Longitudinal and multimodal in vivo imaging of tumor hypoxia and its downstream molecular events.
Tumor hypoxia and the hypoxia-inducible factors (HIFs) play a central role in the development of cancer. To study the relationship between tumor growth, tumor hypoxia, the stabilization of HIF-1alpha, and HIF transcriptional activity, we have established an in vivo imaging tool that allows longitudinal and noninvasive monitoring of these processes in a mouse C51 allograft tumor model. We used positron emission tomography (PET) with the hypoxia-sensitive tracer [(18)F]-fluoromisonidazole (FMISO) to measure tumor hypoxia over 14 days. Stabilization of HIF-1alpha and HIF transcriptional activity were assessed by bioluminescence imaging using the reporter constructs HIF-1alpha-luciferase and hypoxia response element-luciferase, respectively, stably expressed in C51 cells. Interestingly, we did not observe any major change in the level of tumor hypoxia throughout the observation period whereas HIF-1alpha levels and HIF activity showed drastic temporal variations. When comparing the readouts as a function of time we found a good correlation between HIF-1alpha levels and HIF activity. In contrast, there was no significant correlation between the [(18)F]-FMISO PET and HIF readouts. The tool developed in this work allows for the longitudinal study of tumor hypoxia and HIF-1alpha in cancer in an individual animal and will be of value when monitoring the efficacy of therapeutical interventions targeting the HIF pathway.
Lehmann
Steffi
S
Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology, 8093 Zurich, Switzerland.
Stiehl
Daniel P
DP
Honer
Michael
M
Dominietto
Marco
M
Keist
Ruth
R
Kotevic
Ivana
I
Wollenick
Kristin
K
Ametamey
Simon
S
Wenger
Roland H
RH
Rudin
Markus
M
D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives / Q000494:pharmacology; D008954:Models, Biological; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography / Q000379:methods; D020218:Response Elements; D013997:Time Factors; D014158:Transcription, Genetic
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C031843:fluoromisonidazole; D008920:Misonidazole; D008156:Luciferases