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Carbon-ion radiotherapy of human lung cancer

ABSTRACT: Carbon-ion irradiation is an emerging therapeutic option for several tumor entities including lung cancer. Well oxygenated tumor areas compared to a hypoxic environment favor therapeutic photon irradiation efficiency of solid tumors due to increased amounts of DNA damage. The resistance of hypoxic tumor areas towards photon irradiation is enhanced through increased HIF-1 signaling. Here, we compared the effects of oxygen and HIF 1 after photon and carbon-ion irradiation with biological equivalent doses in a human non-small lung cancer model. In hypoxia compared to normoxia, A549 and H1299 cells displayed improved survival after photon irradiation. Knockdown of HIF-1α combined with photon irradiation synergistically delayed tumor growth in vivo. Photon irradiation induced HIF-1α and several of its target genes such as PDK1, GLUT-1, LDHA, and VEGF with subsequent enhanced tumor angiogenesis in vivo, a signaling cascade that was not targeted by carbon-ion irradiation. We present evidence that photons but not carbon-ions induce HIF-1α via mTOR pathway. Importantly, after carbon-ion irradiation in vivo, we observed substantial downregulation of HIF-1α and a drastically delayed tumor growth indicating a considerable higher relative biological effectiveness (RBE) than anticipated from the cell survival data. In sum, our results demonstrate that carbon-ions mediate an improved therapeutic response of tumor treatment compared to photon irradiation that is independent of cell oxygenation and HIF-1 signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45403 | GEO | 2014/04/20

SECONDARY ACCESSION(S): PRJNA193686

REPOSITORIES: GEO

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Carbon-ion radiotherapy of human lung cancer

Project description:Carbon-ion irradiation is an emerging therapeutic option for several tumor entities including lung cancer. Well oxygenated tumor areas compared to a hypoxic environment favor therapeutic photon irradiation efficiency of solid tumors due to increased amounts of DNA damage. The resistance of hypoxic tumor areas towards photon irradiation is enhanced through increased HIF-1 signaling. Here, we compared the effects of oxygen and HIF 1 after photon and carbon-ion irradiation with biological equivalent doses in a human non-small lung cancer model. In hypoxia compared to normoxia, A549 and H1299 cells displayed improved survival after photon irradiation. Knockdown of HIF-1M-NM-1 combined with photon irradiation synergistically delayed tumor growth in vivo. Photon irradiation induced HIF-1M-NM-1 and several of its target genes such as PDK1, GLUT-1, LDHA, and VEGF with subsequent enhanced tumor angiogenesis in vivo, a signaling cascade that was not targeted by carbon-ion irradiation. We present evidence that photons but not carbon-ions induce HIF-1M-NM-1 via mTOR pathway. Importantly, after carbon-ion irradiation in vivo, we observed substantial downregulation of HIF-1M-NM-1 and a drastically delayed tumor growth indicating a considerable higher relative biological effectiveness (RBE) than anticipated from the cell survival data. In sum, our results demonstrate that carbon-ions mediate an improved therapeutic response of tumor treatment compared to photon irradiation that is independent of cell oxygenation and HIF-1 signaling. 16 independent cell cultures were used. Each culture was split into an irradiated and a control plate, yieldin a total of 16 paired samples. Paired samples were analysed in 16 two-color hybridizations. Factors time (after irradiation) with levels 1h and 4h and factor radiation quality with levels C12 and X-rays were analyzed. Each of the 2x2 combinations was analyzed in 4 independent experiments.

2014-04-20 | E-GEOD-45403 | biostudies-arrayexpress

Long term radiation effects in A549 cells - PML knock down and carbon ion vs. photon irradiation

Project description:The aim of our study is to investigate the effects of carbon ion and photon irradiation on A549 tumor cells and analyse how these effects are altered by PML knockdown. Therefore we created PML knockdown A549 cells (shPML) and irradiated them with either 2Gy carbon ion or 6Gy Photon (bioequivalent doses). 4 days after irradiation microarray analysis was performed. All experiments were performed in 3 biological replicates and control groups were transduced with an empty vector.

2023-11-02 | E-MEXP-3965 | biostudies-arrayexpress

Transcription profiling of prostate tumor cell line AT1 inocculated into rats and then subjected to carbon ion or photon radiation

Project description:In the present study approximately 1 to 2 mm3 prostate tumor AT1 was inoculated subcutaneously in the right hind leg of adult male Copenhagen rats. When the tumor diameter exceeded 15 mm, tumors of 5 and 4 rats were irradiated with carbon ion radiation of 37 or 16Gy respectively. Tumors of 5 other rats were irradiated with photon radiation of 37Gy. One animal irradiated with 37 Gy carbon ion radiation and one animal irradiated with photon radiation was sacrificed 12h, 30h, 72h, 7d and 14d after irradiation respectively. One animal irradiated with 16 Gy photon radiation was sacrificed 12h, 60h, 7d and 14d after irradiation respectively. Non-irradiated animals were sacrificed at 60h time point. Tumors were dissected and frozen in liquid nitrogen immediately. Total RNA from tumor material was isolated using the NucleoSpin RNA L kit (#740962.20, Macherey-Nagel). Differential gene expression analysis was performed on the Agilent whole rat genome Oligo Microarray (44k) platform by comparative two dye hybridisation with dye-swaps.

2008-07-18 | E-TABM-481 | biostudies-arrayexpress

Radiation-induced genes expressed in two murine tumors.

Project description:Gene expression profiling was used to identify genes that display radiation-induced transcriptional change over tumor histopathology. Keywords: mouse squamous cell carcinoma, fibrosarcoma and mammary carcinoma, gamma-irradiation, carbon ion irradiation, resected sample, transplanted tissues C3H/HeMs male mice were irradiated by gamma-rays (30Gy, 50Gy, 70Gy) or carbon ions (30Gy) as local irradiation in single doses to hind legs where each tumor was transplanted. Animals were sacrificed either before irradiation (pre) or 1 day after irradiation (day 1) for expression analysis.

2009-03-20 | E-GEOD-5331 | biostudies-arrayexpress

Effect of NDRG3 or HIF-1α knockdown on cell response to hypoxia

Project description:Analysis of Huh-7 hepatocarcinoma cell line depleted of NDRG3 or HIF-1α under hypoxic condition. HIF-1α and NDRG3 have distinct functions in hypoxia responses. Results provide insight into molecular basis of HIF-independent signaling in the development and progression of hypoxic tumors Gene expression profiles of Huh-7 cells stably expressing NDRG3-shRNA or HIF-1α-shRNA under normoxia were compared to gene expression profiles of Huh-7 stable cells under hypoxia for 6, 12 and 24 hours.

2015-07-24 | E-GEOD-55212 | biostudies-arrayexpress

Effect of NDRG3 expression on cell response to hypoxia

2015-07-24 | E-GEOD-59729 | biostudies-arrayexpress

The role of HIF1 in enhancing radio resistance of mouse MSCs

Project description:Mesenchymal stromal cells (MSCs) are multipotent progenitors supporting bone marrow hematopoiesis. MSC have an efficient DNA damage response (DDR) and are consequently reatively radio-resistant cells. Therefore, MSCs are key to hematopoietic reconstitution following total body irradiation (TBI) and bone marrow transplantation (BMT). The bone marrow niche is hypoxic and via the heterodimeric transcription factor Hypoxia-inducible factor-1 (Hif-1), hypoxia enhances the DDR. Using gene knock-down, we have previously shown that the Hif-1α subunit of Hif is involved in MSC radio-resistance, however its exact mechanism of action remains unknown. In order to dissect the involvement of Hif-1α in the DDR, we have generated using CRISPR/Cas9 technology, a stable MS5 mouse MSC cell line lacking Hif-1 expression. Herein, we show that it is the whole Hif-1 transcription factor, and not only the Hif-1α subunit, that modulates the DDR of mouse MSCs, and that this effect is dependent upon the integrity of the DNA binding domain. We have also characterized the Hif-1α-dependent proteomic changes undergone by hypoxic MS5 cells. These findings have important implications for the modulation of MSC radio-resistance in the context of BMT and cancer.

2018-05-16 | PXD006701 | Pride

Carbon ion irradiation plus CTLA4 blockade elicits therapeutic immune responses in a murine tumor model

Project description:Radiotherapy can act as in situ vaccine activating preventive tumor-specific immune responses in treated patients. While carbon ion radiotherapy holds superior biophysical properties over conventional photon irradiation, little is known about the immunological effects induced by this radiation type. Multiple strategies combining radiotherapy with immune checkpoint inhibition (radioimmunotherapy) to enhance anti-tumor immunity have been described, however, results on the immune cell composition in tumors following radioimmunotherapy with carbon ions are lacking. Here, we present a bilateral tumor model based on time-shifted transplantation of murine, Her2+ EO771 tumor cells onto the flanks of immune competent mice followed by selective irradiation of the primal tumor. αCTLA4- but not αPD-L1-based radioimmunotherapy induced complete tumor rejection and mediated eradication of even non-irradiated, distant tumors. Cured mice were protected against EO771 rechallenge indicative of long lasting, tumor-specific immunological memory. Single cell RNA-sequencing and flow cytometric analyses of irradiated tumors revealed activation of NK cells and distinct tumor-associated macrophage clusters with upregulated expression of TNF and IL1 responsive genes. Distant tumors of irradiated mice showed higher frequencies of naïve T cells, which were activated upon combination with CTLA4 blockade. Thus, radioimmunotherapy with carbon ions plus CTLA4 inhibition reshapes the tumor-infiltrating immune cell composition and can induce complete rejection even of non-irradiated tumors. Our data suggest to combine radiotherapy approaches with CTLA4 blockade to achieve durable anti-tumor immunity. Furthermore, evaluation of future radioimmunotherapy approaches should not be restricted to immunological impacts at the irradiation site, but should also consider systemic immunological effects on non-irradiated tumors.

2022-09-30 | GSE214524 | GEO

Gene expression profiles of four murine tumors after carbon-ion (C-ion) or gamma irradiation.

Project description:This study uses microarray analysis to examine the fate of multiple C-ion-irradiated tumors in vivo to gain a comprehensive overview of the changes in gene expression induced by C-ion irradiation. Four murine tumors were irradiated in vivo with C-ions at a single dose, and gamma-rays were used as a reference beam. Keywords: mouse squamous cell carcinoma and fibrosarcoma, carbon ion-irradiation, gamma-irradiation, resected sample, transplanted tissues

2008-06-09 | GSE11629 | GEO

HIF-1α activation is sufficient for the development of MDS

Project description:Hypoxia inducible factor-1α (HIF-1α) is a critical transcription factor for the hypoxic response, angiogenesis, normal hematopoietic stem cell regulation, and cancer development. Importantly, HIF-1α is also a key regulator for immune cell activation. In order to determine whether HIF-1α is sufficient for developing MDS phenotypes, we generated blood specific inducible HIF-1α transgenic mice. Using Vav1-Cre/Rosa26-loxP-Stop-loxP (LSL) rtTA driver, stable HIF-1α can be induced in a doxycycline administration dependent manner. After induction, HIF-1α-induced mice developed thrombocytopenia, leukocytopenia, macrocytic anemia, and multi-lineage dysplasia. We also found activation of both innate and adaptive immunity in HIF-1α- induced mice compared to those from control mice. Taken together, these data suggest that HIF-1α is sufficient to trigger a variety of key MDS features

2018-12-25 | GSE83988 | GEO

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