Cancer-killing, or oncolytic, viruses show promise as therapy for brain tumors.
Clinical trials indicate that oncolytic virus therapy is safe but not as effective as expected in humans.
This study discovered a way that tumor cells block the therapeutic virus. Inhibiting this response might improve the therapy's effectiveness.
COLUMBUS, Ohio – Brain-tumor cells that are infected with a cancer-killing virus release a protein "alarm bell" that warns other tumor cells of the impending infection and enables them to mount a defense against the virus, according to a study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
The infected tumor cells release a protein called CCN1 into the narrow space between cells where it initiates an antiviral response. The response limits the spread of the oncolytic virus through the tumor, reducing its ability to kill cancer cells and limiting the efficacy of the therapy.
The study suggests that cells in general might use this mechanism to help control viral infections, and that blocking the response might improve oncolytic viral therapy for glioblastoma and perhaps future gene therapy treatments.
Oncolytic viruses replicate in tumor cells and kill them. They have shown promise for the treatment of glioblastoma, the most common and deadly form of brain cancer. Patients with glioblastoma survive about 15 months after diagnosis on average, so there is great need for new treatments.
The study was published in a recent issue of the journal Cancer Research.
"We found that, in the extracellular matrix, this protein orchestrates a striking cellular antiviral response that reduces viral replication and limits its cytolytic efficacy," says researcher and principal investigator Balveen Kaur, associate professor of Neurological Surgery at the OSUCCC – James.
"These findings are significant because they reveal a novel mechanism used by infected cells to fight viral infections and alert adjacent uninfected cells to prepare their defenses to fight off forthcoming viral attacks," Kaur says.
Kaur notes that CCN1 helps regulate cellular functions that include adhesion, migration, and proliferation, and that it is overexpressed in 68 percent of glioblastoma specimens.
Previous research led by Kaur found that oncolytic virus therapy induced the release of CCN1 into the tumor microenvironment. For this study, Kaur and her colleagues used glioma cell lines, oncolytic viruses derived from human herpesvirus type 1 (HSV-1), and glioblastoma animal models. Key findings include:
CNN1 expression is upregulated by the oncolytic virus but not by chemotherapy or radiation treatment. Thus, it may be a general response of glioma cells to viral infection.
In the extracellular space, CCN1 reduces viral replication and the killing of glioma cells.
CCN1 induces a type-I interferon antiviral response using an integrin cell-surface receptor.
"Overall, this finding reveals how extracellular signaling can contribute to viral clearance," Kaur says. "We can now utilize this knowledge to improve future viral gene therapy."
Funding from the National Cancer Institute and the National Institute of Neurological Disorders and Stroke supported this research.
Other researchers involved in this study were Amy Haseley, Sean Boone, Jeffrey Wojton, Lianbo Yu, Ji Young Yoo, Jianhua Yu and Michael A. Caligiuri of Ohio State; Kazuhiko Kurozumi of Okayama University, Okayama Japan; and Joseph C. Glorioso of the University of Pittsburgh.
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 40 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only seven centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 210-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top 20 cancer hospitals in the nation as ranked by U.S.News & World Report.
A high quality JPEG of Balveen Kaur, PhD is available here.
Contact: Darrell E. Ward, Medical Center Public Affairs and Media Relations,
614-293-3737, or Darrell.Ward@osumc.edu