Noninvasive de novo imaging of human embryonic stem cell-derived teratoma formation.

Abstract

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 (64)Cu-labeled RGD tetramer ((64)Cu-DOTA-RGD4) for positron emission tomography imaging of teratoma formation by targeting alpha(v)beta(3) integrin. H9 hES cells (2 x 10(6)), 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-[(18)F]fluoro-D-glucose and 3'-deoxy-3'-[(18)F]-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, (64)Cu-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 integrin expression (10.1+/-3.4 versus 1.4+/-1.2 %ID/g; P<0.01). Immunofluorescence staining of CD31 and beta(3) integrin also supported our in vivo imaging results (P<0.05). Moreover, we found that the cells dissociated from teratomas showed higher alpha(v)beta(3) integrin expression than the 2008 cells. In conclusion, by targeting alpha(v)beta(3) integrin, we successfully showed the ability of (64)Cu-DOTA-RGD4 to noninvasively visualize teratoma formation in vivo for the first time.

• Authors: Feng Cao, Zibo Li, Andrew Lee, Zhaofei Liu, Kai Chen, Hui Wang, Weibo Cai, Xiaoyuan Chen, Joseph C Wu
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 7 Pg. 2709-13 (Apr 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19318556 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Copper Radioisotopes
• Heterocyclic Compounds, 1-Ring
• Integrin alphaVbeta3
• Oligopeptides
• Organometallic Compounds
• Radiopharmaceuticals
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• arginyl-glycyl-aspartic acid

Topics

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic (pathology)
• Copper Radioisotopes (chemistry, pharmacokinetics)
• Embryonic Stem Cells (diagnostic imaging, metabolism, pathology)
• Endothelial Cells (pathology)
• Female
• Heterocyclic Compounds, 1-Ring (chemistry, pharmacokinetics)
• Humans
• Integrin alphaVbeta3 (biosynthesis, metabolism)
• Mice
• Mice, Nude
• Neovascularization, Pathologic (diagnostic imaging, metabolism, pathology)
• Oligopeptides (chemistry, pharmacokinetics)
• Organometallic Compounds (chemistry, pharmacokinetics)
• Ovarian Neoplasms (blood supply, diagnostic imaging, pathology)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (chemistry, pharmacokinetics)
• Teratoma (blood supply, diagnostic imaging, metabolism, pathology)
• Transplantation, Heterologous