Page 169 - 2014 Printable Abstract Book
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initiated primary soft tissue sarcomas in FSF-KrasG12D; p53FRT/FRT mice by intramuscular injection of an
adenovirus expressing FlpO recombinase and deleted floxed alleles of Bax or Atm in endothelial cells using
the tissue-specific Cre-driver VE-Cadherin-Cre. We also deleted Atm in tumor cells by intramuscular
injection of 4-hydroxytamoxifen into Pax7-CreER; LSL-KrasG12D; p53FL/FL; AtmFL/FL mice. Deletion of
Bax in endothelial cells did not affect endothelial cell death or tumor response to radiation therapy.
Deletion of Atm in endothelial cells increased radiation-induced cell death of tumor endothelial cells and
prolonged tumor growth delay following a non-curative dose of radiation. However, following a curative
dose of radiation, Atm deletion in endothelial cells did not affect growth delay and failed to increase local
control. In contrast, deletion of Atm specifically in tumor cells increased local control of primary tumors
by radiation therapy. These results demonstrate that tumor cells rather than endothelial cells are the
critical targets that regulate primary tumor eradication by radiation therapy. They also emphasize the
importance of using primary models of cancer to study the role of stromal cells in tumor development
and response to therapy.
(PS2-59) A literature survey of changing trends in modelling radiation lung injury in mice: problems with
1
1
1
the status quo. Carolyn M.S. Buck, BSc of Biology ; Isabel L. Jackson, PhD ; Zeljko Vujaskovic, PhD MD ;
2
1
and Julian D. Down, PhD, University of Maryland School of Medicine, Baltimore, MD and Massachusetts
2
Institute of Technology, Cambridge, MA
Purpose: Within this millennium there has been resurgence in funding and research dealing with
animal models of radiation-induced lung injury to identify and establish predictive biomarkers and
effective mitigating agents that are applicable to humans. Methods: A total 313 research papers using
radiation lung models in mice covering the period of 1970 to 2013 were extensively reviewed for this
study. We went on to examine the various studies using several pertinent parameters including the
murine strain, dose, radiation field, study length, assays and mitigating treatments. Results: Since 2000,
the number of papers on radiation lung injury in mice has more than tripled in comparison to the previous
decade. Whole thorax irradiation has become the standard for the radiation lung injury model in mice.
Distinct trends were seen from 1970 to today with regards to the murine strain, dose, intended pathology
investigated, length of study and assays. Recently, the C57BL/6 strain has been increasingly used in the
majority of these studies (65% since 2000). Nonetheless and in contrast to other mouse strains such as
CBA, C3H and C57L, the data has shown that C57BL/6 mice produced variable results with prolonged and
sex-dependent survival times and with highly questionable assumptions about the underlying pathology.
Early cytokine gene expression profiles have shown a high degree of variability among different
laboratories and remains to be robustly tested as a reliable mechanistic or predictive biomarker of lung
pathology. An analysis of mitigating drug treatments are complicated by the fact that many studies are
currently performed on the C57BL/6 strain and do not establish whether the treatment actually prevents
or simply delays the progression of radiation injury. Conclusion: While no animal model is perfect, the
C57BL/6 strain is the most removed from the radiation response of the lung as expected in humans and
needs to be replaced with more clinically relevant strains such as the C57L. The study lengths also need
to be extended so that the full pathogenesis of whole thorax irradiation injury can be examined, especially
in mitigating drug studies. The lethality endpoint should be used cautiously with greater emphasis on
other assays such as functional and imaging endpoints to determine the specific cause of respiratory
failure.
167 | P a g e
adenovirus expressing FlpO recombinase and deleted floxed alleles of Bax or Atm in endothelial cells using
the tissue-specific Cre-driver VE-Cadherin-Cre. We also deleted Atm in tumor cells by intramuscular
injection of 4-hydroxytamoxifen into Pax7-CreER; LSL-KrasG12D; p53FL/FL; AtmFL/FL mice. Deletion of
Bax in endothelial cells did not affect endothelial cell death or tumor response to radiation therapy.
Deletion of Atm in endothelial cells increased radiation-induced cell death of tumor endothelial cells and
prolonged tumor growth delay following a non-curative dose of radiation. However, following a curative
dose of radiation, Atm deletion in endothelial cells did not affect growth delay and failed to increase local
control. In contrast, deletion of Atm specifically in tumor cells increased local control of primary tumors
by radiation therapy. These results demonstrate that tumor cells rather than endothelial cells are the
critical targets that regulate primary tumor eradication by radiation therapy. They also emphasize the
importance of using primary models of cancer to study the role of stromal cells in tumor development
and response to therapy.
(PS2-59) A literature survey of changing trends in modelling radiation lung injury in mice: problems with
1
1
1
the status quo. Carolyn M.S. Buck, BSc of Biology ; Isabel L. Jackson, PhD ; Zeljko Vujaskovic, PhD MD ;
2
1
and Julian D. Down, PhD, University of Maryland School of Medicine, Baltimore, MD and Massachusetts
2
Institute of Technology, Cambridge, MA
Purpose: Within this millennium there has been resurgence in funding and research dealing with
animal models of radiation-induced lung injury to identify and establish predictive biomarkers and
effective mitigating agents that are applicable to humans. Methods: A total 313 research papers using
radiation lung models in mice covering the period of 1970 to 2013 were extensively reviewed for this
study. We went on to examine the various studies using several pertinent parameters including the
murine strain, dose, radiation field, study length, assays and mitigating treatments. Results: Since 2000,
the number of papers on radiation lung injury in mice has more than tripled in comparison to the previous
decade. Whole thorax irradiation has become the standard for the radiation lung injury model in mice.
Distinct trends were seen from 1970 to today with regards to the murine strain, dose, intended pathology
investigated, length of study and assays. Recently, the C57BL/6 strain has been increasingly used in the
majority of these studies (65% since 2000). Nonetheless and in contrast to other mouse strains such as
CBA, C3H and C57L, the data has shown that C57BL/6 mice produced variable results with prolonged and
sex-dependent survival times and with highly questionable assumptions about the underlying pathology.
Early cytokine gene expression profiles have shown a high degree of variability among different
laboratories and remains to be robustly tested as a reliable mechanistic or predictive biomarker of lung
pathology. An analysis of mitigating drug treatments are complicated by the fact that many studies are
currently performed on the C57BL/6 strain and do not establish whether the treatment actually prevents
or simply delays the progression of radiation injury. Conclusion: While no animal model is perfect, the
C57BL/6 strain is the most removed from the radiation response of the lung as expected in humans and
needs to be replaced with more clinically relevant strains such as the C57L. The study lengths also need
to be extended so that the full pathogenesis of whole thorax irradiation injury can be examined, especially
in mitigating drug studies. The lethality endpoint should be used cautiously with greater emphasis on
other assays such as functional and imaging endpoints to determine the specific cause of respiratory
failure.
167 | P a g e
