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Longitudinal and multimodal in vivo imaging of tumor hypoxia and its downstream molecular events


Lehmann, S; Stiehl, D P; Honer, M; Dominietto, M; Keist, R; Kotevic, I; Wollenick, K; Ametamey, S; Wenger, R H; Rudin, M (2009). Longitudinal and multimodal in vivo imaging of tumor hypoxia and its downstream molecular events. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 106(33):14004-14009.

Abstract

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-1α, 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 [18F]-fluoromisonidazole (FMISO) to measure tumor hypoxia over 14 days. Stabilization of HIF-1α and HIF transcriptional activity were assessed by bioluminescence imaging using the reporter constructs HIF-1α-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-1α levels and HIF activity showed drastic temporal variations. When comparing the readouts as a function of time we found a good correlation between HIF-1α levels and HIF activity. In contrast, there was no significant correlation between the [18F]-FMISO PET and HIF readouts. The tool developed in this work allows for the longitudinal study of tumor hypoxia and HIF-1α in cancer in an individual animal and will be of value when monitoring the efficacy of therapeutical interventions targeting the HIF pathway.

Abstract

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-1α, 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 [18F]-fluoromisonidazole (FMISO) to measure tumor hypoxia over 14 days. Stabilization of HIF-1α and HIF transcriptional activity were assessed by bioluminescence imaging using the reporter constructs HIF-1α-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-1α levels and HIF activity showed drastic temporal variations. When comparing the readouts as a function of time we found a good correlation between HIF-1α levels and HIF activity. In contrast, there was no significant correlation between the [18F]-FMISO PET and HIF readouts. The tool developed in this work allows for the longitudinal study of tumor hypoxia and HIF-1α in cancer in an individual animal and will be of value when monitoring the efficacy of therapeutical interventions targeting the HIF pathway.

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Contributors:Krek, Wilhelm and Frew, Ian; Institute of Cell Biology, ETHZ, Becher, Burkhard, Neuroimmunology, UZH, Fritschy, Jean-Marc, Pharmacol & Toxicol., UZH, Swiss National Foundation, National Center for Research Resources Neural Plasticity and Repair, National Center for Research Resources Computer-Aided and Image-Guided Medical Interventions
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Biomedical Engineering
04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology

04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
170 Ethics
610 Medicine & health
Language:English
Date:21 August 2009
Deposited On:02 Nov 2009 15:51
Last Modified:17 Feb 2018 23:14
Publisher:National Academy of Sciences
ISSN:0027-8424
Additional Information:Copyright: National Academy of Sciences USA
OA Status:Closed
Publisher DOI:https://doi.org/10.1073/pnas.0901194106
PubMed ID:19666490

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