Dataset Information

Pancreatic HIF2? Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm.

ABSTRACT: Background & Aims:Tissue hypoxia controls cell differentiation in the embryonic pancreas, and promotes tumor growth in pancreatic cancer. The cellular response to hypoxia is controlled by the hypoxia-inducible factor (HIF) proteins, including HIF2?. Previous studies of HIF action in the pancreas have relied on loss-of-function mouse models, and the effects of HIF2? expression in the pancreas have remained undefined. Methods:We developed several transgenic mouse models based on the expression of an oxygen-stable form of HIF2?, or indirect stabilization of HIF proteins though deletion of von Hippel-Lindau, thus preventing HIF degradation. Furthermore, we crossed both sets of animals into mice expressing oncogenic KrasG12D in the pancreas. Results:We show that HIF2? is not expressed in the normal human pancreas, however, it is up-regulated in human chronic pancreatitis. Deletion of von Hippel-Lindau or stabilization of HIF2? in mouse pancreata led to the development of chronic pancreatitis. Importantly, pancreatic HIF1? stabilization did not disrupt the pancreatic parenchyma, indicating that the chronic pancreatitis phenotype is specific to HIF2?. In the presence of oncogenic Kras, HIF2? stabilization drove the formation of cysts resembling mucinous cystic neoplasm (MCN) in humans. Mechanistically, we show that the pancreatitis phenotype is linked to expression of multiple inflammatory cytokines and activation of the unfolded protein response. Conversely, MCN formation is linked to activation of Wnt signaling, a feature of human MCN. Conclusions:We show that pancreatic HIF2? stabilization disrupts pancreatic homeostasis, leading to chronic pancreatitis, and, in the context of oncogenic Kras, MCN formation. These findings provide new mouse models of both chronic pancreatitis and MCN, as well as illustrate the importance of hypoxia signaling in the pancreas.

SUBMITTER: Schofield HK

PROVIDER: S-EPMC5904051 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Pancreatic HIF2α Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm.

Schofield Heather K HK Tandon Manuj M Park Min-Jung MJ Halbrook Christopher J CJ Ramakrishnan Sadeesh K SK Kim Esther C EC Shi Jiaqi J Omary M Bishr MB Shah Yatrik M YM Esni Farzad F Pasca di Magliano Marina M

Cellular and molecular gastroenterology and hepatology 20171110 2

<h4>Background & aims</h4>Tissue hypoxia controls cell differentiation in the embryonic pancreas, and promotes tumor growth in pancreatic cancer. The cellular response to hypoxia is controlled by the hypoxia-inducible factor (HIF) proteins, including HIF2α. Previous studies of HIF action in the pancreas have relied on loss-of-function mouse models, and the effects of HIF2α expression in the pancreas have remained undefined.<h4>Methods</h4>We developed several transgenic mouse models based on the ...[more]

PMID: 29693047

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Project description:PurposeThis study aimed to develop and verify a multi-phase (MP) computed tomography (CT)-based radiomics nomogram to differentiate pancreatic serous cystic neoplasms (SCNs) from mucinous cystic neoplasms (MCNs), and to compare the diagnostic efficacy of radiomics models for different phases of CT scans.Materials and methodsA total of 170 patients who underwent surgical resection between January 2011 and December 2018, with pathologically confirmed pancreatic cystic neoplasms (SCN=115, MCN=55) were included in this single-center retrospective study. Radiomics features were extracted from plain scan (PS), arterial phase (AP), and venous phase (VP) CT scans. Algorithms were performed to identify the optimal features to build a radiomics signature (Radscore) for each phase. All features from these three phases were analyzed to develop the MP-Radscore. A combined model comprised the MP-Radscore and imaging features from which a nomogram was developed. The accuracy of the nomogram was evaluated using receiver operating characteristic (ROC) curves, calibration tests, and decision curve analysis.ResultsFor each scan phase, 1218 features were extracted, and the optimal ones were selected to construct the PS-Radscore (11 features), AP-Radscore (11 features), and VP-Radscore (12 features). The MP-Radscore (14 features) achieved better performance based on ROC curve analysis than any single phase did [area under the curve (AUC), training cohort: MP-Radscore 0.89, PS-Radscore 0.78, AP-Radscore 0.83, VP-Radscore 0.85; validation cohort: MP-Radscore 0.88, PS-Radscore 0.77, AP-Radscore 0.83, VP-Radscore 0.84]. The combination nomogram performance was excellent, surpassing those of all other nomograms in both the training cohort (AUC, 0.91) and validation cohort (AUC, 0.90). The nomogram also performed well in the calibration and decision curve analyses.ConclusionsRadiomics for arterial and venous single-phase models outperformed the plain scan model. The combination nomogram that incorporated the MP-Radscore, tumor location, and cystic number had the best discriminatory performance and showed excellent accuracy for differentiating SCN from MCN.

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Dataset Information

Pancreatic HIF2? Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm.

Publications

Pancreatic HIF2α Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm.

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