Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery

PLoS One. 2010 Sep 30;5(9):10.1371/annotation/6e222ad5-b175-4a00-9d04-4d120568a897. doi: 10.1371/annotation/6e222ad5-b175-4a00-9d04-4d120568a897.

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.

Publication types

  • Corrected and Republished Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Published Erratum

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Apoptosis / drug effects
  • Cattle
  • Cell Line, Tumor
  • Ceramides / metabolism
  • Disease Models, Animal
  • Endothelium / cytology
  • Endothelium / drug effects
  • Endothelium / metabolism*
  • Endothelium / radiation effects
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasms / drug therapy*
  • Neoplasms / physiopathology
  • Neoplasms / radiotherapy*
  • Radiation-Sensitizing Agents / therapeutic use*
  • Radiotherapy Dosage
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Ceramides
  • DC101 monoclonal antibody
  • Radiation-Sensitizing Agents
  • Vascular Endothelial Growth Factor A
  • N-palmitoylsphingosine
  • acid sphingomyelinase-1
  • Sphingomyelin Phosphodiesterase