable to other selectively replicating viruses or antitumor strategies that involve application of proapoptotic or cytolytic agents.
Mi
J
J
Division of Medical Genetics, Department of Medicine, University of Washington, 1705 NE Pacific St., Seattle, WA 98195, USA.
Li
Z Y
ZY
Ni
S
S
Steinwaerder
D
D
Lieber
A
A
D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D005799:Genes, Dominant; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000821:virology; D008854:Microscopy, Electron; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020672:I-kappa B Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D020169:Caspases