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Updated: Jul 29, 2025
Live Imaging of Drug Responses in the Tumor Microenvironment in Mouse Models of Breast Cancer
Published on: March 24, 2013
Vascular response patterns to targeted therapies in murine breast cancer models with divergent degrees of malignancy
Emily Hoffmann1, Mirjam Gerwing2, Tobias Krähling2
1Clinic of Radiology, University of Münster, Münster, Germany. emily.hoffmann@ukmuenster.de.
Background:
Response assessment of targeted cancer therapies is becoming increasingly challenging, as it is not adequately assessable with conventional morphological and volumetric analyses of tumor lesions. The tumor microenvironment is particularly constituted by tumor vasculature which is altered by various targeted therapies. The aim of this study was to noninvasively assess changes in tumor perfusion and vessel permeability after targeted therapy in murine models of breast cancer with divergent degrees of malignancy.
Methods:
Low malignant 67NR or highly malignant 4T1 tumor-bearing mice were treated with either the multi-kinase inhibitor sorafenib or immune checkpoint inhibitors (ICI, combination of anti-PD1 and anti-CTLA4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with i.v. injection of albumin-binding gadofosveset was conducted on a 9.4 T small animal MRI. Ex vivo validation of MRI results was achieved by transmission electron microscopy, immunohistochemistry and laser ablation-inductively coupled plasma-mass spectrometry.
Results:
Therapy-induced changes in tumor vasculature differed between low and highly malignant tumors. Sorafenib treatment led to decreased tumor perfusion and endothelial permeability in low malignant 67NR tumors. In contrast, highly malignant 4T1 tumors demonstrated characteristics of a transient window of vascular normalization with an increase in tumor perfusion and permeability early after therapy initiation, followed by decreased perfusion and permeability parameters. In the low malignant 67NR model, ICI treatment also mediated vessel-stabilizing effects with decreased tumor perfusion and permeability, while ICI-treated 4T1 tumors exhibited increasing tumor perfusion with excessive vascular leakage.
Conclusion:
DCE-MRI enables noninvasive assessment of early changes in tumor vasculature after targeted therapies, revealing different response patterns between tumors with divergent degrees of malignancy. DCE-derived tumor perfusion and permeability parameters may serve as vascular biomarkers that allow for repetitive examination of response to antiangiogenic treatment or immunotherapy.
Insights
Dynamic contrast-enhanced MRI noninvasively assesses tumor vascular changes after targeted cancer therapies. Results reveal distinct response patterns in low versus highly malignant breast cancer models, offering potential biomarkers for treatment monitoring.
Area of Science:
- Oncology
- Medical Imaging
- Cancer Biology
Background:
- Assessing targeted cancer therapy response is challenging with conventional methods.
- Tumor vasculature is significantly altered by targeted therapies.
- Understanding these vascular changes is crucial for effective treatment monitoring.
Purpose of the Study:
- To noninvasively assess changes in tumor perfusion and vessel permeability after targeted therapy.
- To investigate these changes in murine breast cancer models with varying malignancy.
- To explore the utility of dynamic contrast-enhanced MRI (DCE-MRI) for response assessment.
Main Methods:
- Utilized low (67NR) and high (4T1) malignancy murine breast cancer models.
- Administered multi-kinase inhibitor sorafenib or immune checkpoint inhibitors (ICI).
- Performed DCE-MRI with albumin-binding gadofosveset, validated with ex vivo techniques.
Main Results:
- Sorafenib decreased perfusion and permeability in 67NR tumors.
- 4T1 tumors showed a transient vascular normalization window with sorafenib.
- ICI treatment affected vasculature differently based on malignancy, with 4T1 tumors exhibiting increased perfusion and leakage.
Conclusions:
- DCE-MRI effectively assesses early tumor vascular changes post-targeted therapy.
- Tumor malignancy influences vascular response patterns to therapy.
- DCE-MRI derived parameters show potential as biomarkers for antiangiogenic and immunotherapy response.
