Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery Journal Article
| Authors: | Truman, J. P.; Garcia-Barros, M.; Kaag, M.; Hambardzumyan, D.; Stancevic, B.; Chan, M.; Fuks, Z.; Kolesnick, R.; Haimovitz-Friedman, A. |
| Article Title: | Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery |
| Abstract: | Background: While there is significant interest in combining anti-angiogenesis therapy with conventional anti-cancer treatment, clinical trials have as of yet yielded limited therapeutic gain, mainly because mechanisms of anti-angiogenic therapy remain to a large extent unknown. Currently, anti-angiogenic tumor therapy is conceptualized to either "normalize" dysfunctional tumor vasculature, or to prevent recruitment of circulating endothelial precursors into the tumor. An alternative biology, restricted to delivery of anti-angiogenics immediately prior to single dose radiotherapy (radiosurgery), is provided in the present study. Methodology/Principal Findings: Genetic data indicate an acute wave of ceramide-mediated endothelial apoptosis, initiated by acid sphingomyelinase (ASMase), regulates tumor stem cell response to single dose radiotherapy, obligatory for tumor cure. Here we show VEGF prevented radiation-induced ASMase activation in cultured endothelium, occurring within minutes after radiation exposure, consequently repressing apoptosis, an event reversible with exogenous C16-ceramide. Anti-VEGFR2 acts conversely, enhancing ceramide generation and apoptosis. In vivo, MCA/129 fibrosarcoma tumors were implanted in asmase+/+ mice or asmase-/- littermates and irradiated in the presence or absence of anti-VEGFR2 DC101 or anti-VEGF G6-31 antibodies. These anti-angiogenic agents, only if delivered immediately prior to single dose radiotherapy, de-repressed radiation-induced ASMase activation, synergistically increasing the endothelial apoptotic component of tumor response and tumor cure. Anti-angiogenic radiosensitization was abrogated in tumors implanted in asmase-/- mice that provide apoptosis-resistant vasculature, or in wild-type littermates pre-treated with anti-ceramide antibody, indicating that ceramide is necessary for this effect. Conclusions/Significance: These studies show that angiogenic factors fail to suppress apoptosis if ceramide remains elevated while anti-angiogenic therapies fail without ceramide elevation, defining a ceramide rheostat that determines outcome of single dose radiotherapy. Understanding the temporal sequencing of anti-angiogenic drugs and radiation enables optimized radiosensitization and design of innovative radiosurgery clinical trials. © 2010 Truman et al. |
| Keywords: | signal transduction; vasculotropin; controlled study; treatment response; vascular endothelial growth factor a; unclassified drug; drug activity; angiogenesis inhibitor; nonhuman; radiation dose; neoplasm; neoplasms; mouse; animal; metabolism; animals; mice; mice, knockout; cell death; cell survival; mus; low drug dose; apoptosis; radiotherapy dosage; animal experiment; animal model; in vivo study; enzyme activation; drug effect; pathology; cell line, tumor; neovascularization, pathologic; vascularization; radiation exposure; time; time factors; monoclonal antibody; endothelium cell; endothelial cells; fibroblast growth factor 2; cancer inhibition; immunology; antibodies, monoclonal; fibrosarcoma; cell culture; gene repression; radiosurgery; tumor cell line; cell membrane; vasculotropin a; single drug dose; cattle; disease models, animal; endothelium; angiogenesis inhibitors; tumor vascularization; radiosensitizing agent; radiation-sensitizing agents; vasculotropin antibody; neovascularization (pathology); radiosensitization; ceramide; ceramides; growth inhibition; sphingomyelin phosphodiesterase; basic fibroblast growth factor; monoclonal antibody dc101; monoclonal antibody g6 31 |
| Journal Title: | PLoS ONE |
| Volume: | 5 |
| Issue: | 9 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2010-09-30 |
| Start Page: | e12310 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0012310 |
| PUBMED: | 20941382 |
| PROVIDER: | scopus |
| PMCID: | PMC2947950 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "Art. No.: e12310" - "Source: Scopus" |
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