Tumor response to radiotherapy regulated by endothelial cell apoptosis

Science. 2003 May 16;300(5622):1155-9. doi: 10.1126/science.1082504.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Bone Marrow Transplantation
  • Disease Models, Animal
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / pathology*
  • Fibrosarcoma / blood supply
  • Fibrosarcoma / radiotherapy*
  • In Situ Nick-End Labeling
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / radiotherapy*
  • Mice
  • Neoplasm Transplantation
  • Neovascularization, Pathologic
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2*
  • Radiation Tolerance
  • Sphingomyelin Phosphodiesterase / genetics
  • bcl-2-Associated X Protein

Substances

  • Bax protein, mouse
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Sphingomyelin Phosphodiesterase