Densely Ionizing Radiation Acts via the Microenvironment to Promote Aggressive Trp53-Null Mammary Carcinomas

Abstract

Densely ionizing radiation, which is present in the space radiation environment and used in radiation oncology, has potentially greater carcinogenic effect compared with sparsely ionizing radiation that is prevalent on earth. Here, we used a radiation chimera in which mice were exposed to densely ionizing 350 MeV/amu Si-particles, g-radiation, or sham-irradiated and transplanted 3 days later with syngeneic Trp53-null mammary fragments. Trp53-null tumors arising in mice irradiated with Si-particles had a shorter median time to appearance and grew faster once detected compared with those in sham-irradiated or g-irradiated mice. Tumors were further classified by markers keratin 8/18 (K18, KRT18), keratin 14 (K14, KRT14) and estrogen receptor (ER, ESR1), and expression profiling. Most tumors arising in sham-irradiated hosts were comprised of both K18-and K14-positive cells (K14/ 18) while those tumors arising in irradiated hosts were mostly K18. Keratin staining was significantly associated with ER status: K14/18 tumors were predominantly ER-positive, whereas K18 tumors were predominantly ERnegative. Genes differentially expressed in K18 tumors compared with K14/18 tumor were associated with ERBB2 and KRAS, metastasis, and loss of E-cadherin. Consistent with this, K18 tumors tended to grow faster and be more metastatic than K14/18 tumors, however, K18 tumors in particle-irradiated mice grew significantly larger and were more metastatic compared with sham-irradiated mice. An expression profile that distinguished K18 tumors arising in particle-irradiated mice compared with sham-irradiated mice was enriched in mammary stem cell, stroma, and Notch signaling genes. These data suggest that carcinogenic effects of densely ionizing radiation are mediated by the microenvironment, which elicits more aggressive tumors compared with similar tumors arising in sham-irradiated hosts. Cancer Res; 74(23); 7137-48. Ó2014 AACR.

A New Approach to Reduce Uncertainties in Space Radiation Cancer Risk Predictions

“…Recent studies are making efforts to develop appropriate mouse models of human risk using genetically engineered mice and other techniques [ 40 , 41 , 44 ], however they have not been used to estimate RBE values at this time. An important source of data on values of RBE or RBE max for high LET radiation is tumor induction and life-shortening studies in mice or rats with HZE particles or fission neutrons (reviewed in [ 45 , 46 ]).…”

“…Several reports [ 25 , 28 , 39 – 41 , 44 ] have suggested that HZE particles and neutrons could produce more lethal tumors compared to tumors produced by low LET radiation or background tumors, which is a qualitative difference not accounted for in current risk estimates. For low LET radiation there is an implicit assumption made by epidemiology models that the tumors induced by radiation are similar to background tumors in a population.…”

“…There is still a vital need to obtain dose response data in mice for estimating RBE’s for a significant number of HZE particle types in several tissues including lung, mammary and digestive tumors where no RBE estimates have been reported. The limited information available suggests qualitative differences may occur in the metastatic potential of mouse tumors produced by different radiation qualities [ 28 , 35 , 41 , 44 ]. This later feature of HZE particle cancer risk was estimated as a large uncertainty for space radiation risk estimates [ 16 ], and calculations reported here agree with this conclusion.…”

Safe days in space with acceptable uncertainty from space radiation exposure

“…Several reports (Fry et al, 1985;Alpen et al, 1993;Dicello et al, 2004;Weil et al, 2009Weil et al, , 2014Grahn et al, 1992;Imaoka et al, 2007;Trani et al, 2010;Datta et al, 2013;Illa-Bochaca et al, 2014;Wang et al, 2015) have suggested that HZE particles and neutrons could produce more lethal tumors compared to tumors produced by low LET radiation or background tumors, which is a qualitative difference not accounted for in current risk estimates. Table 3 summarizes these findings from animal studies with HZE particle beams.…”

“…Mammary tumors in SD rats (Imaoka et al, 2007) or transgenic mice (Illa-Bochaca et al, 2014) Differences in mammary tumor types comparing heavy ions to low LET radiation with more aggressive tumors observed.…”