Dataset Information

Micro-CT imaging of tumor angiogenesis: quantitative measures describing micromorphology and vascularization.

ABSTRACT: Angiogenesis is a hallmark of cancer, and its noninvasive visualization and quantification are key factors for facilitating translational anticancer research. Using four tumor models characterized by different degrees of aggressiveness and angiogenesis, we show that the combination of functional in vivo and anatomical ex vivo X-ray micro-computed tomography (?CT) allows highly accurate quantification of relative blood volume (rBV) and highly detailed three-dimensional analysis of the vascular network in tumors. Depending on the tumor model, rBV values determined using in vivo ?CT ranged from 2.6% to 6.0%, and corresponds well with the values assessed using IHC. Using ultra-high-resolution ex vivo ?CT, blood vessels as small as 3.4 ?m and vessel branches up to the seventh order could be visualized, enabling a highly detailed and quantitative analysis of the three-dimensional micromorphology of tumor vessels. Microvascular parameters such as vessel size and vessel branching correlated very well with tumor aggressiveness and angiogenesis. In rapidly growing and highly angiogenic A431 tumors, the majority of vessels were small and branched only once or twice, whereas in slowly growing A549 tumors, the vessels were much larger and branched four to seven times. Thus, we consider that combining highly accurate functional with highly detailed anatomical ?CT is a useful tool for facilitating high-throughput, quantitative, and translational (anti-) angiogenesis and antiangiogenesis research.

SUBMITTER: Ehling J

PROVIDER: S-EPMC3920056 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Micro-CT imaging of tumor angiogenesis: quantitative measures describing micromorphology and vascularization.

Ehling Josef J Theek Benjamin B Gremse Felix F Baetke Sarah S Möckel Diana D Maynard Juliana J Ricketts Sally-Ann SA Grüll Holger H Neeman Michal M Knuechel Ruth R Lederle Wiltrud W Kiessling Fabian F Lammers Twan T

The American journal of pathology 20131118 2

Angiogenesis is a hallmark of cancer, and its noninvasive visualization and quantification are key factors for facilitating translational anticancer research. Using four tumor models characterized by different degrees of aggressiveness and angiogenesis, we show that the combination of functional in vivo and anatomical ex vivo X-ray micro-computed tomography (μCT) allows highly accurate quantification of relative blood volume (rBV) and highly detailed three-dimensional analysis of the vascular ne ...[more]

PMID: 24262753

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Project description:Micro-CT is widely used for small animal imaging in preclinical studies of cardiopulmonary disease, but further development is needed to improve spatial resolution, temporal resolution, and material contrast. We present a technique for visualizing the changing distribution of iodine in the cardiac cycle with dual source micro-CT.The approach entails a retrospectively gated dual energy scan with optimized filters and voltages, and a series of computational operations to reconstruct the data. Projection interpolation and five-dimensional bilateral filtration (three spatial dimensions + time + energy) are used to reduce noise and artifacts associated with retrospective gating. We reconstruct separate volumes corresponding to different cardiac phases and apply a linear transformation to decompose these volumes into components representing concentrations of water and iodine. Since the resulting material images are still compromised by noise, we improve their quality in an iterative process that minimizes the discrepancy between the original acquired projections and the projections predicted by the reconstructed volumes. The values in the voxels of each of the reconstructed volumes represent the coefficients of linear combinations of basis functions over time and energy. We have implemented the reconstruction algorithm on a graphics processing unit (GPU) with CUDA. We tested the utility of the technique in simulations and applied the technique in an in vivo scan of a C57BL∕6 mouse injected with blood pool contrast agent at a dose of 0.01 ml∕g body weight. Postreconstruction, at each cardiac phase in the iodine images, we segmented the left ventricle and computed its volume. Using the maximum and minimum volumes in the left ventricle, we calculated the stroke volume, the ejection fraction, and the cardiac output.Our proposed method produces five-dimensional volumetric images that distinguish different materials at different points in time, and can be used to segment regions containing iodinated blood and compute measures of cardiac function.We believe this combined spectral and temporal imaging technique will be useful for future studies of cardiopulmonary disease in small animals.

Project description:Background & aimsHepatocellular carcinoma (HCC) typically arises in fibrotic or cirrhotic livers, which are characterized by pathogenic angiogenesis. Myeloid immune cells, specifically tumor-associated macrophages (TAMs), may represent potential novel therapeutic targets in HCC, complementing current ablative or immune therapies. However, the detailed functions of TAM subsets in hepatocarcinogenesis have remained obscure.MethodsTAM subsets were analyzed in-depth in human HCC samples and a combined fibrosis-HCC mouse model, established by i.p. injection with diethylnitrosamine after birth and repetitive carbon tetrachloride (CCl4) treatment for 16 weeks. Based on comprehensively phenotyping TAM subsets (fluorescence-activated cell sorter, transcriptomics) in mice, the function of CCR2+ TAM was assessed by a pharmacologic chemokine inhibitor. Angiogenesis was evaluated by contrast-enhanced micro-computed tomography and histology.ResultsWe show that human CCR2+ TAM accumulate at the highly vascularized HCC border and express the inflammatory marker S100A9, whereas CD163+ immune-suppressive TAM accrue in the HCC center. In the fibrosis-cancer mouse model, we identified 3 major hepatic myeloid cell populations with distinct messenger RNA profiles, of which CCR2+ TAM particularly showed activated inflammatory and angiogenic pathways. Inhibiting CCR2+ TAM infiltration using a pharmacologic chemokine CCL2 antagonist in the fibrosis-HCC model significantly reduced pathogenic vascularization and hepatic blood volume, alongside attenuated tumor volume.ConclusionsThe HCC microenvironment in human patients and mice is characterized by functionally distinct macrophage populations, of which the CCR2+ inflammatory TAM subset has pro-angiogenic properties. Understanding the functional differentiation of myeloid cell subsets in chronically inflamed liver may provide novel opportunities for modulating hepatic macrophages to inhibit tumor-promoting pathogenic angiogenesis.

Dataset Information

Micro-CT imaging of tumor angiogenesis: quantitative measures describing micromorphology and vascularization.

Publications

Micro-CT imaging of tumor angiogenesis: quantitative measures describing micromorphology and vascularization.

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