Page 72 - 2014 Printable Abstract Book
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generalizable understanding of radiation-related second cancer risks for childhood cancer survivors and
for clues about mechanisms of radiation carcinogenesis.
S18 OMICS
The use of global profiling and whole genome technologies has contributed substantially to our
understanding of cellular stress responses to ionizing radiation and to the myriad of abnormalities that
occur in cancer. These ‘omics’ approaches offer a promising future in systems biology and systems
medicine. This symposium will spans the gamut of omics approaches from genomics to gene expression
and proteomics, and to alterations at the small molecule level, metabolomics.
(S1801) Integrating Genetics, Genomics and Biology towards a More Personalized Medicine.
Jeffrey Trent, Tgen, Phoenix, AZ
(S1802) Proteomics and the identification of pathways conferring radiation sensitivity.
Ruth J. Muschel, Oxford University, Oxford, United Kingdom
Proteomics and identification of pathways conferring radiation sensitivity a quantitative characterization
of the secreted proteins from different cells under different conditions now becomes feasible with
quantitative proteomic technology. We employed this type of methodology to determine substrates for
a secreted protease matrix metalloproteinase -9 (MMP-9). This protease is notable as an enhancing factor
in metastasis, but the substrates that it cleaves leading to this enhancement are only incompletely
identified. Using a label-free proteomics approach, we compared the conditioned medium from prostate
cancer cells with and without MMP-9. A number of proteins were identified that were increased in
amount after down regulation of MMP-9 making them candidates to be substrates. And indeed, some of
these candidates are direct substrates for MMP-9. One of the candidates was especially notable as it is
highly expressed in the extracellular matrix of the prostate where it could have an extensive effect on
infiltrating cancer cells. This was a serine protease inhibitor, a serpin called protein nexin-1, PN-1 also
called serpine2. We identified the MMP-9 cleavage sites and showed that in the absence of cleavage and
elimination of MMP-9 that cancer cell invasion was greatly diminished and that tumorigenicity including
in the prostate was reduced. In exploring the actions of PN-1 on prostate cancer, we found that PN-1 has
the capacity to inhibit hedgehog signaling in tissue culture and in vivo.
This led us to ask whether hedgehog signaling might affect the outcome in prostate cancer. In a series of
patient samples from intermediate risk prostate cancer, we found alterations in gene copy number by
array CGH that affect the hedgehog pathway. These changes were significantly correlated with the patient
outcome in this series that had been treated with radiation therapy. Because of these results, we have
begun to explore the effect of hedgehog signaling on the response to radiation in prostate cancer with
the hypothesis that inhibition of hedgehog signaling will enhance the response to radiation.
All together these data show that extracellular proteins can be measured in a quantitative fashion using
label free proteomics and that using these techniques we identified a potential signaling pathway as a
therapeutic target.
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for clues about mechanisms of radiation carcinogenesis.
S18 OMICS
The use of global profiling and whole genome technologies has contributed substantially to our
understanding of cellular stress responses to ionizing radiation and to the myriad of abnormalities that
occur in cancer. These ‘omics’ approaches offer a promising future in systems biology and systems
medicine. This symposium will spans the gamut of omics approaches from genomics to gene expression
and proteomics, and to alterations at the small molecule level, metabolomics.
(S1801) Integrating Genetics, Genomics and Biology towards a More Personalized Medicine.
Jeffrey Trent, Tgen, Phoenix, AZ
(S1802) Proteomics and the identification of pathways conferring radiation sensitivity.
Ruth J. Muschel, Oxford University, Oxford, United Kingdom
Proteomics and identification of pathways conferring radiation sensitivity a quantitative characterization
of the secreted proteins from different cells under different conditions now becomes feasible with
quantitative proteomic technology. We employed this type of methodology to determine substrates for
a secreted protease matrix metalloproteinase -9 (MMP-9). This protease is notable as an enhancing factor
in metastasis, but the substrates that it cleaves leading to this enhancement are only incompletely
identified. Using a label-free proteomics approach, we compared the conditioned medium from prostate
cancer cells with and without MMP-9. A number of proteins were identified that were increased in
amount after down regulation of MMP-9 making them candidates to be substrates. And indeed, some of
these candidates are direct substrates for MMP-9. One of the candidates was especially notable as it is
highly expressed in the extracellular matrix of the prostate where it could have an extensive effect on
infiltrating cancer cells. This was a serine protease inhibitor, a serpin called protein nexin-1, PN-1 also
called serpine2. We identified the MMP-9 cleavage sites and showed that in the absence of cleavage and
elimination of MMP-9 that cancer cell invasion was greatly diminished and that tumorigenicity including
in the prostate was reduced. In exploring the actions of PN-1 on prostate cancer, we found that PN-1 has
the capacity to inhibit hedgehog signaling in tissue culture and in vivo.
This led us to ask whether hedgehog signaling might affect the outcome in prostate cancer. In a series of
patient samples from intermediate risk prostate cancer, we found alterations in gene copy number by
array CGH that affect the hedgehog pathway. These changes were significantly correlated with the patient
outcome in this series that had been treated with radiation therapy. Because of these results, we have
begun to explore the effect of hedgehog signaling on the response to radiation in prostate cancer with
the hypothesis that inhibition of hedgehog signaling will enhance the response to radiation.
All together these data show that extracellular proteins can be measured in a quantitative fashion using
label free proteomics and that using these techniques we identified a potential signaling pathway as a
therapeutic target.
70 | P a g e
