22nd Annual NASA Space Radiation Investigators' Workshop (2011)
7143.pdf
NASA Specialized Center of Research
The contribution of non-targeted effects (NTE) in HZE cancer risk: Overview
M.H. Barcellos-Hoff1, A. Balmain2, S.V.Costes3, S. Demaria1, J.H. Mao3
1
Depts of Radiation Oncology (MHBH) and Pathology (SD) , New York University School of Medicine, 566 First
Ave, New York, NY10016; 2 University of California, San Francisco, Cancer Research Center, San Francisco, CA
94143; 2Lawrence Berkeley National Laboratory, 1 Cyclotron Rd, MS:977, Berkeley, CA 94720
This NSCOR provides experimental and modeling studies to define the efficiency and physiological context in
which high LET radiation increases epithelial cancer risk. Project 1 tests the contributions of NTE to radiation’s
carcinogenic effects using a novel radiation/genetic mammary chimera modeling in which either the host (i.e. nontargeted), or the transplanted epithelium (i.e. targeted) is irradiated. We have completed irradiations for three
experiments in which Balb/c mice were exposed to two fluences (1 vs 3 particles per 100 m2) of 350 MeV/amu Si,
350 MeV/amu Ar or 600 MeV/amu Fe particles. Experiment controls include sham-irradiated hosts and hosts
exposed to 1 Gy -radiation were executed concurrently for each run. Tissues were obtained at 1 wk, 1 month and 3
months for analysis using gene expression, functional analysis and tissue histology (also see abstracts from IllaBochaca and Tang). The analysis of systemic immune function changes induced by different types of radiation in
the phenotype and cytokine production by spleen and lymph nodes cells suggested that all radiation regimens caused
a systemic inflammatory response with variable induction of KC, TNFα and IL-1β at 1 week that returned to normal
by 3 months, and a selective up-regulation of IL-12p70 by high fluence Fe was seen. However, these observations
were not confirmed in a repeat Fe experiment and no specific change was seen with Si. Likewise, no significant
changes were detected in myeloid and lymphoid populations at the indicated times post-radiation. Overall, this
suggests that the changes that are detectable in the spleen, lymph nodes and serum are mild and may be obscured by
environmental effects due to husbandry leading to high levels of "noise". For mammary tumorigenesis, groups of
mice were irradiated with HZE as above and the cleared fat pad subsequently transplanted with Trp53 null
mammary epithelium. Transplantation efficiency was confirmed to be 90+% in all groups. Approximately 100
mammary tumors have been harvested to date. Gene expression profiles of the first set of tumors from the Si
experiment are underway. Two additional experiments consisting of mice aged to 10 months prior to irradiation and
transplantation, and mice after transplantion with Trp53 null mammary epithelium are also under way.
Project 2 investigates the impact of both low and high LET-radiation upon carcinogenesis using the p53 ∆p mouse
model created by our collaborator Geoff Wahl. Interestingly, in response to γ-radiation exposure, and in contrast to
p53 null mice, which primarily develop lymphomas and sarcomas, the p53 ∆p mice exhibit a wide range of tumors
in solid tissues, including those of the lung, liver, brain and kidney. A long-term tumorigenesis study was begun in
November 2010. In total, 110 p53 ∆p mice on a mixed 129/Sv/C57BL/6 background were irradiated with either
29cGy, 81cGy, or 1Gy 600 MeV/amu Fe particles or 1Gy  radiation. In addition, wild-type controls of 129/Sv or
C57BL/6 mice were included. This study is still ongoing. Arising tumors and radiosensitive tissues including the
skin, liver, lung, breast, thymus and spleen are being harvested for both gene expression analysis and histology.
Furthermore, blood samples are taken for blood smears, complete blood count (CBC) and pellets and serum. The
high dose (1 Gy Fe), low dose (29 cGy Fe) and 1 Gy gamma radiation have, to date, seen an equal number of mice
(8 mice) succumb to tumor development. In contrast, a quarter of this number of mice developed cancers (2 mice)
when treated with the medium dose of high LET (81 cGy). As predicted, the wild-type mice on both the 129/SV and
C57BL/6 background have not yet succumbed to any tumor development.
Project 3 provides integrated mechanistic modeling of the biology using Monte Carlo models of DNA damage with
agent-based models (ABM) to simulate the dynamic response of tissue to radiation and to identify the key events
leading to the emergence of a tumor in silico. Modeling will use data from Project 1 that identifies on gene
expression changes that correlate with tumor incidence and from Project 2 that identify the genetic factors increasing
tumor risk. The modeling will be benchmarked in silico functions with those altered during cancer progression in
vivo. Recent developments include an in silico mammary gland consists of interacting agents simulating mammary
epithelial cells, from mammary stem cells to fully differentiated luminal cells. Based on data from the mouse model
in Project 1, by transiently increasing stem cell self-renewal probability and by increasing the rate of "spontaneous
death" due to TGFβ the computational model has begun generating in silico tumors in the agent population. Thus,
the mammary carcinogenesis ABM supports the conclusion that NTE, via increased genomic surveillance and
MaSC self-renewal, can account for accelerated tumor development in irradiated hosts.