Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma
BACKGROUND: The Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors.
METHODS: PDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis®) inhibited Hh signaling.
RESULTS: Precision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model.
CONCLUSION: Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent.
| Errataetall: |
ErratumIn: PLoS One. 2019 Oct 30;14(10):e0224827. - PMID 31665182 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
PloS one - 13(2018), 5 vom: 01., Seite e0194809 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Teichman, Jennifer [VerfasserIn] |
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| Links: |
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| Themen: |
0RLU3VTK5M |
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| Anmerkungen: |
Date Completed 30.07.2018 Date Revised 10.12.2019 published: Electronic-eCollection ErratumIn: PLoS One. 2019 Oct 30;14(10):e0224827. - PMID 31665182 Citation Status MEDLINE |
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| doi: |
10.1371/journal.pone.0194809 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM283625759 |
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| 245 | 1 | 0 | |a Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma |
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| 500 | |a ErratumIn: PLoS One. 2019 Oct 30;14(10):e0224827. - PMID 31665182 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: The Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors | ||
| 520 | |a METHODS: PDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis®) inhibited Hh signaling | ||
| 520 | |a RESULTS: Precision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model | ||
| 520 | |a CONCLUSION: Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent | ||
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