TY - JOUR
T1 - Localized hypoxia results in spatially heterogeneous metabolic signatures in breast tumor models
AU - Jiang, Lu
AU - Greenwood, Tiffany R.
AU - Artemov, Dmitri
AU - Raman, Venu
AU - Winnard, Paul T.
AU - Heeren, Ron M.A.
AU - Bhujwalla, Zaver M.
AU - Glunde, Kristine
N1 - Funding Information:
Abbreviations: Chk, choline kinase; Cho, free choline; CSI, chemical shift imaging; FOV, field of view; GPC, glycerophosphocholine; H&E, hematoxylin and eosin; HIF, hypoxia-inducible factor; HRE, hypoxia response element; MR, magnetic resonance; MRS, magnetic resonance spectroscopy; MRI, magnetic resonance imaging; MRSI, magnetic resonance spectroscopic imaging; MS, mass spectrometry; NA, number of averages; PC, phosphocholine; RARE, rapid acquisition with relaxation enhancement; tCho, total choline-containing compounds; TE, echo time; TMS, tetramethylsilane; TSP, 3-(trimethylsilyl) propionic-2, 2, 3, 3-d4 acid; VEGF, vascular endothelial growth factor Address all correspondence to: Kristine Glunde, PhD, Department of Radiology, Johns Hopkins University School of Medicine, 212 Traylor Bldg, 720 Rutland Ave, Baltimore, MD 21205. E-mail: kglunde@mri.jhu.edu 1This work was supported by the National Institutes of Health (grant R01 CA134695). Received 24 May 2012; Revised 26 June 2012; Accepted 28 June 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.12858
PY - 2012/8
Y1 - 2012/8
N2 - Tumor hypoxia triggers signaling cascades that significantly affect biologic outcomes such as resistance to radiotherapy and chemotherapy in breast cancer. Hypoxic regions in solid tumor are spatially heterogeneous. Therefore, delineating the origin and extent of hypoxia in tumors is critical. In this study, we have investigated the effect of hypoxia on different metabolic pathways, such as lipid and choline metabolism, in a human breast cancer model. Human MDA-MB-231 breast cancer cells and tumors, which were genetically engineered to express red fluorescent tdTomato protein under hypoxic conditions, were used to investigate hypoxia. Our data were obtained with a novel three-dimensional multimodal molecular imaging platform that combines magnetic resonance (MR) imaging, MR spectroscopic imaging (MRSI), and optical imaging of hypoxia and necrosis. A higher concentration of noninvasively detected total choline-containing metabolites (tCho) and lipid CH3 localized in the tdTomato-fluorescing hypoxic regions indicated that hypoxia can upregulate tCho and lipid CH3 levels in this breast tumor model. The increase in tCho under hypoxia was primarily due to elevated phosphocholine levels as shown by in vitro MR spectroscopy. Elevated lipid CH3 levels detected under hypoxia were caused by an increase in mobile MR-detectable lipid droplets, as demonstrated by Nile Red staining. Our findings demonstrate that noninvasive MRSI can help delineate hypoxic regions in solid tumors by means of detecting the metabolic outcome of tumor hypoxia, which is characterized by elevated tCho and lipid CH3.
AB - Tumor hypoxia triggers signaling cascades that significantly affect biologic outcomes such as resistance to radiotherapy and chemotherapy in breast cancer. Hypoxic regions in solid tumor are spatially heterogeneous. Therefore, delineating the origin and extent of hypoxia in tumors is critical. In this study, we have investigated the effect of hypoxia on different metabolic pathways, such as lipid and choline metabolism, in a human breast cancer model. Human MDA-MB-231 breast cancer cells and tumors, which were genetically engineered to express red fluorescent tdTomato protein under hypoxic conditions, were used to investigate hypoxia. Our data were obtained with a novel three-dimensional multimodal molecular imaging platform that combines magnetic resonance (MR) imaging, MR spectroscopic imaging (MRSI), and optical imaging of hypoxia and necrosis. A higher concentration of noninvasively detected total choline-containing metabolites (tCho) and lipid CH3 localized in the tdTomato-fluorescing hypoxic regions indicated that hypoxia can upregulate tCho and lipid CH3 levels in this breast tumor model. The increase in tCho under hypoxia was primarily due to elevated phosphocholine levels as shown by in vitro MR spectroscopy. Elevated lipid CH3 levels detected under hypoxia were caused by an increase in mobile MR-detectable lipid droplets, as demonstrated by Nile Red staining. Our findings demonstrate that noninvasive MRSI can help delineate hypoxic regions in solid tumors by means of detecting the metabolic outcome of tumor hypoxia, which is characterized by elevated tCho and lipid CH3.
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U2 - 10.1593/neo.12858
DO - 10.1593/neo.12858
M3 - Article
C2 - 22952426
AN - SCOPUS:84865232136
SN - 1522-8002
VL - 14
SP - 732
EP - 741
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 8
ER -