Analysis of the growth dynamics of angiogenesis-dependent and -independent experimental glioblastomas by multimodal small-animal PET and MRI.
The hypothesis of this study was that distinct experimental glioblastoma phenotypes resembling human disease can be noninvasively distinguished at various disease stages by imaging in vivo.


METHODS
Cultured spheroids from 2 human glioblastomas were implanted into the brains of nude rats. Glioblastoma growth dynamics were followed by PET using (18)F-FDG, (11)C-methyl-l-methionine ((11)C-MET), and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and by MRI at 3-6 wk after implantation. For image validation, parameters were coregistered with immunohistochemical analysis.


RESULTS
Two tumor phenotypes (angiogenic and infiltrative) were obtained. The angiogenic phenotype showed high uptake of (11)C-MET and (18)F-FLT and relatively low uptake of (18)F-FDG. (11)C-MET was an early indicator of vessel remodeling and tumor proliferation. (18)F-FLT uptake correlated to positive Ki67 staining at 6 wk. T1- and T2-weighted MR images displayed clear tumor delineation with strong gadolinium enhancement at 6 wk. The infiltrative phenotype did not accumulate (11)C-MET and (18)F-FLT and impaired the (18)F-FDG uptake. In contrast, the Ki67 index showed a high proliferation rate. The extent of the infiltrative tumors could be observed by MRI but with low contrast.


CONCLUSIONS
For angiogenic glioblastomas, noninvasive assessment of tumor activity corresponds well to immunohistochemical markers, and (11)C-MET was more sensitive than (18)F-FLT at detecting early tumor development. In contrast, infiltrative glioblastoma growth in the absence of blood-brain barrier breakdown is difficult to noninvasively follow by existing imaging techniques, and a negative (18)F-FLT PET result does not exclude the presence of proliferating glioma tissue. The angiogenic model may serve as an advanced system to study imaging-guided antiangiogenic and antiproliferative therapies.
Westfälische Wilhelm-University Münster (WWU), European Institute for Molecular Imaging (EIMI), Münster, Germany.
Thomas
T
Viel
Krishna M
KM
Talasila
Parisa
P
Monfared
Jian
J
Wang
Jan F
JF
Jikeli
Yannic
Y
Waerzeggers
Bernd
B
Neumaier
Heiko
H
Backes
Narve
N
Brekka
Frits
F
Thorsen
Daniel
D
Stieber
Simone P
SP
Niclou
Alexandra
A
Winkeler
Bertrand
B
Tavitian
Mathias
M
Hoehn
Rolf
R
Bjerkvig
Hrvoje
H
Miletic
Andreas H
AH
Jacobs
D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology*; D003627:Data Interpretation, Statistical; D015224:Dideoxynucleosides; D018450:Disease Progression; D019788:Fluorodeoxyglucose F18; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008715:Methionine / Q000031:analogs & derivatives; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000473:pathology*; D016612:Paraffin Embedding; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D051381:Rats; D011923:Rats, Nude; D023041:Xenograft Model Antitumor Assays
D015224:Dideoxynucleosides; D019394:Ki-67 Antigen; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D008715:Methionine; C038344:methionine methyl ester; C002854:alovudine