Investigating the Effects of Radiation Exposure on Lung Carcinogenesis



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Although it is the second most diagnosed cancer in both males and females, lung cancer accounts for the most cancer-related deaths worldwide. Radiation-induced carcinogenesis is a major concern for therapeutic radiation oncology as well as for astronauts on long-term missions. The large surface area of the lung makes it a prominent target for radiation exposure. From analysis of several human populations such as atomic bomb survivors, it is evident that the lung is remarkably susceptible to radiation-induced cancer. However, this data cannot be extrapolated to assess the risk in astronauts because of differences between terrestrial and space radiation. Due to lack of understanding of how the ionizing space radiation affects cellular functions and carcinogenesis, there is a need to develop in vitro and in vivo systems. Using immortalized human bronchial epithelial cells (HBECs) we have developed a novel three-dimensional (3D) culture system. When cultured on top of reconstituted basement membrane with lung fetal fibroblasts cultured below, HBECs form budding and branching structures resembling branching morphogenesis during lung development. HBECs in this culture system maintain markers of multiple cell types in the airway epithelium indicative of their multipotent potential. Studies to determine the effects of radiation on HBECs in 3D cultures are ongoing. Radiation-induced carcinogenesis may require changes to the immune system and tumor microenvironment therefore we utilized the LA1 K-ras mouse model to analyze the effects of terrestrial and space radiation. Mice irradiated with simulated solar particle events (SPE) and silicon particle radiation (types of radiation in space) had a significantly shorter lifespan in contrast to unirradiated cohorts or mice irradiated with equivalent terrestrial radiation. A significant increase in invasive carcinoma was also observed in mice irradiated with SPE and silicon particle radiation but not with terrestrial radiation. Analysis of mice 70 days post-irradiation suggests that chronic inflammation is a likely contributor to tumor progression. CDDO-EA an anti-oxidant/anti-inflammatory modulator was tested as a potential radio-protector. A significant decrease in carcinoma was observed in mice fed a CDDO-EA countermeasure diet. These observations suggest that the lung is highly susceptible to carcinogenesis upon irradiation and countermeasure compounds may mitigate this outcome.

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Bronchi, Cell Transformation, Neoplastic, Lung Neoplasms, Neoplasms, Radiation-Induced


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