Browsing by Subject "Neoplasms, Radiation-Induced"
Now showing 1 - 5 of 5
- Results Per Page
- Sort Options
Item Effects of Radiation Exposure on Lung Carcinogenesis(2010-01-12) Delgado, Oliver; Shay, Jerry W.Lung cancer is one of the most prevalent forms of cancer in both men and women with over 1.3 million annual related deaths worldwide. Analysis of several human populations exposed to radiation reveals that the lung is remarkably susceptible to the carcinogenic effects of radiation exposure. The considerable lung surface area and slow rate of epithelial turnover may have causal roles in this vulnerability. This may be due to the increased probability that a progenitor cell of the lung, which is proposed to be the cancer-initiating cell, may acquire multiple carcinogenic alterations from radiation exposure. Currently, the lung is believed to have several facultative progenitor cells, situated throughout the lung epithelium, that are regionally restricted in their regenerative capacity. Normal human bronchial epithelial cells (HBECs), immortalized through the expression of Cdk4 and hTERT, provide a sustainable cell reagent for the evaluation of the radiation effects in vitro. These HBECs retain a novel multipotent capacity in vitro (capable of differentiating into both central and peripheral lung cell types) and thus may represent an unrestricted progenitor of the adult lung that resembles an embryonic progenitor. Studies to determine whether the differentiation state influences radiation exposure effects, such as DNA damage and repair, are ongoing. As cellular responses change upon the acquisition of oncogenic mutations, the effects of fractionated or acute radiation exposure on lung carcinogenesis in vivo were determined utilizing the transgenic LA1 K-ras mouse model of lung cancer compared to wildtype littermates. Radiation-induced carcinogenesis is a major concern not only for cancer patients being treated with therapeutic radiation but also for astronauts on long-term space missions. X-ray radiation did not affect the incidence or progression of lung carcinogenesis in this mouse model of lung cancer. High-energy 56Fe- particle irradiation (a type of radiation present in deep space), however, significantly increased the incidence of invasive carcinoma when administered as a fractionated dose but not as a single acute dose. These results demonstrate that pre-initiated lesions may be more susceptible to malignant transformation upon exposure to radiation. Thus, radiation may have an impact on both lung cancer initiation and progression.Item Genetic Events Underlying Radiation-Induced Gliomagenesis(2012-07-10) Camacho, Cristel Vanessa; Burma, SandeepGlioblastoma multiforme (GBM) are highly lethal brain tumors for which exposure to ionizing radiation is the only known risk factor. GBM is characterized by alterations in three core signaling pathways: 1) RTK-PI3K-Akt, 2) ARF-MDM2-p53, and 3) Ink4a-RB1. We have developed in vitro and in vivo models in order to objectively evaluate the risk of developing malignant gliomas from exposure to ionizing radiation (IR). DNA double-strand breaks (DSBs) are the most deleterious lesion inflicted by IR. We hypothesize that DSBs cooperate with pre-existing tumor suppressor loss to trigger IR-induced transformation. We demonstrate that complex DSBs induced by high linear-energy transfer (LET) Fe ions are repaired slowly and incompletely, while those induced by low-LET gamma rays are repaired efficiently by mammalian cells. The incomplete repair of Fe-induced damage results in persistent DNA damage signaling and culminates in high levels of senescence and increased cell killing. // To examine long-term carcinogenic consequences, we used ‘sensitized’ Ink4a/Arf-knockout astrocytes, which are immortal but not tumorigenic. We find that Fe ions are potently tumorigenic when directed to these astrocytes, generating tumors with much higher frequency and shorter latency compared to tumors.Item Investigating the Effects of Particle Radiation Exposure on Lung Carcinogenesis(2019-04-16) Luitel, Krishna; Shay, Jerry W.; Chen, Benjamin P.; Aroumougame, Asaithamby; Akbay, Esra A.Lung cancer accounts for more cancer-related deaths than any other cancer type among both men and women. The overall increase in radiation risk for human cancer types has been substantiated by the epidemiological data obtained from atomic bomb survivors and uranium mine workers. The lung has a large surface area which makes it a prominent target for radiation exposure making it susceptible to radiation-induced cancer. Recently particle radiation therapy such as the use of protons and carbon has increased in the treatment of cancer. The long-term biological effects of proton radiation remain less well characterized in terms of radiotherapy and well as for astronauts during deep space explorations. We compared the long-term side effects of proton radiation to equivalent doses of X-rays in the initiation and progression of premalignant lesions in a transgenic mouse lung cancer model (K-rasLA1). We show proton irradiation causes more complex DNA damage that is not completely repaired resulting in increased oxidative stress in the lungs both acutely and persistently. Proton irradiated mice had lower median survival and increased carcinoma incidence as compared to un-irradiated controls or X-ray exposed mice. Additionally, the space radiation environment consists of a wide variety of ion species with a various range of energies. To understand the effects of mixed ion beam radiation, we exposed K-rasLA-1 mice with three ion beams: Proton (H), Helium (He), and Silicon (Si) at a low dose rate of 0.5cGy/min. Using the three ion beams, we performed whole body irradiation in two different orders: 3B-1 (H-He-Si) and 3B-2 (Si-He-H) and used only H as a reference. We found that whole-body irradiation with 3B-1 increases the incidence of cancer initiation and systemic oxidative stress in mice 100 days post-irradiation compared to 3B-2 and H irradiation. Additionally, we saw an increase in adenomas with atypia and adenocarcinomas in 3B-1 irradiated mice but not in 3B-2 and H irradiated mice. We also found that a non-toxic anti-inflammatory, anti-oxidative radioprotector (CDDO-EA) reduced 3B-1 induced oxidative stress and cancer initiation almost back to baseline. Thus, exposure to 3B-1 elicits significant changes in lung cancer initiation that can be mitigated using CDDO-EA.Item Investigating the Effects of Radiation Exposure on Lung Carcinogenesis(2014-07-10) Kaisani, Aadil A.; Scaglioni, Pier Paolo; Shay, Jerry W.; Story, Michael; Mendelson, Carole R.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.Item Sunlight and skin cancer(1981-04-23) Bergstresser, Paul R.