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PURPOSE: To examine whether inherent factors produce differences in lung morbidity in response to carbon ion (C-ion) irradiation, and to identify the molecules that have a key role in strain-dependent adverse effects in the lung. \nMETHODS AND MATERIALS: Three strains of female mice (C3H/He Slc, C57BL/6J Jms Slc, and A/J Jms Slc) were locally irradiated in the thorax with either C-ion beams (290 MeV/n, in 6 cm spread-out Bragg peak) or with (137)Cs gamma-rays as a reference beam. We performed survival assays and histologic examination of the lung with hematoxylin-eosin and Masson's trichrome staining. In addition, we performed immunohistochemical staining for hyaluronic acid (HA), CD44, and Mac3 and assayed for gene expression. \nRESULTS: The survival data in mice showed a between-strain variance after C-ion irradiation with 10 Gy. The median survival time of C3H/He was significantly shortened after C-ion irradiation at the higher dose of 12.5 Gy. Histologic examination revealed early-phase hemorrhagic pneumonitis in C3H/He and late-phase focal fibrotic lesions in C57BL/6J after C-ion irradiation with 10 Gy. Pleural effusion was apparent in C57BL/6J and A/J mice, 168 days after C-ion irradiation with 10 Gy. Microarray analysis of irradiated lung tissue in the three mouse strains identified differential expression changes in growth differentiation factor 15 (Gdf15), which regulates macrophage function, and hyaluronan synthase 1 (Has1), which plays a role in HA metabolism. Immunohistochemistry showed that the number of CD44-positive cells, a surrogate marker for HA accumulation, and Mac3-positive cells, a marker for macrophage infiltration in irradiated lung, varied significantly among the three mouse strains during the early phase. \nCONCLUSIONS: This study demonstrated a strain-dependent differential response in mice to C-ion thoracic irradiation. Our findings identified candidate molecules that could be implicated in the between-strain variance to early hemorrhagic pneumonitis after C-ion irradiation.

Purpose: To clarity how carbon-ion radiotherapy on primary tumors affects the characteristics of subsequently-arising metastatic tumor cells. Methods and Materials: Mouse squamous cell carcinomas, NR-S1, in synergic C3H/HeMsNrs mice were irradiated with a single dose of 5-50 Gy of carbon-ions (C-ion) (290 MeV/nucleon, 6 cm spread-out Bragg peak) or gamma-rays (GAMMA-rays) (137Cs source) as a reference beam. The volume of the primary tumors and the number of metastatic nodules in lung were studied, and histological analysis and microarray analysis of laser-microdissected tumor cells were also performed. Results: Including 5 Gy of C-ion and 8 Gy of GAMMA-rays, which did not inhibit the primary tumor growth, all doses used in this study inhibited lung metastasis significantly. Pathological findings showed no difference among the metastatic tumor nodules in the non-irradiated, carbon-ion-irradiated, and GAMMA- ray-irradiated groups. Clustering analysis of expression profiles among metastatic tumors and primary tumors revealed a single cluster consisting of metastatic tumors different from their original primary tumors, indicating that the expression profiles of the metastatic tumor cells were not affected by the local application of C-ion radiotherapy or GAMMA-ray radiotherapy. Conclusion: We found no difference in the incidence and histology, and only small differences in expression profile, of distant metastasis between local C-ion and GAMMA-ray radiotherapy. The application of local radiotherapy per se or the type of radiotherapy applied did not influence the transcriptional changes caused by metastasis in tumor cells.