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Noninvasive De novo Imaging of Human Embryonic Stem Cell–Derived Teratoma Formation

¹ Cardiology Department of Xijing Hospital, Xi'an, China; and Departments of ² Radiology and ³ Medicine, Stanford University School of Medicine, Stanford, California

Requests for reprints: Joseph C. Wu, Stanford University School of Medicine, Stanford, CA 94305. Phone: 650-736-2246; Fax: 650-736-0234; E-mail: joewu{at}stanford.edu and Xiaoyuan Chen, Stanford University School of Medicine, Stanford, CA 94305. E-mail: shawchen{at}stanford.edu.

Key Words: stem cell • teratoma • angiogenesis • microPET • _vβ₃ integrin

Teratoma formation can be a serious drawback after the therapeutic transplantation of human embryonic stem (hES) cells. Therefore, noninvasive imaging of teratomas could be a valuable tool for monitoring patients undergoing hES cell treatment. Here, we investigated the angiogenic process within teratomas derived from hES cells and now report the first example of using ⁶⁴Cu-labeled RGD tetramer (⁶⁴Cu-DOTA-RGD4) for positron emission tomography imaging of teratoma formation by targeting _vβ₃ integrin. H9 hES cells (2 x 10⁶), stably expressing firefly luciferase, and enhanced green fluorescence protein (Fluc-eGFP) were injected into adult nude mice (n = 12) s.c. Eight weeks after transplantation, these hES cell grafts evolved into teratomas as confirmed by longitudinal bioluminescence imaging. Under micropositron emission tomography imaging, 2-deoxy-2-[¹⁸F]fluoro-D-glucose and 3'-deoxy-3'-[¹⁸F]-fluorothymidine both failed to detect hES cell–derived teratomas (0.8 ± 0.5 versus 1.1 ± 0.4 %ID/g, respectively; P = not significant versus background signals). By contrast, ⁶⁴Cu-DOTA-RGD4 revealed specific and prominent uptake in vascularized teratoma and significantly lower uptake in control tumors (human ovarian carcinoma 2008 cell line), which had low intergrin expression (10.1 ± 3.4 versus 1.4 ± 1.2 %ID/g; P < 0.01). Immunofluorescence staining of CD31 and β₃ integrin also supported our in vivo imaging results (P < 0.05). Moreover, we found that the cells dissociated from teratomas showed higher _vβ₃ integrin expression than the 2008 cells. In conclusion, by targeting _vβ₃ integrin, we successfully showed the ability of ⁶⁴Cu-DOTA-RGD4 to noninvasively visualize teratoma formation in vivo for the first time. [Cancer Res 2009;69(7):2709–13]