Copper-64-diacetyl-bis (N4-methylthiosemicarbazone) accumulates in rich regions of CD133+ highly tumorigenic cells in mouse colon carcinoma☆
Received 13 November 2009; received in revised form 23 December 2009; accepted 29 December 2009. published online 11 February 2010.
Abstract
Introduction
64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM) is a potential imaging agent of hypoxic tumor for use with PET. Recent literature demonstrated that cancer cells expressing CD133, which is a frequently used marker for so-called cancer stem cells or cancer stem cell-like cells (collectively referred to here as CSCs), contribute to tumor's therapeutic resistance and metastasis ability. Culturing under hypoxia is also reported to enlarge the proportion of CD133+ cells, which would indicate survival advantage of CD133+ cells under hypoxia. Here, we investigated the relationships between 64Cu-ATSM accumulation and existence of CD133+ cells using mouse colon carcinoma (colon-26) tumor.
Methods
Intratumor distribution of 64Cu-ATSM and 18F-fluorodeoxyglucose (18FDG) was compared with immunohistochemical staining for CD133 with a colon-26 model. In vitro characterization of CD133+ colon-26 cells was also performed.
Results
In colon-26 tumors, 64Cu-ATSM localized preferentially in regions with a high density of CD133+ cells. The percentage of CD133+ cells was 11-fold higher in 64Cu-ATSM high-uptake regions compared with 18FDG high- (but 64Cu-ATSM low-) uptake regions. CD133+ colon-26 cells showed characteristics previously linked with CSCs in other cancer cell lines, such as high colony-forming ability, high tumor-initiating ability and enrichment under hypoxic cultivation. The proportion of CD133+ cells was enlarged by culturing under glucose starvation as well as hypoxia, and 64Cu-ATSM uptake was increased under such conditions.
Conclusions
Our findings showed that, in colon-26 tumors, 64Cu-ATSM accumulates in rich regions of CD133+ cells with characteristics of CSCs. Therefore 64Cu-ATSM could be a potential imaging agent for rich regions of CD133+ cells, associated with CSCs, within tumors.
aBiomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan
bFaculty of Engineering, University of Fukui, Eiheiji, Fukui 910-8507, Japan
cFaculty of Medical Sciences, University of Fukui, Eiheiji, Fukui 910-1193, Japan
dMolecular Imaging Center, National Institute of Radiological Sciences, Inage, Chiba 263-8555, Japan
eMallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Corresponding author. Biomedical Imaging Research Center, University of Fukui, Shimoaizuki, Eiheiji, Fukui 910-1193, Japan. Tel.: +81 776 61 8491; fax: +81 776 61 8170.
☆ This work was supported in part by the Grants-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science, Japan (JSPS) (to Y.Y.); the Joint Research Grant from the Wakasa Wan Energy Research Center, Japan (to Y.F. and Y.Y.); the Research for Promoting Technological Seeds from Japan Science and Technology Agency, Japan (to Y.Y.); the 21st Century Centers of Excellence (COE) program from the JSPS (to Y.F.); and the Grant-in-Aid for Tumor Research from the Ministry of Health, Labor and Welfare, Japan 15-2 (to Y.F.).
ABSTRACT