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Adenovirus-mediated gene expression imaging to directly detect sentinel lymph node metastasis of prostate cancer

Nature Medicine volume 14, pages 882–888 (2008)Cite this article

Abstract

The accurate assessment of nodal involvement in prostate cancer is crucial to planning treatment, yet there is a shortage of noninvasive imaging techniques capable of visualizing nodal lesions directly. This study demonstrates the feasibility of using recombinant human adenoviral vectors to detect nodal metastases in a human prostate cancer model. This was achieved by the prostate-restricted expression of optical and positron emission tomography (PET) imaging reporter genes by the viral vector coupled with the innate lymphotropic properties of adenovirus. We show that peritumoral administration of these vectors results in the direct detection of reporter gene expression in metastatic lesions within sentinel lymph nodes. Notably, this approach parallels the current lymphoscintigraphy method but enables the direct PET visualization of sentinel lymph node metastases, eliminating the need for invasive lymphadenectomy. These findings may lead to more effective diagnostic and therapeutic strategies for individuals with advanced-stage prostate cancer.

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Figure 1: Adenovirus as a lymphotropic particle.
Figure 2: Monitoring lymph node metastasis in a prostate cancer xenograft model.
Figure 3: TSTA adenovirus–mediated detection of macroscopic lesions in lymph nodes by optical and PET imaging.
Figure 4: Detection of occult lymph node metastasis with bioluminescence and PET imaging.
Figure 5: Detection of occult LN metastasis in orthotopic xenograft model.

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Acknowledgements

We thank M.E. Black (Washington State University) for antibody to HSV-tk. We appreciate the discussions provided by E. Brakenhielm, A. Cochran and J. DeKernion. This work is supported by the US National Cancer Institute Specialized Programs of Research Excellence (SPORE) program grants P50 CA092131 and RO1 CA101904-01, US Department of Defense grant DAMD17-03-1-0095 and the Prostate Cancer Foundation (to L.W.) and by US National Cancer Institute grant 2U24 CA092865 (to A.F.C.). J.B.B. is supported by UCLA Research Training in Pharmacological Sciences grant T32-GM008652 and US Department of Defense grant CDMRP 07-1-0064. We are indebted to the technical support provided by W. Ladno, J. Edwards and A. Luu of Crump Institute of Molecular Imaging.

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Authors and Affiliations

  1. Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, 90095-1735, California, USA

    Jeremy B Burton, David J Mulholland, David Stout, Arion F Chatziioannou, Michael E Phelps, Hong Wu & Lily Wu

  2. Department of Urology, Crump Institute for Molecular Imaging and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, 90095-1735, California, USA

    Mai Johnson, Makoto Sato & Lily Wu

  3. Department of Bioengineering, Crump Institute for Molecular Imaging and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, 90095-1735, California, USA

    Sok Boon S Koh & Lily Wu

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Contributions

J.B.B. performed most of the experiments and prepared the manuscript. M.J. assisted in mouse imaging. M.S. prepared the adenoviral vectors. S.B.S.K. prepared the fluorescent-tagged virus. D.J.M. and H.W. provided the Pten-null mice and helpful advice. D.S., A.F.C. and M.E.P. provided imaging technical support. L.W. supervised the project.

Corresponding author

Correspondence to Lily Wu.

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Competing interests

D.S. is a consultant with Siemens Preclinical Solutions and a stock owner of Molecular Imaging Products.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1 and 2 (PDF 1433 kb)

Supplementary Video 1

Progression of 18FLT PET/CT detectable lymph node metastasis following resection of primary tumor, CWR22Rv-1. (MOV 17034 kb)

Supplementary Video 2

18FHBG PET/CT video of AdTSTA-sr39tk mediated visualization of sentinel lymph node metastasis. (MOV 3621 kb)

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Burton, J., Johnson, M., Sato, M. et al. Adenovirus-mediated gene expression imaging to directly detect sentinel lymph node metastasis of prostate cancer. Nat Med 14, 882–888 (2008). https://doi.org/10.1038/nm.1727

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