Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy
Introduction: Conventional morphologic and volumetric assessment of treatment response is not suitable for adequately assessing responses to targeted cancer therapy. The aim of this study was to evaluate changes in tumor composition after targeted therapy in murine models of breast cancer with diffe...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523323001596 |
| _version_ | 1797685293844791296 |
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| author | M. Gerwing E. Hoffmann C. Geyer A. Helfen B. Maus R. Schinner L. Wachsmuth W. Heindel M. Eisenblaetter C. Faber M. Wildgruber |
| author_facet | M. Gerwing E. Hoffmann C. Geyer A. Helfen B. Maus R. Schinner L. Wachsmuth W. Heindel M. Eisenblaetter C. Faber M. Wildgruber |
| author_sort | M. Gerwing |
| collection | DOAJ |
| description | Introduction: Conventional morphologic and volumetric assessment of treatment response is not suitable for adequately assessing responses to targeted cancer therapy. The aim of this study was to evaluate changes in tumor composition after targeted therapy in murine models of breast cancer with differing degrees of malignancy via non-invasive magnetic resonance imaging (MRI). Materials and methods: Mice bearing highly malignant 4T1 tumors or low malignant 67NR tumors were treated with either a combination of two immune checkpoint inhibitors (ICI, anti-PD1 and anti-CTLA-4) or the multi-tyrosine kinase inhibitor sorafenib, following experiments with macrophage-depleting clodronate-loaded liposomes and vessel-stabilizing angiopoietin-1. Mice were imaged on a 9.4 T small animal MRI system with a multiparametric (mp) protocol, comprising T1 and T2 mapping and diffusion-weighted imaging. Tumors were analyzed ex vivo with histology. Results and discussions: All treatments led to an increase in non-viable areas, but therapy-induced intratumoral changes differed between the two tumor models and the different targeted treatments. While ICI treatment led to intratumoral hemorrhage, sorafenib treatment mainly induced intratumoral necrosis. Treated 4T1 tumors showed increasing and extensive areas of necrosis, in comparison to 67NR tumors with only small, but also increasing, necrotic areas. After either of the applied treatments, intratumoral heterogeneity, was increased in both tumor models, and confirmed ex vivo by histology. Apparent diffusion coefficient with subsequent histogram analysis proved to be the most sensitive MRI sequence. In conclusion, mp MRI enables to assess dedicated therapy-related intratumoral changes and may serve as a biomarker for treatment response assessment. |
| first_indexed | 2024-03-12T00:42:06Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-03-12T00:42:06Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-48052c5966bf4f8ea45d896888f3858a2023-09-15T04:39:27ZengElsevierTranslational Oncology1936-52332023-11-0137101773Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancyM. Gerwing0E. Hoffmann1C. Geyer2A. Helfen3B. Maus4R. Schinner5L. Wachsmuth6W. Heindel7M. Eisenblaetter8C. Faber9M. Wildgruber10Clinic of Radiology, University of Münster, Münster, Germany; Corresponding author.Clinic of Radiology, University of Münster, Münster, GermanyClinic of Radiology, University of Münster, Münster, GermanyClinic of Radiology, University of Münster, Münster, GermanyClinic of Radiology, University of Münster, Münster, GermanyDepartment of Radiology, University Hospital, LMU Munich, Munich, GermanyClinic of Radiology, University of Münster, Münster, GermanyClinic of Radiology, University of Münster, Münster, GermanyDepartment of Diagnostic and Interventional Radiology, Medical Faculty OWL, University of Bielefeld, Bielefeld, GermanyClinic of Radiology, University of Münster, Münster, GermanyClinic of Radiology, University of Münster, Münster, Germany; Department of Radiology, University Hospital, LMU Munich, Munich, GermanyIntroduction: Conventional morphologic and volumetric assessment of treatment response is not suitable for adequately assessing responses to targeted cancer therapy. The aim of this study was to evaluate changes in tumor composition after targeted therapy in murine models of breast cancer with differing degrees of malignancy via non-invasive magnetic resonance imaging (MRI). Materials and methods: Mice bearing highly malignant 4T1 tumors or low malignant 67NR tumors were treated with either a combination of two immune checkpoint inhibitors (ICI, anti-PD1 and anti-CTLA-4) or the multi-tyrosine kinase inhibitor sorafenib, following experiments with macrophage-depleting clodronate-loaded liposomes and vessel-stabilizing angiopoietin-1. Mice were imaged on a 9.4 T small animal MRI system with a multiparametric (mp) protocol, comprising T1 and T2 mapping and diffusion-weighted imaging. Tumors were analyzed ex vivo with histology. Results and discussions: All treatments led to an increase in non-viable areas, but therapy-induced intratumoral changes differed between the two tumor models and the different targeted treatments. While ICI treatment led to intratumoral hemorrhage, sorafenib treatment mainly induced intratumoral necrosis. Treated 4T1 tumors showed increasing and extensive areas of necrosis, in comparison to 67NR tumors with only small, but also increasing, necrotic areas. After either of the applied treatments, intratumoral heterogeneity, was increased in both tumor models, and confirmed ex vivo by histology. Apparent diffusion coefficient with subsequent histogram analysis proved to be the most sensitive MRI sequence. In conclusion, mp MRI enables to assess dedicated therapy-related intratumoral changes and may serve as a biomarker for treatment response assessment.http://www.sciencedirect.com/science/article/pii/S1936523323001596Therapy response assessmentMultiparametric MRIMurine breast cancerTumor heterogeneity |
| spellingShingle | M. Gerwing E. Hoffmann C. Geyer A. Helfen B. Maus R. Schinner L. Wachsmuth W. Heindel M. Eisenblaetter C. Faber M. Wildgruber Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy Translational Oncology Therapy response assessment Multiparametric MRI Murine breast cancer Tumor heterogeneity |
| title | Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy |
| title_full | Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy |
| title_fullStr | Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy |
| title_full_unstemmed | Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy |
| title_short | Intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy |
| title_sort | intratumoral heterogeneity after targeted therapy in murine cancer models with differing degrees of malignancy |
| topic | Therapy response assessment Multiparametric MRI Murine breast cancer Tumor heterogeneity |
| url | http://www.sciencedirect.com/science/article/pii/S1936523323001596 |
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