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P. 236
sensitive to tissue water motion (diffusion, capillary perfusion). Multiple DWI with increased motion
st
sensitivity (multi-b DWI) yields a bi-exponential signal decay, where perfusion dominates the 1
nd
exponential and diffusion the 2 , allowing voxelwise quantification of diffusion (D) and perfusion fraction
2
(f), non-invasively . We aimed to investigate the potential of multi-b DWI to monitor radiation induced
tumor cell apoptosis and capillary function in-vivo. Mice with s.c. human carcinoid GOT1 tumors received
15 MBq 177 Lu-octreotate i.v. on day 0 (absorbed tumor dose ≈ 3.0 Gy). Multi-b DWI was performed on
3
anesthetized mice on day -1, 1, 3, 8 and 13 with full tumor coverage (0.3*0.3*1.0 mm voxels, Bruker 7T
3
system). Tumor volumes were determined as previously described . Model fitting was performed to
determine D and f (bi-exponential model) and ADC (mono-exponential model). Mean tumor D, f, ADC and
volume of day x were compared to day -1. Relative tumor volume day 1, 3, 8 and 13 was 96, 93, 92 and
2
112 % of that at day -1. D [µm /ms] (±std) was higher day 1: 0.77±0.07 (p=0.05) and 3: 0.81±0.08 (p=0.007)
(day -1: 0.71±0.09). ADC [µm /ms] was higher day 3: 0.89±0.09 (p=0.04) (day -1: 0.71±0.09). f [%] was
2
higher day 1: 22±9 (day -1: 16±4) and lower day 8: 11±2 but was not different from f at day -1 at the p<0.05
level. Tumor cell apoptosis increase extracellular space and should facilitate molecular diffusion,
consistent with increasing D and ADC in this study. It could also facilitate perfusion temporarily, before
endothelial apoptosis reduce capillary function, which would explain the tendency of f in our
measurements, suggesting a higher f on day 1, followed by a reduction on day 3-8. The results indicate
that multi-b DWI may reveal radiation induced effects on solid tumors earlier than morphological changes.
Multi-b DWI may be useful for early monitoring of radiation-induced treatment effects after therapy.
1 Garcia-Barros et al., Science, 2003 2 Le Bihan et al., Radiology, 1986
3 Montelius et al., BMC Medical Imaging, 2012
(PS4-03) Development of cancer-associated fibroblasts and their role in tumor radioresistance. Jason D.
Domogauer, BS; Sonia M. De Toledo, PhD; Roger W. Howell, PhD; and Edouard I. Azzam, PhD
Rutgers-New Jersey Medical School, Newark, NJ
Cancer-Associated Fibroblasts (CAFs) comprise ~ 50-70% of the tumor microenvironment (TME);
they have been implicated in tumor initiation, progression, metastasis, and recurrence. Clinical
observations have suggested that CAFs may be radioresistant compared to normal fibroblasts, and that
CAFs may rescue neighboring tumor cells that have received an otherwise lethal dose of ionizing radiation
(IR). Such properties imply that CAFs contribute to therapy failure and poor overall patient survival. Yet,
characterization of CAF generation and elucidation of the mechanisms underlying their enhanced
radioresistance and capacity to protect neighboring tumor cells is only emerging. Such research is of
immense importance in improving our understanding of how the TME affects the efficacy of radiotherapy.
Here, we investigate molecular changes of CAF development when apparently normal human fibroblasts
are cocultured with breast cancer cells, and explore mechanisms that may underlie their responses to IR.
Preliminary characterization of CAF development in our model has revealed reduced expression of
senescence-associated β-galactosidase expression in human fibroblasts when grown on the opposing side
of a transwell insert (1 µm pores) containing MCF7 or MDA-MB-231 breast cancer cells. Enhanced
oxidative stress, judged by increased levels of reactive oxygen species and protein carbonylation, were
also observed in the developing CAFs. Strikingly, these effects were associated with enhanced activity of
manganese superoxide dismutase and modulation of active catalase beginning at 48 h and increasing at
120 h of co-culture. Importantly, a decrease in micronucleus frequency (indicator of DNA damage) was
observed in CAFs irradiated acutely with 50 cGy of 137Cs γ rays in the presence of cocultured (120 h)
234 | P a g e
st
sensitivity (multi-b DWI) yields a bi-exponential signal decay, where perfusion dominates the 1
nd
exponential and diffusion the 2 , allowing voxelwise quantification of diffusion (D) and perfusion fraction
2
(f), non-invasively . We aimed to investigate the potential of multi-b DWI to monitor radiation induced
tumor cell apoptosis and capillary function in-vivo. Mice with s.c. human carcinoid GOT1 tumors received
15 MBq 177 Lu-octreotate i.v. on day 0 (absorbed tumor dose ≈ 3.0 Gy). Multi-b DWI was performed on
3
anesthetized mice on day -1, 1, 3, 8 and 13 with full tumor coverage (0.3*0.3*1.0 mm voxels, Bruker 7T
3
system). Tumor volumes were determined as previously described . Model fitting was performed to
determine D and f (bi-exponential model) and ADC (mono-exponential model). Mean tumor D, f, ADC and
volume of day x were compared to day -1. Relative tumor volume day 1, 3, 8 and 13 was 96, 93, 92 and
2
112 % of that at day -1. D [µm /ms] (±std) was higher day 1: 0.77±0.07 (p=0.05) and 3: 0.81±0.08 (p=0.007)
(day -1: 0.71±0.09). ADC [µm /ms] was higher day 3: 0.89±0.09 (p=0.04) (day -1: 0.71±0.09). f [%] was
2
higher day 1: 22±9 (day -1: 16±4) and lower day 8: 11±2 but was not different from f at day -1 at the p<0.05
level. Tumor cell apoptosis increase extracellular space and should facilitate molecular diffusion,
consistent with increasing D and ADC in this study. It could also facilitate perfusion temporarily, before
endothelial apoptosis reduce capillary function, which would explain the tendency of f in our
measurements, suggesting a higher f on day 1, followed by a reduction on day 3-8. The results indicate
that multi-b DWI may reveal radiation induced effects on solid tumors earlier than morphological changes.
Multi-b DWI may be useful for early monitoring of radiation-induced treatment effects after therapy.
1 Garcia-Barros et al., Science, 2003 2 Le Bihan et al., Radiology, 1986
3 Montelius et al., BMC Medical Imaging, 2012
(PS4-03) Development of cancer-associated fibroblasts and their role in tumor radioresistance. Jason D.
Domogauer, BS; Sonia M. De Toledo, PhD; Roger W. Howell, PhD; and Edouard I. Azzam, PhD
Rutgers-New Jersey Medical School, Newark, NJ
Cancer-Associated Fibroblasts (CAFs) comprise ~ 50-70% of the tumor microenvironment (TME);
they have been implicated in tumor initiation, progression, metastasis, and recurrence. Clinical
observations have suggested that CAFs may be radioresistant compared to normal fibroblasts, and that
CAFs may rescue neighboring tumor cells that have received an otherwise lethal dose of ionizing radiation
(IR). Such properties imply that CAFs contribute to therapy failure and poor overall patient survival. Yet,
characterization of CAF generation and elucidation of the mechanisms underlying their enhanced
radioresistance and capacity to protect neighboring tumor cells is only emerging. Such research is of
immense importance in improving our understanding of how the TME affects the efficacy of radiotherapy.
Here, we investigate molecular changes of CAF development when apparently normal human fibroblasts
are cocultured with breast cancer cells, and explore mechanisms that may underlie their responses to IR.
Preliminary characterization of CAF development in our model has revealed reduced expression of
senescence-associated β-galactosidase expression in human fibroblasts when grown on the opposing side
of a transwell insert (1 µm pores) containing MCF7 or MDA-MB-231 breast cancer cells. Enhanced
oxidative stress, judged by increased levels of reactive oxygen species and protein carbonylation, were
also observed in the developing CAFs. Strikingly, these effects were associated with enhanced activity of
manganese superoxide dismutase and modulation of active catalase beginning at 48 h and increasing at
120 h of co-culture. Importantly, a decrease in micronucleus frequency (indicator of DNA damage) was
observed in CAFs irradiated acutely with 50 cGy of 137Cs γ rays in the presence of cocultured (120 h)
234 | P a g e
