Journal
CANCER RESEARCH
Volume 70, Issue 20, Pages 8179-8186Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-1871
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Funding
- NIH [R01 CA105125, R01 CA085704]
- D.K. Ludwig Fund for Cancer Research
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Severe combined immunodeficient (SCID) mice carry a germ-line mutation in DNA-PK, associated with deficiency in recognition and repair DNA double-strand breaks. Thus, SCID cells and tissues display increased sensitivity to radiation-induced postmitotic (clonogenic) cell death. Nonetheless, the single-radiation doses required for 50% permanent local control (TCD50) of tumors implanted in SCID mice are not significantly different from the TCD50 values of the same tumors in wild-type hosts. Whereas the tumor stroma is derived from the host, the observation that tumors implanted in SCID mice do not exhibit hypersensitivity to radiation might imply that stromal endothelial elements do not contribute substantially to tumor cure by ionizing radiation. Here, we challenge this notion, testing the hypothesis that ASMase-mediated endothelial apoptosis, which results from plasma membrane alterations, not DNA damage, is a crucial element in the cure of tumors in SCID mice by single-dose radiotherapy (SDRT). We show that the endothelium in MCA/129 fibrosarcomas and B16 melanomas exhibits a wild-type apoptotic phenotype in SCID hosts, abrogated in tumors in SCIDasmase-/- littermates, which also acquire resistance to SDRT. Conversion into a radioresistant tumor phenotype when implanted in SCIDasmase-/- hosts provides compelling evidence that cell membrane ASMase-mediated microvascular dysfunction, rather than DNA damage-mediated endothelial clonogenic lethality, plays a mandatory role in the complex pathophysiologic mechanism of tumor cure by SDRT, and provides an explanation for the wild-type SDRT responses reported in tumors implanted in SCID mice. Cancer Res; 70(20); 8179-86. (C) 2010 AACR.
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