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Science 16 May 2003:
Vol. 300. no. 5622, pp. 1155 - 1159
DOI: 10.1126/science.1082504

Reports

Tumor Response to Radiotherapy Regulated by Endothelial Cell Apoptosis

Monica Garcia-Barros,1 Francois Paris,1 Carlos Cordon-Cardo,2 David Lyden,3 Shahin Rafii,5 Adriana Haimovitz-Friedman,4 Zvi Fuks,4* Richard Kolesnick1*{dagger}

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.

1 Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
2 Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
3 Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
4 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
5 Department of Hematology-Oncology, Cornell University Medical College, New York, NY 10021, USA.



* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: r-kolesnick{at}ski.mskcc.org

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Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria.
C. Bettegowda, L. H. Dang, R. Abrams, D. L. Huso, L. Dillehay, I. Cheong, N. Agrawal, S. Borzillary, J. M. McCaffery, E. L. Watson, et al. (2003)
PNAS 100, 15083-15088
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Diagnosing Lynch syndrome: is the answer in the mouth?.
H K Roy and H T Lynch (2003)
Gut 52, 1665-1667
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The Cyclin-Dependent Kinase Inhibitor Flavopiridol Potentiates {gamma}-Irradiation-Induced Apoptosis in Colon and Gastric Cancer Cells.
C. Jung, M. Motwani, J. Kortmansky, F. M. Sirotnak, Y. She, M. Gonen, A. Haimovitz-Friedman, and G. K. Schwartz (2003)
Clin. Cancer Res. 9, 6052-6061
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Translating angiogenesis research into the clinic: the challenges ahead.
H G Augustin (2003)
Br. J. Radiol. 76, S3-S10
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Microvascular Function Regulates Intestinal Crypt Response to Radiation.
J. G. Maj, F. Paris, A. Haimovitz-Friedman, E. Venkatraman, R. Kolesnick, and Z. Fuks (2003)
Cancer Res. 63, 4338-4341
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