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Ultrasound biomicroscopy permits in vivo characterization of zebrafish liver tumors

Nature Methods volume 4, pages 551–553 (2007)Cite this article

Abstract

Zebrafish are a valuable vertebrate model to study carcinogenesis, but noninvasive imaging is challenging because adult fish are not transparent. Here we show that tumors could be readily detected in vivo using high-resolution microscopic ultrasound in zebrafish. We successfully obtained tissue perfusion calculations and cellular aspirates, and analyzed tumor progression and response to treatment. Ultrasound biomicroscopy allows longitudinal studies of tumor development and real-time assessment of therapeutic effects in zebrafish.

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Figure 1: Normal anatomy can be visualized in live adult zebrafish by ultrasound imaging.
Figure 2: Ultrasound can be used for noninvasive cancer detection in zebrafish.
Figure 3: Characterization of zebrafish tumor vascularity, progression and response to treatment.

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Acknowledgements

We thank T. Coulthard and T. Potdevin at VisualSonics for their assistance with microbubble and power Doppler analyses, respectively. Histology services were provided by J. Williams and J. Kutok at the Hematopathology Core Lab of the Dana-Farber/Harvard Cancer Center. We thank J. Glickman (Department of Pathology, Brigham and Women's Hospital) for assistance with histopathological analysis. This research was supported by a Friends of Dana-Farber fellowship (W.G.), an American Gastroenterological Association/AstraZeneca Fellowship-Faculty Transition Award (W.G.), US National Institute of Diabetes and Digestive and Kidney Diseases 5 K08 DK 071940-02 (W.G.), The American Cancer Society (T.E.N.), US National Institutes of Health (L.I.Z.) and Howard Hughes Medical Institute (L.I.Z.).

Author information

Author notes

  1. Wolfram Goessling and Trista E North: These authors contributed equally to this work.

Authors and Affiliations

  1. Stem Cell Program, Hematology/Oncology, Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Wolfram Goessling, Trista E North & Leonard I Zon

  2. Gastrointestinal Unit, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Wolfram Goessling

Authors
  1. Wolfram Goessling
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  2. Trista E North
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  3. Leonard I Zon
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Contributions

W.G. and T.E.N. conducted all ultrasound analyses, histopathological examinations and chemical treatments described. W.G., T.E.N. and L.I.Z. wrote the manuscript.

Corresponding author

Correspondence to Leonard I Zon.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 1–2, Supplementary Methods. (PDF 592 kb)

Supplementary Movie 1

Animation of 3D image reconstruction. The fish shown in Figures 3a-d underwent serial ultrasound imaging. 3D reconstruction of the fish was performed using the ultrasound software, and the volumes of both the entire tumor and a cyst within the tumor were determined (tumor volume shown in blue, cyst volume shown in red). Free rotation of the 3D reconstruction enables the assessment of tissue relationships from different angles. (MOV 1983 kb)

Supplementary Movie 2

Pulsewave Doppler analysis of a tumor vessel. The fish shown in Figures 3a-d and Supplementary Movie 1 underwent pulsewave Doppler analysis of a blood vessel feeding the tumor. The vessel analyzed is bracketed by red parallel lines (right center panel), and the corresponding Doppler pulsewave is shown (lower panel). (MOV 1528 kb)

Supplementary Movie 3

Microbubble contrast demonstrates tumor perfusion. A microbubble suspension was injected directly into the zebrafish heart. The enhanced contrast caused by the microbubbles is colored in green. A brief ultrasound pulse leads to destruction of the bubbles in the target area (indicated by red bars in the movie timeline) and subsequent ablation of the signal. The contrast re-emerges over time and allows calculation of perfusion velocity rates as depicted in Figure 3h. (MOV 1469 kb)

Supplementary Movie 4

Ultrasound-guided aspiration of a liver tumor. A tumor-bearing fish was subjected to in vivo aspiration of a liver tumor using a micromanipulator and a syringe equipped with a 23-Gauge needle. The needle and tumor were positioned in the same ultrasound imaging plane to allow direct visualization during the aspiration. Aspirates were sufficient for cytological analysis and transplantation. 10/12 fish survived this procedure. (MOV 1039 kb)

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Goessling, W., North, T. & Zon, L. Ultrasound biomicroscopy permits in vivo characterization of zebrafish liver tumors. Nat Methods 4, 551–553 (2007). https://doi.org/10.1038/nmeth1059

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