TY - JOUR
T1 - Synchrotron Radiation X-ray Fluorescence Elemental Mapping in Healthy versus Malignant Prostate Tissues Provides New Insights into the Glucose-Stimulated Zinc Trafficking in the Prostate As Discovered by MRI
AU - Clavijo Jordan, Veronica
AU - Al-Ebraheem, Alia
AU - Geraki, Kalotina
AU - Dao, Erica
AU - Martins, Andre F.
AU - Chirayil, Sara
AU - Farquharson, Michael
AU - Sherry, A. Dean
N1 - Funding Information:
V.C.J. carried out in vivo MRI, μSR-XRF experiments, data analysis, and prepared the manuscript. A.A.-E. prepared tissue for μSR-XRF imaging and carried out μSR-XRF experiments and analysis of the XRF data. K.G. carried out the μSR-XRF experiments and analysis. E.D. prepared tissue and analyzed XRF data. A.F.M. and S.C. designed and synthesized zinc sensors. M.F. carried out μSR-XRF experiments and analysis. V.C.J. and A.D.S. conceived the project and drafted the manuscript. All authors have given approval to the final version of the manuscript. Financial support from the National Institutes of Health (DK-095416), the Cancer Prevention and Research Institute of Texas (RP180178), and the Robert A. Welch Foundation (AT-584) are gratefully acknowledged. The authors declare no competing financial interest.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/10/21
Y1 - 2019/10/21
N2 - Prostatic zinc content is a known biomarker for discriminating normal healthy tissue from benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Given that zinc content is not readily measured without a tissue biopsy, we have been exploring noninvasive imaging methods to detect these diagnostic differences using a zinc-responsive MRI contrast agent. During imaging studies in mice, we observed that a bolus of glucose stimulates secretion of zinc from the prostate of fasted mice. This discovery allowed the use of a Gd-based zinc sensor to detect differential zinc secretion in regions of healthy versus malignant prostate tissue in a transgenic adenocarcinoma mouse model of PCa. Here, we used a zinc-responsive MRI agent to detect zinc release across the prostate during development of malignancy and confirm the loss of total tissue zinc by synchrotron radiation X-ray fluorescence (μSR-XRF). Quantitative μSR-XRF results show that the lateral lobe of the mouse prostate uniquely accumulates high concentrations of zinc, 1.06 ± 0.08 mM, and that the known loss of zinc content in the prostate is only observed in the lateral lobe during development of PCa. Additionally, we confirm that lesions identified by a loss of zinc secretion indeed represent malignant neoplasia and that the relative zinc concentration in the lesion is reduced to 0.370 ± 0.001 mM. The μSR-XRF data also provided insights into the mechanism of zinc secretion by showing that glucose promotes movement of zinc pools (∼1 mM) from the glandular lumen of the lateral lobe of the mouse prostate into the stromal/smooth muscle surrounding the glands. Co-localization of zinc and gadolinium in the stromal/smooth muscle areas as detected by μSR-XRF confirm that glucose initiates secretion of zinc from intracellular compartments into the extracellular spaces of the gland where it binds to the Gd-based agent and albumin promoting MR image enhancement.
AB - Prostatic zinc content is a known biomarker for discriminating normal healthy tissue from benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Given that zinc content is not readily measured without a tissue biopsy, we have been exploring noninvasive imaging methods to detect these diagnostic differences using a zinc-responsive MRI contrast agent. During imaging studies in mice, we observed that a bolus of glucose stimulates secretion of zinc from the prostate of fasted mice. This discovery allowed the use of a Gd-based zinc sensor to detect differential zinc secretion in regions of healthy versus malignant prostate tissue in a transgenic adenocarcinoma mouse model of PCa. Here, we used a zinc-responsive MRI agent to detect zinc release across the prostate during development of malignancy and confirm the loss of total tissue zinc by synchrotron radiation X-ray fluorescence (μSR-XRF). Quantitative μSR-XRF results show that the lateral lobe of the mouse prostate uniquely accumulates high concentrations of zinc, 1.06 ± 0.08 mM, and that the known loss of zinc content in the prostate is only observed in the lateral lobe during development of PCa. Additionally, we confirm that lesions identified by a loss of zinc secretion indeed represent malignant neoplasia and that the relative zinc concentration in the lesion is reduced to 0.370 ± 0.001 mM. The μSR-XRF data also provided insights into the mechanism of zinc secretion by showing that glucose promotes movement of zinc pools (∼1 mM) from the glandular lumen of the lateral lobe of the mouse prostate into the stromal/smooth muscle surrounding the glands. Co-localization of zinc and gadolinium in the stromal/smooth muscle areas as detected by μSR-XRF confirm that glucose initiates secretion of zinc from intracellular compartments into the extracellular spaces of the gland where it binds to the Gd-based agent and albumin promoting MR image enhancement.
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U2 - 10.1021/acs.inorgchem.9b01132
DO - 10.1021/acs.inorgchem.9b01132
M3 - Review article
C2 - 31260276
AN - SCOPUS:85073641979
VL - 58
SP - 13654
EP - 13660
JO - Inorganic Chemistry
JF - Inorganic Chemistry
SN - 0020-1669
IS - 20
ER -