Comparison of conventional and novel PET tracers for imaging mesothelioma in nude mice with subcutaneous and intrapleural xenografts.
BACKGROUND
Malignant mesothelioma is a highly aggressive tumor originating in the pleura, peritoneum and pericardium, and the prognosis of patients undergoing current treatment remains poor. To develop new therapies, it is important to have a noninvasive imaging system for evaluating the efficacy of such prospective treatments. We have established clinically relevant mouse models and evaluated conventional and novel positron emission tomography (PET) tracers.


METHODS
Epithelioid and sarcomatoid mesothelioma cells were inoculated subcutaneously and intrapleurally into nude mice. Biodistribution and PET imaging studies were conducted by injecting [(18)F]fluoro-2-deoxy-D-glucose (FDG), 3'-[(18)F]fluoro-3'-doxythymidine (FLT) or 4'-methyl-[(11)C]thiothymidine (S-dThd) into the mouse models. In vitro cellular uptake of [(14)C]FDG and [(3)H]FLT and thymidine kinase 1 (TK(1)) activity in both cell lines were measured. Expression of glucose transporter 1 (GLUT-1) and Ki-67 in xenografted tumors was evaluated by immunohistochemical staining.


RESULTS
In epithelioid mesothelioma models, biodistribution experiments showed that tumor uptake of [(11)C]S-dThd was significantly higher than that of [(18)F]FDG. On the other hand, in sarcomatoid models, [(18)F]FDG showed significantly higher accumulation than the other two tracers. These differential uptakes of the three tracers were confirmed by PET imaging. The cellular uptake of [(14)C]FDG and [(3)H]FLT and TK(1) activity in sarcomatoid cells were higher than those of epithelioid cells. GLUT-1 protein was strongly expressed in sarcomatoid but not in epithelioid tumor. We observed a high percentage of Ki-67-positive cells in both epithelioid and sarcomatoid tumors.


CONCLUSIONS
We established nude mouse models of epithelioid and sarcomatoid subtypes of mesothelioma. PET tracers applicable for the evaluation of epithelioid and sarcomatoid mesothelioma would vary: [(18)F]FLT and [(11)C]S-dThd seemed suitable for the epithelioid subtype and [(18)F]FDG seemed suitable for the sarcomatoid subtype in our mouse models. Our results indicated that cellular uptake and TK(1) activity in vitro are not always consistent with tracer uptake of [(18)F]FLT and [(11)C]S-dThd in vivo. These mouse models and PET imaging might be useful tools for evaluating new and effective treatments in mesothelioma.
Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Atsushi B
AB
Tsuji
Chizuru
C
Sogawa
Aya
A
Sugyo
Hitomi
H
Sudo
Jun
J
Toyohara
Mitsuru
M
Koizumi
Masaaki
M
Abe
Okio
O
Hino
Yoshi-nobu
YN
Harada
Takako
T
Furukawa
Kazutoshi
K
Suzuki
Tsuneo
T
Saga
D000818:Animals; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000276:immunology; D006801:Humans; D007279:Injections, Subcutaneous; D019394:Ki-67 Antigen / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D000090204:Mesothelin; D008654:Mesothelioma / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D051379:Mice; D008819:Mice, Nude; D035422:Pleural Cavity; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D014183:Transplantation, Heterologous
D058851:GPI-Linked Proteins; D051272:Glucose Transporter Type 1; D019394:Ki-67 Antigen; D008562:Membrane Glycoproteins; D011849:Radioactive Tracers; D000090204:Mesothelin