Molecular ultrasound assessment of tumor angiogenesis

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Drive, Room H1307, Stanford, CA, USA.
Angiogenesis (Impact Factor: 4.88). 06/2010; 13(2):175-88. DOI: 10.1007/s10456-010-9175-z
Source: PubMed

ABSTRACT Angiogenesis, the growth of new blood vessels, plays a critical role in progression of tumor growth and metastasis, making it an attractive target for both cancer imaging and therapy. Several molecular markers, including those that are involved in the angiogenesis signaling pathway and those unique to tumor angiogenic vessels, have been identified and can be used as targets for molecular imaging of cancer. With the introduction of ultrasound contrast agents that can be targeted to those molecular markers, targeted contrast-enhanced ultrasound (molecular ultrasound) imaging has become an attractive imaging modality to non-invasively assess tumor angiogenesis at the molecular level. The advantages of molecular ultrasound imaging such as high temporal and spatial resolution, non-invasiveness, real-time imaging, relatively low cost, lack of ionizing irradiation and wide availability among the imaging community will further expand its roles in cancer imaging and drug development both in preclinical research and future clinical applications.

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Available from: Marybeth Pysz, Apr 28, 2014
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    • "In the field of oncology, the development of new ultrasound contrast agents is focused on their specific targeting to improve contrast-enhanced visualization of the circulation and angiogenesis (Deshpande et al. 2010), to detect specific markers of tumor growth or to vectorize therapeutic drugs (Foster et al. 2011; Kiessling et al. 2009, 2012; Moestue et al. 2012; Postema and Gilja 2011; Smith et al. 2011). The specificity of functionalized microbubbles is obtained by attaching a ligand (antibodies, peptides, etc) to their surface that makes them capable of binding to a particular target within the vasculature (Moestue et al. 2012). "
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    ABSTRACT: Expression levels of endoglin, αv integrin and vascular endothelial growth factor receptor 2 (VEGFR2) were investigated using targeted, contrast-enhanced ultrasonography in murine melanoma tumor models. Microvasculature and expression levels of biomarkers were investigated using specific contrast agents conjugated with biotinylated monoclonal antibodies. Ultrasound signal intensity from bound contrast agents was evaluated in two groups of mice: control mice and mice treated with sorafenib. Expression levels were analyzed by immunohistochemistry. Endoglin biomarkers were more highly expressed than αv integrin and VEGFR2. Endoglin decreased in the sorafenib group, whereas it tended to increase with time in the control group. Targeted ultrasound contrast agents may be used for non-invasive longitudinal evaluation of tumor angiogenesis during tumor growth or therapeutic treatment in preclinical studies. Endoglin protein, which plays an important role in angiogenesis, seems to be a target of interest for detection of cancer and for prediction of therapeutic efficacy.
    Ultrasound in Medicine & Biology 10/2014; 41(1). DOI:10.1016/j.ultrasmedbio.2014.06.014 · 2.21 Impact Factor
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    • "To date, there are clinical and traditional imaging techniques for the evaluation of trastuzumab therapy in patients with Her- 2–positive breast cancer [4]. However, the measurement of tumor size by the clinical palpation and imaging examinations will not always be good methods for the assessment of therapy response [5] [23]. Earlier assessment of trastuzumab effects on Her-2–positive breast cancer before morphologic changes can avoid exposing unnecessary possible side effects and costs from this therapy. "
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    ABSTRACT: Our study aimed to monitor the trastuzumab therapy response of murine tumor xenograft model with human epidermal growth factor receptor 2 (Her-2)-positive breast cancer using ultrasound targeted apoptosis imaging. We prepared targeted apoptosis ultrasound probes by nanobubble (NB) binding with Annexin V. In vitro, we investigated the binding rate of NB-Annexin V with breast cancer apoptotic cells after the trastuzumab treatment. In vivo, tumor-bearing mice underwent ultrasound targeted imaging over 7 days. After imaging was completed, the tumors were excised to determine Her-2 and caspase-3 expression by immunohistochemistry (IHC). The correlation between parameters of imaging and histologic results was then analyzed. For seeking the ability of targeted NB binding with apoptotic tumor cells (Her-2 positive), we found that binding rate in the treatment group was higher than that of the control group in vitro (P = .001). There were no differences of tumor sizes in all groups over the treatment process in vivo (P = .98). However, when using ultrasound imaging to visualize tumors by targeted NB in vivo, we observed that the mean and peak intensities from NBs gradually increased in the treatment group after trastuzumab therapy (P = .001). Furthermore, these two parameters were significantly associated with caspase-3 expression of tumor excised samples (P = .0001). Ultrasound targeted apoptosis imaging can be a non-invasive technique to evaluate the early breast tumor response to trastuzumab therapy.
    Translational oncology 03/2014; 7(2). DOI:10.1016/j.tranon.2014.02.015 · 2.88 Impact Factor
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    • "In the era of targeted medicine, knowledge of specific molecular tumor characteristics has become more important. Molecular imaging using targeted ultrasound contrast agent can monitor tumor progression non-invasively [9]. The principle behind ultrasonic molecular imaging is the selective adherence of microbubble contrast agents to biomarkers expressed on the endothelium [10]. "
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    ABSTRACT: Angiosarcoma is a biologically aggressive vascular malignancy with a high metastatic potential. In the era of targeted medicine, knowledge of specific molecular tumor characteristics has become more important. Molecular imaging using targeted ultrasound contrast agents can monitor tumor progression non-invasively. Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. We hypothesize that SFRP2-directed imaging could be a novel approach to imaging the tumor vasculature. To develop an SFRP2 contrast agent, SFRP2 polyclonal antibody was biotinylated and incubated with streptavidin-coated microbubbles. SVR angiosarcoma cells were injected into nude mice, and when tumors were established the mice were injected intravenously with the SFRP2 -targeted contrast agent, or a control streptavidin-coated contrast agent. SFRP2 -targeted contrast agent detected tumor vasculature with significantly more signal intensity than control contrast agent: the normalized fold-change was 1.6±0.27 (n = 13, p = 0.0032). The kidney was largely devoid of echogenicity with no significant difference between the control contrast agent and the SFRP2-targeted contrast agent demonstrating that the SFRP2-targeted contrast agent was specific to tumor vessels. Plotting average pixel intensity obtained from SFRP2-targeted contrast agent against tumor volume showed that the average pixel intensity increased as tumor volume increased. In conclusion, molecularly-targeted imaging of SFRP2 visualizes angiosarcoma vessels, but not normal vessels, and intensity increases with tumor size. Molecular imaging of SFRP2 expression may provide a rapid, non-invasive method to monitor tumor regression during therapy for angiosarcoma and other SFRP2 expressing cancers, and contribute to our understanding of the biology of SFRP2 during tumor development and progression.
    PLoS ONE 01/2014; 9(1):e86642. DOI:10.1371/journal.pone.0086642 · 3.23 Impact Factor
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