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Famke Aeffner, Nathan T Martin, Mirza Peljto, Joshua C Black, Justin K Major, Maryam Jangani, Michael O Ports, Joseph S Krueger, G David Young
Tissue image analysis (tIA) is emerging as a powerful tool for quantifying biomarker expression and distribution in complex diseases and tissues. Pancreatic ductal adenocarcinoma (PDAC) develops in a highly complex and heterogeneous tissue environment and, generally, has a very poor prognosis. Early detection of PDAC is confounded by limited knowledge of the pre-neoplastic disease stages and limited methods to quantitatively assess disease heterogeneity. We sought to develop a tIA approach to assess the most common PDAC precursor lesions, pancreatic intraepithelial neoplasia (PanIN), in tissues from Kras(LSL-G12D/+); Trp53(LSL-R172H/+); Pdx-Cre (KPC) mice, a validated model of PDAC development...
October 24, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
Qiang Zhang, Yaqing Zhang, Joshua D Parsels, Ines Lohse, Theodore S Lawrence, Marina Pasca di Magliano, Yi Sun, Meredith A Morgan
Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-Kras(G12D);Fbxw7(fl/fl) (KFC(fl/fl)) compound mice. We found that KFC(fl/fl) mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age...
October 17, 2016: Neoplasia: An International Journal for Oncology Research
A Holma-Suutari, P Ruokojärvi, A A Komarov, D A Makarov, V V Ovcharenko, A N Panin, H Kiviranta, S Laaksonen, M Nieminen, M Viluksela, A Hallikainen
BACKGROUND: The Finnish and Russian animal species (semi-domesticated reindeer, Finnish wild moose, Baltic grey seal and Baltic herring) samples were biomonitored in terrestrial and aquatic environments for polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs). RESULTS: Grey seal (Halichoerus grypus) was clearly the most contaminated species. The mean PBDE concentration in grey seal was 115 ng/g fat, and the highest WHO-PCDD/F-PCB-TEQ (toxic equivalent set by WHO) was 327 pg/g fat...
2016: Environmental Sciences Europe
Lei You, Xiaoxia Ren, Yongxing Du, Wenjing Zhao, Ming Cui, Ge Chen, Yupei Zhao
Pathogenesis of pancreatic ductal adenocarcinoma (PDAC) is thought to develop through the progression of precursor lesions, known as pancreatic intraepithelial neoplasias (PanIN). In the present study, we showed that c-Fos promoted proliferation, cell cycle and migration in pancreatic cancer cells. Caerulein was used to accelerate the pathogenesis of Pdx-cre; KrasG12D mice. During PanIN formation and development of PDAC, the expression of ERK and c-Fos increased concomitantly. When ERK activity was inhibited by U0126, the expression of c-Fos also decreased...
October 13, 2016: Oncology Reports
Faiyaz Notta, Michelle Chan-Seng-Yue, Mathieu Lemire, Yilong Li, Gavin W Wilson, Ashton A Connor, Robert E Denroche, Sheng-Ben Liang, Andrew M K Brown, Jaeseung C Kim, Tao Wang, Jared T Simpson, Timothy Beck, Ayelet Borgida, Nicholas Buchner, Dianne Chadwick, Sara Hafezi-Bakhtiari, John E Dick, Lawrence Heisler, Michael A Hollingsworth, Emin Ibrahimov, Gun Ho Jang, Jeremy Johns, Lars G T Jorgensen, Calvin Law, Olga Ludkovski, Ilinca Lungu, Karen Ng, Danielle Pasternack, Gloria M Petersen, Liran I Shlush, Lee Timms, Ming-Sound Tsao, Julie M Wilson, Christina K Yung, George Zogopoulos, John M S Bartlett, Ludmil B Alexandrov, Francisco X Real, Sean P Cleary, Michael H Roehrl, John D McPherson, Lincoln D Stein, Thomas J Hudson, Peter J Campbell, Steven Gallinger
Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently...
October 12, 2016: Nature
Su-Tang Lo, Pamela Pantazopouos, Zdravka Medarova, Anna Moore
Underglycosylated mucin 1 antigen (uMUC1) is a proven biomarker of cancer progression relevant to many malignancies including pancreatic ductal adenocarcinoma (PDAC). However, while ample evidence exists of the expression of total MUC1, little is known about the abundance of the underglycolsylated form of the antigen and its significance in disease progression. Such knowledge is important because the underglycosylated form of MUC1 is intimately linked to metastatic potential. Here, we investigated the expression uMUC1 at various stages of PDAC including pancreatic intraepithelial neoplasia (PanIN)...
2016: American Journal of Cancer Research
Francisco Sánchez-Bueno, Rocío García-Pérez, María Antonia Claver Valderas, Jesús de la Peña Moral, Laura Frutos Esteban, Eduardo Ortiz Ruiz, Matilde Fuster Quiñonero, Pascual Parrilla Paricio
INTRODUCTION: In pancreatic ductal adenocarcinoma (PDA), surgical resection is the only curative treatment, but due to its late clinical presentation only 15-25% patients are candidates for curative resection. The aim of this prospective, single-center study is to determine the diagnostic utility of preoperative PET-CT for early detection of PDA and early panIN lesions. METHODS: We studied the histopathological features of PDA and different panIN lesions in 139 surgical samples from patients undergoing pancreatic resection (from 2010-2014), comparing these results with preoperative PET-CT and MDCT study...
October 3, 2016: Cirugía Española
Simona Gurzu, Tivadar Bara, Tivadar Bara, Annamaria Fetyko, Ioan Jung
The aim of this study was to present a case of enteric duplication cyst and criteria for a proper differential diagnosis. A 51-year-old male was hospitalized for pancreatic tail neoplasm and distal pancreatectomy with splenectomy was performed. During surgery, a jejunal cystic lesion was incidentally detected and jejunectomy was performed. Microscopically, the cyst was observed to be covered by Keratin 7/Keratin 20 positive intestinal type epithelium and the muscularis layer was shared by the cyst and adjacent jejunum, without a cleavage plane between the cyst wall and jejunal muscularis propria...
September 16, 2016: World Journal of Clinical Cases
Takahiro Kishikawa, Motoyuki Otsuka, Takeshi Yoshikawa, Motoko Ohno, Hideaki Ijichi, Kazuhiko Koike
Highly repetitive tandem arrays at the centromeric and pericentromeric regions in chromosomes, previously considered silent, are actively transcribed, particularly in cancer. This aberrant expression occurs even in K-ras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To examine the biological roles of the satellite RNAs in carcinogenesis, we construct mouse PanIN-derived cells expressing major satellite (MajSAT) RNA and show increased malignant properties. We find an increase in frequency of chromosomal instability and point mutations in both genomic and mitochondrial DNA...
2016: Nature Communications
Kevin A Meyer, Christopher K Neeley, Nicki A Baker, Alexandra R Washabaugh, Carmen G Flesher, Barbara S Nelson, Timothy L Frankel, Carey N Lumeng, Costas A Lyssiotis, Michelle L Wynn, Andrew D Rhim, Robert W O'Rourke
Adipocytes promote progression of multiple cancers, but their role in pancreatic intraepithelial neoplasia (PanIN) and ductal adenocarcinoma (PDAC) is poorly defined. Nutrient transfer is a mechanism underlying stromal cell-cancer crosstalk. We studied the role of adipocytes in regulating in vitro PanIN and PDAC cell proliferation with a focus on glutamine metabolism. Murine 3T3L1 adipocytes were used to model adipocytes. Cell lines derived from PKCY mice were used to model PanIN and PDAC. Co-culture was used to study the effect of adipocytes on PanIN and PDAC cell proliferation in response to manipulation of glutamine metabolism...
September 2016: Biochemistry and Biophysics Reports
Chi-Hin Wong, You-Jia Li, Yang-Chao Chen
Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC...
August 21, 2016: World Journal of Gastroenterology: WJG
Nagaraj S Nagathihalli, Jason A Castellanos, Michael N VanSaun, Xizi Dai, Mahogany Ambrose, Qiaozhi Guo, Yanhua Xiong, Nipun B Merchant
Pancreatic ductal adenocarcinoma (PDAC) is a dynamic tumor supported by several stromal elements such as pancreatic stellate cells (PSC). Significant crosstalk exists between PSCs and tumor cells to stimulate oncogenic signaling and malignant progression of PDAC. However, how PSCs activate intercellular signaling in PDAC cells remains to be elucidated. We have previously shown that activated signal transducer and activator of transcription 3 (STAT3) signaling is a key component in the progression of pancreatic neoplasia...
September 1, 2016: Oncotarget
Emmanuelle Martinez, Isabelle Crenon, Françoise Silvy, Jean Del Grande, Alice Mougel, Dolores Barea, Frederic Fina, Jean-Paul Bernard, Mehdi Ouaissi, Dominique Lombardo, Eric Mas
Pancreatic adenocarcinoma (PDAC) is a dismal disease. The lack of specific symptoms still leads to a delay in diagnosis followed by death within months for most patients. Exon 11 of the bile salt-dependent lipase (BSDL) gene encoding variable number of tandem repeated (VNTR) sequences has been involved in pancreatic pathologies. We hypothesized that BSDL VNTR sequences may be mutated in PDAC. The amplification of BSDL VNTR from RNA extracted from pancreatic SOJ-6 cells allowed us to identify a BSDL amplicon in which a cytosine residue is inserted in a VNTR sequence...
September 1, 2016: Oncotarget
A I Kozelskaya, A V Panin, I A Khlusov, P V Mokrushnikov, B N Zaitsev, D I Kuzmenko, G Yu Vasyukov
The toxic effect of Al2O3, SiО2 and ZrО2 nanoparticles on red blood cells of Wistar rats was studied in vitro using the atomic force microscopy and the fluorescence analysis. Transformation of discocytes into echinocytes and spherocytes caused by the metal oxide nanoparticles was revealed. It was shown that only extremely high concentration of the nanoparticles (2mg/ml) allows correct estimating of their effect on the cell morphology. Besides, it was found out that the microviscosity changes of red blood cell membranes treated with nanoparticles began long before morphological modifications of the cells...
December 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Mandar Deepak Muzumdar, Kimberly Judith Dorans, Katherine Minjee Chung, Rebecca Robbins, Tuomas Tammela, Vasilena Gocheva, Carman Man-Chung Li, Tyler Jacks
Although it has become increasingly clear that cancers display extensive cellular heterogeneity, the spatial growth dynamics of genetically distinct clones within developing solid tumours remain poorly understood. Here we leverage mosaic analysis with double markers (MADM) to trace subclonal populations retaining or lacking p53 within oncogenic Kras-initiated lung and pancreatic tumours. In both models, p53 constrains progression to advanced adenocarcinomas. Comparison of lineage-related p53 knockout and wild-type clones reveals a minor role of p53 in suppressing cell expansion in lung adenomas...
2016: Nature Communications
Johannes von Burstin, Friedrich Bachhuber, Mariel Paul, Roland M Schmid, Anil K Rustgi
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly types of cancer, and the majority of pancreatic cancer deaths is caused by metastasis. Therapeutic options for systemic disease are limited, in particular due to the heterogeneous events leading to tumor dissemination. Previous studies highlighted an association of the homeodomain transcription factor MEIS1 with a ductal phenotype in pancreatic tissue architecture. Using immunohistochemistry, we demonstrate that MEIS1 is expressed in aberrant duct structures of Ela-TGFα transgenic mice as well as in pancreatic intraepithelial neoplasia (PanINs), primary PDAC, and metastatic disease in Ptf1a(Cre/+) ;LSL-Kras(G12D/+) mice...
September 1, 2016: Molecular Carcinogenesis
Jingjing Gong, Glenn Belinsky, Usman Sagheer, Xuchen Zhang, Paul J Grippo, Chuhan Chung
An increase in autophagy characterizes pancreatic carcinogenesis, but the signals that regulate this process are incompletely understood. Because canonical Wnt/β-catenin signaling is necessary for the transition from early to advanced pancreatic intraepithelial neoplasia (PanIN) lesions, we assessed whether Wnt ligands and endogenous inhibitors of Wnt signaling modulate autophagy. In this study, canonical Wnt3a ligand induced autophagy markers and vacuoles in murine PanIN cells. Furthermore, pigment epithelium-derived factor (PEDF), a secreted glycoprotein known for its anti-tumor properties, blocked Wnt3a-directed induction of autophagy proteins...
October 14, 2016: Journal of Biological Chemistry
François Huaux, Virginie d'Ursel de Bousies, Marie-Astrid Parent, Micaela Orsi, Francine Uwambayinema, Raynal Devosse, Saloua Ibouraadaten, Yousof Yakoub, Nadtha Panin, Mihaly Palmai-Pallag, Pierre van der Bruggen, Christian Bailly, Riccardo Marega, Etienne Marbaix, Dominique Lison
BACKGROUND: The asbestos-like toxicity of some engineered carbon nanotubes (CNT), notably their capacity to induce mesothelioma, is a serious cause of concern for public health. Here we show that carcinogenic CNT induce an early and sustained immunosuppressive response characterized by the accumulation of monocytic Myeloid Derived Suppressor Cells (M-MDSC) that counteract effective immune surveillance of tumor cells. METHODS: Wistar rats and C57BL/6 mice were intraperitoneally injected with carcinogenic multi-walled Mitsui-7 CNT (CNT-7) or crocidolite asbestos...
2016: Particle and Fibre Toxicology
S Ueberberg, H Jütte, W Uhl, W E Schmidt, M A Nauck, E Montanya, A Tannapfel, J J Meier
AIMS/HYPOTHESIS: Incretin-based therapies have been associated with an increased risk of pancreatitis. Recently, various histological abnormalities have been reported in human pancreatic tissue from brain-dead organ donors that had been exposed to incretin-based drugs. In the present study we examined pancreatic tissue collected at surgery. METHODS: Human pancreatic tissue from seven type 2-diabetic patients treated with incretin-based drugs (type 2-I), six diabetic patients without incretin treatment (type 2-NI), eleven patients without diabetes (no diabetes) and nine brain-dead organ donors (BDOD) was examined...
August 22, 2016: Diabetes, Obesity & Metabolism
Y Sugiyama, J Sasajima, Y Mizukami, K Koizumi, T Kawamoto, Y Ono, H Karasaki, H Tanabe, M Fujiya, Y Kohgo
The hedgehog pathway is known to promote proliferation of pancreatic ductal adenocarcinoma (PDA) and has been shown to restrain tumor progression. To understand how hedgehog causes these effects, we sought to carefully examine protein expression of hedgehog signaling components during different tumor stages. Genetically engineered mice, Pdx1-Cre;LSL-KrasG12D and Pdx1-Cre;LSL-KrasG12D;p53lox/+, were utilized to model distinct phases of tumorigenesis, pancreatic intraepithelial neoplasm (PanIN) and PDA. Human pancreatic specimens of intraductal papillary mucinous neoplasm (IPMN) and PDA were also employed...
June 2016: Polish Journal of Pathology: Official Journal of the Polish Society of Pathologists
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