Tumor response to radiotherapy regulated by endothelial cell apoptosis.
About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Monica
M
Garcia-Barros
Francois
F
Paris
Carlos
C
Cordon-Cardo
David
D
Lyden
Shahin
S
Rafii
Adriana
A
Haimovitz-Friedman
Zvi
Z
Fuks
Richard
R
Kolesnick
D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology*; D005354:Fibrosarcoma / Q000098:blood supply / Q000532:radiotherapy*; D020287:In Situ Nick-End Labeling; D008546:Melanoma, Experimental / Q000098:blood supply / Q000532:radiotherapy*; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D011836:Radiation Tolerance; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D013108:Sphingomyelin Phosphodiesterase