Differential microstructure and physiology of brain and bone metastases in a rat breast cancer model by diffusion and
Matthew D Budde1, Eric Gold, E Kay Jordan
1Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Building 10, B1N256, Bethesda, MD 20892, USA. buddem@mail.nih.gov
Abstract:
Pharmacological approaches to treat breast cancer metastases in the brain have been met with limited success. In part, the impermeability of the blood brain barrier (BBB) has hindered delivery of chemotherapeutic agents to metastatic tumors in the brain. BBB-permeable chemotherapeutic drugs are being developed, and noninvasively assessing the efficacy of these agents will be important in both preclinical and clinical settings. In this regard, dynamic contrast enhanced (DCE) and diffusion weighted imaging (DWI) are magnetic resonance imaging (MRI) techniques to monitor tumor vascular permeability and cellularity, respectively. In a rat model of metastatic breast cancer, we demonstrate that brain and bone metastases develop with distinct physiological characteristics as measured with MRI. Specifically, brain metastases have limited permeability of the BBB as assessed with DCE and an increased apparent diffusion coefficient (ADC) measured with DWI compared to the surrounding brain. Microscopically, brain metastases were highly infiltrative, grew through vessel co-option, and caused extensive edema and injury to the surrounding neurons and their dendrites. By comparison, metastases situated in the leptomenengies or in the bone had high vascular permeability and significantly lower ADC values suggestive of hypercellularity. On histological examination, tumors in the bone and leptomenengies were solid masses with distinct tumor margins. The different characteristics of these tissue sites highlight the influence of the microenvironment on metastatic tumor growth. In light of these results, the suitability of DWI and DCE to evaluate the response of chemotherapeutic and anti-angiogenic agents used to treat co-opted brain metastases, respectively, remains a formidable challenge.
Insights
Magnetic resonance imaging (MRI) reveals distinct physiological characteristics of breast cancer brain metastases versus bone metastases. Dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI) show differences in blood-brain barrier (BBB) permeability and cellularity, impacting treatment assessment.
Area of Science:
- Neuro-oncology
- Medical imaging
- Cancer metastasis
Background:
- Treating brain metastases from breast cancer is challenging due to the blood-brain barrier (BBB) limiting drug delivery.
- Noninvasive methods are needed to assess treatment efficacy for brain metastases.
- Dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI) are MRI techniques for evaluating tumor vascular permeability and cellularity.
Purpose of the Study:
- To investigate the distinct physiological characteristics of brain and bone metastases in a rat model of breast cancer using MRI.
- To assess the suitability of DCE and DWI for monitoring treatment response in different metastatic sites.
Main Methods:
- Utilized a rat model of metastatic breast cancer.
- Employed magnetic resonance imaging (MRI), including dynamic contrast-enhanced (DCE) and diffusion-weighted imaging (DWI).
- Correlated MRI findings with histological examination of brain, leptomeningeal, and bone metastases.
Main Results:
- Brain metastases exhibited limited BBB permeability (DCE) and increased apparent diffusion coefficient (ADC) on DWI, indicating infiltrative growth and edema.
- Leptomeningeal and bone metastases showed high vascular permeability (DCE) and lower ADC values, suggesting hypercellularity and distinct tumor margins.
- MRI demonstrated significant physiological differences between brain and bone metastases, influenced by the microenvironment.
Conclusions:
- Breast cancer metastases in the brain and bone possess distinct physiological characteristics detectable by MRI.
- The infiltrative nature of brain metastases and their interaction with the BBB present challenges for evaluating therapeutic responses.
- DWI and DCE show potential for characterizing metastatic sites but require careful interpretation for treatment efficacy assessment, especially for co-opted brain metastases.
