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

Jean Philip Truman, Mónica García-Barros, Matthew Kaag, Dolores Hambardzumyan, Branka Stancevic, Michael Chan, Zvi Fuks, Richard Kolesnick, Adriana Haimovitz-Friedman

Research output: Contribution to journalArticle

87 Citations (Scopus)

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 C 16 -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.

Original languageEnglish (US)
Article numbere12310
JournalPloS one
Volume5
Issue number8
DOIs
StatePublished - Oct 20 2010

Fingerprint

Radiosurgery
ceramides
Ceramides
Tumors
Membranes
neoplasms
Radiotherapy
radiotherapy
Sphingomyelin Phosphodiesterase
apoptosis
Neoplasms
Dosimetry
Apoptosis
therapeutics
Radiation
dosage
Vascular Endothelial Growth Factor A
Acids
clinical trials
acids

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Truman, J. P., García-Barros, M., Kaag, M., Hambardzumyan, D., Stancevic, B., Chan, M., ... Haimovitz-Friedman, A. (2010). Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery. PloS one, 5(8), [e12310]. https://doi.org/10.1371/journal.pone.0012310
Truman, Jean Philip ; García-Barros, Mónica ; Kaag, Matthew ; Hambardzumyan, Dolores ; Stancevic, Branka ; Chan, Michael ; Fuks, Zvi ; Kolesnick, Richard ; Haimovitz-Friedman, Adriana. / Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery. In: PloS one. 2010 ; Vol. 5, No. 8.
@article{eb20cf4243fc4571a8b625485bea6143,
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 C 16 -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.",
author = "Truman, {Jean Philip} and M{\'o}nica Garc{\'i}a-Barros and Matthew Kaag and Dolores Hambardzumyan and Branka Stancevic and Michael Chan and Zvi Fuks and Richard Kolesnick and Adriana Haimovitz-Friedman",
year = "2010",
month = "10",
day = "20",
doi = "10.1371/journal.pone.0012310",
language = "English (US)",
volume = "5",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

Truman, JP, García-Barros, M, Kaag, M, Hambardzumyan, D, Stancevic, B, Chan, M, Fuks, Z, Kolesnick, R & Haimovitz-Friedman, A 2010, 'Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery', PloS one, vol. 5, no. 8, e12310. https://doi.org/10.1371/journal.pone.0012310

Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery. / Truman, Jean Philip; García-Barros, Mónica; Kaag, Matthew; Hambardzumyan, Dolores; Stancevic, Branka; Chan, Michael; Fuks, Zvi; Kolesnick, Richard; Haimovitz-Friedman, Adriana.

In: PloS one, Vol. 5, No. 8, e12310, 20.10.2010.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery

AU - Truman, Jean Philip

AU - García-Barros, Mónica

AU - Kaag, Matthew

AU - Hambardzumyan, Dolores

AU - Stancevic, Branka

AU - Chan, Michael

AU - Fuks, Zvi

AU - Kolesnick, Richard

AU - Haimovitz-Friedman, Adriana

PY - 2010/10/20

Y1 - 2010/10/20

N2 - 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 C 16 -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.

AB - 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 C 16 -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.

UR - http://www.scopus.com/inward/record.url?scp=77957890055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957890055&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0012310

DO - 10.1371/journal.pone.0012310

M3 - Article

C2 - 20941382

AN - SCOPUS:77957890055

VL - 5

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e12310

ER -