Copper-64-diacetyl-bis (N4-methylthiosemicarbazone) accumulates in rich regions of CD133+ highly tumorigenic cells in mouse colon carcinoma.
BACKGROUND
(64)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-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 (64)Cu-ATSM accumulation and existence of CD133(+) cells using mouse colon carcinoma (colon-26) tumor.


METHODS
Intratumor distribution of (64)Cu-ATSM and (18)F-fluorodeoxyglucose ((18)FDG) 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, (64)Cu-ATSM localized preferentially in regions with a high density of CD133(+) cells. The percentage of CD133(+) cells was 11-fold higher in (64)Cu-ATSM high-uptake regions compared with (18)FDG high- (but (64)Cu-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 (64)Cu-ATSM uptake was increased under such conditions.


CONCLUSIONS
Our findings showed that, in colon-26 tumors, (64)Cu-ATSM accumulates in rich regions of CD133(+) cells with characteristics of CSCs. Therefore (64)Cu-ATSM could be a potential imaging agent for rich regions of CD133(+) cells, associated with CSCs, within tumors.
Yoshii
Yukie
Y
Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193, Japan.
Furukawa
Takako
T
Kiyono
Yasushi
Y
Watanabe
Ryo
R
Waki
Atsuo
A
Mori
Tetsuya
T
Yoshii
Hiroshi
H
Oh
Myungmi
M
Asai
Tatsuya
T
Okazawa
Hidehiko
H
Welch
Michael J
MJ
Fujibayashi
Yasuhisa
Y
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001692:Biological Transport; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011849:Radioactive Tracers; D013882:Thiosemicarbazones / Q000378:metabolism*
D000071916:AC133 Antigen; D015703:Antigens, CD; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D006023:Glycoproteins; D009942:Organometallic Compounds; D010455:Peptides; C000606024:Prom1 protein, mouse; D011849:Radioactive Tracers; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D019788:Fluorodeoxyglucose F18; D005947:Glucose