Host Age is a Systemic Regulator of Gene Expression Impacting Cancer Progression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE66414 | GEO | 2015/03/03
SECONDARY ACCESSION(S): PRJNA276847
REPOSITORIES: GEO
Similar Datasets
Project description:Given that aging is the major determinant of cancer incidence, and that cancer incidence is dictated in large part by processes modulating progression of existing subclinical cancers, we demonstrate that aging may be an organizing axis for identifying cancer progression-modulating processes. This would permit the broad understanding of the aging process to directly inform the question of what changes in aggregate host signaling favor cancer progression. Exploring this idea, a syngeneic murine Lewis lung cancer model in adolescent (68 days), young adult (143 days), middle-aged (551 days), and old (736 days) C57BL/6 mice was used to identify the signaling and functional processes varying significantly with host age. As anticipated, many of these specific endpoints proved to be major determinants of cancer progression. Older hosts demonstrated decreased angiogenesis, decreased metabolism and dysregulated apoptosis, all identified as hallmarks of cancer progression. Transforming growth factor 1, downregulated in older hosts, was also identified as a central player in these systemic processes. It is concluded that the strong host-age dependence here observed for tumor advancement facilitates the identification of an overarching tumor control dynamic exerted by the host. Revealed is insight into a mechanistic basis for the role of aging on modulation of tumor progression that may be therapeutically exploitable. 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, 20 tumor samples from adolescent, 10 from young adult, 10 from middle-aged, and 20 from old mice, were used. All replicate samples were run individually. 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. Data were corrected through normalization of the housekeeping genes, quantile normalized, then imported into MultiExperiment Viewer, MeV for analysis. Statistically significant genes were determined by applying a one-way ANOVA with an adjusted Bonferroni correction and false discovery rate (FDR) < 0.05 that resulted in a list of significant genes.
2015-03-03 | E-GEOD-66414 | biostudies-arrayexpress
Project description:Age plays a major role in tumor incidence and is an important consideration when modeling the carcinogenesis process or estimating cancer risks. Epidemiological data show that from adolescence through middle age, cancer incidence increases with age. This effect is commonly attributed to a lifetime accumulation of cellular, particularly DNA, damage. However, during middle-age, the incidence begins to decelerate and, for many tumor sites, it actually decreases at sufficiently advanced ages. We investigated if the observed deceleration and potential decrease in incidence could be attributed to a decreased capacity of older hosts to support tumor progression, and whether HZE (high atomic number (Z), high energy (E)) radiation differentially modulates tumor progression in young versus middle-age hosts, issues relevant to estimating carcinogenesis risk for astronauts. Lewis lung carcinoma (LLC) cells were injected into syngeneic mice (143 and 551 days old), which were then subject to whole-body 56Fe irradiation (1GeV/amu). Three findings emerged: 1) among unirradiated animals, substantial inhibition of tumor progression and significantly decreased tumor growth rates were seen for middle-aged mice compared to young mice; 2) whole-body 56Fe irradiation (1GeV/amu) inhibited tumor progression in both young and in middle-aged mice (with greater suppression seen in case of young animals), with little effect on tumor growth rates; and 3) 56Fe irradiation (1GeV/amu) suppressed tumor progression in young mice, to a degree not significantly different than transiting from young to middle-aged. Thus, 56Fe irradiation (1GeV/amu) acted similar to aging with respect to tumor progression. We further investigated the molecular underpinnings driving the radiation modulation of tumor dynamics in young and middle-aged mice. Through global gene expression analysis, the key players, FASN, AKT1, and the CXCL12/CXCR4 complex, were determined to be contributory. In sum, these findings demonstrate a reduced capacity of middle-aged hosts to support the progression phase of carcinogenesis and identify molecular factors contributory to HZE radiation modulation of tumor progression as a function of age.
2013-06-13 | GSE45606 | GEO
Project description:Age plays a major role in tumor incidence and is an important consideration when modeling the carcinogenesis process or estimating cancer risks. Epidemiological data show that from adolescence through middle age, cancer incidence increases with age. This effect is commonly attributed to a lifetime accumulation of cellular, particularly DNA, damage. However, during middle-age, the incidence begins to decelerate and, for many tumor sites, it actually decreases at sufficiently advanced ages. We investigated if the observed deceleration and potential decrease in incidence could be attributed to a decreased capacity of older hosts to support tumor progression, and whether HZE (high atomic number (Z), high energy (E)) radiation differentially modulates tumor progression in young versus middle-age hosts, issues relevant to estimating carcinogenesis risk for astronauts. Lewis lung carcinoma (LLC) cells were injected into syngeneic mice (143 and 551 days old), which were then subject to whole-body 56Fe irradiation (1GeV/amu). Three findings emerged: 1) among unirradiated animals, substantial inhibition of tumor progression and significantly decreased tumor growth rates were seen for middle-aged mice compared to young mice; 2) whole-body 56Fe irradiation (1GeV/amu) inhibited tumor progression in both young and in middle-aged mice (with greater suppression seen in case of young animals), with little effect on tumor growth rates; and 3) 56Fe irradiation (1GeV/amu) suppressed tumor progression in young mice, to a degree not significantly different than transiting from young to middle-aged. Thus, 56Fe irradiation (1GeV/amu) acted similar to aging with respect to tumor progression. We further investigated the molecular underpinnings driving the radiation modulation of tumor dynamics in young and middle-aged mice. Through global gene expression analysis, the key players, FASN, AKT1, and the CXCL12/CXCR4 complex, were determined to be contributory. In sum, these findings demonstrate a reduced capacity of middle-aged hosts to support the progression phase of carcinogenesis and identify molecular factors contributory to HZE radiation modulation of tumor progression as a function of age. 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. The number of tumor sample replicates used from each condition is as follows: 10 samples from young unirradiated mice, 8 samples from young irradiated mice, 7 samples from middle-aged unirradiated mice, 5 samples from middle-aged irradiated mice. Total RNA was isolated and purified using Trizol (Invitrogen) or RNeasy (Qiagen), quantified and qualified using Agilent Bioanalyzer (Agilent) and samples were deemed suitable for amplification and hybridization if they had O.D. 260/280 = 1.7 - 2.1, 28s/18s = 2:1, RIN (RNA integrity number) >7. Total RNA of 500ng per sample was amplified using Ambion TotalPrep (Ambion), and 1.5µg of the product was loaded onto the chips. Following hybridization at 55C, the chips were washed and then scanned using the Illumina iScan (Illumina), and the data were analyzed using GenomeStudio (Illumina). Data were first analyzed for gene expression and then culled for present genes (genes that meet the criteria of detection p-value < 0.05). Expression above background was included in an expressed genes working data set for further analyses. Rank variant normalization was applied to the data before extensive analysis. Differential gene expression analysis was used to compare to the reference group, young unirradiated mice, and genes were then evaluated and validated.
2013-06-13 | E-GEOD-45606 | biostudies-arrayexpress
Project description:From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy. For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the well-established role of diet, exercise and small molecules that target the pace of metabolic aging. Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.
2020-07-03 | GSE127001 | GEO
Project description:The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes possibly share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, developed from genetically different ERBB2-positive transgenic mice generated by a backcross, is more aggressive in younger than in older mice, similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. This model included the serum levels of HDL-cholesterol and magnesium that were determined at a disease-free stage, and total AKT1 and glutathione concentrations in the liver at the time of necropsy. Later we defined the grade of aging due to oxidative stress as the increment of aging, which was the difference between the predicted biological age and the chronological age. This comparison permitted the identification of the biologically younger mice with less oxidative stress and older mice with more oxidative stress than would be expected according to their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. We identified genomic regions on chromosomes 2 and 15 that were linked to the grade of oxidative aging. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of oxidative aging and tumour aggressiveness. This study shows part of the complex interactions between breast cancer and aging.
2017-06-14 | GSE99962 | GEO
Project description:Cancer is a disease of aging, and incidence and mortality from all cancers increase logarithmically after the age of 45. Older patients have a much poorer prognosis for melanomas of equal stage, compared to younger individuals. The role of the tumor microenvironment in modulating cancer behavior is widely recognized. We hypothesized that age-related changes in the tumor microenvironment could affect the progression of melanoma. We demonstrate that the aging microenvironment increases the invasion of melanoma cells. Using skin fibroblasts isolated from healthy donors, we have built artificial skin and demonstrate that melanoma cells invade more rapidly when exposed to aged fibroblasts. In a mouse model of melanoma (YUMM1.7, BrafV600E/Cdkn2a-/-/Pten-/-), congeneic to C57/BL6 mice, melanomas invade faster in aged mice. Gene expression analyses suggest that melanoma cells are undergoing DNA damage when exposed to an aged microenvironment, and we confirm this in cellular assays. Proteomics analysis of aging fibroblasts suggest that fibroblasts secrete molecules (laminin b2, Wnt inhibitors) associated with increased resistance to targeted therapy. Indeed, melanoma cells injected into aged mice respond less well to PLX4720 than those injected into young mice. This suggests that exciting new drugs targeting the BRAF pathway may be less effective in aging patients.
2016-04-08 | GSE57445 | GEO
Project description:We developed a mouse model that captures radiation effects on host biology by transplanting unirradiated Trp53 null mammary tissue to sham or irradiated hosts. Gene expression profiles of tumors that arose in irradiated mice are distinct from those that arose in naM-CM-/ve hosts. Host irradiation induces a metaprofile consisting of gene modules representing stem cells, cell motility, macrophages and autophagy. Human orthologs of the host irradiation metaprofile discriminated between radiation-preceded and sporadic human thyroid cancers. An irradiated host centroid was strongly associated with estrogen receptor negative breast cancer. When applied to sporadic human breast cancers, the irradiated host metaprofile strongly associated with basal-like and claudin-low breast cancer intrinsic subtypes. Comparing host irradiation in the context of TGFM-NM-2 levels showed that inflammation was robustly associated with claudin-low tumors. The association of the irradiated host metaprofiles with estrogen receptor negative status and claudin-low subtype suggests that host processes similar to those induced by radiation underlie sporadic cancers. Total RNA was extracted from mammary tumors derived from transplantations of non-irradiated p53null mammary fragments into irradiated hosts. We analyized a total of 32 p53null tumors from irradiated wild type mice: 9 from sham-irradiated hosts, and 23 from irradiated hosts. We also analyzed 24 tumors from irradiated TGFb1 heterozygote hosts: 6 from sham-irradiated hosts, and 18 from irradiated hosts.
2013-04-04 | E-GEOD-42742 | biostudies-arrayexpress
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.
2014-01-01 | GSE45609 | GEO
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2023-12-14 | MTBLS7612 | MetaboLights
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