Microarray of healthy heart tissue of mouse (BALB/c nude female mice) after proton-beam treatment to cure breast cancer
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ABSTRACT: Proton irradiation: 2, 6 and 9 Gy + untreated controls Times after irradiation: 3 and 10 days Associated pubblication: Sala, C.; Tarozzi, M.; Simonetti, G.; Pazzaglia, M.; Cammarata, F.P.; Russo, G.; Acquaviva, R.; Cirrone, G.A.P.; Petringa, G.; Catalano, R.; et al. Impact on the Transcriptome of Proton Beam Irradiation Targeted at Healthy Cardiac Tissue of Mice. Cancers 2024.
Project description:Proton irradiation is touted for its improved tumor targeting due to the physical advantages of ion beams for radiotherapy. Recent studies from our laboratory have shown that, in addition to targeting advantages, proton irradiation can inhibit angiogenic and immune factors and thereby modulate tumor progression. High-energy protons also constitute a principal component of the galactic cosmic rays to which astronauts are exposed. Increased understanding of the biological effects of proton exposure would thus contribute to both improved cancer therapy and carcinogenesis risk assessment for space travel. In addition, age plays a major role in tumor incidence and is a critical consideration for estimating cancer risk. We investigated the effects of host age and proton exposure on tumor progression. Tumor lag time and growth dynamics were tracked following injection of murine Lewis lung carcinoma (LLC) cells into young (68 day) versus old (736 day) mice with or without coincident irradiation. Tumor progression was suppressed in old compared to young mice. Differences in progression were further modulated by proton irradiation (1GeV), with increased inhibition evident in old mice. Through global transcriptome analysis, TGFβ1 and TGFβ2 were determined to be key players that contributed to the tumor dynamics observed. These findings point to older hosts providing decreased systemic tumor support, which can be further inhibited by proton irradiation.
Project description:Genome wide DNA methylation profiling of estrogene receptor postive breast cancer cell line MCF-7, treating proton beam. The Illumina Infinium Human Methylation 450k Bead chip was used to obtain DNA methylation profiles across approximately 450,000 CpGs. This profiling indicates that proton beam induces epigenetic and cellular changes. Genomic DNA obtained from MCF-7 effected by proton beam
Project description:Literature data report the helpful role of specific molecularly based signatures to predict response to treatment in cancer, including breast cancer (BC) disease. As known, BC is a heterogeneous disease presenting distinct subtypes with different clinical outcomes. Thus, the choice of a unique treatment plan for all BC patients, including radiation therapy (RT), may be not the best option. Technological advances in RT are evolving with the use of proton beams, which reduce the dose administered to the heart compared to conventional RT. However, limitate data regarding proton-induced molecular changes are currently available. The aim of this study was therefore to study gene expression profiles induced by proton irradiation with 0.5, 2 and 9 Gy of Ionizing radiation (IR) doses in breast cells. The great amount of data here collected, represent an useful tool to better understand the molecular mechanisms elicited by proton irradiation, thereby filling the existing lack of data in the literature.
Project description:Genome wide DNA methylation profiling of estrogene receptor postive breast cancer cell line MCF-7, treating proton beam. The Illumina Infinium Human Methylation 450k Bead chip was used to obtain DNA methylation profiles across approximately 450,000 CpGs. This profiling indicates that proton beam induces epigenetic and cellular changes.
Project description:Proton irradiation is touted for its improved tumor targeting due to the physical advantages of ion beams for radiotherapy. Recent studies from our laboratory have shown that, in addition to targeting advantages, proton irradiation can inhibit angiogenic and immune factors and thereby modulate tumor progression. High-energy protons also constitute a principal component of the galactic cosmic rays to which astronauts are exposed. Increased understanding of the biological effects of proton exposure would thus contribute to both improved cancer therapy and carcinogenesis risk assessment for space travel. In addition, age plays a major role in tumor incidence and is a critical consideration for estimating cancer risk. We investigated the effects of host age and proton exposure on tumor progression. Tumor lag time and growth dynamics were tracked following injection of murine Lewis lung carcinoma (LLC) cells into young (68 day) versus old (736 day) mice with or without coincident irradiation. Tumor progression was suppressed in old compared to young mice. Differences in progression were further modulated by proton irradiation (1GeV), with increased inhibition evident in old mice. Through global transcriptome analysis, TGFβ1 and TGFβ2 were determined to be key players that contributed to the tumor dynamics observed. These findings point to older hosts providing decreased systemic tumor support, which can be further inhibited by proton irradiation. For genome-wide expression profiling of tumor tissue, Mouse WG-6 BeadArray chips (Illumina, San Diego, CA) were used. Total RNA was amplified with the Ambion Illumina TotalPrep Amplification Kit (Ambion, Austin, TX) and labeled from all replicate biological samples for each condition. For tumor replicates, thirty tumor samples from adolescent and thirty tumor samples from old mice, for a total of 60 tumor samples, were used. All replicate samples were run individually. For each age group, ten tumor samples had received proton irradiation while twenty tumor samples were from unirradiated mice (as described above). Total RNA was isolated and purified using TRIzol (Invitrogen) and quantified using an Agilent Bioanalyzer. Samples were deemed suitable for amplification and hybridization if they had 28s/18s = 2:1, RIN >7. Total RNA of 500ng per sample was amplified using AmbionTotalPrep, and 1.5ug of the product was loaded onto the chips. Following hybridization at 55C, the chips were washed and then scanned using the Illumina iScan System. The data was checked with GenomeStudio (Illumina) for quality control. In GenomeStudio, data was background subtracted and rank invariant normalization was applied. Data was imported into MultiExperiment Viewer, MeV, for statistical analysis. The statistically significant genes were determined using MeV by applying a one-way ANOVA analysis with standard Bonferroni correction with a FDR <0.05 that resulted in a list of significant genes. Average gene expression signals <10 were filtered out due to signal being
Project description:Age plays a crucial role in the interplay between tumor and host; with further perturbations induced by irradiation. Proton irradiation on tumors induces biological modulations including inhibition of angiogenic and immune factors critical to “hallmark” processes impacting tumor development, in addition to physical targeting advantages. These advantages have provided promising results for proton therapy in cancer. Additionally, protons have implications for carcinogenesis risk of 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 is 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 0.5Gy (1GeV) 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 to old subjects. Increases in cell cycling and immunosuppression in irradiated adolescent hosts with CDK2, MCM7, CD74, and RUVBL2 as the key players were involved in the regulatory changes in host environment response (i.e. spleen). These results suggest a significant biological component to proton irradiation, operative through host age, that would indicate a modulation of host’s ability to support carcinogenesis in adolescence and the bestowal of resistance to immunosuppression, carcinogenesis, and genetic perturbation by old age.
Project description:Proton (PT) therapy represents an alternative to conventional X-ray therapy, and its clinical application for cancer treatment is on the rise due to associated dose deposit advantages. However, our knowledge of biological responses to PT, in comparison to X-ray, remains in its infancy. Identification of PT specific molecular signals is an important opportunity for the discovery of biomarkers and synergistic drugs. We have profiled the transcriptome regulation of lymphoma cells exposed to clinical sources of PT and X-ray radiation, respectively. Subsequent analysis demonstrated both common and radiation-specific deregulation of gene expression. Gene set enrichment discovered pathways unique to PT \ that contribute to the unfolded protein response (UPR) and mitochondrial transport.
Project description:Novel particle therapy was implemented into standard-of-care for cancer patients during the last years. However, experimental studies investigating cellular and molecular mechanisms are lacking although prognostic biomarker are urgently needed. The cancer stem cell (CSC)-related marker aldehyde dehydrogenase (ALDH) is known to impact on prostate cancer radiosensitivity through affecting defense against reactive oxygen species (ROS), reducing DNA damage repair and increasing cell survival. Surprisingly, we could show in a previous study that ionizing radiation itself enriches for ALDH-positive CSCs in a time- and dose-dependent manner through alteration in histone methylation. Within the present study, we investigated CSC marker dynamics upon proton beam irradiation and hypothesized that this novel particle therapy may have increased CSC targeting potential due to its increased ionization potential compared to conventional photon irradiation. However, we found that proton irradiation is affecting cellular dynamics and escape from cell death.