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radiation or radiation plus 5AC, indicating a proper checkpoint 1 pathway response. 5AC-alone had no
effect. However, in SUM-159 but not MDA-MB-231 cells, 5AC treatment reduced basal levels of
phosphorylated pChk2 as well as abrogated radiation-induced phosphorylation. When we analyzed p21,
p27, CDK2, and CDK4, it was found that 5AC treatment led to greatly reduced levels of these cell cycle
proteins, regardless of exposure to radiation. Analysis of cell cycle showed redistribution of 5AC-treated
cells (with or without radiation) toward the S and G2 phase of the cell cycle. These data suggest that
altered cell cycle kinetics through disruption of checkpoint signaling or cell cycle regulator expression is
a potential mechanism for radiosensitization of breast cancer by DNMT inhibitors.
(PS2-27) Proton irradiation as a function of host age: systemic analysis of tumor progression, tumor
microenvironment and host tissue response. Afshin Beheshti, PhD; Justin Wage; Michael Peluso; Philip
Hahnfeldt, PhD; and Lynn Hlatky, PhD, Tufts Univ. School of Medicine / GRI, Boston, MA
The use of proton radiotherapy is on the rise, due to the improved ability to localize targeting over
standard photon radiotherapy. Recent studies from our laboratory demonstrate that in addition to this
physical targeting advantage, proton irradiation induces favorable biological modulations including
inhibition of angiogenic and immune factors critical to “hallmark” processes impacting tumor
development. These biological implications for proton radiation also impact carcinogenesis risk from
space travel (due to the high proportion of high energy protons in space radiation). It is also becoming
evident that age plays a crucial role in the delicate interplay between the tumor and the host; an interplay
already known to be perturbed by radiation. We investigated how tumor progression and host tissue are
altered with age, with or without proton exposure. Tumor dynamics were tracked following injection of
murine Lewis lung carcinoma cells into syngeneic C57BL/6 mice of different ages, adolescent (68 day)
versus old (736 day), with or without three fractionations of 0.5Gy (1GeV) proton irradiation. Tumor
growth rates and progression due to host age were modulated by whole-body proton irradiation (1GeV),
with increased inhibition evident only in the old mice. Global transcriptome analysis was performed on
tumor and splenic tissue, revealing that TGFβ1 and TGFβ2 were key factors involved in driving the tumor
dynamics in the old hosts, whereas increases in cell cycling and immunosuppression with CDK2, MCM7,
and RUVBL2 were the key players involved in the observed regulatory changes in host environmental
response (i.e. spleen) in adolescent hosts. Surprisingly, transcriptome analysis indicated that proton
irradiation of younger hosts caused a significant predisposition for carcinogenesis progression as
compared to old subjects. One possible explanation for these findings may be a decreased ability of the
host to support tumor progression, i.e. a reduction in the host ‘carrying capacity’ afforded to tumor
growth. These results suggest a significant biological component to proton radiation, operative through
the host that may favorably augment the well-recognized physical advantages of this radiation modality.
This work was supported by NASA grant NNJ06HA28G/NNX11AK26G and by U54CA149233 from the NCI
(LH).
149 | P a g e
effect. However, in SUM-159 but not MDA-MB-231 cells, 5AC treatment reduced basal levels of
phosphorylated pChk2 as well as abrogated radiation-induced phosphorylation. When we analyzed p21,
p27, CDK2, and CDK4, it was found that 5AC treatment led to greatly reduced levels of these cell cycle
proteins, regardless of exposure to radiation. Analysis of cell cycle showed redistribution of 5AC-treated
cells (with or without radiation) toward the S and G2 phase of the cell cycle. These data suggest that
altered cell cycle kinetics through disruption of checkpoint signaling or cell cycle regulator expression is
a potential mechanism for radiosensitization of breast cancer by DNMT inhibitors.
(PS2-27) Proton irradiation as a function of host age: systemic analysis of tumor progression, tumor
microenvironment and host tissue response. Afshin Beheshti, PhD; Justin Wage; Michael Peluso; Philip
Hahnfeldt, PhD; and Lynn Hlatky, PhD, Tufts Univ. School of Medicine / GRI, Boston, MA
The use of proton radiotherapy is on the rise, due to the improved ability to localize targeting over
standard photon radiotherapy. Recent studies from our laboratory demonstrate that in addition to this
physical targeting advantage, proton irradiation induces favorable biological modulations including
inhibition of angiogenic and immune factors critical to “hallmark” processes impacting tumor
development. These biological implications for proton radiation also impact carcinogenesis risk from
space travel (due to the high proportion of high energy protons in space radiation). It is also becoming
evident that age plays a crucial role in the delicate interplay between the tumor and the host; an interplay
already known to be perturbed by radiation. We investigated how tumor progression and host tissue are
altered with age, with or without proton exposure. Tumor dynamics were tracked following injection of
murine Lewis lung carcinoma cells into syngeneic C57BL/6 mice of different ages, adolescent (68 day)
versus old (736 day), with or without three fractionations of 0.5Gy (1GeV) proton irradiation. Tumor
growth rates and progression due to host age were modulated by whole-body proton irradiation (1GeV),
with increased inhibition evident only in the old mice. Global transcriptome analysis was performed on
tumor and splenic tissue, revealing that TGFβ1 and TGFβ2 were key factors involved in driving the tumor
dynamics in the old hosts, whereas increases in cell cycling and immunosuppression with CDK2, MCM7,
and RUVBL2 were the key players involved in the observed regulatory changes in host environmental
response (i.e. spleen) in adolescent hosts. Surprisingly, transcriptome analysis indicated that proton
irradiation of younger hosts caused a significant predisposition for carcinogenesis progression as
compared to old subjects. One possible explanation for these findings may be a decreased ability of the
host to support tumor progression, i.e. a reduction in the host ‘carrying capacity’ afforded to tumor
growth. These results suggest a significant biological component to proton radiation, operative through
the host that may favorably augment the well-recognized physical advantages of this radiation modality.
This work was supported by NASA grant NNJ06HA28G/NNX11AK26G and by U54CA149233 from the NCI
(LH).
149 | P a g e
