Abstract
Glioblastoma multiforme (GBM) is the most common and lethal form of brain cancer and these tumors are highly resistant to chemo- and radiotherapy. Radioresistance is thought to result from a paucity of molecular oxygen in hypoxic tumor regions, resulting in reduced DNA damage and enhanced cellular defense mechanisms. Efforts to counteract tumor hypoxia during radiotherapy are limited by an attendant increase in the sensitivity of healthy brain tissue to radiation. However, the presence of heightened levels of molecular oxygen during radiotherapy, while conventionally deemed critical for adjuvant oxygen therapy to sensitize hypoxic tumor tissue, might not actually be necessary. We evaluated the concept that pre-treating tumor tissue by transiently elevating tissue oxygenation prior to radiation exposure could increase the efficacy of radiotherapy, even when radiotherapy is administered after the return of tumor tissue oxygen to hypoxic baseline levels. Using nude mice bearing intracranial U87-luciferase xenografts, and in vitro models of tumor hypoxia, the efficacy of oxygen pretreatment for producing radiosensitization was tested. Oxygen-induced radiosensitization of tumor tissue was observed in GBM xenografts, as seen by suppression of tumor growth and increased survival. Additionally, rodent and human glioma cells, and human glioma stem cells, exhibited prolonged enhanced vulnerability to radiation after oxygen pretreatment in vitro, even when radiation was delivered under hypoxic conditions. Over-expression of HIF-1α reduced this radiosensitization, indicating that this effect is mediated, in part, via a change in HIF-1-dependent mechanisms. Importantly, an identical duration of transient hyperoxic exposure does not sensitize normal human astrocytes to radiation in vitro. Taken together, these results indicate that briefly pre-treating tumors with elevated levels of oxygen prior to radiotherapy may represent a means for selectively targeting radiation-resistant hypoxic cancer cells, and could serve as a safe and effective adjuvant to radiation therapy for patients with GBM.
Highlights
Primary malignant gliomas are the most common type of brain cancer in adults, with an estimated 23,000 people newly diagnosed each year in the U.S [1]
Ethics statement Primary human Glioblastoma multiforme (GBM) cultures enriched for glioma stem cells (GSCs) termed 0308 were initially obtained from surgical resections from GBM patients (‘‘Following informed consent, human tumor samples classified as GBM based on World Health Organization (WHO) criteria were obtained from patients undergoing surgical treatment at the National Institutes of Health in accordance with the appropriate Institutional Review Boards.’’) as previously described [27]
In order to assess the impact of this pretreatment protocol on tissue oxygen levels, a Licox oxygen probe was used to measure levels of dissolved oxygen in both tumor, and contralateral healthy brain tissue of the same brain, in tumor-bearing mice at day 14 post-tumor implant (PTI) (Figure 1A)
Summary
Primary malignant gliomas are the most common type of brain cancer in adults, with an estimated 23,000 people newly diagnosed each year in the U.S [1]. Glioblastoma multiforme (GBM) - the most common and deadly form of these tumors - remains an incurable disease, and even with the most aggressive treatment protocols available the average life expectancy for patients diagnosed with GBM is 12–15 months [2]. The World Health Organization (WHO) classifies GBM as a Grade IV primary brain tumor, characterized by its rapid cell proliferation, cellular atypia, angiogenesis, and aggressive invasion of tumor cells into healthy brain tissue [3]. The rapid rate of tumor growth can outstrip neovascularization, creating diffusion distances too great to provide sufficient blood flow, and poorly orchestrated angiogenesis can lead to incompetent, leaky, and blunted blood vessels [4,5,6]. Tumor hypoxia in GBM is an important factor in tumor aggression and progression, and represents a significant impediment for the success of chemo- and radiotherapies [7,8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
