Bile acids mediate liver-bone marrow crosstalk
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE325236 | GEO | 2026/04/12
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the following subset Series: GSE38976: Gene expression profiles of whole blood cells and the fraction enriched with tumor-infiltrating inflammatory cells of Balb/c athymic mice with Hepa1-6 tumors GSE38979: Gene expression profiles of blood and the enriched fraction of tumor-infiltrating inflammatory cells of C57Bl/6 mice with Hepa1-6 tumors GSE38980: Gene expression profiles of whole blood cells of C57Bl/6 mice with Hepa1-6 tumors GSE38981: Gene expression profiles of Hepa1-6 tumors in C57Bl/6 mice Refer to individual Series
2012-07-02 | E-GEOD-39075 | biostudies-arrayexpress
Project description:Purpose: Preclinical model systems should faithfully reflect the complexity of the human pathology. In hepatocellular carcinoma (HCC), the tumor vasculature is of particular interest in diagnosis and therapy. By comparing two commonly applied preclinical model systems, diethylnitrosamine induced (DEN) and orthotopically implanted (McA) rat HCC, we aimed to measure tumor biology non-invasively and identify differences between the models.<br>Experimental design: DEN and McA tumor development was monitored by magnetic resonance imaging (MRI) and positron emission tomography (PET). A slice-based correlation of imaging and histopathology was performed. Array CGH analyses were applied to determine genetic heterogeneity. Therapy response to sorafenib was tested in DEN and McA tumors.<br>Results: Histologically and biochemically confirmed liver damage resulted in increased 18F-fluordeoxyglucose (FDG) PET uptake and perfusion in DEN animals only. DEN tumors exhibited G1-3 grading compared to uniform G3 grading of McA tumors. Array comparative genomic hybridization revealed a highly variable chromosomal aberration pattern in DEN tumors. Heterogeneity of DEN tumors was reflected in more variable imaging parameter values. DEN tumors exhibited lower mean growth rates and FDG uptake and higher diffusion and perfusion values compared to McA tumors. To test the significance of these differences, the multikinase inhibitor sorafenib was administered, resulting in reduced volume growth kinetics and perfusion in the DEN group only.<br>Conclusion: This work depicts the feasibility and importance of in depth preclinical tumor model characterization and suggests the DEN model as a promising model system of multifocal nodular HCC in future therapy studies.
2016-03-25 | E-MTAB-3507 | biostudies-arrayexpress
Project description:This study examines how systemic immune responses and liver immune activity influence liver tumor development. In a diethylnitrosamine (DEN)‑induced mouse model of hepatocellular carcinoma, mice were fed different diets for 26 weeks to assess the impact of metabolic and inflammatory conditions on tumor progression. Tumor burden varied across diets, with increased tumor formation in some diets and a diet with combined cholesterol and cholic acid showing tumor burdens similar to controls. Flow cytometry revealed that mice on the combined diet exhibited the strongest expansion and activation of bone marrow hematopoietic stem and progenitor cells (HSPCs). RNA‑seq was performed on tumor and non‑tumor liver tissues to profile diet‑associated transcriptional changes, and weighted gene co‑expression network analysis (WGCNA) identified conserved immune‑related gene expression modules. Enhanced systemic hematopoietic responses were associated with stronger liver immune gene expression and increased innate immune cell infiltration, correlating with reduced tumor burden. These findings highlight a link between systemic hematopoietic activation, hepatic immune responses, and liver tumor outcomes.
2026-04-12 | GSE325237 | GEO
Project description:Mice developing diethylnitrosamine (DEN)-induced hepatocellular carcinoma were transfected in vivo with Gas1 by hydrodynamic gene delivery. The treatment significantly (p < 0.05) reduced the number of large tumors (more than 2 mm diameter) and histological analyses revealed that the number of carcinoma foci in liver was reduced in favor of less malignant lesions, such as hyperplastic areas, and that the number of lung metastases was also diminished. To study the effects of DEN and the subsequent transfection with Gas1, an expression microarray experiment was designed in which the transcription of 20758 genes in liver was determined. A triangular analysis of microarray data shows that transfection with Gas1 restores the level of transcription level of 182 out of the 698 genes, whose expression was affected by DEN. Therefore, transfection of liver tumor-bearing animals with Gas1 significantly reduces the size and proliferative activity of tumors and restores the transcriptional profile of the liver.
2015-07-31 | GSE63574 | GEO
Project description:Mice developing diethylnitrosamine (DEN)-induced hepatocellular carcinoma were transfected in vivo with Gas1 by hydrodynamic gene delivery. The treatment significantly (p < 0.05) reduced the number of large tumors (more than 2 mm diameter) and histological analyses revealed that the number of carcinoma foci in liver was reduced in favor of less malignant lesions, such as hyperplastic areas, and that the number of lung metastases was also diminished. To study the effects of DEN and the subsequent transfection with Gas1, an expression microarray experiment was designed in which the transcription of 20758 genes in liver was determined. A triangular analysis of microarray data shows that transfection with Gas1 restores the level of transcription level of 182 out of the 698 genes, whose expression was affected by DEN. Therefore, transfection of liver tumor-bearing animals with Gas1 significantly reduces the size and proliferative activity of tumors and restores the transcriptional profile of the liver. Here we studied effects of diethylnitrosamine treatment of mice on the transcription of 20758 liver genes and the consequences of transfecting the livers with Gas1.
2015-07-31 | E-GEOD-63574 | biostudies-arrayexpress
Project description:Background and Aims: The chemical carcinogen diethylnitrosamine (DEN) is often used to induce HCC in mice. Curiously, several labs have reported that the removal of oncoproteins from hepatocytes exacerbated DEN induced HCC, with mechanisms unknown. This study aimed at deciphering molecular mechanisms underlying the tumor suppressive effect of oncoproteins. Approach and Results: We generated mutant mouse lines with hepatocyte-specific deletions of Met, Ptpn11/Shp2, Ikkβ, or ctnnb1/β-catenin and assessed DEN-induced tumorigenesis in the wild-type and mutant mice. To systematically examine genetic and molecular signaling alternations, we performed whole exome and RNA-sequencing on liver samples collected at the pre-cancer and established cancer stages. Although the mutational profiles of DEN-induced tumors were barely different in wild-type and mutant mice, oncoprotein ablation increased DEN-induced mutational burdens, especially in Shp2-deficient tumors. RNA-sequencing revealed multiple changes in signaling pathways, in particular, upregulated epithelial-mesenchymal transition, cell migration, and tumor metastasis, as well as downregulated small molecule metabolism that was affected by oncoprotein ablation. We identified key molecules and pathways that are associated with hepatic innate immunity and implicated in liver tumorigenesis. In addition, we unveiled markedly changed expression of a few miRNAs in the human HCC database. Conclusions: The aggravation of DEN-induced HCC progression seen on oncoprotein ablation could be caused by common and distinct genomic and signaling alterations. This study reveals a new level of complexity in hepatocarcinogenesis and elucidates molecular mechanisms underlying tumor evolution and recurrence.
2024-08-13 | GSE246914 | GEO
Project description:Chronological change of gene expression profile of whole blood cells and features of the fraction enriched with tumor-infiltrating inflammatory cells of Balb/c athymic mice with Hepa1-6 tumors Two-condition experiment
2012-07-02 | E-GEOD-38976 | biostudies-arrayexpress
Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level. RNA from liver tumors derived from from DEN treated TTD+ mice TTD- mice and RNA from normal liver 48h-72h after doxycycline induced transient telomere dysfunction in TTD+ and TTD- liver were isolated and RNA was extracted. Agilent Mouse 4x44K v2 arrays were used. DNA from liver tumors and corrresponding kidney as control derived from from DEN treated TTD+ mice, TTD- mice and mTERC-/- G3 mice was isolated and extracted using Phenol/Chloroform. Agilent Mouse 4x44K and Mouse 1x244K arrays were used.
2012-03-30 | E-GEOD-36813 | biostudies-arrayexpress
Project description:As the central hub metabolic organ bodily, the liver is paramount to keep whole-body energy homeostasis. Further, mitochondria are the central metabolic hub within cells to connect the main catabolized, energy production, and hormonal signaling pathways. It is evident that mitochondrial dysfunction may play a critical role in the development of NASH. Accordingly, understanding the underlying mechanisms of mitochondrial dysfunction is of importance to develop therapies for NASH. Here, we report that mice with hepatocyte-specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. The hepatocellular nodules were developed in 3-month DEN-treated Tid1-/- mice. At the age of 6 months, the DEN-treated Tid1-/- mice showed a higher number of tumors and greater tumor size than the DEN-treated Tid1+/- mice, followed by the DEN-treated WT mice. To gain insights into the mRNA changes during NASH-HCC progress, we performed an RNA-seq analysis with livers collected from 6-month DEN-treated mice.
2022-07-02 | E-MTAB-9974 | biostudies-arrayexpress
Project description:MHC-I loss is a prevalent mechanism for immune evasion and resistance to immunotherapy. However, the mechanisms by which MHC-I loss shapes the tumor microenvironment (TME) and influences the interactions between MHC-I-deficient tumors and immune cells, ultimately affecting tumor growth, remain largely unknown. Here, we found that MHC-I/B2M loss increased tumor growth rates in the MC38, AKR and LLC1 tumor models, but surprisingly led to regression of Hepa1-6 tumors. The effect of MHC-I/B2M loss on tumor growth was associated with the changes in immune infiltrates. CD4+ T cell, NK cells and macrophages were required to suppress the growth of MHC-I-deficient Hepa1-6 tumors, with CD4+ T cells appearing essential for maintaining of the tumoricidal phenotype of monocytes/macrophages and for recruiting NK cells and monocytes/macrophages. Moreover, the differential infiltration of CD4+ T cells was attributed to the upregulation of CXCL16 expression in Hepa1-6 upon loss of MHC-I/B2M, and the downregulation of CXCL16 due to MHC-I deficiency in other tumor models. CXCL16 exhibited a potent antitumor effect on MHC-I-deficient tumors by recruiting CD4+ T cells. In summary, CXCL16-driven CD4+ T cells are central regulators of antitumor immunity against MHC-I-deficient tumors.
2026-03-01 | GSE303349 | GEO