Abstract
When monitoring response to cancer therapy, it is important to differentiate changes in glucose tracer uptake caused by altered delivery versus a true metabolic shift. Here, we propose an optical imaging method to quantify glucose uptake and correct for in vivo delivery effects. Glucose uptake was measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-D-glucose (2-NBDG) in mice implanted with dorsal skin flap window chambers. Additionally, vascular oxygenation (SO2) was calculated using only endogenous hemoglobin contrast. Results showed that the delivery factor proposed for correction, “RD”, reported on red blood cell velocity and injected 2-NBDG dose. Delivery-corrected 2-NBDG uptake (2-NBDG60/RD) inversely correlated with blood glucose in normal tissue, indicating sensitivity to glucose demand. We further applied our method in metastatic 4T1 and nonmetastatic 4T07 murine mammary adenocarcinomas. The ratio 2-NBDG60/RD was increased in 4T1 tumors relative to 4T07 tumors yet average SO2 was comparable, suggesting a shift toward a “Warburgian” (aerobic glycolysis) metabolism in the metastatic 4T1 line. In heterogeneous regions of both 4T1 and 4T07, 2-NBDG60/RD increased slightly but significantly as vascular oxygenation decreased, indicative of the Pasteur effect in both tumors. These data demonstrate the utility of delivery-corrected 2-NBDG and vascular oxygenation imaging for differentiating metabolic phenotypes in vivo.
Highlights
Due to advances in genetic profiling, a host of targeted therapies has been developed to pinpoint specific mutations in cancer [1, 2]
The first aim of the current study was to demonstrate that the ratio 2-NBDG60/RD serves as a delivery-corrected measure of glucose uptake in murine dorsal skin flap window chamber models containing normal tissues and tumors
Our results showed that 2-NBDG60/RD was an effective endpoint for comparing in vivo glucose uptake of metastatic 4T1 and nonmetastatic 4T07 murine mammary adenocarcinomas derived from the same spontaneous parental tumor [30]
Summary
Due to advances in genetic profiling, a host of targeted therapies has been developed to pinpoint specific mutations in cancer [1, 2]. Several drugs have been developed that inhibit PI3K signaling, which is dysregulated in cancers of the breast, colon, and ovary, among others [3,4,5,6]. Some of these targeted therapies can improve tumor perfusion, and delivery of imaging agents such as FDG, while independently modifying intrinsic glucose demand [7]. Highly angiogenic tumors or tumors with aberrant vascular signaling may have limited capacity for nutrient or drug delivery [8]. It is important to identify whether perceived changes in glucose uptake are caused by vascular or true glycolytic changes
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