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Pancreatic Neoplasms: HELP
Articles by Lizhi Zhang
Based on 32 articles published since 2010
(Why 32 articles?)
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Between 2010 and 2020, Lizhi Zhang wrote the following 32 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Primary leiomyosarcoma of the pancreas: study of 9 cases and review of literature. 2010

Zhang, Hongying / Jensen, Mark H / Farnell, Michael B / Smyrk, Thomas C / Zhang, Lizhi. ·Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. ·Am J Surg Pathol · Pubmed #21107091.

ABSTRACT: Primary pancreatic leiomyosarcomas are rare lesions and not well described, yet they are the most common primary pancreatic sarcoma. English-language medical literature reports 29 cases as single cases or small series. A systematized nomenclature of medicine (SNOMED) search of Mayo Clinic surgical pathology files from 1994 to 2006 identified 22 primary pancreatic leiomyosarcomas. Nine patients with pancreatic leiomyosarcoma were diagnosed and treated at our institution (5 males and 4 females; mean age at diagnosis, 63 y; range, 39 to 87 y) are described, with a literature review. In situ hybridization for Epstein-Barr virus (EBV)-encoded RNA (EBER) was conducted in all cases to exclude EBV-associated smooth muscle tumor (EBV-SMT). Seven of the 9 patients presented with abdominal pain, weight loss, and jaundice. Seven tumors (mean, 10.7 cm; range, 1.0 to 30 cm) were located in the pancreatic head and 2 in the tail. Histologic findings of primary pancreatic leiomyosarcomas (7 spindle and 2 epithelioid) were similar to leiomyosarcomas of other sites. All tumors stained positive for smooth muscle actin and desmin and negative for KIT. No case showed EBER positivity. Pancreaticoduodenectomy was done in 4 patients; 3 patients had palliative procedures, and 2 had biopsy only. No lymph node metastasis was identified in 4 resected tumors, but liver metastases were present in 4 patients. All patients died; 5 deaths were known to be disease related (overall mean survival, 31 months; range, 5 to 98 mo). Historical cases showed similar clinicopathologic findings. These pancreatic leiomyosarcoma lesions have the same morphologic features as their counterparts of other sites. EBER testing should be conducted--especially for pediatric patients--to rule out EBV-SMT. The tumor is likely to metastasize to liver but not regional lymph nodes. Extensive surgical resection should be advocated, even when morphologic results show a low-grade lesion.

2 Article Pancreatic tumor cell metastasis is restricted by MT1-MMP binding protein MTCBP-1. 2019

Qiang, Li / Cao, Hong / Chen, Jing / Weller, Shaun G / Krueger, Eugene W / Zhang, Lizhi / Razidlo, Gina L / McNiven, Mark A. ·Biochemistry and Molecular Biology Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN. · Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. · Department of Laboratory Medicine, Mayo Clinic, Rochester, MN. · Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN. · Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN mmcniven@mayo.edu. ·J Cell Biol · Pubmed #30487181.

ABSTRACT: The process by which tumor cells mechanically invade through surrounding stroma into peripheral tissues is an essential component of metastatic dissemination. The directed recruitment of the metalloproteinase MT1-MMP to invadopodia plays a critical role in this invasive process. Here, we provide mechanistic insight into MT1-MMP cytoplasmic tail binding protein 1 (MTCBP-1) with respect to invadopodia formation, matrix remodeling, and invasion by pancreatic tumor cells. MTCBP-1 localizes to invadopodia and interacts with MT1-MMP. We find that this interaction displaces MT1-MMP from invadopodia, thereby attenuating their number and function and reducing the capacity of tumor cells to degrade matrix. Further, we observe an inverse correlation between MTCBP-1 and MT1-MMP expression both in cultured cell lines and human pancreatic tumors. Consistently, MTCBP-1-expressing cells show decreased ability to invade in vitro and metastasize in vivo. These findings implicate MTCBP-1 as an inhibitor of the metastatic process.

3 Article High-Grade Dysplasia in Resected Main-Duct Intraductal Papillary Mucinous Neoplasm (MD-IPMN) is Associated with an Increased Risk of Subsequent Pancreatic Cancer. 2019

Majumder, Shounak / Philip, Nissy A / Singh Nagpal, Sajan Jiv / Takahashi, Naoki / Mara, Kristin C / Kendrick, Michael L / Smyrk, Thomas C / Zhang, Lizhi / Levy, Michael J / Gleeson, Ferga C / Petersen, Bret T / Pearson, Randall K / Topazian, Mark D / Vege, Santhi Swaroop / Chari, Suresh T. ·Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. · Department of Internal Medicine, Saint Peter University Hospital, Trenton, NJ, USA. · Division of Abdominal Imaging and Radiology, Mayo Clinic, Rochester, MN, 55905, USA. · Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA. · Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, 55905, USA. ·Am J Gastroenterol · Pubmed #30413822.

ABSTRACT: BACKGROUND: There is lack of consensus on post-operative surveillance for resected non-invasive intraductal papillary neoplasms (IPMNs). In this study we explored risk factors for subsequent PC in patients with MD-IPMN undergoing partial pancreatectomy. METHODS: We searched the Mayo Clinic surgical pathology database for all cases of resected MD-IPMN between 1997 and 2014. Cases with histologically confirmed main pancreatic duct involvement either isolated or in a mixed pattern with branch-duct involvement were included. Outcomes of PC in the remnant pancreas, and death related to MD-IPMN were assessed with survival analyses (Kaplan-Meier and Cox regression). RESULTS: Among the 179 patients with resected MD-IPMN the incidence of concomitant PC and high-grade dysplasia (HGD) in the resected specimen was 23 and 14%, respectively. The mean duration of follow-up was 4.31 years (range 0.12-13.5 years). Excluding 28 subjects who either underwent initial total pancreatectomy or partial pancreatectomy with surgical margins positive for PC/HGD, the 5-year incidence of subsequent PC was 12%, including 60.6% and 15.6% in those with initial PC and HGD, respectively. The 10-year incidence of PC was 21.2% overall, 60.6% for PC, 38.3% for HGD, and 3.0% for LGD. Risk of subsequent PC was significantly higher for those with initial PC compared with HGD (HR = 4.95, 95% CI: 1.63-15.03, p = 0.005 and for HGD compared with LGD (HR = 11.30, 95% CI: 1.55-82.26, p = 0.017). CONCLUSIONS: Patients with MD-IPMN with PC or HGD undergoing segmental pancreatectomy are at higher risk of subsequent PC and may benefit from post-operative surveillance. The post-operative surveillance intervals in resected MD-IPMNs need to be tailored based on dysplasia grade.

4 Article c-MYC amplification and c-myc protein expression in pancreatic acinar cell carcinomas. New insights into the molecular signature of these rare cancers. 2018

La Rosa, Stefano / Bernasconi, Barbara / Vanoli, Alessandro / Sciarra, Amedeo / Notohara, Kenji / Albarello, Luca / Casnedi, Selenia / Billo, Paola / Zhang, Lizhi / Tibiletti, Maria Grazia / Sessa, Fausto. ·Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, 25 rue du Bugnon, 1011, Lausanne, Switzerland. stefano.larosa@chuv.ch. · Department of Medicine and Surgery, University of Insubria, Varese, Italy. · Department of Molecular Medicine, University of Pavia, Pavia, Italy. · Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, 25 rue du Bugnon, 1011, Lausanne, Switzerland. · Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan. · Pathology Unit, San Raffaele Scientific Institute, Milan, Italy. · Centre de Pathologie, Strasbourg, France. · Unit of Pathology, Ospedale Civile, Legnano, Italy. · Department of Pathology, Mayo Clinic, Rochester, MN, USA. · Department of Pathology, ASST-Sette Laghi, Varese, Italy. ·Virchows Arch · Pubmed #29721608.

ABSTRACT: The molecular alterations of pancreatic acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MANECs) are not completely understood, and the possible role of c-MYC amplification in tumor development, progression, and prognosis is not known. We have investigated c-MYC gene amplification in a series of 35 ACCs and 4 MANECs to evaluate its frequency and a possible prognostic role. Gene amplification was investigated using interphasic fluorescence in situ hybridization analysis simultaneously hybridizing c-MYC and the centromere of chromosome 8 probes. Protein expression was immunohistochemically investigated using a specific monoclonal anti-c-myc antibody. Twenty cases had clones with different polysomies of chromosome 8 in absence of c-MYC amplification, and 5 cases had one amplified clone and other clones with chromosome 8 polysomy, while the remaining 14 cases were diploid for chromosome 8 and lacked c-MYC amplification. All MANECs showed c-MYC amplification and/or polysomy which were observed in 54% pure ACCs. Six cases (15.3%) showed nuclear immunoreactivity for c-myc, but only 4/39 cases showed simultaneous c-MYC amplification/polysomy and nuclear protein expression. c-myc immunoreactivity as well as c-MYC amplification and/or chromosome 8 polysomy was not statistically associated with prognosis. Our study demonstrates that a subset of ACCs shows c-MYC alterations including gene amplification and chromosome 8 polysomy. Although they are not associated with a different prognostic signature, the fact that these alterations are present in all MANECs suggests a role in the acinar-neuroendocrine differentiation possibly involved in the pathogenesis of MANECs.

5 Article Endoscopic Ultrasound-Guided Fine-Needle Biopsies From Pancreatic Ductal Adenocarcinomas Can Be Used to Quantify PD-L1. 2018

Gleeson, Ferga C / Zhang, Lizhi / Roden, Anja C / Levy, Michael J. ·Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: gleeson.ferga@mayo.edu. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. ·Clin Gastroenterol Hepatol · Pubmed #29306039.

ABSTRACT: -- No abstract --

6 Article Undifferentiated Pancreatic Carcinomas Display Enrichment for Frequency and Extent of PD-L1 Expression by Tumor Cells. 2017

Lehrke, Heidi D / Graham, Rondell P / McWilliams, Robert R / Lam-Himlin, Dora M / Smyrk, Thomas C / Jenkins, Sarah / Dong, Haidong / Zhang, Lizhi. ·Department of Laboratory Medicine and Pathology. · Department of Oncology. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ. · Division of Biomedical Statistics & Informatics. · Department of Immunology, Mayo Clinic, Rochester, MN. ·Am J Clin Pathol · Pubmed #29069274.

ABSTRACT: Objectives: Programmed death ligand 1 (PD-L1) expression in pancreatic ductal adenocarcinoma (PDA) has been described, but unselected PDAs have shown limited clinical responsiveness to anti-programmed death 1 (PD-1)/PD-L1 therapy. Methods: We studied 24 cases of undifferentiated pancreatic carcinoma (UPC) using immunohistochemistry for PD-L1 (E1L3N clone), CD3, CD20, CD68, and DNA mismatch repair proteins in this study. Slides were scored for extent of PD-L1 expression on tumor cells and tumor-infiltrating immune cells. Results: PD-L1 expression was more frequent in UPCs than in PDAs (63% vs 15%, P < .01). The extent of PD-L1 expression was greater in UPCs, with 13 (87%) of 15 cases containing 10% or more positive tumor cells compared with three of seven PDAs (P = .05). Both tumor groups showed similar numbers of tumor-infiltrating T cells, B cells, and macrophages. Conclusions: UPC is enriched for PD-L1 expression in frequency and extent, relative to conventional PDA. Anti-PD-1/PD-L1 agents may represent a valuable therapeutic approach for this subset of highly aggressive pancreatic carcinoma.

7 Article Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1-MAPK Interaction. 2017

Jin, Xin / Pan, Yunqian / Wang, Liguo / Ma, Tao / Zhang, Lizhi / Tang, Amy H / Billadeau, Daniel D / Wu, Heshui / Huang, Haojie. ·Department of Digestive Surgical Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. · Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota. · Department of Medical Informatics and Statistics, Mayo Clinic College of Medicine, Rochester, Minnesota. · Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota. · Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia. · Leroy T. Canoles Jr. Cancer Center, Eastern Virginia Medical School, Norfork, Virginia. · Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota. · Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. huang.haojie@mayo.edu heshuiwu@163.com. · Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota. huang.haojie@mayo.edu heshuiwu@163.com. ·Cancer Res · Pubmed #28720574.

ABSTRACT: Dysregulation of the MAPK pathway correlates with progression of pancreatic ductal adenocarcinoma (PDAC) progression. IQ motif containing GTPase-activating protein 1 (IQGAP1) is a MAPK scaffold that directly regulates the activation of RAF, MEK, and ERK. Fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis, is transcriptionally downregulated in various cancers, including PDAC. Here, we demonstrate that FBP1 acts as a negative modulator of the IQGAP1-MAPK signaling axis in PDAC cells. FBP1 binding to the WW domain of IQGAP1 impeded IQGAP1-dependent ERK1/2 phosphorylation (pERK1/2) in a manner independent of FBP1 enzymatic activity. Conversely, decreased FBP1 expression induced pERK1/2 levels in PDAC cell lines and correlated with increased pERK1/2 levels in patient specimens. Treatment with gemcitabine caused undesirable activation of ERK1/2 in PDAC cells, but cotreatment with the FBP1-derived small peptide inhibitor FBP1 E4 overcame gemcitabine-induced ERK activation, thereby increasing the anticancer efficacy of gemcitabine in PDAC. These findings identify a primary mechanism of resistance of PDAC to standard therapy and suggest that the FBP1-IQGAP1-ERK1/2 signaling axis can be targeted for effective treatment of PDAC.

8 Article The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis. 2017

Liou, Geou-Yarh / Bastea, Ligia / Fleming, Alicia / Döppler, Heike / Edenfield, Brandy H / Dawson, David W / Zhang, Lizhi / Bardeesy, Nabeel / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. · Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. · Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN 55905, USA. · Center for Cancer Research, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, 02115 MA, USA. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: storz.peter@mayo.edu. ·Cell Rep · Pubmed #28514653.

ABSTRACT: The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM]), which then gives rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly decreased the accumulation of alternatively activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

9 Article USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling. 2017

Luo, Kuntian / Li, Yunhui / Yin, Yujiao / Li, Lei / Wu, Chenming / Chen, Yuping / Nowsheen, Somaira / Hu, Qi / Zhang, Lizhi / Lou, Zhenkun / Yuan, Jian. ·Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China. · Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, China. · Department of Oncology, Mayo Clinic, Rochester, MN, USA. · Medical Scientist Training Program, Mayo Clinic School of Medicine, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA. · Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. · Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China yuanjian229@hotmail.com. ·EMBO J · Pubmed #28363942.

ABSTRACT: The AKT pathway is a fundamental signaling pathway that mediates multiple cellular processes, such as cell proliferation and survival, angiogenesis, and glucose metabolism. We recently reported that the immunophilin FKBP51 is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP-mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation. However, the regulation of FKBP51-PHLPP-AKT pathway remains unclear. Here we report that a deubiquitinase, USP49, is a new regulator of the AKT pathway. Mechanistically, USP49 deubiquitinates and stabilizes FKBP51, which in turn enhances PHLPP's capability to dephosphorylate AKT Furthermore, USP49 inhibited pancreatic cancer cell proliferation and enhanced cellular response to gemcitabine in a FKBP51-AKT-dependent manner. Clinically, decreased expression of USP49 in patients with pancreatic cancer was associated with decreased FKBP51 expression and increased AKT phosphorylation. Overall, our findings establish USP49 as a novel regulator of AKT pathway with a critical role in tumorigenesis and chemo-response in pancreatic cancer.

10 Article Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions. 2016

Liou, Geou-Yarh / Döppler, Heike / DelGiorno, Kathleen E / Zhang, Lizhi / Leitges, Michael / Crawford, Howard C / Murphy, Michael P / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA. · The Biotechnology Centre of Oslo, University of Oslo, 0349 Oslo, Norway. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. · MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: storz.peter@mayo.edu. ·Cell Rep · Pubmed #26947075.

ABSTRACT: The development of pancreatic cancer requires the acquisition of oncogenic KRas mutations and upregulation of growth factor signaling, but the relationship between these is not well established. Here, we show that mutant KRas alters mitochondrial metabolism in pancreatic acinar cells, resulting in increased generation of mitochondrial reactive oxygen species (mROS). Mitochondrial ROS then drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to PanIN. This is mediated via the ROS-receptive kinase protein kinase D1 and the transcription factors NF-κB1 and NF-κB2, which upregulate expression of the epidermal growth factor, its ligands, and their sheddase ADAM17. In vivo, interception of KRas-mediated generation of mROS reduced the formation of pre-neoplastic lesions. Hence, our data provide insight into how oncogenic KRas interacts with growth factor signaling to induce the formation of pancreatic cancer.

11 Article GSK-3β Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression. 2016

Baumgart, Sandra / Chen, Nai-Ming / Zhang, Jin-San / Billadeau, Daniel D / Gaisina, Irina N / Kozikowski, Alan P / Singh, Shiv K / Fink, Daniel / Ströbel, Philipp / Klindt, Caroline / Zhang, Lizhi / Bamlet, William R / Koenig, Alexander / Hessmann, Elisabeth / Gress, Thomas M / Ellenrieder, Volker / Neesse, Albrecht. ·Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, University of Marburg, Marburg, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota. · Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois. · Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona. · Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany. · Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota. · Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, Minnesota. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. albrecht.neesse@med.uni-goettingen.de. ·Mol Cancer Ther · Pubmed #26823495.

ABSTRACT: We aimed to investigate the mechanistic, functional, and therapeutic role of glycogen synthase kinase 3β (GSK-3β) in the regulation and activation of the proinflammatory oncogenic transcription factor nuclear factor of activated T cells (NFATc2) in pancreatic cancer. IHC, qPCR, immunoblotting, immunofluorescence microscopy, and proliferation assays were used to analyze mouse and human tissues and cell lines. Protein-protein interactions and promoter regulation were analyzed by coimmunoprecipitation, DNA pulldown, reporter, and ChIP assays. Preclinical assays were performed using a variety of pancreatic cancer cells lines, xenografts, and a genetically engineered mouse model (GEMM). GSK-3β-dependent SP2 phosphorylation mediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3β also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation. For NFATc2-STAT3 complex formation, GSK-3β-mediated phosphorylation of STAT3 at Y705 is required to stimulate euchromatin formation of NFAT target promoters, such as cyclin-dependent kinase-6, which promotes tumor growth. Finally, preclinical experiments suggest that targeting the NFATc2-STAT3-GSK-3β module inhibits proliferation and tumor growth and interferes with inflammation-induced pancreatic cancer progression in Kras(G12D) mice. In conclusion, we describe a novel mechanism by which GSK-3β fine-tunes NFATc2 and STAT3 transcriptional networks to integrate upstream signaling events that govern pancreatic cancer progression and growth. Furthermore, the therapeutic potential of GSK-3β is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer.

12 Article TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer. 2016

La Rosa, Stefano / Bernasconi, Barbara / Frattini, Milo / Tibiletti, Maria Grazia / Molinari, Francesca / Furlan, Daniela / Sahnane, Nora / Vanoli, Alessandro / Albarello, Luca / Zhang, Lizhi / Notohara, Kenji / Casnedi, Selenia / Chenard, Marie-Pierre / Adsay, Volkan / Asioli, Sofia / Capella, Carlo / Sessa, Fausto. ·Department of Pathology, Ospedale di Circolo, viale Borri 57, 21100, Varese, Italy. stefano.larosa@ospedale.varese.it. · Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy. · Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland. · Department of Pathology, Ospedale di Circolo, viale Borri 57, 21100, Varese, Italy. · Department of Molecular Medicine, University of Pavia, Pavia, Italy. · Pathology Unit, San Raffaele Scientific Institute, Milan, Italy. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. · Department of Pathology, Kurashiki Central Hospital, Kurashiki, Japan. · Centre de Pathologie, Strasbourg, France. · Department of Pathology, Hospital De Hautepierre, Strasbourg, France. · Department of Pathology, Emory University, Atlanta, GA, USA. · Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. ·Virchows Arch · Pubmed #26586531.

ABSTRACT: The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.

13 Article Comparison of Three Ki-67 Index Quantification Methods and Clinical Significance in Pancreatic Neuroendocrine Tumors. 2015

Kroneman, Trynda N / Voss, Jesse S / Lohse, Christine M / Wu, Tsung-Teh / Smyrk, Thomas C / Zhang, Lizhi. ·Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. ·Endocr Pathol · Pubmed #26072124.

ABSTRACT: The Ki-67 index is essential in the pathological reports for pancreatic neuroendocrine tumors. There are three methods to determine the Ki-67 index including eyeball estimation, manual counting, or automated digital imaging analysis. The goal of this study was to compare the three quantification methods with the clinical outcome to determine the best method for clinical practice. Ki-67 immunostaining was performed on 97 resected pancreatic neuroendocrine tumors. The three methods of quantification were employed: (1) an average of eyeball estimation by three pathologists; (2) manual counting of at least 500 tumor cells; and (3) digital imaging analysis quantitation by selecting 8-10 hot spot regions. All tumors were graded according to the 2010 WHO grading system. The three quantification methods for the Ki-67 index had almost perfect agreement. The concordance between manual counting and digital imaging analysis and between manual counting and average eyeball estimation were 0.97 and 0.88, respectively. The concordance among the three pathologists' eyeball estimation was 0.86. All three methods correlated with patients' survival using the 2010 WHO grading system. Eyeball estimation scores were significantly less than those of the other two methods and tended to downgrade more tumors to grade 1, but they had higher predictive ability for survival and recurrence. The WHO system using the mitotic rate could also separate patients with different survival and even downgraded more tumors to grade 1. The results suggest the necessity of a consensus among pathologists for the method to determine the Ki-67 index and proper cutoff of the Ki-67 index for better clinical correlation.

14 Article The string sign for diagnosis of mucinous pancreatic cysts. 2015

Bick, Benjamin L / Enders, Felicity T / Levy, Michael J / Zhang, Lizhi / Henry, Michael R / Abu Dayyeh, Barham K / Chari, Suresh T / Clain, Jonathan E / Farnell, Michael B / Gleeson, Ferga C / Kendrick, Michael L / Pearson, Randall K / Petersen, Bret T / Rajan, Elizabeth / Vege, Santhi Swaroop / Topazian, Mark. ·Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States. · Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States. · Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, United States. · Department of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, Minnesota, United States. ·Endoscopy · Pubmed #25730281.

ABSTRACT: BACKGROUND AND STUDY AIMS: Pancreas cyst fluid analysis does not provide optimal discrimination between mucinous and nonmucinous cysts. The aim of this study was to assess the performance characteristics of the "string sign" - a test performed at the time of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), for the diagnosis of mucinous pancreatic cysts (branch duct intraductal papillary mucinous neoplasms [bIPMN] and mucinous cystic neoplasms). PATIENTS AND METHODS: Patients undergoing EUS-FNA of pancreatic cystic lesions at one referral center between 2003 and 2012 were included. The string sign was performed prospectively, and was considered positive if ≥ 1 cm string formed in cyst fluid and lasted for ≥ 1 second. Performance characteristics of the string sign and a sequential cyst fluid test interpretation model were assessed. RESULTS: For 98 histologically proven cases, the sensitivity, specificity, positive predictive value, and negative predictive value of the string sign for diagnosis of mucinous cysts were 58 % (95 % confidence interval [CI] 44 % - 70 %), 95 % (83 % - 99 %), 94 % (81 % - 99 %), and 60 % (46 % - 72 %), respectively. When string sign results and carcinoembryonic antigen (CEA) concentration (≥ 200 ng/mL) were combined, diagnostic accuracy improved from 74 % and 83 %, respectively, to 89 % (P ≤ 0.03). Among bIPMN, a positive string sign was associated with gastric and intestinal epithelial subtypes. The sequential cyst fluid test interpretation model (including cytology, mucin stain, CEA, and string sign) yielded an overall sensitivity for mucinous lesions of 96 %, with a specificity of 90 %. CONCLUSIONS: The string sign is highly specific for diagnosis of mucinous pancreatic cysts, and improves overall diagnostic accuracy of pancreatic cyst fluid analysis. Sequential cyst fluid test interpretation yields high diagnostic sensitivity and specificity for mucinous cysts.

15 Article Mutant KRAS-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions. 2015

Liou, Geou-Yarh / Döppler, Heike / Necela, Brian / Edenfield, Brandy / Zhang, Lizhi / Dawson, David W / Storz, Peter. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. · Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. storz.peter@mayo.edu. ·Cancer Discov · Pubmed #25361845.

ABSTRACT: SIGNIFICANCE: We here show that oncogenic KRAS in pancreatic acinar cells upregulates the expression of ICAM-1 to attract macrophages. Hence, our results reveal a direct cooperative mechanism between oncogenic Kras mutations and the inflammatory environment to drive the initiation of pancreatic cancer.

16 Article Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A. 2014

Hoskins, Jason W / Jia, Jinping / Flandez, Marta / Parikh, Hemang / Xiao, Wenming / Collins, Irene / Emmanuel, Mickey A / Ibrahim, Abdisamad / Powell, John / Zhang, Lizhi / Malats, Nuria / Bamlet, William R / Petersen, Gloria M / Real, Francisco X / Amundadottir, Laufey T. ·Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA, Department of Laboratory Medicine and Pathology and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain. · Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain. · Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and. · Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA. · Department of Laboratory Medicine and Pathology and. · Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and. · Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA, Department of Laboratory Medicine and Pathology and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain amundadottirl@mail.nih.gov. ·Carcinogenesis · Pubmed #25233928.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is driven by the accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. New approaches to investigating disruptions of gene expression networks promise to uncover key regulators and pathways in carcinogenesis. We performed messenger RNA-sequencing in pancreatic normal (n = 10) and tumor (n = 8) derived tissue samples, as well as in pancreatic cancer cell lines (n = 9), to determine differential gene expression (DE) patterns. Sub-network enrichment analyses identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in pancreatic tumor tissues and cells (median P = 7.56×10(-7), median rank = 1, range = 1-25). To explore the effects of HNF1A expression in pancreatic tumor-derived cells, we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines (PANC-1 and MIA PaCa-2) and observed growth inhibition (5.3-fold, P = 4.5×10(-5) for MIA PaCa-2 clones; 7.2-fold, P = 2.2×10(-5) for PANC-1 clones), and a G0/G1 cell cycle arrest and apoptosis upon induction. These effects correlated with HNF1A-induced down-regulation of 51 of 84 cell cycle genes (e.g. E2F1, CDK2, CDK4, MCM2/3/4/5, SKP2 and CCND1), decreased expression of anti-apoptotic genes (e.g. BIRC2/5/6 and AKT) and increased expression of pro-apoptotic genes (e.g. CASP4/9/10 and APAF1). In light of the established role of HNF1A in the regulation of pancreatic development and homeostasis, our data suggest that it also functions as an important tumor suppressor in the pancreas.

17 Article Tumor cell-derived MMP3 orchestrates Rac1b and tissue alterations that promote pancreatic adenocarcinoma. 2014

Mehner, Christine / Miller, Erin / Khauv, Davitte / Nassar, Aziza / Oberg, Ann L / Bamlet, William R / Zhang, Lizhi / Waldmann, Jens / Radisky, Evette S / Crawford, Howard C / Radisky, Derek C. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224 U S A; · Department of Pathology, Mayo Clinic, Jacksonville, Florida; · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; · Department of Pathology, Mayo Clinic, Rochester, Minnesota; and. · Department of Visceral-, Thoracic- and Vascular Surgery, Unikliniken Marburg Und Giessen, Marburg, Germany. · Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224 U S A; radisky.derek@mayo.edu. ·Mol Cancer Res · Pubmed #24850902.

ABSTRACT: IMPLICATIONS: MMP3 acts as a coconspirator of oncogenic KRAS in pancreatic cancer tumorigenesis and progression, both through Rac1b-mediated phenotypic control of pancreatic cancer cells themselves, and by giving rise to the tumorigenic microenvironment; these findings also point to inhibition of this pathway as a potential therapeutic strategy for pancreatic cancer.

18 Article Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression. 2014

Mills, Lisa D / Zhang, Lizhi / Marler, Ronald / Svingen, Phyllis / Fernandez-Barrena, Maite G / Dave, Maneesh / Bamlet, William / McWilliams, Robert R / Petersen, Gloria M / Faubion, William / Fernandez-Zapico, Martin E. ·From the Schulze Center for Novel Therapeutics. · Laboratory Medicine and Pathology. · the Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Scottsdale, Arizona 85259. · Laboratory of Epigenetics and Chromatin Dynamics. · Division of Biomedical Statistics and Informatics. · Department of Oncology, and. · Division of Epidemiology, Mayo Clinic, Rochester, Minnesota 55905 and. · From the Schulze Center for Novel Therapeutics, fernandezzapico.martin@mayo.edu. ·J Biol Chem · Pubmed #24737325.

ABSTRACT: The role of GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC). Interestingly, in this model, GLI1 played a tumor-protective function, where survival of GKO/KPC mice was reduced compared with KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and severe leukopenia. In vivo and in vitro expression studies identified FAS and FAS ligand (FASL) as potential mediators of this phenomenon. The FAS/FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation and reporter assays identified FAS and FASL as direct targets of GLI1, whereas GKO/KPC mice showed lower levels of this ligand compared with KPC animals. Finally, decreased levels of apoptosis were detected in tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help with the design and analysis of trials targeting GLI1-related pathways.

19 Article CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells. 2014

Jia, Jinping / Bosley, Allen D / Thompson, Abbey / Hoskins, Jason W / Cheuk, Adam / Collins, Irene / Parikh, Hemang / Xiao, Zhen / Ylaya, Kris / Dzyadyk, Marta / Cozen, Wendy / Hernandez, Brenda Y / Lynch, Charles F / Loncarek, Jadranka / Altekruse, Sean F / Zhang, Lizhi / Westlake, Christopher J / Factor, Valentina M / Thorgeirsson, Snorri / Bamlet, William R / Hewitt, Stephen M / Petersen, Gloria M / Andresson, Thorkell / Amundadottir, Laufey T. ·Authors' Affiliations: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics; Pediatric Oncology Branch; Laboratory of Pathology; Division of Cancer Control and Population Sciences; Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda; Laboratory of Proteomics and Analytical Technologies, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research; Laboratory of Protein Dynamics and Signaling and Laboratory of Cell & Developmental Signaling, NCI-Frederick, Frederick, Maryland; Keck School of Medicine, University of Southern California, Los Angeles, California; University of Hawaii Cancer Center, Honolulu, Hawaii; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; and Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Authors' Affiliations: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics; Pediatric Oncology Branch; Laboratory of Pathology; Division of Cancer Control and Population Sciences; Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda; Laboratory of Proteomics and Analytical Technologies, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research; Laboratory of Protein Dynamics and Signaling and Laboratory of Cell & Developmental Signaling, NCI-Frederick, Frederick, Maryland; Keck School of Medicine, University of Southern California, Los Angeles, California; University of Hawaii Cancer Center, Honolulu, Hawaii; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; and Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota amundadottirl@mail.nih.gov. ·Cancer Res · Pubmed #24648346.

ABSTRACT: Genome-wide association studies (GWAS) of 10 different cancers have identified pleiotropic cancer predisposition loci across a region of chromosome 5p15.33 that includes the TERT and CLPTM1L genes. Of these, susceptibility alleles for pancreatic cancer have mapped to the CLPTM1L gene, thus prompting an investigation of the function of CLPTM1L in the pancreas. Immunofluorescence analysis indicated that CLPTM1L localized to the endoplasmic reticulum where it is likely embedded in the membrane, in accord with multiple predicted transmembrane domains. Overexpression of CLPTM1L enhanced growth of pancreatic cancer cells in vitro (1.3-1.5-fold; PDAY7 < 0.003) and in vivo (3.46-fold; PDAY68 = 0.039), suggesting a role in tumor growth; this effect was abrogated by deletion of two hydrophilic domains. Affinity purification followed by mass spectrometry identified an interaction between CLPTM1L and non-muscle myosin II (NMM-II), a protein involved in maintaining cell shape, migration, and cytokinesis. The two proteins colocalized in the cytoplasm and, after treatment with a DNA-damaging agent, at the centrosomes. Overexpression of CLPTM1L and depletion of NMM-II induced aneuploidy, indicating that CLPTM1L may interfere with normal NMM-II function in regulating cytokinesis. Immunohistochemical analysis revealed enhanced staining of CLPTM1L in human pancreatic ductal adenocarcinoma (n = 378) as compared with normal pancreatic tissue samples (n = 17; P = 1.7 × 10(-4)). Our results suggest that CLPTM1L functions as a growth-promoting gene in the pancreas and that overexpression may lead to an abrogation of normal cytokinesis, indicating that it should be considered as a plausible candidate gene that could explain the effect of pancreatic cancer susceptibility alleles on chr5p15.33.

20 Article APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation. 2014

Furlan, Daniela / Sahnane, Nora / Bernasconi, Barbara / Frattini, Milo / Tibiletti, Maria Grazia / Molinari, Francesca / Marando, Alessandro / Zhang, Lizhi / Vanoli, Alessandro / Casnedi, Selenia / Adsay, Volkan / Notohara, Kenji / Albarello, Luca / Asioli, Sofia / Sessa, Fausto / Capella, Carlo / La Rosa, Stefano. ·Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy. ·Virchows Arch · Pubmed #24590585.

ABSTRACT: Genetic and epigenetic alterations involved in the pathogenesis of pancreatic acinar cell carcinomas (ACCs) are poorly characterized, including the frequency and role of gene-specific hypermethylation, chromosome aberrations, and copy number alterations (CNAs). A subset of ACCs is known to show alterations in the APC/β-catenin pathway which includes mutations of APC gene. However, it is not known whether, in addition to mutation, loss of APC gene function can occur through alternative genetic and epigenetic mechanisms such as gene loss or promoter methylation. We investigated the global methylation profile of 34 tumor suppressor genes, CNAs of 52 chromosomal regions, and APC gene alterations (mutation, methylation, and loss) together with APC mRNA level in 45 ACCs and related peritumoral pancreatic tissues using methylation-specific multiplex ligation probe amplification (MS-MLPA), fluorescence in situ hybridization (FISH), mutation analysis, and reverse transcription-droplet digital PCR. ACCs did not show an extensive global gene hypermethylation profile. RASSF1 and APC were the only two genes frequently methylated. APC mutations were found in only 7 % of cases, while APC loss and methylation were more frequently observed (48 and 56 % of ACCs, respectively). APC mRNA low levels were found in 58 % of cases and correlated with CNAs. In conclusion, ACCs do not show extensive global gene hypermethylation. APC alterations are frequently involved in the pathogenesis of ACCs mainly through gene loss and promoter hypermethylation, along with reduction of APC mRNA levels.

21 Article Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. 2014

Basturk, Olca / Tang, Laura / Hruban, Ralph H / Adsay, Volkan / Yang, Zhaohai / Krasinskas, Alyssa M / Vakiani, Efsevia / La Rosa, Stefano / Jang, Kee-Taek / Frankel, Wendy L / Liu, Xiuli / Zhang, Lizhi / Giordano, Thomas J / Bellizzi, Andrew M / Chen, Jey-Hsin / Shi, Chanjuan / Allen, Peter / Reidy, Diane L / Wolfgang, Christopher L / Saka, Burcu / Rezaee, Neda / Deshpande, Vikram / Klimstra, David S. ·Departments of *Pathology ***Surgery †††Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY †Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center ‡‡‡Department of Surgery, Johns Hopkins University, Baltimore, MD ‡Department of Pathology, Emory University, Atlanta, GA §Department of Pathology, Penn State Hershey MC, Hershey ∥Department of Pathology, University of Pittsburgh, Pittsburgh, PA **Department of Pathology, Ohio State University, Columbus ††Department of Pathology, Cleveland Clinic, Cleveland, OH ‡‡Department of Pathology, Mayo Clinic, Rochester, MN §§Department of Pathology, University of Michigan, Ann Arbor, MI ∥∥Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA ¶¶Department of Pathology, Indiana University, Indianapolis, IN ##Department of Pathology, Vanderbilt University, Nashville, TN §§§Department of Pathology, Massachusetts General Hospital, Boston, MA ¶Department of Pathology, Ospedale di Circolo, Varese, Italy #Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. ·Am J Surg Pathol · Pubmed #24503751.

ABSTRACT: BACKGROUND: In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited. DESIGN: A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed. RESULTS: The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively. CONCLUSIONS: Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.

22 Article Clinical characteristics and overall survival in patients with anaplastic pancreatic cancer. 2014

Clark, Clancy J / Arun, Janani S / Graham, Rondell P / Zhang, Lizhi / Farnell, Michael / Reid-Lombardo, Kaye M. ·Division of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, Minnesota, USA. ·Am Surg · Pubmed #24480210.

ABSTRACT: Anaplastic pancreatic cancer (APC) is a rare undifferentiated variant of pancreatic ductal adenocarcinoma with poor overall survival (OS). The aim of this study was to evaluate the clinical outcomes of APC compared with differentiated pancreatic ductal adenocarcinoma. We conducted a retrospective review of all patients treated at the Mayo Clinic with pathologically confirmed APC from 1987 to 2011. After matching with control subjects with pancreatic ductal adenocarcinoma, OS was evaluated using Kaplan-Meier estimates and log-rank test. Sixteen patients were identified with APC (56.3% male, median age 57 years). Ten patients underwent exploration of whom eight underwent pancreatectomy. Perioperative morbidity was 60 per cent with no mortality. The median OS was 12.8 months. However, patients with APC who underwent resection had longer OS compared with those who were not resected, 34.1 versus 3.3 months (P = 0.001). After matching age, sex, tumor stage, and year of operation, the median OS was similar between patients with APC and those with ductal adenocarcinoma treated with pancreatic resection, 44.1 versus 39.9 months, (P = 0.763). Overall survival for APC is poor; however, when resected, survival is similar to differentiated pancreatic ductal adenocarcinoma.

23 Article Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor. 2013

Murphy, Stephen J / Hart, Steven N / Lima, Joema Felipe / Kipp, Benjamin R / Klebig, Mitchell / Winters, Jennifer L / Szabo, Csilla / Zhang, Lizhi / Eckloff, Bruce W / Petersen, Gloria M / Scherer, Steven E / Gibbs, Richard A / McWilliams, Robert R / Vasmatzis, George / Couch, Fergus J. ·Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota. ·Gastroenterology · Pubmed #23912084.

ABSTRACT: BACKGROUND & AIMS: Increasing grade of pancreatic intraepithelial neoplasia (PanIN) has been associated with progression to pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that control progression from PanINs to PDAC are not well understood. We investigated the genetic alterations involved in this process. METHODS: Genomic DNA samples from laser-capture microdissected PDACs and adjacent PanIN2 and PanIN3 lesions from 10 patients with pancreatic cancer were analyzed by exome sequencing. RESULTS: Similar numbers of somatic mutations were identified in PanINs and tumors, but the mutational load varied greatly among cases. Ten of the 15 isolated PanINs shared more than 50% of somatic mutations with associated tumors. Mutations common to tumors and clonally related PanIN2 and PanIN3 lesions were identified as genes that could promote carcinogenesis. KRAS and TP53 frequently were altered in PanINs and tumors, but few other recurrently modified genes were detected. Mutations in DNA damage response genes were prevalent in all samples. Genes that encode proteins involved in gap junctions, the actin cytoskeleton, the mitogen-activated protein kinase signaling pathway, axon guidance, and cell-cycle regulation were among the earliest targets of mutagenesis in PanINs that progressed to PDAC. CONCLUSIONS: Early stage PanIN2 lesions appear to contain many of the somatic gene alterations required for PDAC development.

24 Article Rare ALK expression but no ALK rearrangement in pancreatic ductal adenocarcinoma and neuroendocrine tumors. 2013

Graham, Rondell P D / Oliveira, Andre M / Zhang, Lizhi. ·Division of Anatomic Pathology, Mayo Clinic, Rochester, MN 55905, USA. ·Pancreas · Pubmed #23851431.

ABSTRACT: OBJECTIVES: Anaplastic lymphoma kinase (ALK) gene rearrangements were first identified in anaplastic large cell lymphomas. Subsequently, they have been observed in other tumor types with ALK-rearranged tumors demonstrating responsiveness to ALK inhibitors. The aggressiveness of pancreatic ductal adenocarcinoma warrants the examination of ALK rearrangements in pancreatic cancer as a potential therapeutic target. Immunohistochemical expression of ALK1 correlates with ALK rearrangements in other tumors. We performed ALK immunohistochemistry on samples of pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors using 2 tissue microarrays. METHODS: ALK1 expression was scored for each case as 0, 1+, 2+, or 3+ using established criteria. Fluorescence in situ hybridization using a break-apart assay with probes for ALK was performed to detect ALK rearrangement in ALK1-positive cases. RESULTS: All 46 neuroendocrine tumors were negative for ALK1. Of 140 ductal adenocarcinoma cases, 5 showed immunoreactivity for ALK1: 1 was 3+, 2 were 2+, and 2 were 1+. However, fluorescence in situ hybridization for ALK rearrangement was negative in all 5 cases. CONCLUSIONS: The results demonstrate that ALK1 expression is uncommon in both pancreatic ductal adenocarcinoma and neuroendocrine tumors. Rare ALK1 expression is not induced by ALK translocation, and ALK is unlikely to be a therapeutic target in pancreatic tumors.

25 Article Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. 2013

Mills, Lisa D / Zhang, Yaqing / Marler, Ronald J / Herreros-Villanueva, Marta / Zhang, Lizhi / Almada, Luciana L / Couch, Fergus / Wetmore, Cynthia / Pasca di Magliano, Marina / Fernandez-Zapico, Martin E. ·Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, Minnesota 55905, USA. ·J Biol Chem · Pubmed #23482563.

ABSTRACT: Although the biological role of KRAS is clearly established in carcinogenesis, the molecular mechanisms underlying this phenomenon are not completely understood. In this study, we provide evidence of a novel signaling network regulated by the transcription factor GLI1 mediating KRAS-induced carcinogenesis. Using pancreatic cancer (a disease with high prevalence of KRAS mutations) as a model, we show that loss of GLI1 blocks the progression of KRAS-induced pancreatic preneoplastic lesions in mice with pancreas-specific Cre-activated oncogenic mutant kras. Mice lacking GLI1 develop only low-grade lesions at low frequency, and in most cases, the pancreata are histologically normal. Further characterization of the phenotype showed a decrease in the activation of STAT3 in pancreatic preneoplastic lesions; STAT3 is a transcription factor required for the development of premalignant lesions and their progression into pancreatic cancer. Analysis of the mechanisms revealed a key role for GLI1 in maintaining the levels of activated STAT3 through the modulation of IL-6 signaling. GLI1 binds to the IL-6 mouse promoter and regulates the activity and expression of this cytokine. This newly identified GLI1/IL-6 axis is active in fibroblasts, a known source of IL-6 in the tumor microenvironment. Sonic hedgehog induces GLI1 binding to the IL-6 promoter and increases IL-6 expression in fibroblasts in a paracrine manner. Finally, we demonstrate that mutant KRAS initiates this cascade by inducing the expression of Sonic hedgehog in cancer cells. Collectively, these results define a novel role for GLI1 in carcinogenesis acting as a downstream effector of oncogenic KRAS in the tumor microenvironment.

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