Tumor Response to Radiotherapy Regulated by Endothelial Cell Apoptosis
Monica Garcia-Barros, Francois Paris, Carlos Cordon-Cardo, David Lyden, Shahin Rafii, Adriana Haimovitz-Friedman, Zvi Fuks, Richard Kolesnick- Multidisciplinary
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.