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Imaging of Angiogenesis: Clinical Techniques and Novel Imaging Methods

James M. Provenzale1

1 Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC 27710.


Figure 1
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  		Fig. 1A —62-year-old man with glioblastoma multiforme. Depiction of changes in leakage of contrast material (a reflection of degree of permeability across blood-brain barrier) after administration of antiangiogenic agent directed against vascular endothelial growth factor (VEGF) receptor tyrosine kinase. Series of images shows additional physiologic information provided by dynamic imaging relative to solely anatomic information provided by conventional MRI. Because imaging findings solely reflect effect of angiogenesis (i.e., permeability), this technique is an example of indirect imaging of angiogenesis. Contrast-enhanced axial T1-weighted image obtained before therapy shows large enhancing mass located in left temporal lobe.

 

Figure 2
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  		Fig. 1B —62-year-old man with glioblastoma multiforme. Depiction of changes in leakage of contrast material (a reflection of degree of permeability across blood-brain barrier) after administration of antiangiogenic agent directed against vascular endothelial growth factor (VEGF) receptor tyrosine kinase. Series of images shows additional physiologic information provided by dynamic imaging relative to solely anatomic information provided by conventional MRI. Because imaging findings solely reflect effect of angiogenesis (i.e., permeability), this technique is an example of indirect imaging of angiogenesis. Color-coded map derived from dynamic contrast-enhanced imaging sequence before therapy (corresponding to A) shows degrees of contrast enhancement (changes in signal intensity) normalized against signal intensity in normal tissue. Color-coded map indicates relative degrees of permeability in each pixel, with blue pixels representing signal intensity that is 120-149% of normal tissue, green pixels representing 140-159% of normal tissue, and red pixels representing > 160% of normal tissue. Note that most pixels are in > 160% range, indicating marked leakage of contrast material.

 

Figure 3
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  		Fig. 1C —62-year-old man with glioblastoma multiforme. Depiction of changes in leakage of contrast material (a reflection of degree of permeability across blood-brain barrier) after administration of antiangiogenic agent directed against vascular endothelial growth factor (VEGF) receptor tyrosine kinase. Series of images shows additional physiologic information provided by dynamic imaging relative to solely anatomic information provided by conventional MRI. Because imaging findings solely reflect effect of angiogenesis (i.e., permeability), this technique is an example of indirect imaging of angiogenesis. Contrast-enhanced axial T1-weighted image obtained 30 days after initiation of therapy shows mild decrease in size of mass.

 

Figure 4
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  		Fig. 1D —62-year-old man with glioblastoma multiforme. Depiction of changes in leakage of contrast material (a reflection of degree of permeability across blood-brain barrier) after administration of antiangiogenic agent directed against vascular endothelial growth factor (VEGF) receptor tyrosine kinase. Series of images shows additional physiologic information provided by dynamic imaging relative to solely anatomic information provided by conventional MRI. Because imaging findings solely reflect effect of angiogenesis (i.e., permeability), this technique is an example of indirect imaging of angiogenesis. Color-coded map derived from dynamic contrast-enhanced imaging sequence obtained 30 days after initiation of therapy (corresponding to C) shows moderate decrease in total number of color-coded pixels but, importantly, marked decrease in number of pixels at middle and high end of contrast leakage range (green and red pixels). Changes in degree of leakage of contrast material (reflecting changes in degree of permeability) can be substantially greater than changes in enhancing tumor size.

 

Figure 5
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  		Fig. 2A —Perfusion CT image of rectal carcinoma performed to assess response to chemotherapy and radiation therapy. (Reprinted with permission from Sahani DV, Kalva SP, Hamberg LM, et al. Assessing tumor perfusion and treatment response in rectal cancer with multisection CT: initial observations. Radiology 2005; 234:785-792 [36].) Color-coded blood flow map in which areas of highest blood flow are shown in red, followed by yellow, indicates regions of highest blood flow are scattered throughout much of central portion of mass.

 

Figure 6
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  		Fig. 2B —Perfusion CT image of rectal carcinoma performed to assess response to chemotherapy and radiation therapy. (Reprinted with permission from Sahani DV, Kalva SP, Hamberg LM, et al. Assessing tumor perfusion and treatment response in rectal cancer with multisection CT: initial observations. Radiology 2005; 234:785-792 [36].) Color-coded permeability-surface area product map—in which areas of highest permeability-surface area product are shown in red and yellow—indicates that regions of highest permeability are scattered throughout much of tumor.

 

Figure 7
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  		Fig. 3A —Use of photoacoustic imaging to depict angiogenesis after subcutaneous injection of pancreatic tumor cells in a rat. Using this technique, light is converted into sound by optical absorption. A laser serves as light source; light, which is predominantly absorbed by hemoglobin, causes small focal temperature increase and restriction in dilation of RBCs. In turn, local pressure increases are generated, producing ultrasonic waves that allow 3D reconstruction of position of blood vessels. Regions of maximal acoustic source strength are shown in red, followed by yellow. (Reprinted with permission from Siphanto RI, Thumma KK, Kolkman RGM, et al. Serial noninvasive photoacoustic imaging of neovascularization in tumor angiogenesis. Optics Express 2005; 13:89-95 [45].) On day 3 after tumor implantation, regions of neoangiogenesis are seen in green in one region of image.

 

Figure 8
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  		Fig. 3B —Use of photoacoustic imaging to depict angiogenesis after subcutaneous injection of pancreatic tumor cells in a rat. Using this technique, light is converted into sound by optical absorption. A laser serves as light source; light, which is predominantly absorbed by hemoglobin, causes small focal temperature increase and restriction in dilation of RBCs. In turn, local pressure increases are generated, producing ultrasonic waves that allow 3D reconstruction of position of blood vessels. Regions of maximal acoustic source strength are shown in red, followed by yellow. (Reprinted with permission from Siphanto RI, Thumma KK, Kolkman RGM, et al. Serial noninvasive photoacoustic imaging of neovascularization in tumor angiogenesis. Optics Express 2005; 13:89-95 [45].) On day 7 after tumor implantation, regions of prominent angiogenesis are present throughout much of image.

 

Figure 9
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  		Fig. 4A —Use of {alpha}{nu}ß3 integrin-targeted microbubbles to directly depict angiogenesis in intracerebral gliomas in rats. (Reprinted with permission from Ellegala DB, Leong-Poi H, Carpenter JE, et al. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to {alpha}{nu}ß3. Circulation 2003; 108:336-341 [49].) Contrast-enhanced sonogram of blood flow in coronal plane shows tumor mass (T) and metastasis (M) adjacent to cerebral ventricles (V).

 

Figure 10
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  		Fig. 4B —Use of {alpha}{nu}ß3 integrin-targeted microbubbles to directly depict angiogenesis in intracerebral gliomas in rats. (Reprinted with permission from Ellegala DB, Leong-Poi H, Carpenter JE, et al. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to {alpha}{nu}ß3. Circulation 2003; 108:336-341 [49].) Confocal microscopy shows targeted microbubble (arrow) in tumor vessel.

 

Figure 11
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  		Fig. 4C —Use of {alpha}{nu}ß3 integrin-targeted microbubbles to directly depict angiogenesis in intracerebral gliomas in rats. (Reprinted with permission from Ellegala DB, Leong-Poi H, Carpenter JE, et al. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to {alpha}{nu}ß3. Circulation 2003; 108:336-341 [49].) Color-coded map of signal enhancement produced by microbubbles that corresponds to A. This map, in which greatest signal enhancement is shown in white and less profound signal enhancement in red, shows regions of prominent microbubble deposition, indicating areas of marked angiogenesis.

 

Figure 12
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  		Fig. 5A —Direct imaging of angiogenesis in mouse model of atherosclerosis using MRI and paramagnetic nanoparticles targeted against {alpha}{nu}ß3 integrin. (Reprinted with permission from Winter PM, Morawski AM, Caruthers SD, et al. Molecular imaging of angiogenesis in early-stage atherosclerosis with {alpha}{nu}ß3-integrin-targeted nanoparticles. Circulation 2003; 108:2270-2274 [51].) Axial image through aorta using T1-weighted spin-echo fat-suppressed black-blood imaging before administration of targeted paramagnetic nanoparticles shows walls of aorta (arrowhead) are relatively isointense to surrounding tissue.

 

Figure 13
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  		Fig. 5B —Direct imaging of angiogenesis in mouse model of atherosclerosis using MRI and paramagnetic nanoparticles targeted against {alpha}{nu}ß3 integrin. (Reprinted with permission from Winter PM, Morawski AM, Caruthers SD, et al. Molecular imaging of angiogenesis in early-stage atherosclerosis with {alpha}{nu}ß3-integrin-targeted nanoparticles. Circulation 2003; 108:2270-2274 [51].) Axial image using same technique and at same location as A after administration of paramagnetic nanoparticles and after subjecting image to semiautomated segmentation shows enhancement of regions of angiogenesis in aortic wall.

 

Figure 14
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  		Fig. 5C —Direct imaging of angiogenesis in mouse model of atherosclerosis using MRI and paramagnetic nanoparticles targeted against {alpha}{nu}ß3 integrin. (Reprinted with permission from Winter PM, Morawski AM, Caruthers SD, et al. Molecular imaging of angiogenesis in early-stage atherosclerosis with {alpha}{nu}ß3-integrin-targeted nanoparticles. Circulation 2003; 108:2270-2274 [51].) Color-coded signal enhancement image of B in which regions of greatest enhancement are seen in yellow indicates that some portions of aortic wall have regions of greater enhancement (and greater angiogenesis).

 

Figure 15
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  		Fig. 6 —Direct imaging of angiogenesis in rabbit tumor model using MRI and paramagnetic nanoparticles targeted against {alpha}{nu}ß3 integrin. Color-coded contrast-enhanced T1-weighted image of carcinoma implanted in rabbit shows areas of contrast enhancement coded by yellow pixels, which represent deposition of nanoparticles in regions of angiogenesis. Note that distribution is preferentially in tumor periphery. (Reprinted with permission from Winter PM, Caruthers SD, Kassner A, et al. Molecular imaging of angiogenesis in nascent Vx-2 rabbit tumors using a novel {alpha}{nu}ß3-targeted nanoparticle and 1.5 Tesla magnetic resonance imaging. Cancer Res 2003; 63:5838-5843 [52].)

 

Figure 16
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  		Fig. 7A —Direct imaging of angiogenesis using IV infusion of endothelial precursor cells labeled with superparamagnetic particles 2 days after intracerebral implantation of glioma cells in mice. (Reprinted with permission from Anderson SA, Glod J, Arbab AS, et al. Noninvasive MRI of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 2005; 105:420-425 [54].) Coronal 3D RARE image obtained 11 days after tumor implantation shows migration of radiolabeled cells into tumor periphery (arrow).

 

Figure 17
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  		Fig. 7B —Direct imaging of angiogenesis using IV infusion of endothelial precursor cells labeled with superparamagnetic particles 2 days after intracerebral implantation of glioma cells in mice. (Reprinted with permission from Anderson SA, Glod J, Arbab AS, et al. Noninvasive MRI of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 2005; 105:420-425 [54].) Ex vivo coronal gradient-echo image shows rim of hypointense signal caused by deposition of radiolabeled endothelial precursor cells in tumor margins.

 

Figure 18
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  		Fig. 8 —PET direct imaging of angiogenesis uses radiotracer composed of monoclonal antibody that binds to human vascular endothelial growth factor (VEGF) labeled with a positron-emitting radionuclide, iodine-124. Imaging of tumor-bearing mouse in coronal (left), sagittal (middle), and transverse (right) planes shows focal accumulation of antibody in tumor. (Reprinted with permission from Collingridge DR, Carroll VA, Glaser M, et al. The development of [(124)I]iodinated-VG76e: a novel tracer for imaging vascular endothelial growth factor in vivo using positron emission tomography. Cancer Res 2002; 62:5912-5919 [56].)

 

Figure 19
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  		Fig. 9A —Use of rotational microCT to perform direct imaging of angiogenesis in ex vivo specimens in rabbit tumor model. (Reprinted with kind permission of Springer Science and Business Media from Maehara N. Experimental microcomputed tomography study of the 3D microangioarchitecture of tumors. Eur Radiol 2003; 13:1559-1565 [57]. MicroCT scan 1 day after tumor implantation shows small cluster of abnormal vessels (arrow) at tumor site.

 

Figure 20
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  		Fig. 9B —Use of rotational microCT to perform direct imaging of angiogenesis in ex vivo specimens in rabbit tumor model. (Reprinted with kind permission of Springer Science and Business Media from Maehara N. Experimental microcomputed tomography study of the 3D microangioarchitecture of tumors. Eur Radiol 2003; 13:1559-1565 [57]. On day 3 after tumor implantation in another rabbit than that shown in A, a larger conglomeration of abnormal arteries and veins (arrow) than shown in A is seen at tumor site.

 

Figure 21
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  		Fig. 9C —Use of rotational microCT to perform direct imaging of angiogenesis in ex vivo specimens in rabbit tumor model. (Reprinted with kind permission of Springer Science and Business Media from Maehara N. Experimental microcomputed tomography study of the 3D microangioarchitecture of tumors. Eur Radiol 2003; 13:1559-1565 [57]. Seven days after tumor implantation in a third rabbit, clusters of tortuous, dilated vessels are seen at margins of tumor (arrowheads), and new small vessels (arrow) are seen centrally.

 

Figure 22
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  		Fig. 10 —Use of optical imaging with near-infrared fluorescent probe to perform direct imaging of angiogenesis in mouse model in which a non-small cell carcinoma line was implanted. Molecular probe is targeted against {alpha}{nu}ß3 integrin. Molecular probe was infused into a tail vein 24 hours before imaging. Fluorescence image shows high degree of fluorescence (denoted by blue, followed by green) in tumor, indicating binding of {alpha}{nu}ß3 integrin at sites of angiogenesis in tumor. (Reprinted with permission from Achilefu S, Bloch S, Markiewicz MA, et al. Synergistic effects of light-emitting probes and peptides for targeting and monitoring integrin expression. Proc Natl Acad Sci 2005; 102:7976-7981 [61]. Copyright 2005, National Academy of Sciences, U.S.A.).

 

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