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Published on: July 30, 2018
Induced apoptosis supports spread of adenovirus vectors in tumors
1Division of Medical Genetics, Department of Medicine, University of Washington, 1705 NE Pacific St., Seattle, WA 98195, USA.
Abstract:
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.
Insights
Anticancer viruses spread better when tumor cell death (apoptosis) occurs after new virus particles assemble. This enhanced viral release and spread delays tumor growth, offering new strategies for cancer therapy.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Viral pathogenesis
Background:
- Selectively replicating viruses are promising anticancer agents, requiring efficient tumor spread and oncolysis for efficacy.
- Viral spread and release mechanisms are critical for effective oncolytic virotherapy.
- The role of apoptosis timing in viral replication and dissemination remains incompletely understood.
Purpose of the Study:
- To investigate the hypothesis that apoptosis induced after viral assembly supports viral release and spread.
- To determine the impact of apoptosis timing on oncolytic virus production and dissemination.
- To evaluate the therapeutic potential of apoptosis-induced viral spread in preclinical cancer models.
Main Methods:
- Utilized an adenovirus vector engineered to replicate in human tumor cell lines.
- Introduced a dominant-negative I-kappaB to sensitize tumor cells to TNF-alpha-mediated apoptosis.
- Assessed viral production, release, and spread using in vitro and in vivo models (subcutaneous tumors, liver metastases) with electron microscopy and tumor growth assays.
Main Results:
- Apoptosis induced during viral DNA replication impaired virus production.
- Apoptosis occurring after virion assembly significantly enhanced viral release and dissemination from infected cells.
- Electron microscopy revealed viral particles within apoptotic bodies, suggesting a mechanism for cell-to-cell spread.
- In vivo studies demonstrated that apoptosis-induced viral spread delayed tumor growth in subcutaneous and liver metastasis models.
Conclusions:
- Inducing apoptosis after viral assembly, rather than during replication, optimizes oncolytic virus release and spread.
- Apoptotic bodies serve as a vehicle for viral dissemination, enhancing therapeutic efficacy.
- These findings support the development of combined therapeutic strategies involving oncolytic viruses and pro-apoptotic agents for improved cancer treatment.
