Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation.
The family of vascular endothelial growth factor (VEGF) proteins include potent and specific mitogens for vascular endothelial cells that function in the lation of angiogenesis Inhibition of VEGF-induced angiogenesis either by neutralizing antibodies or dominant-negative soluble receptor, blocks the growth of primary and metastatic experimental tumors Here we report that VEGF expression is induced in Lewis lung carcinomas (LLCs) both in vitro and vivo after exposure to ionizing radiation (IR) and in human tumor cell lines (Seg-1 esophageal adenocarcinoma, SQ20B squamous cell carcinoma, T98 and U87 glioblastomas, and U1 melanoma) in vitro. The biological significance of IR-induced VEGF production is supported by our finding that treatment of tumor-bearing mice (LLC, Seg-1, SQ20B, and U87) with a neutralizing antibody to VEGF-165 before irradiation is associated with a greater than additive antitumor effect. In vitro, the addition of VEGF decreases IR-induced killing of human umbilical vein endothelial cells, and the anti-VEGF treatment potentiates IR-induced lethality of human umbilical vein endothelial cells. Neither recombinant VEGF protein nor neutralizing antibody to VEGF affects the radiosensitivity of tumor cells These findings support a model in which induction of VEGF by IR contributes to the protection of tumor blood vessels from radiation-mediated cytotoxicity and thereby to tumor radioresistance.
Department of Radiation and Cellular Oncology, University of Chicago, Illinois 60637, USA.
D H
DH
Gorski
M A
MA
Beckett
N T
NT
Jaskowiak
D P
DP
Calvin
H J
HJ
Mauceri
R M
RM
Salloum
S
S
Seetharam
A
A
Koons
D M
DM
Hari
D W
DW
Kufe
R R
RR
Weichselbaum
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000150:complications / Q000503:physiopathology / Q000532:radiotherapy*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013312:Stress, Physiological / Q000235:genetics / Q000503:physiopathology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000528:radiation effects; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011838:Radiation-Sensitizing Agents; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors