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Published on: February 17, 2019
Impact of stromal sensitivity on radiation response of tumors implanted in SCID hosts revisited
Mónica García-Barros1, Tin Htwe Thin, Jerzy Maj
1Laboratory of Signal Transduction and Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center; Department of Pathology, Columbia University, New York, NY 10065, USA.
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 TCD(50) 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 SCID(asmase-/-) littermates, which also acquire resistance to SDRT. Conversion into a radioresistant tumor phenotype when implanted in SCID(asmase-/-) 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.
Insights
Severe combined immunodeficient (SCID) mice do not show increased radiation sensitivity in tumors. This study reveals acid sphingomyelinase (ASMase)-mediated endothelial apoptosis, not DNA damage, is crucial for tumor cure via single-dose radiotherapy (SDRT).
Area of Science:
- Oncology
- Radiation Biology
- Molecular Biology
Background:
- Severe combined immunodeficient (SCID) mice have DNA repair deficiencies, leading to increased sensitivity to DNA double-strand breaks.
- SCID mice tumors typically show no increased sensitivity to radiation therapy (RT) compared to wild-type hosts, suggesting host stroma may not be critical for RT cure.
- This challenges the assumption that DNA damage is the primary mechanism of RT-induced tumor cell death.
Purpose of the Study:
- To investigate the role of acid sphingomyelinase (ASMase)-mediated endothelial apoptosis in tumor response to single-dose radiotherapy (SDRT) in SCID mice.
- To test the hypothesis that plasma membrane alterations, rather than DNA damage, are key to RT-induced tumor cure in SCID mice.
Main Methods:
- Implanting MCA/129 fibrosarcomas and B16 melanomas into SCID mice and SCID(asmase-/-) littermates.
- Assessing the apoptotic phenotype of tumor endothelium in both host types.
- Evaluating tumor response to single-dose radiotherapy (SDRT) in SCID and SCID(asmase-/-) hosts.
Main Results:
- Endothelium in tumors grown in SCID mice exhibited a wild-type apoptotic phenotype.
- This wild-type apoptotic phenotype was abrogated in tumors grown in SCID(asmase-/-) hosts.
- Tumors in SCID(asmase-/-) hosts displayed radioresistance to SDRT, unlike those in SCID mice.
Conclusions:
- Cell membrane ASMase-mediated microvascular dysfunction, not DNA damage-induced endothelial lethality, is essential for tumor cure by SDRT.
- This finding explains the lack of increased SDRT sensitivity observed in tumors implanted in SCID mice.
- The study highlights a novel mechanism involving endothelial apoptosis and microvascular integrity in radiotherapy response.
