Fusion mapping strategy finds link between tumor choline rates and hypoxia

September 13, 2004

CONTEXT: Hypoxia inducible factor (HIF-1) mediates how cancer cells respond in a microenvironment that lacks normal oxygen concentration. Under normal conditions, HIF-1a is subject to ubiquitination and proteosomal degradation. In response to hypoxia, ubiquitination of HIF-1a decreases dramatically, and the activity of its transcriptional activation domain increases. HIF-1 can act as a transcriptional activator for several glycolic enzymes and key genes, including vascular endothelial growth factor. Target genes contain hypoxia response elements (HRE), including HIF-1 binding sites. By placing green fluorescence protein (GFP) expression under the control of an HRE, it is possible to indirectly detect HIF-1 activity and hypoxia in tissues, according to principal investigator Dr. Zaver Bhujwalla, director of the molecular imaging laboratory at Johns Hopkins University.

RESULTS: At the 2004 ISMRM meeting, Bhujwalla reported that MR, MR spectroscopy, and optical imaging can be used in combination to map vascular volume, permeability, total choline, lactate/lipid levels, and hypoxia. Vascular and metabolic maps of seven tumors were obtained by MR for vascular imaging and MRS for metabolic imaging. Optimal imaging of GFP expression in freshly sectioned tumor tissue was used to visualize hypoxia in relation to the vascular and metabolic maps. Five of seven tumors examined demonstrated colocalization of GFP with high total choline. High permeability was found in and around the GFP and regions of high total choline. Lactate/lipid signal was coincident with some regions of high vascular volume.

IMPLICATIONS: These in vivo data are consistent with cell perfusion studies of the PC-3 cell line under normoxic and hypoxic conditions. The data suggest that hypoxia is a driving factor in the high total choline observed in the tumors, Bhujwalla said.