Densely Ionizing Radiation Acts via the Microenvironment to Promote Aggressive Trp53 Null Mammary Carcinomas
Menée à l'aide d'un modèle murin de carcinome mammaire, cette étude montre que, par rapport aux autres rayonnements ionisants, les rayonnements à forte densité d'ionisation (utilisés en radiothérapie) favorisent le développement de tumeurs plus agressives en agissant sur leur micro-environnement
Densely ionizing radiation, which is present in the space radiation environment and used in radiation oncology, has potentially greater carcinogenic effect compared to 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, gamma-radiation, or sham-irradiated and transplanted 3 days later with syngeneic Trp53 null mammary fragments. Trp53 null tumors arising in mice densely irradiated had a shorter median time to appearance and grew faster once detected compared to those in sham-irradiated or gamma-irradiated mice. Tumors were further classified by markers keratin 8/18 (K18, KRT18), keratin 14 (K14, KRT18) 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 expressed mostly K18. Keratin staining was significantly associated with ER status. K14/18 tumors were predominantly ER positive while K18 tumors were predominantly ER negative. Genes differentially expressed in K18 tumors compared to K14/18 tumor were associated with ERBB2 and KRAS, metastasis and loss of E-cadherin. Although K18 tumors tended to grow faster and be more metastatic than K14/18 tumors, K18 tumors in particle-irradiated mice grew significantly larger compared to controls and were more metastatic compared to sham-irradiated mice. An expression profile that distinguished K18 tumors arising in particle-irradiated compared sham-irradiated mice was enriched in mammary stem cell, stroma, and Notch signaling genes. These data suggest that the carcinogenic effects of densely ionizing radiation is mediated by the microenvironment, which elicits more aggressive tumors compared to similar tumors arising in sham-irradiated hosts.