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Article

Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy

1
Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
2
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
3
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
5
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
6
School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(10), 3722; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103722
Received: 1 April 2020 / Revised: 20 May 2020 / Accepted: 22 May 2020 / Published: 25 May 2020
While pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of pancreatic cancer may result in improved outcomes and therefore, methods for early detection of cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial neoplasias (PanINs) have been identified as premalignant precursor lesions to pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (1H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice in vivo, following injection of hyperpolarized [1-13C] pyruvate. The alanine-to-lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of alanine transaminase (ALT) and lactate dehydrogenase (LDH) enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (kPA and kPL) can be used as metabolic imaging biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations. View Full-Text
Keywords: metabolic plasticity and PanINs progression; metabolic imaging; metabolic rewiring; kinetic rate constant and modeling; early detection; pancreatic cancer; hyperpolarization; MRS metabolic plasticity and PanINs progression; metabolic imaging; metabolic rewiring; kinetic rate constant and modeling; early detection; pancreatic cancer; hyperpolarization; MRS
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MDPI and ACS Style

Dutta, P.; Castro Pando, S.; Mascaro, M.; Riquelme, E.; Zoltan, M.; Zacharias, N.M.; Gammon, S.T.; Piwnica-Worms, D.; Pagel, M.D.; Sen, S.; Maitra, A.; Shams, S.; McAllister, F.; Bhattacharya, P.K. Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy. Int. J. Mol. Sci. 2020, 21, 3722. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103722

AMA Style

Dutta P, Castro Pando S, Mascaro M, Riquelme E, Zoltan M, Zacharias NM, Gammon ST, Piwnica-Worms D, Pagel MD, Sen S, Maitra A, Shams S, McAllister F, Bhattacharya PK. Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy. International Journal of Molecular Sciences. 2020; 21(10):3722. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103722

Chicago/Turabian Style

Dutta, Prasanta, Susana Castro Pando, Marilina Mascaro, Erick Riquelme, Michelle Zoltan, Niki M. Zacharias, Seth T. Gammon, David Piwnica-Worms, Mark D. Pagel, Subrata Sen, Anirban Maitra, Shayan Shams, Florencia McAllister, and Pratip K. Bhattacharya 2020. "Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy" International Journal of Molecular Sciences 21, no. 10: 3722. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103722

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