Assessing breast cancer angiogenesis in vivo: which susceptibility contrast MRI biomarkers are relevant?

Kim, Eugene; Cebulla, Jana; Ward, B. Douglas; Rhie, Kevin; Zhang, Jiangyang; Pathak, Arvind P.

doi:10.1002/mrm.24530

Cited by 25 publications

(30 citation statements)

References 50 publications

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“…For all imaging sequences, in-plane resolution = 125 µm, slice thickness = 1 mm, and the number of slices varied to cover the entire extent of each tumor. The imaging time for each mouse was approximately 1 h. Further details of the imaging protocol and sequences can be found in [12]. …”

Section: Methodsmentioning

confidence: 99%

“…ADC,

R_{2}^{*}

, and R 2 maps were computed on a voxel-wise basis using methods described by us in [12]. Briefly, ADC maps were calculated from the DWI images using DTI Studio (H Jiang and S Mori, Department of Radiology, Johns Hopkins University, Baltimore, MD).…”

Section: Methodsmentioning

confidence: 99%

“…Magnetic resonance imaging (MRI) has demonstrated the potential to provide such translational biomarkers of angiogenesis [11]. For example, steady-state susceptibility contrast (SSC) MRI has been used to measure blood volume, vessel size, and vessel density [12]. It is an established preclinical technique wherein an intravascular (super) paramagnetic contrast agent (e.g., ultra-small superparamagnetic iron oxide nanoparticles) is administered to increase the magnetic susceptibility gradients between the intra- and extravascular spaces.…”

Section: Introductionmentioning

confidence: 99%

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Vasculature-specific MRI reveals differential anti-angiogenic effects of a biomimetic peptide in an orthotopic breast cancer model

et al. 2014

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Translational vasculature-specific MRI biomarkers were used to measure the effects of a novel anti-angiogenic biomimetic peptide in an orthotopic MDA-MB-231 human triple-negative breast cancer model at an early growth stage. In vivo diffusion-weighted and steady-state susceptibility contrast (SSC) MRI was performed pre-treatment and 2 weeks post-treatment in tumor volume-matched treatment and control groups (n = 5/group). Treatment response was measured by changes in tumor volume; baseline transverse relaxation time (T2); apparent diffusion coefficient (ADC); and SSC-MRI metrics of blood volume, vessel size, and vessel density. These vasculature-specific SSC-MRI biomarkers were compared to the more conventional, non-vascular biomarkers (tumor growth, ADC, and T2) in terms of their sensitivity to anti-angiogenic treatment response. After 2 weeks of peptide treatment, tumor growth inhibition was evident but not yet significant, and the changes in ADC or T2 were not significantly different between treated and control groups. In contrast, the vascular MRI biomarkers revealed a significant anti-angiogenic response to the peptide after 2 weeks—blood volume and vessel size decreased, and vessel density increased in treated tumors; the opposite was seen in control tumors. The MRI results were validated with histology—H&E staining showed no difference in tumor viability between groups, while peptide-treated tumors exhibited decreased vascularity. These results indicate that translational SSC-MRI biomarkers are able to detect the differential effects of anti-angiogenic therapy on the tumor vasculature before significant tumor growth inhibition or changes in tumor viability.

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Section: Methodsmentioning

confidence: 99%

“…ADC,

R_{2}^{*}

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vasculature-specific MRI reveals differential anti-angiogenic effects of a biomimetic peptide in an orthotopic breast cancer model

et al. 2014

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“…Although 3D vascular networks of tumors grown in animal tumor models can be generated from μ -CT data [48, 49], such techniques are not applicable to humans. Therefore, 3D vascular trees of tumors and surrounding host tissue are algorithmically constructed, following methods developed by us previously and applied to model vasculature in melanomas and gliomas [28, 50–54].…”

Section: Theoretical Modelsmentioning

confidence: 99%

Computational Model for Tumor Oxygenation Applied to Clinical Data on Breast Tumor Hemoglobin Concentrations Suggests Vascular Dilatation and Compression

et al. 2016

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We present a computational model for trans-vascular oxygen transport in synthetic tumor and host tissue blood vessel networks, aiming at qualitatively explaining published data of optical mammography, which were obtained from 87 breast cancer patients. The data generally show average hemoglobin concentration to be higher in tumors versus host tissue whereas average oxy-to total hemoglobin concentration (vascular segment RBC-volume-weighted blood oxygenation) can be above or below normal. Starting from a synthetic arterio-venous initial network the tumor vasculature was generated by processes involving cooption, angiogenesis, and vessel regression. Calculations of spatially resolved blood flow, hematocrit, oxy- and total hemoglobin concentrations, blood and tissue oxygenation were carried out for ninety tumor and associated normal vessel networks starting from various assumed geometries of feeding arteries and draining veins. Spatial heterogeneity in the extra-vascular partial oxygen pressure distribution can be related to various tumor compartments characterized by varying capillary densities and blood flow characteristics. The reported higher average hemoglobin concentration of tumors is explained by growth and dilatation of tumor blood vessels. Even assuming sixfold metabolic rate of oxygen consumption in tumorous versus host tissue, the predicted oxygen hemoglobin concentrations are above normal. Such tumors are likely associated with high tumor blood flow caused by high-caliber blood vessels crossing the tumor volume and hence oxygen supply exceeding oxygen demand. Tumor oxy- to total hemoglobin concentration below normal could only be achieved by reducing tumor vessel radii during growth by a randomly selected factor, simulating compression caused by intra-tumoral solid stress due to proliferation of cells and extracellular matrix. Since compression of blood vessels will impede chemotherapy we conclude that tumors with oxy- to total hemoglobin concentration below normal are less likely to respond to chemotherapy. Such behavior was recently reported for neo-adjuvant chemotherapy of locally advanced breast tumors.

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“…Mouse Lewis lung carcinoma was shown to have a vascular volume around 5 %, determined by high resolution micro-CT (computed tomography) after in vivo perfusion with Microfil ® [35]. MDA-MB-231 mouse tumor xenografts were reported to have a vascular volume of ~5 %, measured by micro-CT [36]. It should not be a surprise that DCE-MRI produced higher vascular volumes, since it includes the vascular volume of capillaries (corrected for permeability) that are not rendered by Microfil ® CT due to the limited efficiency of filling in the capillaries and the volume averaging effect during thresholding of the vasculature in micro-CT images [35].…”

Section: Discussionmentioning

confidence: 99%

Water exchange-minimizing DCE-MRI protocol to detect changes in tumor vascular parameters: effect of bevacizumab/paclitaxel combination therapy

Zhu

Kato

Artemov

2013

Magn Reson Mater Phy

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Objective The purpose of this study was to assess changes in the tumor microvasculature induced by combination antiangiogenic therapy in MCF-7 breast tumor mouse models, using a noninvasive DCE-MRI method that minimizes the effect of water exchange. Materials and methods 3D quantitative DCE-MRI images were acquired with a heavily T1-weighted saturation recovery gradient echo sequence with a recovery delay of 20 ms. Tumor vascular volume (VV) and vascular permeability-surface area product (PS) were obtained through a linear regression of the albumin-Gd-DTPA-enhanced dynamic image intensity on MCF-7 breast tumor mouse models treated with combination bevacizumab/paclitaxel therapy. Results Measured tumor VV values were significantly higher than the values that have been reported previously using quantitative T1 mapping, and are in good agreement with micro-CT (computed tomography) results reported earlier from other tumor models. A trend of decreasing tumor PS was detected in the group of MCF-7 tumor bearing mice treated with the bevacizumab/paclitaxel combination regimen. Conclusion VV and PS maps obtained by a heavily T1-weighted acquisition protocol revealed the large peripheral blood vessels as well as the permeable areas within the tumor. A 12-day/three-dose combination treatment of bevacizumab and paclitaxel resulted in delayed tumor growth and a trend of decreasing tumor vascular permeability surface area product.

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Assessing breast cancer angiogenesis in vivo: which susceptibility contrast MRI biomarkers are relevant?

Abstract: As "relative" biomarkers are more easily computed from steady-state susceptibility contrast-MRI (i.e., without additional MRI measurements) than "absolute" biomarkers, it makes them promising candidates for assessing breast cancer angiogenesis in vivo.

Cited by 25 publications

References 50 publications

Vasculature-specific MRI reveals differential anti-angiogenic effects of a biomimetic peptide in an orthotopic breast cancer model

Vasculature-specific MRI reveals differential anti-angiogenic effects of a biomimetic peptide in an orthotopic breast cancer model

Computational Model for Tumor Oxygenation Applied to Clinical Data on Breast Tumor Hemoglobin Concentrations Suggests Vascular Dilatation and Compression

Water exchange-minimizing DCE-MRI protocol to detect changes in tumor vascular parameters: effect of bevacizumab/paclitaxel combination therapy

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