Abstract
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.
Highlights
Detection of pancreatic cancer (PC) at early stages remains a great challenge in clinical oncology
Engineered mouse (GEM) models (P48:Cre; LSL-KRASG12D (KC)) with progression of pancreatic intraepithelial neoplasia (PanINs) lesions and control animals (P48:Cre or WT C57BL/6) without pancreatic lesions were employed in our study
We performed an active lactate dehydrogenase (LDH) and alanine transaminase (ALT) enzymes assay on the different PanINs tissues
Summary
Detection of pancreatic cancer (PC) at early stages remains a great challenge in clinical oncology. Detection of PDAC is unusual and typically incidental, with the majority (~85%) presenting with locally advanced or metastatic disease, when surgery, the only curative modality, is not an option. PDAC is associated with a dire prognosis and a 5-year survival rate of only 8% [7]. Despite these grim numbers, there is unequivocal evidence that diagnosis of PDAC at earlier, resectable stages has a profoundly favorable impact on prognosis. The absence of early symptoms and lack of a reliable screening test have created a critical need for identifying and developing new non-invasive biomarkers for pancreatic cancer early detection [10]. There is an urgency to develop novel methods for the detection of pancreatic cancer preneoplastic lesions
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