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.
Garcia-Barros
Monica
M
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Paris
Francois
F
Cordon-Cardo
Carlos
C
Lyden
David
D
Rafii
Shahin
S
Haimovitz-Friedman
Adriana
A
Fuks
Zvi
Z
Kolesnick
Richard
R
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