Page 199 - 2014 Printable Abstract Book
P. 199
137 Cs gamma radiation were used to compare the responses between low- or high-LET radiations. NF-kB
TM
activation by EMSA and TNF-α determination by bead-based immunoassay with FCAP Array software
demonstrated a sustained activation of the NF-kB-TNF-α feedback cycle in both low- and high-LET
radiation exposures. Chromosome instability determined at 36-72 population doubling confirmed the
transmissible instability. The extent of genomic instability during neoplastic progression is being validated
using comparative genomic hybridization (CGH) array analysis. Concurrent development of acquired
survival advantage examined by (a) NF-kB mediated anti-apoptotic pathway, and (b) the extended life
span due to NF-kB-mediated transcriptional activation of telomerase reverse transcriptase promoter
regulation favor the genetically aberrant cells to carry over to subsequent generations. We investigated
the ability of pro-tumorigenic cells to grow as a palpable tumor in nude mice in an in vivo
study to determine the role of the NF-kB-TNF-α feedback loop in transformation and the acquired
neoplastic/pre-malignant phenotype. Cells representing three human tumor models (breast, lung and
skin) were used. Cells were exposed to three repeated doses of 80 cGy before and after blocking TNF-α-
NF-kB signaling with pathway-specific inhibitors. A 24 h interval was maintained between each exposure.
The exposed pro-tumorigenic cells, further maintained in the culture, were examined for tumorigenic
potentials in nude mice. The results clearly indicated that the TNF-α-NF-kB signaling-mediated positive
feedback cycle initiated upon particle radiation exposure played a vital role in predisposing the pro-
tumorigenic cells to the pre-malignant phenotype.
(PS3-16) Cancer gene profiles in mouse thymus and spleen after return from the STS-135 mission in
2
2
1
1
space. Daila S. Gridley, PhD ; Xiao W. Mao, Md ; Louis S. Stodieck, PhD ; Virginia L. Ferguson, PhD ; Ted
1
1
3
1
A. Bateman, PhD ; Maria Moldovan ; Christopher E. Cunningham ; Tamako A. Jones ; Jerry M. Slater,
1
1
1
MD ; Michael J. Pecaut, PhD Loma Linda University, Loma Linda, CA ; University of Colorado, Boulder,
2
3
CO ; and University of North Carolina, Chapel Hill, NC
Purpose and background: Current predictions of cancer risk in astronauts are based on minimal
data and large uncertainties. Our previous results with mice flown in space have shown numerous immune
system abnormalities that could increase risk for cancer. In the present study, we evaluated expression of
genes related to cancer in both the thymus and spleen. Methods: Within 3-5 hours after Space Shuttle
Atlantis returned from a ~13-day mission (STS-135), thymuses and spleens from female C57BL/6 mice
were weighed and then snap frozen in liquid N2. Samples from ground controls exposed to matched
experimental conditions (e.g., environment, study duration, etc.) were housed in similar animal enclosure
modules (AEM) and obtained for comparison with the flight (FLT) mice. Expression of 84 cancer-related
genes was determined by quantitative reverse transcription polymerase chain reaction (RT-PCR). Pathway
analysis (Myc apoptosis signaling and G1/S checkpoint regulation) was used to map relationships among
the genes. Results: Although significance was not obtained for thymus mass, spleen mass alone and
relative to body mass was significantly decreased in FLT mice (P<0.05). In FLT thymuses, 15/84 genes had
altered expression (P<0.05; up: Casp8, Fgfr2, Figf, Hgf, Igf1, Itga4, Ncam1, Pdgfa, Pik3r1, Serpinb2, Sykb;
down: Cdc25a, E2f1, Mmp9, Myc). In the spleen, 8/84 genes were affected in FLT mice compared to AEM
controls (P<0.05; up: Cdkn2a; down: Birc5, Casp8, Ctnnb1, Map2k1, Mdm2, Nfkb1, Pdgfa). Conclusions:
The results showed that a relatively short mission in space had a significant impact on gene expression in
both organs. The findings also indicate that immune system aberrations due to stressors associated with
space travel should be included when estimating risk for pathologies such as cancer.
197 | P a g e
TM
activation by EMSA and TNF-α determination by bead-based immunoassay with FCAP Array software
demonstrated a sustained activation of the NF-kB-TNF-α feedback cycle in both low- and high-LET
radiation exposures. Chromosome instability determined at 36-72 population doubling confirmed the
transmissible instability. The extent of genomic instability during neoplastic progression is being validated
using comparative genomic hybridization (CGH) array analysis. Concurrent development of acquired
survival advantage examined by (a) NF-kB mediated anti-apoptotic pathway, and (b) the extended life
span due to NF-kB-mediated transcriptional activation of telomerase reverse transcriptase promoter
regulation favor the genetically aberrant cells to carry over to subsequent generations. We investigated
the ability of pro-tumorigenic cells to grow as a palpable tumor in nude mice in an in vivo
study to determine the role of the NF-kB-TNF-α feedback loop in transformation and the acquired
neoplastic/pre-malignant phenotype. Cells representing three human tumor models (breast, lung and
skin) were used. Cells were exposed to three repeated doses of 80 cGy before and after blocking TNF-α-
NF-kB signaling with pathway-specific inhibitors. A 24 h interval was maintained between each exposure.
The exposed pro-tumorigenic cells, further maintained in the culture, were examined for tumorigenic
potentials in nude mice. The results clearly indicated that the TNF-α-NF-kB signaling-mediated positive
feedback cycle initiated upon particle radiation exposure played a vital role in predisposing the pro-
tumorigenic cells to the pre-malignant phenotype.
(PS3-16) Cancer gene profiles in mouse thymus and spleen after return from the STS-135 mission in
2
2
1
1
space. Daila S. Gridley, PhD ; Xiao W. Mao, Md ; Louis S. Stodieck, PhD ; Virginia L. Ferguson, PhD ; Ted
1
1
3
1
A. Bateman, PhD ; Maria Moldovan ; Christopher E. Cunningham ; Tamako A. Jones ; Jerry M. Slater,
1
1
1
MD ; Michael J. Pecaut, PhD Loma Linda University, Loma Linda, CA ; University of Colorado, Boulder,
2
3
CO ; and University of North Carolina, Chapel Hill, NC
Purpose and background: Current predictions of cancer risk in astronauts are based on minimal
data and large uncertainties. Our previous results with mice flown in space have shown numerous immune
system abnormalities that could increase risk for cancer. In the present study, we evaluated expression of
genes related to cancer in both the thymus and spleen. Methods: Within 3-5 hours after Space Shuttle
Atlantis returned from a ~13-day mission (STS-135), thymuses and spleens from female C57BL/6 mice
were weighed and then snap frozen in liquid N2. Samples from ground controls exposed to matched
experimental conditions (e.g., environment, study duration, etc.) were housed in similar animal enclosure
modules (AEM) and obtained for comparison with the flight (FLT) mice. Expression of 84 cancer-related
genes was determined by quantitative reverse transcription polymerase chain reaction (RT-PCR). Pathway
analysis (Myc apoptosis signaling and G1/S checkpoint regulation) was used to map relationships among
the genes. Results: Although significance was not obtained for thymus mass, spleen mass alone and
relative to body mass was significantly decreased in FLT mice (P<0.05). In FLT thymuses, 15/84 genes had
altered expression (P<0.05; up: Casp8, Fgfr2, Figf, Hgf, Igf1, Itga4, Ncam1, Pdgfa, Pik3r1, Serpinb2, Sykb;
down: Cdc25a, E2f1, Mmp9, Myc). In the spleen, 8/84 genes were affected in FLT mice compared to AEM
controls (P<0.05; up: Cdkn2a; down: Birc5, Casp8, Ctnnb1, Map2k1, Mdm2, Nfkb1, Pdgfa). Conclusions:
The results showed that a relatively short mission in space had a significant impact on gene expression in
both organs. The findings also indicate that immune system aberrations due to stressors associated with
space travel should be included when estimating risk for pathologies such as cancer.
197 | P a g e
