Impact of stromal sensitivity on radiation response of tumors implanted in SCID hosts revisited

Mónica García-Barros, Tin Htwe Thin, Jerzy Maj, Carlos Cordon-Cardo, Adriana Haimovitz-Friedman, Zvi Fuks, Richard Kolesnick

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

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 (TCD 50) 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.

Original languageEnglish
Pages (from-to)8179-8186
Number of pages8
JournalCancer Research
Volume70
Issue number20
DOIs
StatePublished - 15 Oct 2010
Externally publishedYes

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