Non-invasive imaging for studying anti-angiogenic therapy effects

Summary

Noninvasive imaging plays an emerging role in preclinical and clinical cancer research and has high potential to improve clinical translation of new drugs. This article summarises and discusses tools and methods to image tumour angiogenesis and monitor anti-angiogenic therapy effects. In this context, micro-computed tomography (?CT) is recommended to visualise and quantify the micro-architecture of functional tumour vessels. Contrast-enhanced ultrasound (US) and magnetic resonance imaging (MRI) are favourable tools to assess functional vascular parameters, such as perfusion and relative blood volume. These functional parameters have been shown to indicate antiangiogenic therapy response at an early stage, before changes in tumour size appear. For tumour characterisation, the imaging of the molecular characteristics of tumour blood vessels, such as receptor expression, might have an even higher diagnostic potential and has been shown to be highly suitable for therapy monitoring as well. In this context, US using targeted microbubbles is currently evaluated in clinical trials as an important tool for the molecular characterisation of the angiogenic endothelium. Other modalities, being preferably used for molecular imaging of vessels and their surrounding stroma, are photoacoustic imaging (PAI), near-infrared fluorescence optical imaging (OI), MRI, positron emission tomography (PET) and single photon emission computed tomography (SPECT). The latter two are particularly useful if very high sensitivity is needed, and/or if the molecular target is difficult to access. Carefully considering the pros and cons of different imaging modalities in a multimodal imaging setup enables a comprehensive longitudinal assessment of the (micro)morphology, function and molecular regulation of tumour vessels.

Keywords

Angiogenesis - functional imaging - molecular imaging - vessel normalisation - cancer therapy

• References

• 1 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27-31.
• 2 Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011; 473: 298-307.
• 3 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674.
• 4 Bergers G, Benjamin LE. Tumourigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3: 401-410.
• 5 Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002; 2: 795-803.
• 6 Baluk P, Hashizume H, McDonald DM. Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev 2005; 15: 102-111.
• 7 McDonald DM, Choyke PL. Imaging of angiogenesis: from microscope to clinic. Nat Med 2003; 9: 713-725.
• 8 Miller JC, Pien HH, Sahani D. et al. Imaging angiogenesis: applications and potential for drug development. J Natl Cancer Inst 2005; 97: 172-187.
• 9 Lederle W, Palmowski M, Kiessling F. Imaging in the age of molecular medicine: monitoring of anti-angiogenic treatments. Curr Pharm Biotechnol 2012; 13: 595-608.
• 10 Lee TY, Purdie TG, Stewart E. CT imaging of angiogenesis. Q J Nucl Med 2003; 47: 171-187.
• 11 d’Assignies G, Couvelard A, Bahrami S. et al. Pancreatic endocrine tumours: tumour blood flow assessed with perfusion CT reflects angiogenesis and correlates with prognostic factors. Radiology 2009; 250: 407-416.
• 12 Ohno Y, Koyama H, Matsumoto K. et al. Differentiation of malignant and benign pulmonary nodules with quantitative first-pass 320-detector row perfusion CT versus FDG PET/CT. Radiology 2011; 258: 599-609.
• 13 Schambach SJ, Bag S. Steil et al. Ultrafast high-resolution in vivo volume-CTA of mice cerebral vessels. Stroke 2009; 40: 1444-1450.
• 14 Figueiredo G, Brockmann C, Boll H. et al. Comparison of digital subtraction angiography, micro-computed tomography angiography and magnetic resonance angiography in the assessment of the cerebrovascular system in live mice. Clin Neuroradiol 2012; 22: 21-28.
• 15 Bartling SH, Stiller W, Semmler W. et al. Small animal computed tomography imaging. Curr Med Imaging Rev 2007; 3: 45-49.
• 16 Vera DR, Mattrey RF. A molecular CT blood pool contrast agent. Acad Radiol 2002; 9: 784-792.
• 17 Kao CY, Hoffman EA, Beck KC. et al. Long-residence-time nano-scale liposomal iohexol for X-ray-based blood pool imaging. Acad Radiol 2003; 10: 475-483.
• 18 De Vries A, Custers E, Lub J. et al. Block-copolymer-stabilized iodinated emulsions for use as CT contrast agents. Biomaterials 2010; 31: 6537-6544.
• 19 Kiessling F, Greschus S, Lichy M. et al. Volumetric computed tomography (VCT): a new technology for noninvasive, high-resolution monitoring of tumour angiogenesis. Nat Med 2004; 10: 1133-1138.
• 20 Eisa F, Brauweiler R, Hupfer M. et al. Dynamic contrast-enhanced micro-CT on mice with mammary carcinoma for the assessment of antiangiogenic therapy response. Eur Radiol 2012; 22: 900-907.
• 21 Tai JH, Tessier J, Ryan AJ. et al. Assessment of acute antivascular effects of vandetanib with high-resolution dynamic contrast-enhanced computed tomographic imaging in a human colon tumour xenograft model in the nude rat. Neoplasia 2010; 12: 697-707.
• 22 Bäuerle T, Bartling S, Berger M. et al. Imaging anti-angiogenic treatment response with DCE-VCT, DCE-MRI and DWI in an animal model of breast cancer bone metastasis. Eur J Radiol 2010; 73: 280-287.
• 23 Granton PV, Pollmann SI, Ford NL. et al. Implementation of dual- and triple-energy cone-beam micro-CT for postreconstruction material decomposition. Med Phys 2008; 35: 5030-5042.
• 24 Gremse F, Grouls C, Palmowski M. et al. Virtual elastic sphere processing enables reproducible quantification of vessel stenosis at CT and MR angiography. Radiology 2011; 260: 709-717.
• 25 Savai R, Langheinrich AC, Schermuly RT. et al. Evaluation of angiogenesis using micro-computed tomography in a xenograft mouse model of lung cancer. Neoplasia 2009; 11: 46-56.
• 26 Papenfuss HD, Gross JF, Intaglietta M. et al. A transparent access chamber for the rat dorsal skin fold. Microvasc Res 1979; 18: 311-318.
• 27 Leunig M, Yuan F, Menger MD. et al. Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice. Cancer Res 1992; 52: 6553-6560.
• 28 Lichtenbeld HC, Barendsz-Janson AF, van Essen H. et al. Angiogenic potential of malignant and non-malignant human breast tissues in an in vivo angiogenesis model. Int J Cancer 1998; 77: 455-459.
• 29 Vakoc BJ, Lanning RM, Tyrrell JA. et al. Three-dimensional microscopy of the tumour microenvironment in vivo using optical frequency domain imaging. Nat Med 2009; 15: 1219-1223.
• 30 Hansen-Algenstaedt N, Joscheck C, Schaefer C. et al. Long-term observation reveals time-course-dependent characteristics of tumour vascularisation. Eur J Cancer 2005; 41: 1073-1085.
• 31 Kiessling F, Jugold M, Woenne EC. et al. Non-invasive assessment of vessel morphology and function in tumours by magnetic resonance imaging. Eur Radiol 2007; 17: 2136-2148.
• 32 Glunde K, Jiang L, Moestue SA. et al. MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer. NMR Biomed 2011; 24: 673-690.
• 33 Bonekamp S, Corona-Villalobos CP, Kamel IR. Oncologic applications of diffusion-weighted MRI in the body. J Magn Reson Imaging 2012; 35: 257-279.
• 34 Wheaton AJ, Miyazaki M. Non-contrast enhanced MR angiography: physical principles. J Magn Reson Imaging 2012; 36: 286-304.
• 35 Doblas S, He T, Saunders D. et al. Glioma morphology and tumour-induced vascular alterations revealed in seven rodent glioma models by in vivo magnetic resonance imaging and angiography. J Magn Reson Imaging 2010; 32: 267-275.
• 36 Kiessling F, Farhan N, Lichy MP. et al. Dynamic contrast-enhanced magnetic resonance imaging rapidly indicates vessel regression in human squamous cell carcinomas grown in nude mice caused by VEGF receptor 2 blockade with DC101. Neoplasia 2004; 6: 213-223.
• 37 Luo Y, Jiang F, Cole TB. et al. A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumour vasculature in an orthotopic rat glioma model. Cancer Chemother Pharmacol 2012; 69: 911-921.
• 38 Dafni H, Kim SJ, Bankson JA. et al. Macromolecular dynamic contrast-enhanced (DCE)-MRI detects reduced vascular permeability in a prostate cancer bone metastasis model following anti-platelet-derived growth factor receptor (PDGFR) therapy, indicating a drop in vascular endothelial growth factor receptor (VEGFR) activation. Magn Reson Med 2008; 60: 822-833.
• 39 Lee L, Sharma S, Morgan B. et al. Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. Cancer Chemother Pharmacol 2006; 57: 761-771.
• 40 Morgan B, Thomas AL, Drevs J. et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J Clin Oncol 2003; 21: 3955-3964.
• 41 Liu G, Rugo HS, Wilding G. et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumours: results from a phase I study. J Clin Oncol 2005; 23: 5464-5473.
• 42 Troprès I, Lamalle L, Péoc’h M. et al. In vivo assessment of tumoural angiogenesis. Magn Reson Med 2004; 51: 533-541.
• 43 Zwick S, Strecker R, Kiselev V. et al. Assessment of vascular remodeling under antiangiogenic therapy using DCE-MRI and vessel size imaging. J Magn Reson Imaging 2009; 29: 1125-1133.
• 44 Walker-Samuel S, Boult JK, McPhail LD. et al. Non-invasive in vivo imaging of vessel calibre in orthotopic prostate tumour xenografts. Int J Cancer 2012; 130: 1284-1293.
• 45 Gilad AA, Israely T, Dafni H. et al. Functional and molecular mapping of uncoupling between vascular permeability and loss of vascular maturation in ovarian carcinoma xenografts: the role of stroma cells in tumour angiogenesis. Int J Cancer 2005; 117: 202-211.
• 46 Gross S, Gilead A, Scherz A. et al. Monitoring photodynamic therapy of solid tumours online by BOLD-contrast MRI. Nat Med 2003; 9: 1327-1331.
• 47 Cai K, Shore A, Singh A. et al. Blood oxygen level dependent angiography (BOLDangio) and its potential applications in cancer research. NMR Biomed 2012; 25: 1125-1132.
• 48 Kiessling F, Huppert J, Zhang C. et al. RGD-labeled USPIO inhibits adhesion and endocytotic activity of alpha v beta3-integrin-expressing glioma cells and only accumulates in the vascular tumour compartment. Radiology 2009; 253: 462-469.
• 49 Frascione D, Diwoky C, Almer G. et al. Ultrasmall superparamagnetic iron oxide (USPIO)-based liposomes as magnetic resonance imaging probes. Int J Nanomedicine 2012; 7: 2349-2359.
• 50 Mulder WJ, Strijkers GJ, van Tilborg GA. et al. Lipid-based nanoparticles for contrast-enhanced MRI and molecular imaging. NMR Biomed 2006; 19: 142-164.
• 51 Mulder WJ, van der Schaft DW, Hautvast PA. et al. Early in vivo assessment of angiostatic therapy efficacy by molecular MRI. FASEB J 2007; 21: 378-383.
• 52 Kiessling F, Morgenstern B, Zhang C. Contrast agents and applications to assess tumour angiogenesis in vivo by magnetic resonance imaging. Curr Med Chem 2007; 14: 77-91.
• 53 Sipkins DA, Cheresh DA, Kazemi MR. et al. Detection of tumour angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging. Nat Med 1998; 4: 623-626.
• 54 Makowski MR, Wiethoff AJ, Blume U. et al. Assessment of atherosclerotic plaque burden with an elastin-specific magnetic resonance contrast agent. Nat Med 2011; 17: 383-388.
• 55 Zhang C, Jugold M, Woenne EC. et al. Specific targeting of tumour angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner. Cancer Res 2007; 67: 1555-1562.
• 56 Kiessling F, Huppert J, Palmowski M. Functional and molecular ultrasound imaging: concepts and contrast agents. Curr Med Chem 2009; 16: 627-642.
• 57 Iordanescu I, Becker C, Zetter B. et al. Tumour vascularity: evaluation in a murine model with contrast-enhanced color Doppler US effect of angiogenesis inhibitors. Radiology 2002; 222: 460-467.
• 58 Denis F, Bougnoux P, de Poncheville L. et al. In vivo quantitation of tumour vascularisation assessed by Doppler sonography in rat mammary tumours. Ultrasound Med Biol 2002; 28: 431-437.
• 59 Jugold M, Palmowski M, Huppert J. et al. Volumetric high-frequency Doppler ultrasound enables the assessment of early antiangiogenic therapy effects on tumour xenografts in nude mice. Eur Radiol 2008; 18: 753-758.
• 60 Krix M, Kiessling F, Essig M. et al. Low mechanical index contrast-enhanced ultrasound better reflects high arterial perfusion of liver metastases than arterial phase computed tomography. Invest Radiol 2004; 39: 216-222.
• 61 Palmowski M, Lederle W, Gaetjens J. et al. Comparison of conventional time-intensity curves vs. maximum intensity over time for post-processing of dynamic contrast-enhanced ultrasound. Eur J Radiol 2010; 75: 149-153.
• 62 Rix A, Lederle W, Siepmann M. et al. Evaluation of high frequency ultrasound methods and contrast agents for characterising tumour response to anti-angiogenic treatment. Eur J Radiol 2012; 81: 2710-2716.
• 63 Sirsi SR, Flexman ML, Vlachos F. et al. Contrast ultrasound imaging for identification of early responder tumour models to anti-angiogenic therapy. Ultrasound Med Biol 2012; 38: 1019-1029.
• 64 Palmowski M, Huppert J, Hauff P. et al. Vessel fractions in tumour xenografts depicted by flow- or contrast-sensitive three-dimensional high-frequency Doppler ultrasound respond differently to antiangiogenic treatment. Cancer Res 2008; 68: 7042-7049.
• 65 Krix M, Kiessling F, Vosseler S. et al. Sensitive noninvasive monitoring of tumour perfusion during antiangiogenic therapy by intermittent bolus-contrast power Doppler sonography. Cancer Res 2003; 63: 8264-8270.
• 66 Palmowski M, Morgenstern B, Hauff P. et al. Pharmacodynamics of streptavidin-coated cyanoacrylate microbubbles designed for molecular ultrasound imaging. Invest Radiol 2008; 43: 162-169.
• 67 Kiessling F, Fokong S, Koczera P. et al. Ultrasound microbubbles for molecular diagnosis, therapy, and theranostics. J Nucl Med 2012; 53: 345-348.
• 68 Palmowski M, Huppert J, Ladewig G. et al. Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects. Mol Cancer Ther 2008; 7: 101-109.
• 69 Palmowski M, Peschke P, Huppert J. et al. Molecular ultrasound imaging of early vascular response in prostate tumours irradiated with carbon ions. Neoplasia 2009; 11: 856-863.
• 70 Pysz MA, Foygel K, Rosenberg J. et al. Antiangiogenic cancer therapy: monitoring with molecular US and a clinically translatable contrast agent (BR55). Radiology 2010; 256: 519-527.
• 71 Bzyl J, Palmowski M, Rix A. et al. The high angiogenic activity in very early breast cancer enables reliable imaging with VEGFR2-targeted microbubbles (BR55). Eur Radiol 2012; 23: 468-475.
• 72 Eisenblätter M, Höltke C, Persigehl T. et al. Optical techniques for the molecular imaging of angiogenesis. Eur J Nucl Med Mol Imaging 2010; 37 (Suppl. 01) 127-137.
• 73 Ale A, Ermolayev V, Herzog E. et al. FMT-XCT: in vivo animal studies with hybrid fluorescence molecular tomography-X-ray computed tomography. Nat Methods 2012; 9: 615-620.
• 74 Kunjachan S, Gremse F, Theek B. et al. Non-invasive optical imaging of nanomedicine biodistribution. ACS Nano 2012; 7: 252-262.
• 75 Zhang Q, Bindokas V, Shen J. et al. Time-course imaging of therapeutic functional tumour vascular normalisation by antiangiogenic agents. Mol Cancer Ther 2011; 10: 1173-1184.
• 76 Lederle W, Arns S, Rix A. et al. Failure of annexin-based apoptosis imaging in the assessment of antiangiogenic therapy effects. EJNMMI Res 2011; 1: 26.
• 77 Chang SK, Rizvi I, Solban N. et al. In vivo optical molecular imaging of vascular endothelial growth factor for monitoring cancer treatment. Clin Cancer Res 2008; 14: 4146-4153.
• 78 Wang H, Chen K, Niu G. et al. Site-specifically biotinylated VEGF(121) for near-infrared fluorescence imaging of tumour angiogenesis. Mol Pharm 2009; 6: 285-294.
• 79 Terwisscha van Scheltinga AG, van Dam GM, Nagengast WB. et al. Intraoperative near-infrared fluorescence tumour imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies. J Nucl Med 2011; 52: 1778-1785.
• 80 Snoeks T, Löwik C, Kaijzel E. In vivo optical approaches to angiogenesis imaging. Angiogenesis 2010; 13: 135-147.
• 81 Zhang N, Fang Z, Contag PR. et al. Tracking angiogenesis induced by skin wounding and contact hypersensitivity using a Vegfr2-luciferase transgenic mouse. Blood 2004; 103: 617-626.
• 82 Kishimoto J, Ehama R, Ge Y. et al. In vivo detection of human vascular endothelial growth factor promoter activity in transgenic mouse skin. Am J Pathol 2000; 157: 103-110.
• 83 Wang Y, Iyer M, Annala A. et al. Noninvasive indirect imaging of vascular endothelial growth factor gene expression using bioluminescence imaging in living transgenic mice. Physiol Genomics 2006; 24: 173-180.
• 84 Wang LV, Hu S. Photoacoustic tomography: in vivo imaging from organelles to organs. Science 2012; 335: 1458-1462.
• 85 Laufer J, Zhang E, Raivich G. et al. Three-dimensional noninvasive imaging of the vasculature in the mouse brain using a high resolution photoacoustic scanner. Appl Opt 2009; 48: D299-306.
• 86 De la Zerda A, Zavaleta C, Keren S. et al. Carbon nanotubes as photoacoustic molecular imaging agents in living mice. Nat Nanotechnol 2008; 3: 557-562.
• 87 Cai X, Li L, Krumholz A. et al. Multi-scale molecular photoacoustic tomography of gene expression. PLoS One 2012; 7: e43999.
• 88 Cai W, Chen X. Multimodality molecular imaging of tumour angiogenesis. J Nucl Med 2008; 49 (Suppl. 02) 113S-28S.
• 89 Cai W, Chen K, Mohamedali KA. et al. PET of vascular endothelial growth factor receptor expression. J Nucl Med 2006; 47: 2048-2056.
• 90 Cao F, Li Z, Lee A. et al. Noninvasive de novo imaging of human embryonic stem cell-derived teratoma formation. Cancer Res 2009; 69: 2709-2713.
• 91 Liu Z, Jia B, Zhao H. et al. Specific targeting of human integrin α(v)β (3) with (111)In-labeled Abegrin™ in nude mouse models. Mol Imaging Biol 2011; 13: 112-120.
• 92 Jia B, Shi J, Yang Z. et al. 99mTc-labeled cyclic RGDfK dimer: initial evaluation for SPECT imaging of glioma integrin alphavbeta3 expression. Bioconjug Chem 2006; 17: 1069-1076.
• 93 Yang M, Gao H, Yan Y. et al. PET imaging of early response to the tyrosine kinase inhibitor ZD4190. Eur J Nucl Med Mol Imaging 2011; 38: 1237-1247.
• 94 Jin ZH, Furukawa T, Claron M. et al. Positron emission tomography imaging of tumour angiogenesis and monitoring of antiangiogenic efficacy using the novel tetrameric peptide probe (64)Cu-cyclam-RAFT-c(-RGDfK-) (4). Angiogenesis 2012; 15: 569-580.
• 95 Jati A, Tatlτ S, Morgan JA. et al. Imaging features of bone metastases in patients with gastrointestinal stromal tumours. Diagn Interv Radiol 2012; 18: 391-396.
• 96 Schwarzenberg J, Czernin J, Cloughesy TF. et al. 3‘-deoxy-3‘-18F-fluorothymidine PET and MRI for early survival predictions in patients with recurrent malignant glioma treated with bevacizumab. J Nucl Med 2012; 53: 29-36.
• 97 Metz S, Ganter C, Lorenzen S. et al. Phenotyping of tumour biology in patients by multimodality multiparametric imaging: relationship of microcirculation, alphavbeta3 expression, and glucose metabolism. J Nucl Med 2010; 51: 1691-1698.
• 98 Bach-Gansmo T, Danielsson R, Saracco A. et al. Integrin receptor imaging of breast cancer: a proof-of-concept study to evaluate 99mTc-NC100692. J Nucl Med 2006; 47: 1434-1439.
• 99 Van der Veldt AA, Lubberink M, Bahce I. et al. Rapid decrease in delivery of chemotherapy to tumours after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 2012; 21: 82-91.
• 100 Fokong S, Theek B, Wu Z. et al. Image-guided, targeted and triggered drug delivery to tumours using polymer-based microbubbles. J Control Release 2012; 163: 75-81.