Molecular imaging of angiogenesis

Neeman, Michal; Gilad, Assaf A.; Dafni, Hagit; Cohen, Batya

doi:10.1002/jmri.20774

Cited by 38 publications

(29 citation statements)

References 141 publications

(210 reference statements)

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“…Meanwhile, depletion of oxygen and energy supply may have reached a state that is no longer compatible with tumor cell viability and thus tumor shrinkage initiates. These findings are in line with previous studies investigating the effect of VEGFR2 antibodies on tumor xenografts with noninvasive imaging modalities such as MRI, CT and ultrasound [4,6,[8][9][10][11]. Correspondingly, the histological analysis confirmed a significant reduction in micro vessel density upon therapy.…”

Section: Discussionsupporting

confidence: 93%

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Volumetric high-frequency Doppler ultrasound enables the assessment of early antiangiogenic therapy effects on tumor xenografts in nude mice

et al. 2007

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The sensitivity of Doppler ultrasound below 10 MHz to assess antiangiogenic therapy effects in tumor xenografts has been shown to be limited. Thus, our aim was to evaluate high-frequency volumetric power-Doppler ultrasound (HF-VPDU) for monitoring antiangiogenic treatments. Squamous cell carcinoma xenografts grown in nude mice were scanned with HF-VPDU at a center frequency of 30 MHz. Images with 200-microm slice thicknesses were recorded and merged into a three-dimensional dataset, of which the relative color pixel density was determined. Animals received either VEGFR2 antibodies or 0.9% NaCl and were examined at days 0, 3 and 6 of treatment. After the last examination, tumors were resected and their vascularization characterized by immunohistology. At day 6, the volumes of treated and untreated tumors were not significantly different yet. In contrast, mean tumor vascularization in treated animals had decreased to 44%, while in the control group it had increased to 152% (P < 0.01). In correspondence, vessel density, as determined by CD31 staining, was 0.19 +/- 0.10% in treated and 0.92 +/- 0.41% in untreated tumors (P < 0.01). Additionally, the fraction of mature (SMA-positive) vessels increased under therapy. Thus, HF-VPDU can be considered as an easily applicable and fast method to screen high animal numbers for antiangiogenic therapy effects.

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Section: Discussionsupporting

confidence: 93%

“…In animal models, surrogate markers of tumor vascularization, as determined by computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission CT (SPECT) and ultrasound, have proven to be sensitive and early indicators of therapy response [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Volumetric high-frequency Doppler ultrasound enables the assessment of early antiangiogenic therapy effects on tumor xenografts in nude mice

et al. 2007

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“…4,5,7,26). Molecular imaging may even be capable to indicate early therapy response of tumors (e.g., down-regulation of growth factor receptors) occurring before the change of tumor volume.…”

Section: Discussionmentioning

confidence: 99%

“…1). In this context, the ability to visualize noninvasively and quantify the regulation of different marker molecules longitudinally would be extremely valuable in preclinical research (4). Moreover, it would open new perspectives for the monitoring of tumor suppression (e.g., antiangiogenic therapies in patients; refs.…”

Section: Introductionmentioning

confidence: 99%

Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects

Palmowski

Huppert

Ladewig

et al. 2008

Molecular Cancer Therapeutics

157

113

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Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric ''multitarget quantification'' and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and A v B 3 integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and A v B 3 integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and A v B 3 integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and A v B 3 integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo.

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“…In this respect, surrogate markers of tumor vascularization can be determined noninvasively by magnetic resonance imaging (MRI; refs. [4][5][6], computed tomography (7)(8)(9), positron emission tomography, and single-photon emission computed tomography (10,11). In addition, ultrasound has been used successfully as a cheap, fast, and easily applicable method for serial imaging of animals with high throughput (12,13).…”

Section: Introductionmentioning

confidence: 99%

Vessel Fractions in Tumor Xenografts Depicted by Flow- or Contrast-Sensitive Three-Dimensional High-Frequency Doppler Ultrasound Respond Differently to Antiangiogenic Treatment

et al. 2008

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High-frequency volumetric Power Doppler ultrasound (HF-VPDU) captures flow-dependent signals in blood vessels and can be used to assess antiangiogenic therapy effects in rodent tumors. However, the sensitivity is limited to vessels larger than capillaries. Contrast-enhanced HF-VPDU reveals all perfused vessels by assessing stimulated acoustic emissions from disintegrating microbubbles. Thus, we investigated whether flow-sensitive and contrast-enhanced HF-VPDU can depict different vessel fractions and assess their early response to antiangiogenic therapy. Mice with A431 tumors were scanned before and after administration of polybutylcyanoacrylate microbubbles by HF-VPDU. Animals received either antiangiogenic treatment (SU11248) or a control substance and were imaged repeatedly over 9 days. At each time point, tumors were removed for immunohistochemical analysis. During growth of untreated tumors, vascularization decreased correspondingly on flow-sensitive and contrast-enhanced scans. Treated tumors showed a significantly (P < 0.05) stronger decline in vascularization than controls, which was more pronounced in contrast-enhanced scans. Surprisingly, whereas vascularization remained low in contrast-enhanced scans, flow-sensitive ultrasound indicated a reincrease after day 6 with a higher vascularization than the controls at day 9. Histologic evaluation indicated that immature vessels degraded markedly on therapy, whereas large mature vessels on the tumor periphery were more therapy resistant and drew closer due to tumor shrinkage. In conclusion, contrast-enhanced HF-VPDU and flow-sensitive HF-VPDU are both capable of assessing the effects of antiangiogenic therapy. Because contrast-sensitive ultrasound is more sensitive for small immature vessels and flow-sensitive ultrasound mostly captures large vessels at the tumor periphery, the combination of both methods can provide evidence of vascular maturity in tumors. [Cancer Res 2008;68(17):7042-9]

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Molecular imaging of angiogenesis

Cited by 38 publications

References 141 publications

Volumetric high-frequency Doppler ultrasound enables the assessment of early antiangiogenic therapy effects on tumor xenografts in nude mice

Volumetric high-frequency Doppler ultrasound enables the assessment of early antiangiogenic therapy effects on tumor xenografts in nude mice

Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects

Vessel Fractions in Tumor Xenografts Depicted by Flow- or Contrast-Sensitive Three-Dimensional High-Frequency Doppler Ultrasound Respond Differently to Antiangiogenic Treatment

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