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Significance

Cancer stem cells (CSCs) are thought to be responsible for growth and dissemination of many malignant tumors and for relapse after therapy. Therefore methods for the noninvasive imaging of CSCs could have profound consequences for diagnosis and therapy monitoring in oncology. However, clinically applicable methods for noninvasive CSC imaging are still lacking. The AC133 epitope of CD133 is one of the most intensely investigated CSC markers and is particularly important for aggressive brain tumors. Here we describe the development of clinically relevant tracers that permit high-sensitivity and high-resolution monitoring of AC133⁺ glioblastoma stem cells in both subcutaneous and intracerebral xenograft tumors using positron emission tomography and near-infrared fluorescence imaging, two clinically highly relevant imaging modalities.

Abstract

A technology that visualizes tumor stem cells with clinically relevant tracers could have a broad impact on cancer diagnosis and treatment. The AC133 epitope of CD133 currently is one of the best-characterized tumor stem cell markers for many intra- and extracranial tumor entities. Here we demonstrate the successful noninvasive detection of AC133⁺ tumor stem cells by PET and near-infrared fluorescence molecular tomography in subcutaneous and orthotopic glioma xenografts using antibody-based tracers. Particularly, microPET with ⁶⁴Cu-NOTA-AC133 mAb yielded high-quality images with outstanding tumor-to-background contrast, clearly delineating subcutaneous tumor stem cell-derived xenografts from surrounding tissues. Intracerebral tumors as small as 2–3 mm also were clearly discernible, and the microPET images reflected the invasive growth pattern of orthotopic cancer stem cell-derived tumors with low density of AC133⁺ cells. These data provide a basis for further preclinical and clinical use of the developed tracers for high-sensitivity and high-resolution monitoring of AC133⁺ tumor stem cells.

Footnotes

• ¹S.G., F.B. and S.P. contributed equally to this work.

• ²To whom correspondence should be addressed. E-mail: gabriele.niedermann@uniklinik-freiburg.de.

• Author contributions: F.B., S.P., M.M., M.B., H.M., and G.N. designed research; S.G., F.B., S.P., M.M., M.H., R.G., K.K., and M.B. performed research; M.H., J.S., C.C.H.-M., and A.-L.G. contributed new reagents/analytic tools; S.G., F.B., S.P., M.M., E.F., R.G., X.Z., M.B., W.W., H.M., and G.N. analyzed data; and F.B., S.P., E.F., M.H., W.W., and G.N. wrote the paper.

• The authors declare no conflict of interest.

• This article is a PNAS Direct Submission.

• This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1314189111/-/DCSupplemental.

Freely available online through the PNAS open access option.

SOURCE

http://www.pnas.org/content/early/2014/01/23/1314189111.abstract?elq=c31a4384e08144c2810397dc605e4d0c&elqCampaignId=11