title: Proton irradiation impacts age-driven modulations of cancer progression influenced by immune system transcriptome modifications from splenic tissue.
abstract: Age plays a crucial role in the interplay between tumor and host, with additional impact due to irradiation. Proton irradiation of tumors induces biological modulations including inhibition of angiogenic and immune factors critical to 'hallmark' processes impacting tumor development. Proton irradiation has also provided promising results for proton therapy in cancer due to targeting advantages. Additionally, protons may contribute to the carcinogenesis risk from space travel (due to the high proportion of high-energy protons in space radiation). Through a systems biology approach, we investigated how host tissue (i.e. splenic tissue) of tumor-bearing mice was altered with age, with or without whole-body proton exposure. Transcriptome analysis was performed on splenic tissue from adolescent (68-day) versus old (736-day) C57BL/6 male mice injected with Lewis lung carcinoma cells with or without three fractionations of 0.5 Gy (1-GeV) proton irradiation. Global transcriptome analysis indicated that proton irradiation of adolescent hosts caused significant signaling changes within splenic tissues that support carcinogenesis within the mice, as compared with older subjects. Increases in cell cycling and immunosuppression in irradiated adolescent hosts with CDK2, MCM7, CD74 and RUVBL2 indicated these were the key genes involved in the regulatory changes in the host environment response (i.e. the spleen). Collectively, these results suggest that a significant biological component of proton irradiation is modulated by host age through promotion of carcinogenesis in adolescence and resistance to immunosuppression, carcinogenesis and genetic perturbation associated with advancing age.
authors.affiliation: Center of Cancer Systems Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Wage
authors.affiliation: Center of Cancer Systems Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Ma
authors.affiliation: Center of Cancer Systems Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Peluso
authors.affiliation: Center of Cancer Systems Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Clare
authors.initials: C
authors.lastname: Lamont
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Tufts Cancer Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Evens
authors.affiliation: Center of Cancer Systems Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Hahnfeldt
authors.affiliation: Center of Cancer Systems Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Hlatky
authors.affiliation: Center of Cancer Systems Biology, Tufts University School of Medicine, Boston, MA, USA Molecular Oncology Research Institute, Tufts Medical Center, Tufts Cancer Center, Tufts University School of Medicine, Boston, MA, USA afshin.beheshti@tufts.edu.
authors.forename: Afshin
authors.initials: A
authors.lastname: Beheshti
mesh_terms: D000367:Age Factors; D000818:Animals; D018827:Carcinoma, Lewis Lung; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007107:Immune System / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology*; D011522:Protons; D011839:Radiation, Ionizing; D013154:Spleen / Q000276:immunology / Q000473:pathology* / Q000528:radiation effects; D059467:Transcriptome
chemical_list: D011522:Protons
keywords: aging and cancer; bioinformatics; immunosuppression; protons; spleen; transcriptome analysis; tumor microenvironment; tumor progression