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Sample records for ductal adenocarcinoma cells

  1. Stem cells as the root of pancreatic ductal adenocarcinoma

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    Balic, Anamaria; Dorado, Jorge; Alonso-Gomez, Mercedes; Heeschen, Christopher, E-mail: christopher.heeschen@cnio.es

    2012-04-01

    Emerging evidence suggests that stem cells play a crucial role not only in the generation and maintenance of different tissues, but also in the development and progression of malignancies. For the many solid cancers, it has now been shown that they harbor a distinct subpopulation of cancer cells that bear stem cell features and therefore, these cells are termed cancer stem cells (CSC) or tumor-propagating cells. CSC are exclusively tumorigenic and essential drivers for tumor progression and metastasis. Moreover, it has been shown that pancreatic ductal adenocarcinoma does not only contain one homogeneous population of CSC rather than diverse subpopulations that may have evolved during tumor progression. One of these populations is called migrating CSC and can be characterized by CXCR4 co-expression. Only these cells are capable of evading the primary tumor and traveling to distant sites such as the liver as the preferred site of metastatic spread. Clinically even more important, however, is the observation that CSC are highly resistant to chemo- and radiotherapy resulting in their relative enrichment during treatment and rapid relapse of disease. Many laboratories are now working on the further in-depth characterization of these cells, which may eventually allow for the identification of their Achilles heal and lead to novel treatment modalities for fighting this deadly disease.

  2. Cell-free plasma microRNA in pancreatic ductal adenocarcinoma and disease controls

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    Carlsen, Anting Liu; Joergensen, Maiken Thyregod; Knudsen, Steen;

    2013-01-01

    There are no tumor-specific biochemical markers for pancreatic ductal adenocarcinoma (PDAC). Tissue-specific gene expression including microRNA (miRNA) profiling, however, identifies specific PDAC signatures. This study evaluates associations between circulating, cell-free plasma-miRNA profiles...

  3. Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models

    NARCIS (Netherlands)

    Ricci, C.; Mota, C.M.; Moscato, S.; Alessandro, D' D.; Ugel, S.; Sartoris, S.; Bronte, V.; Boggi, U.; Campani, D.; Funel, N.; Moroni, L.; Danti, S.

    2014-01-01

    We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol

  4. Comparative Proteomic Profiling of Pancreatic Ductal Adenocarcinoma Cell Lines

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    Kim, Yikwon; Han, Dohyun; Min, Hophil; Jin, Jonghwa; Yi, Eugene C.; Kim, Youngsoo

    2014-01-01

    Pancreatic cancer is one of the most fatal cancers and is associated with limited diagnostic and therapeutic modalities. Currently, gemcitabine is the only effective drug and represents the preferred first-line treatment for chemotherapy. However, a high level of intrinsic or acquired resistance of pancreatic cancer to gemcitabine can contribute to the failure of gemcitabine treatment. To investigate the underlying molecular mechanisms for gemcitabine resistance in pancreatic cancer, we performed label-free quantification of protein expression in intrinsic gemcitabine-resistant and - sensitive human pancreatic adenocarcinoma cell lines using our improved proteomic strategy, combined with filter-aided sample preparation, single-shot liquid chromatography-mass spectrometry, enhanced spectral counting, and a statistical method based on a power law global error model. We identified 1931 proteins and quantified 787 differentially expressed proteins in the BxPC3, PANC-1, and HPDE cell lines. Bioinformatics analysis identified 15 epithelial to mesenchymal transition (EMT) markers and 13 EMT-related proteins that were closely associated with drug resistance were differentially expressed. Interestingly, 8 of these proteins were involved in glutathione and cysteine/methionine metabolism. These results suggest that proteins related to the EMT and glutathione metabolism play important roles in the development of intrinsic gemcitabine resistance by pancreatic cancer cell lines. PMID:25518923

  5. Expression of the "stem cell marker" CD133 in pancreas and pancreatic ductal adenocarcinomas

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    Sakariassen Per

    2008-02-01

    Full Text Available Abstract Background It has been suggested that a small population of cells with unique self-renewal properties and malignant potential exists in solid tumors. Such "cancer stem cells" have been isolated by flow cytometry, followed by xenograft studies of their tumor-initiating properties. A frequently used sorting marker in these experiments is the cell surface protein CD133 (prominin-1. The aim of this work was to examine the distribution of CD133 in pancreatic exocrine cancer. Methods Fifty-one cases of pancreatic ductal adenocarcinomas were clinically and histopathologically evaluated, and immunohistochemically investigated for expression of CD133, cytokeratin 19 and chromogranin A. The results were interpreted on the background of CD133 expression in normal pancreas and other normal and malignant human tissues. Results CD133 positivity could not be related to a specific embryonic layer of organ origin and was seen mainly at the apical/endoluminal surface of non-squamous, glandular epithelia and of malignant cells in ductal arrangement. Cytoplasmic CD133 staining was observed in some non-epithelial malignancies. In the pancreas, we found CD133 expressed on the apical membrane of ductal cells. In a small subset of ductal cells and in cells in centroacinar position, we also observed expression in the cytoplasm. Pancreatic ductal adenocarcinomas showed a varying degree of apical cell surface CD133 expression, and cytoplasmic staining in a few tumor cells was noted. There was no correlation between the level of CD133 expression and patient survival. Conclusion Neither in the pancreas nor in the other investigated organs can CD133 membrane expression alone be a criterion for "stemness". However, there was an interesting difference in subcellular localization with a minor cell population in normal and malignant pancreatic tissue showing cytoplasmic expression. Moreover, since CD133 was expressed in shed ductal cells of pancreatic tumors and was

  6. Generation of Rat Monoclonal Antibodies Against Human Pancreatic Ductal Adenocarcinoma Cells.

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    Higashi, Kiyoshi; Fujii, Nobuaki; Kushida, Masahiko; Yamada, Keita; Suzuki, Noriyuki; Saito, Koichi; Tachibana, Taro

    2016-06-01

    Pancreatic ductal adenocarcinoma is an aggressive tumor with a poor prognosis. Biomarkers that can detect the tumor in its early stages when it may be amenable to curative resection might improve prognosis. To discover novel markers expressed in primary pancreatic cancer, we generated a panel of monoclonal antibodies against pancreatic ductal adenocarcinoma cell line BxPC3 using a rat medial iliac lymph node method. The antigen recognized by 1B5A5 was expressed on the cell surface and secreted into the conditioned medium of BxPC3 cells, and characterized as glycoproteins with molecular mass between 60 and 90 kDa. A wide range of molecular weights of 1B5A5 antigen in several pancreatic cancer cell lines were observed. Immunohistochemistry using a human multiple organ tumor tissue array showed an enhanced expression of 1B5A5 antigen in pancreas, lung, stomach, breast, urinary bladder, colon, and cervix uteri cancers. Immunoprecipitation followed by proteomic analyses identified CEACAM6 as a 1B5A5 antigen. In addition, western blot analysis results indicated that the 1B5A5 epitope is located within an amino-terminal domain of CEACAM6. These results raised the possibility that our approach could lead to discovery of novel biomarkers for the early stage of cancers in a relatively short period of time.

  7. Trophoblast glycoprotein promotes pancreatic ductal adenocarcinoma cell metastasis through Wnt/planar cell polarity signaling.

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    He, Ping; Jiang, Shuheng; Ma, Mingze; Wang, Yang; Li, Rongkun; Fang, Fang; Tian, Guangang; Zhang, Zhigang

    2015-07-01

    Trophoblast glycoprotein (TPBG), a 72 kDa glycoprotein was identified using a monoclonal antibody, which specifically binds human trophoblast. The expression of TPBG in normal tissues is limited; however, it is upregulated in numerous types of cancer. When TPBG is expressed at a high level, this usually indicates a poor clinical outcome. In the present study, it was demonstrated that TPBG was more commonly observed in human pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissue. Immunohistochemical analysis of PDAC tissue microarrays indicated that the expression of TPBG in PDAC tissues was closely correlated with the tumor-node-metastasis stage of the tumor. Silencing of TPBG in PDAC cell lines resulted in a decreased ability of cancer cell migration and invasion. Further investigation demonstrated that the Wnt/planar cell polarity signaling pathway was suppressed, as the expression of Wnt5a and the activation of c-Jun N-terminal kinase was inhibited following TPBG knockdown. In conclusion, the present study provided evidence that TPBG is involved in PDAC metastasis, and that TPBG and its associated signaling pathways may be a suitable target for PDAC therapy.

  8. Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma.

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    Vizio, Barbara; Mauri, Francesco A; Prati, Adriana; Trivedi, Pritesh; Giacobino, Alice; Novarino, Anna; Satolli, Maria Antonietta; Ciuffreda, Libero; Camandona, Michele; Gasparri, Guido; Bellone, Graziella

    2012-01-01

    Chemoresistance and self-renewal of cancer stem cells (CSC), found in many tumors including pancreatic ductal adenocarcinoma (PDAC), are believed to underlie tumor mass regrowth. The distribution of cells carrying the putative stem-cell markers CD133, Nestin, Notch1-4, Jagged1 and 2, ABCG2 and aldehyde dehydrogenase (ALDH1) was assessed immunohistochemically using PDAC and normal pancreas tissue microarrays. The immunoreactivity was semi-quantitatively graded against the normal pancreas and was correlated with the differentiation grade and disease stage. No statistical significant differences were found between normal pancreas and PDAC in the expression of Nestin, Notch1, 3 and 4, ABCG2 or ALDH1. Notch2 and Jagged1 and 2 expression were increased in PDAC. CD133-positive cells were above-normal in PDAC, but the difference was not statistically significant. Nestin, Notch1-4, Jagged1, ABCG2 and ALDH1 immunostaining scores were not correlated with tumor grade or disease stage. CD133 and Notch2 expression was significantly inversely correlated with tumor grade, but not disease stage. Notch3 immunostaining positively correlated with tumor stage, but not with differentiation grade. Jagged2 protein expression correlated inversely with disease stage, but not with tumor grade. From the clinical standpoint, improved delineation of the tumor CSC signature, putatively responsible for tumor initiation and recurrence after initial response to chemotherapy, may offer novel therapeutic targets for this highly lethal cancer.

  9. Monocarboxylate transporters MCT1 and MCT4 regulate migration and invasion of pancreatic ductal adenocarcinoma cells

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    Kong, Su Chii; Nøhr-Nielsen, Asbjørn; Zeeberg, Katrine

    2016-01-01

    OBJECTIVES: Novel treatments for pancreatic ductal adenocarcinoma (PDAC) are severely needed. The aim of this work was to explore the roles of H-lactate monocarboxylate transporters 1 and 4 (MCT1 and MCT4) in PDAC cell migration and invasiveness. METHODS: Monocarboxylate transporter expression...... and MCT4 (messenger RNA, protein) were robustly expressed in all PDAC lines, localizing to the plasma membrane. Lactate influx capacity was highest in AsPC-1 cells and lowest in HPDE cells and was inhibited by the MCT inhibitor α-cyano-4-hydroxycinnamate (4-CIN), MCT1/MCT2 inhibitor AR-C155858......, or knockdown of MCT1 or MCT4. PDAC cell migration was largely unaffected by MCT1/MCT2 inhibition or MCT1 knockdown but was reduced by 4-CIN and by MCT4 knockdown (BxPC-3). Invasion measured in Boyden chamber (BxPC-3, Panc-1) and spheroid outgrowth (BxPC-3) assays was attenuated by 4-CIN and AR-C155858...

  10. Neurotensin is a Versatile Modulator of In Vitro Human Pancreatic Ductal Adenocarcinoma Cell (PDAC Migration

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    Tatjana Mijatovic

    2007-01-01

    Full Text Available Background: While the neurotensin (NT roles in pancreatic cancer growth are well documented, its effects on pancreatic cancer cell migration have not been described. Methods: The NT-induced effects on the migration process of human pancreatic ductal adenocarcinoma cells (PDACs were characterized by means of various assays including computer-assisted video-microscopy, fluorescence microscopy, ELISA-based, small GTPase pull-down and phosphorylation assays. Results: The NT-induced modifications on in vitro PDACs migration largely depended on the extra-cellular matrix environment and cell propensity to migrate collectively or individually. While NT significantly reduced the level of migration of collectively migrating PDACs on vitronectin, it significantly increased the level of individually migrating PDACs. These effects were mainly mediated through the sortilin/NTR3 receptor. Neurotensin both induced altered expression of αV and β5 integrin subunits in PDACs cultured on vitronectin resulting in modified adhesion abilities, and caused modifications to the organization of the actin cytoskeleton through the NT-mediated activation of small Rho GTPases. While the NT effects on individually migrating PDACs were mediated at least through the EGFR/ERK signaling pathways, those on collectively migrating PDACs appeared highly dependent on the PI 3-kinase pathway. Conclusion: This study strongly suggests the involvement of neurotensin in the modulation of human PDAC migration.

  11. ROCK signalling induced gene expression changes in mouse pancreatic ductal adenocarcinoma cells

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    Rath, Nicola; Kalna, Gabriela; Clark, William; Olson, Michael F.

    2016-01-01

    The RhoA and RhoC GTPases act via the ROCK1 and ROCK2 kinases to promote actomyosin contraction, resulting in directly induced changes in cytoskeleton structures and altered gene transcription via several possible indirect routes. Elevated activation of the Rho/ROCK pathway has been reported in several diseases and pathological conditions, including disorders of the central nervous system, cardiovascular dysfunctions and cancer. To determine how increased ROCK signalling affected gene expression in pancreatic ductal adenocarcinoma (PDAC) cells, we transduced mouse PDAC cell lines with retroviral constructs encoding fusion proteins that enable conditional activation of ROCK1 or ROCK2, and subsequently performed RNA sequencing (RNA-Seq) using the Illumina NextSeq 500 platform. We describe how gene expression datasets were generated and validated by comparing data obtained by RNA-Seq with RT-qPCR results. Activation of ROCK1 or ROCK2 signalling induced significant changes in gene expression that could be used to determine how actomyosin contractility influences gene transcription in pancreatic cancer. PMID:27824338

  12. Synchronous gastric adenocarcinoma and pancreatic ductal adenocarcinoma

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    Mirko Muroni; Francesco D'Angelo; Massimo Pezzatini; Simone Sebastiani; Samantha Noto; Emanuela Pilozzi; Giovanni Ramacciato

    2010-01-01

    BACKGROUND: The association between gastric and pancreatic carcinoma is a relatively rare condition. In gastric carcinoma patients, the prevalence of second tumors varies 2.8% to 6.8% according to the reported statistics. Gastric cancer associated with pancreatic cancer is uncommon. METHODS: We report a case of a 73-year-old patient hospitalized for vomiting and weight loss. Esophagogastro-duodenoscopy demonstrated an ulcerative lesion of the gastric antrum. Computed tomography and magnetic resonance showed a gastric thickening in the antral and pyloric portion and a nodular mass (3×1.7 cm) in the uncinate portion of the pancreas. RESULTS: The patient underwent pancreaticoduoden-ectomy according to Whipple regional typeⅠFortner. Histological examination of the specimen demonstrated a moderately differentiated adenocarcinoma of the stomach and a poorly differentiated ductal adenocarcinoma of the pancreas. CONCLUSIONS: Long survival is rare in patients with associated gastric and pancreatic cancer. Surgical resection remains the only potentially curative treatment.

  13. ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth.

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    Rath, Nicola; Morton, Jennifer P; Julian, Linda; Helbig, Lena; Kadir, Shereen; McGhee, Ewan J; Anderson, Kurt I; Kalna, Gabriela; Mullin, Margaret; Pinho, Andreia V; Rooman, Ilse; Samuel, Michael S; Olson, Michael F

    2017-02-01

    Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a Kras(G12D)/p53(R172H) mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three-dimensional collagen matrices by increasing matrix remodeling activities. RNA sequencing revealed a coordinated program of ROCK-induced genes that facilitate extracellular matrix remodeling, with greatest fold-changes for matrix metalloproteinases (MMPs) Mmp10 and Mmp13 MMP inhibition not only decreased collagen degradation and invasion, but also reduced proliferation in three-dimensional contexts. Treatment of Kras(G12D)/p53(R172H) PDAC mice with a ROCK inhibitor prolonged survival, which was associated with increased tumor-associated collagen. These findings reveal an ancillary role for increased ROCK signaling in pancreatic cancer progression to promote extracellular matrix remodeling that facilitates proliferation and invasive tumor growth.

  14. Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models.

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    Ricci, Claudio; Mota, Carlos; Moscato, Stefania; D'Alessandro, Delfo; Ugel, Stefano; Sartoris, Silvia; Bronte, Vincenzo; Boggi, Ugo; Campani, Daniela; Funel, Niccola; Moroni, Lorenzo; Danti, Serena

    2014-01-01

    We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs.

  15. Mounting Pressure in the Microenvironment: Fluids, Solids, and Cells in Pancreatic Ductal Adenocarcinoma.

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    DuFort, Christopher C; DelGiorno, Kathleen E; Hingorani, Sunil R

    2016-06-01

    The microenvironment influences the pathogenesis of solid tumors and plays an outsized role in some. Our understanding of the stromal response to cancers, particularly pancreatic ductal adenocarcinoma, has evolved from that of host defense to tumor offense. We know that most, although not all, of the factors and processes in the microenvironment support tumor epithelial cells. This reappraisal of the roles of stromal elements has also revealed potential vulnerabilities and therapeutic opportunities to exploit. The high concentration in the stroma of the glycosaminoglycan hyaluronan, together with the large gel-fluid phase and pressures it generates, were recently identified as primary sources of treatment resistance in pancreas cancer. Whereas the relatively minor role of free interstitial fluid in the fluid mechanics and perfusion of tumors has been long appreciated, the less mobile, gel-fluid phase has been largely ignored for historical and technical reasons. The inability of classic methods of fluid pressure measurement to capture the gel-fluid phase, together with a dependence on xenograft and allograft systems that inaccurately model tumor vascular biology, has led to an undue emphasis on the role of free fluid in impeding perfusion and drug delivery and an almost complete oversight of the predominant role of the gel-fluid phase. We propose that a hyaluronan-rich, relatively immobile gel-fluid phase induces vascular collapse and hypoperfusion as a primary mechanism of treatment resistance in pancreas cancers. Similar properties may be operant in other solid tumors as well, so revisiting and characterizing fluid mechanics with modern techniques in other autochthonous cancers may be warranted.

  16. Connexin-43 channels are a pathway for discharging lactate from glycolytic pancreatic ductal adenocarcinoma cells.

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    Dovmark, T H; Saccomano, M; Hulikova, A; Alves, F; Swietach, P

    2017-08-10

    Glycolytic cancer cells produce large quantities of lactate that must be removed to sustain metabolism in the absence of oxidative phosphorylation. The only venting mechanism described to do this at an adequate rate is H(+)-coupled lactate efflux on monocarboxylate transporters (MCTs). Outward MCT activity is, however, thermodynamically inhibited by extracellular acidity, a hallmark of solid tumours. This inhibition would feedback unfavourably on metabolism and growth, raising the possibility that other venting mechanisms become important in under-perfused tumours. We investigated connexin-assembled gap junctions as an alternative route for discharging lactate from pancreatic ductal adenocarcinoma (PDAC) cells. Diffusive coupling (calcein transmission) in vitro was strong between Colo357 cells, weaker yet hypoxia-inducible between BxPC3 cells, and very low between MiaPaCa2 cells. Coupling correlated with levels of connexin-43 (Cx43), a protein previously linked to late-stage disease. Evoked lactate dynamics, imaged in Colo357 spheroids using cytoplasmic pH as a read-out, indicated that lactate anions permeate gap junctions faster than highly-buffered H(+) ions. At steady-state, junctional transmission of lactate (a chemical base) from the spheroid core had an alkalinizing effect on the rim, producing therein a milieu conducive for growth. Metabolite assays demonstrated that Cx43 knockdown increased cytoplasmic lactate retention in Colo357 spheroids (diameter ~150 μm). MiaPaCa2 cells, which are Cx43 negative in monolayer culture, showed markedly increased Cx43 immunoreactivity at areas of invasion in orthotopic xenograft mouse models. These tissue areas were associated with chronic extracellular acidosis (as indicated by the marker LAMP2 near/at the plasmalemma), which can explain the advantage of junctional transmission over MCT in vivo. We propose that Cx43 channels are important conduits for dissipating lactate anions from glycolytic PDAC cells. Furthermore

  17. Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis.

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    Morvaridi, Susan; Dhall, Deepti; Greene, Mark I; Pandol, Stephen J; Wang, Qiang

    2015-11-16

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis.

  18. A comparison study of pancreatic acinar cell carcinoma with ductal adenocarcinoma using computed tomography in Chinese patients

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    Wang Q

    2016-09-01

    Full Text Available Qingbing Wang,1,2 Xiaolin Wang,1,2 Rongfang Guo,2,3 Guoping Li1,2 1Department of Interventional Radiology, Zhongshan Hospital, Fudan University, 2Shanghai Institute of Medical Imaging, 3Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China Abstract: Pancreatic acinar cell carcinoma (ACC is a rare tumor that is difficult to diagnose preoperatively. The aim of this study was to evaluate and describe the computed tomography (CT features of ACC and compare the results with pancreatic ductal adenocarcinoma (DAC for improving preoperative diagnosis. The control group consisted of 34 patients with DAC collected from the pathology electronic database. The CT imaging from nine patients with pathologically confirmed ACC was retrospectively reviewed. Two radiologists independently assessed the tumor location, size, texture, and enhancement patterns. We found that 64.3% (9/14 of ACC tumors were homogeneous and 35.7% (5/14 had necrosis. The percentage of common bile duct and pancreatic ductal dilation was 14.3% (2/14 and 7.1% (1/14, respectively. The mean size of ACC was 50.1±24.2 mm. The mean attenuation of ACC was 35.4±3.9 Hounsfield unit (HU before enhancement, 73.1±42.9 HU in arterial phase, and 71.8±15.6 HU in port venous phase. It is difficult to distinguish ACC from DAC preoperatively only based on CT findings. However, compared with DAC, we found that ACC tumors are likely to be larger and contain more heterogeneous intratumoral necrotic hypovascular regions, and less pancreatic ductal and common biliary dilation. Keywords: acinar cell carcinoma, computed tomography, pancreatic ductal carcinoma, pancreas

  19. The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells

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    Giannuzzo, Andrea; Pedersen, Stine Helene Falsig; Novak, Ivana

    2015-01-01

    BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development...... and therapies are needed. PDAC is characterized by a complex microenvironment, in which cancer and stromal cells release different molecules, such as ATP. ATP can be transported and/or exocytosed from active cancer cells and released from dying cells in the necrotic core of the cancer. We hypothesized that one...... of the ATP receptors, the P2X7 receptor (P2X7R) could be an important player in PDAC behaviour. METHODS: We determined the expression (real time PCR and Western blot) and localization (immunofluorescence) of P2X7R in human PDAC cell lines (AsPC-1, BxPC-3, Capan-1, MiaPaCa-2, Panc-1) and a "normal" human...

  20. The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells

    DEFF Research Database (Denmark)

    Giannuzzo, Andrea; Pedersen, Stine Helene Falsig; Novak, Ivana

    2015-01-01

    BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development...... of the ATP receptors, the P2X7 receptor (P2X7R) could be an important player in PDAC behaviour. METHODS: We determined the expression (real time PCR and Western blot) and localization (immunofluorescence) of P2X7R in human PDAC cell lines (AsPC-1, BxPC-3, Capan-1, MiaPaCa-2, Panc-1) and a "normal" human...... pancreatic duct epithelial cell line (HPDE). The function of P2X7R in proliferation (BrdU assay), migration (wound assay) and invasion (Boyden chamber with matrigel) was characterized. Furthermore, we studied P2X7R-dependent pore formation (YoPro-1 assay) and cell death (caspase and annexin V / propidium...

  1. Pancreatic ductal adenocarcinoma screening: New perspectives

    Institute of Scientific and Technical Information of China (English)

    Raffaele Pezzilli; Dario Fabbri; Andrea Imbrogno

    2012-01-01

    Pancreatic ductal adenocarcinoma accounts for more than 90% of all pancreatic cancers and its incidence has increased significantly worldwide.Patients with pancreatic ductal adenocarcinoma have a poor outcome and more than 95% of the people affected die from the disease within 12 mo after diagnosis.Surgery is the first-line treatment in the case of resectable neoplasm,but only 20% of patients are candidates for this approach.One of the reasons there are few candidates for surgery is that,during the early phases of the disease,the symptoms are poor or non-specific.Early diagnosis is of crucial importance to improve patient outcome; therefore,we are looking for a good screening test.The screening test must identify the disease in an early stage in order to be effective; having said this,a need exists to introduce the concept of "early" ductal adenocarcinoma.It has been reported that at least five additional years after the occurrence of the initiating mutation are required for the acquisition of metastatic ability of pancreatic adenocarcinoma and patients die an average of two years thereafter.We have reviewed the most recent literature in order to evaluate the present and future perspectives of screening programs of this deadly disease.

  2. SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

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    Wuebben, Erin L.; Wilder, Phillip J.; Cox, Jesse L.; Grunkemeyer, James A.; Caffrey, Thomas; Hollingsworth, Michael A.; Rizzino, Angie

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 – a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC. PMID:27145457

  3. Genetics and biology of pancreatic ductal adenocarcinoma

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    Ying, Haoqiang; Dey, Prasenjit; Yao, Wantong; Kimmelman, Alec C.; Draetta, Giulio F.; Maitra, Anirban; DePinho, Ronald A.

    2016-01-01

    With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. PMID:26883357

  4. MiR-221 Promotes Capan-2 Pancreatic Ductal Adenocarcinoma Cells Proliferation by Targeting PTEN-Akt

    Directory of Open Access Journals (Sweden)

    Wenzhuo Yang

    2016-05-01

    Full Text Available Background/Aims: MicroRNAs (miRNAs, miRs have emerged as critical regulators of cancer cell proliferation. The effect of miR-221 on cancer cell growth could be significantly changeable in different cell lines. Although miR-221 was reported to promote the cell growth of pancreatic ductal adenocarcinoma (PDAC cells, its role in Capan-2 cell line is largely unknown. Methods: Capan-2 cells were transfected with miR-221 mimics, inhibitors, or negative controls. Cell Counting Kit-8 was used to determine cell viability. EdU staining and cell cycle analysis were used to measure cell proliferation. Western blotting was used to detect the expression levels of PTEN and phospho-Akt. The PI3K-Akt pathway activator SC-79 and inhibitor LY294002 were used to perform the rescue experiment in determining cell proliferation. Results: Overexpressing miR-221 significantly increased cell vitality and promoted cell proliferation and G1-to-S phase transition of the cell cycle in Capan-2 cells, while inhibition of miR-221 decreased that. The protein level of PTEN in Capan-2 cells was downregulated by overexpressing miR-221, while upregulated by inhibiting miR-221. Consistently, enhanced phosphorylation of AktSer473 was observed in miR-221 overexpressed Capan-2 cells, and the opposite result was found in miR-221 inhibited cells. LY294002 restored the pro-proliferation effect of miR-221 on Capan-2 cells, while SC-79 had no additional effect on cell proliferation in Capan-2 cells transfected with miR-221 mimics. Conclusion: Our study indicates that miR-221 is an oncogenic miRNA which promotes Capan-2 cells proliferation by targeting PTEN-Akt pathway.

  5. "Ductal adenocarcinoma in anular pancreas".

    Science.gov (United States)

    Benassai, Giacomo; Perrotta, Stefano; Furino, Ermenegildo; De Werra, Carlo; Aloia, Sergio; Del Giudice, Roberto; Amato, Bruno; Vigliotti, Gabriele; Limite, Gennaro; Quarto, Gennaro

    2015-09-01

    The annular pancreas is a congenital anomaly in which pancreatic tissue partially or completely surrounds the second portion of the duodenum. Its often located above of papilla of Vater (85%), rarely below (15%). This pancreatic tissue is often easily dissociable to the duodenum but there is same cases where it the tissue is into the muscolaris wall of the duodenum. We describe three case of annular pancreas hospitalized in our facility between January 2004 and January 2009. There were 2 male 65 and 69 years old respectively and 1 female of 60 years old, presented complaining of repeated episodes of mild epigastric pain. Laboratory tests (including tumor markers), a direct abdomen X-ray with enema, EGDS and total body CT scan were performed to study to better define the diagnosis. EUS showed the presence of tissue infiltrating the muscle layer all around the first part of duodenum. Biopsies performed found the presence of pancreatic tissue with focal areas of adenocarcinoma. Subtotal gastrectomy with Roux was performed. The histological examinations shows an annular pancreas of D1 with multiple focal area of adenocarcinoma. (T1aN0M0). We performed a follow up at 5 years. One patients died after 36 months for cardiovascular hit. Two patients, one male and one female, was 5-years disease-free. Annular pancreas is an uncommon congenital anomaly which usually presents itself in infants and newborn. Rarely it can present in late adult life with wide range of clinical severities thereby making its diagnosis difficult. Pre-operative diagnosis is often difficult. CT scan can illustrate the pancreatic tissue encircling the duodenum. ERCP and MRCP are useful in outlining the annular pancreatic duct. Surgery still remains necessary to confirm diagnosis and bypassing the obstructed segment. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

  6. SIRT 1 Overexpression is Associated with Metastasis of Pancreatic Ductal Adenocarcinoma (PDAC) and Promotes Migration and Growth of PDAC Cells.

    Science.gov (United States)

    Li, Siqin; Hong, Hua; Lv, Huicheng; Wu, Guozhu; Wang, Zhigang

    2016-05-12

    BACKGROUND SIRT 1, as a class III histone deacetylase (HDAC), is implicated in the initiation and progression of malignancies. However, the association of SIRT 1 with tumorigenesis or progression of pancreatic ductal adenocarcinoma (PDAC) is not clear. MATERIAL AND METHODS In our study we investigated SIRT 1 expression in PDAC samples and evaluated the association of SIRT 1 level with the clinical and pathological characteristics of PDAC patients. We investigated the role of SIRT 1 in the migration and growth of PDAC PANC-1 or BxPC-3 cells using gain-of-function and loss-of-function approach. RESULTS We demonstrated that SIRT 1 mRNA level was significantly promoted in intra-tumor tissues compared to peri-tumor tissues of PDAC; and SIRT 1 overexpression was markedly associated with distant or lymph node (LN) metastasis of these PDAC tissues. Moreover, the in vitro wound healing assay demonstrated that SIRT 1 overexpression with lentivirus vector markedly promoted the migration of PANC-1 or BxPC-3 cells, whereas SIRT 1 knockdown using SIRT 1 specific siRNA transfection significantly inhibited the migration of PDAC cells. The colony forming assay confirmed SIRT 1 promotion of the growth of PANC-1 or BxPC-3 cells. CONCLUSIONS In summary, SIRT 1 overexpression is significantly associated with metastasis of PDAC, and overexpressed SIRT 1 plays an important role in pancreatic cancer cell migration and growth. Our data warrants further studies on SIRT 1 as a novel chemotherapeutic target in PDAC.

  7. Verteporfin suppresses cell survival, angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP-TEAD complex.

    Science.gov (United States)

    Wei, Honglong; Wang, Fuhai; Wang, Yong; Li, Tao; Xiu, Peng; Zhong, Jingtao; Sun, Xueying; Li, Jie

    2017-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. The Yes-associated protein-1 (YAP) plays a critical role in cell proliferation, apoptosis and angiogenesis. Verteporfin is a photosensitizer used in photodynamic therapy and also a small molecular inhibitor of the Hippo-YAP pathway. However, little is known about whether verteporfin could inhibit YAP activity in PDAC cells. Our present results showed that verteporfin suppressed the proliferation of human PDAC PANC-1 and SW1990 cells by arresting cells at the G1 phase, and inducing apoptosis in dose- and time-dependent manners. Verteporfin also inhibited the tumor growth on the PDAC xenograft model. Treatment with verteporfin led to downregulation of cyclinD1 and cyclinE1, modulation of Bcl-2 family proteins and activation of PARP. In addition, verteporfin exhibited an inhibitory effect on angiogenesis and vasculogenic mimicry via suppressing Ang2, MMP2, VE-cadherin, and α-SMA expression in vitro and in vivo. Mechanism studies demonstrated that verteporfin impaired YAP and TEAD interaction to suppress the expression of targeted genes. Our results provide a foundation for repurposing verteporfin as a promising anti-tumor drug in the treatment of pancreatic cancer by targeting the Hippo pathway. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  8. Myoepithelial cells from pleomorphic adenoma are not influenced by tumor conditioned media from breast ductal adenocarcinoma and melanoma cells: An in vitro study.

    Science.gov (United States)

    Martinez, Elizabeth Ferreira; Demasi, Ana Paula Dias; Napimoga, Marcelo Henrique; Silva, Carolina Amália Barcellos; Navarini, Natalia Festugatto; Araújo, Ney Soares; DE Araújo, Vera Cavalcanti

    2015-01-01

    Myoepithelial cells have been implicated in the regulation of the transition from in situ to invasive neoplasia in salivary gland tumors. Considering the importance of the microenvironment of the tumor, the present in vitro study therefore analyzed the morphological and phenotypic changes undergone by benign myoepithelial cells from pleomorphic adenoma (PA) stimulated by tumor-conditioned medium. The benign myoepithelial cells were obtained from PA and were cultured with fibronectin extracellular matrix protein, supplemented with tumor-conditioned medium, which was harvested from breast ductal adenocarcinoma AU-565 and melanoma Hs 852.T cells. The morphological alterations were assessed by immunofluorescence analysis using vimentin antibody. The α-smooth muscle actin (α-SMA) and fibroblast growth factor (FGF)-2 proteins were analyzed by indirect immunofluorescence and quantitative polymerase chain reaction (qPCR). No morphological changes were observed in the myoepithelial cells cultured in fibronectin protein under stimulation from either tumor-conditioned medium. The immunofluorescence results, which were supported by qPCR analysis, revealed that only α-SMA was upregulated in the fibronectin substratum, with or without tumor-conditioned medium obtained from breast ductal adenocarcinoma and melanoma cells. No significant difference in FGF-2 mRNA expression was detected when the cells were cultured either in the tumor-conditioned medium or in the fibronectin substratum. The tumor-conditioned medium harvested from breast ductal adenocarcinoma and melanoma did not affect myoepithelial cell differentiation and function, which was reflected by the fact that there was no observed increase in α-SMA and FGF-2 expression, respectively.

  9. Successful Salvage Chemotherapy with FOLFIRINOX for Recurrent Mixed Acinar Cell Carcinoma and Ductal Adenocarcinoma of the Pancreas in an Adolescent Patient

    Directory of Open Access Journals (Sweden)

    Sarah Pfrommer

    2013-09-01

    Full Text Available Pancreatic tumors are rare in children and adolescents. Here, we report the case of a 15-year-old boy who presented with a mixed acinar cell carcinoma/ductal adenocarcinoma with blastomatous components. He received multimodal treatment including various chemotherapy regimens and multistep surgery including liver transplantation. Introduction of FOLFIRINOX after relapse repeatedly achieved a durable metabolic and clinical response with good quality of life.

  10. Successful Salvage Chemotherapy with FOLFIRINOX for Recurrent Mixed Acinar Cell Carcinoma and Ductal Adenocarcinoma of the Pancreas in an Adolescent Patient.

    Science.gov (United States)

    Pfrommer, Sarah; Weber, Achim; Dutkowski, Philipp; Schäfer, Niklaus G; Müllhaupt, Beat; Bourquin, Jean-Pierre; Breitenstein, Stefan; Pestalozzi, Bernhard C; Stenner, Frank; Renner, Christoph; D'Addario, Giannicola; Graf, Hans-Jörg; Knuth, Alexander; Clavien, Pierre-Alain; Samaras, Panagiotis

    2013-01-01

    Pancreatic tumors are rare in children and adolescents. Here, we report the case of a 15-year-old boy who presented with a mixed acinar cell carcinoma/ductal adenocarcinoma with blastomatous components. He received multimodal treatment including various chemotherapy regimens and multistep surgery including liver transplantation. Introduction of FOLFIRINOX after relapse repeatedly achieved a durable metabolic and clinical response with good quality of life.

  11. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3(+)Treg cells in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Wang, X; Lang, M; Zhao, T; Feng, X; Zheng, C; Huang, C; Hao, J; Dong, J; Luo, L; Li, X; Lan, C; Yu, W; Yu, M; Yang, S; Ren, H

    2016-12-19

    Forkheadbox protein 3 (FOXP3), initially identified as a key transcription factor for regulatory T cells (Treg cells), was also expressed in many tumors including pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC progression remains elusive. In this study, we utilized 120 PDAC tissues after radical resection to detect cancer-FOXP3 and Treg cells by immunohistochemistry and evaluated clinical and pathological features of these patients. Cancer-FOXP3 was positively correlated with Treg cells accumulation in tumor tissues derived from PDAC patients. In addition, high cancer-FOXP3 expression was associated with increased tumor volumes and poor prognosis in PDAC especially combined with high levels of Treg cells. Overexpression of cancer-FOXP3 promoted the tumor growth in immunocompetent syngeneic mice but not in immunocompromised or Treg cell-depleted mice. Furthermore, CCL5 was directly trans-activated by cancer-FOXP3 and promoted the recruitment of Treg cells from peripheral blood to the tumor site in vitro and in vivo. This finding has been further reinforced by the evidence that Treg cells recruitment by cancer-FOXP3 was impaired by neutralization of CCL5, thereby inhibiting the growth of PDAC. In conclusion, cancer-FOXP3 serves as a prognostic biomarker and a crucial determinant of immunosuppressive microenvironment via recruiting Treg cells by directly trans-activating CCL5. Therefore, cancer-FOXP3 could be used to select patients with better response to CCL5/CCR5 blockade immunotherapy.Oncogene advance online publication, 19 December 2016; doi:10.1038/onc.2016.458.

  12. Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715.

    Science.gov (United States)

    Slee, Roger B; Grimes, Brenda R; Bansal, Ruchi; Gore, Jesse; Blackburn, Corinne; Brown, Lyndsey; Gasaway, Rachel; Jeong, Jaesik; Victorino, Jose; March, Keith L; Colombo, Riccardo; Herbert, Brittney-Shea; Korc, Murray

    2014-02-01

    Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy.

  13. THE SUBTYPES OF PANCREATIC DUCTAL ADENOCARCINOMAS

    Directory of Open Access Journals (Sweden)

    Apeksha Kakkar

    2016-12-01

    Full Text Available Being the 4th leading cause of cancer deaths in the U.S. and with a global increase in incidence, above 80% of pancreatic cancers are locally advanced or metastatic at the time of diagnosis. As surgical resection is the only hope for a cure, the answer is probably in early screening, proper classification and right therapy. The advancing research will likely lead to a better understanding of Pancreatic Ductal Adenocarcinoma (PDAC as well as enhance the techniques for screening, diagnosis, accurate subtyping and enable the use of targeted therapy. Thus, instead of clubbing together various subtypes of PDAC for trials, improving the subcategorization will ensure statistical significance for the academicians, and the clinicians would avoid administration of placebo drug to a vast number of patients.

  14. Targeting Pancreatic Ductal Adenocarcinoma Acidic Microenvironment

    Science.gov (United States)

    Cruz-Monserrate, Zobeida; Roland, Christina L.; Deng, Defeng; Arumugam, Thiruvengadam; Moshnikova, Anna; Andreev, Oleg A.; Reshetnyak, Yana K.; Logsdon, Craig D.

    2014-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, accounting for ~40,000 deaths annually. The dismal prognosis for PDAC is largely due to its late diagnosis. Currently, the most sensitive diagnosis of PDAC requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that is highly operator dependent. Here we took advantage of a general characteristic of solid tumors, the acidic microenvironment that is generated as a by-product of metabolism, to develop a novel approach of using pH (Low) Insertion Peptides (pHLIPs) for imaging of PDAC. We show that fluorescently labeled pHLIPs can localize and specifically detect PDAC in human xenografts as well as PDAC and PanIN lesions in genetically engineered mouse models. This novel approach may improve detection, differential diagnosis and staging of PDAC.

  15. Pancreatic ductal adenocarcinoma associated with pancreatic ductal intraepithelial neoplasia:repor t of a case

    Institute of Scientific and Technical Information of China (English)

    Rajkumar Krishnasamy; Shaleen Agarwal; Shivendra Singh; Sunil Puri; Puja Sakhuja; Anil K Agarwal

    2007-01-01

    BACKGROUND:The presence of pancreatic ductal intraepithelial neoplasia in patients with chronic pancreatitis is a risk factor for development of pancreatic adenocarcinoma. METHOD: A case of pancreatic ductal adenocarcinoma associated with pancreatic ductal intraepithelial neoplasia was diagnosed in the setting of chronic pancreatitis. RESULTS:Distal pancreatectomy combined with splenec-tomy was performed with a diagnosis of pancreatic body carcinoma. Histopathological examination suggested adenocarcinoma associated with pancreatic ductal intraepithelial neoplasia. The tumor was detected in the remaining head of the pancreas, for which a total pancreatectomy was done. CONCLUSIONS: When a patient with pancreatic ductal intraepithelial neoplasia associated with adenocarcinoma of the pancreas in the setting of chronic pancreatitis is at an increased risk of recurrence in the remaining pancreatic parenchyma, total pancreatectomy may be feasible.

  16. ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC)

    DEFF Research Database (Denmark)

    Sauter, Daniel Rafael Peter; Novak, Ivana; Pedersen, Stine Helene Falsig;

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival rates of all cancers. ANO1 (TMEM16A) is a recently identified Ca2+-activated Cl- channel (CaCC) that is upregulated in several tumors. Although ANO1 was subject to extensive studies in the recent years, its pathophysiological f...... intracellular calcium concentration. Functional studies on PDAC behavior showed that surprisingly inhibition of ANO1 did not influence cellular proliferation. On the other hand, we found ANO1 channel to be pivotal in PDAC cell migration as assessed in wound healing experiments....

  17. Primary clear cell ductal adenocarcinoma of the pancreas: A case report and clinicopathologic literature review

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    Yashpal Modi

    2014-01-01

    Full Text Available We present a very rare, interesting case of a carcinoma of the pancreas with predominantly abundant clear cell morphology. According to the WHO classification, primary clear cell carcinoma of the pancreas is classified as a rare "miscellaneous" carcinoma. The tumor was observed in the distal body and tail of the pancreas of a 74-year-old woman. The histopathology of tumor cells showed well-defined cell membranes, clear cytoplasm, and prominent cell boundaries. Immunohistochemical (IHC staining showed positive reactions to antibodies against vimentin, cytokeratin 7 (CK-7, mucicarmine (MUC-1, periodic acid-Schiff (PAS, periodic acid-Schiff with diastase (PASD, carcinoembryonic antigen (CEA, and Carbohydrate Antigen 19-9 (CA 19-9. On the other hand, IHC staining was negative for alpha-fetoprotein (AFP, cytokeratin 20 (CK-20, HMB45, chromogranin, and synaptophysin. The patient was subsequently diagnosed with a primary solid-type pancreatic clear cell carcinoma with hepatic metastasis. Herein, we report this rare case and include a review of the current literature of this tumor.

  18. MicroRNAs in pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Jong Y Park; James Helm; Domenico Coppola; Donghwa Kim; Mokenge Malafa; Seung Joon Kim

    2011-01-01

    Ductal adenocarcinoma of the pancreas is a lethal cancer for which the only chance of long-term survival belongs to the patient with localized disease in whom a potentially curative resection can be done.Therefore,biomarkers for early detection and new therapeutic strategies are urgently needed.miRNAs are a recently discovered class of small endogenous non-coding RNAs of about 22 nucleotides that have gained attention for their role in downregulation of mRNA expression at the posttranscriptional level.miRNAs regulate proteins involved in critical cellular processes such as differentiation,proliferation,and apoptosis.Evidence suggests that deregulated miRNA expression is involved in carcinogenesis at many sites,including the pancreas.Aberrant expression of miRNAs may upregulate the expression of oncogenes or downregulate the expression of tumor suppressor genes,as well as play a role in other mechanisms of carcinogenesis.The purpose of this review is to summarize our knowledge of deregulated miRNA expression in pancreatic cancer and discuss the implication for potential translation of this knowledge into clinical practice.

  19. RABL6A Promotes Oxaliplatin Resistance in Tumor Cells and Is a New Marker of Survival for Resected Pancreatic Ductal Adenocarcinoma Patients.

    Science.gov (United States)

    Muniz, Viviane P; Askeland, Ryan W; Zhang, Xuefeng; Reed, Sara M; Tompkins, Van S; Hagen, Jussara; McDowell, Bradley D; Button, Anna; Smith, Brian J; Weydert, Jamie A; Mezhir, James J; Quelle, Dawn E

    2013-07-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by early recurrence following pancreatectomy, rapid progression, and chemoresistance. Novel prognostic and predictive biomarkers are urgently needed to both stratify patients for clinical trials and select patients for adjuvant therapy regimens. This study sought to determine the biological significance of RABL6A (RAB, member RAS oncogene family-like protein 6 isoform A), a novel pancreatic protein, in PDAC. Analyses of RABL6A protein expression in PDAC specimens from 73 patients who underwent pancreatic resection showed that RABL6A levels are altered in 74% of tumors relative to adjacent benign ductal epithelium. Undetectable RABL6A expression, found in 7% (5/73) of patients, correlated with improved overall survival (range 41 to 118 months with 3/5 patients still living), while patients with RABL6A expression had a worse outcome (range 3.3 to 100 months, median survival 20.3 months) (P = 0.0134). In agreement with those findings, RABL6A expression was increased in pancreatic cancer cell lines compared to normal pancreatic epithelial cells, and its knockdown inhibited pancreatic cancer cell proliferation and induced apoptosis. Moreover, RABL6A depletion selectively sensitized cells to oxaliplatin-induced arrest and death. This work reveals that RABL6A promotes the proliferation, survival, and oxaliplatin resistance of PDAC cells, whereas its loss is associated with extended survival in patients with resected PDAC. Such data suggest RABL6A is a novel biomarker of PDAC and potential target for anticancer therapy.

  20. ANO1 (TMEM16A) in pancreatic ductal adenocarcinoma (PDAC)

    DEFF Research Database (Denmark)

    Sauter, Daniel Rafael Peter; Novak, Ivana; Pedersen, Stine Helene Falsig

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival rates of all cancers. ANO1 (TMEM16A) is a recently identified Ca2+-activated Cl- channel (CaCC) that is upregulated in several tumors. Although ANO1 was subject to extensive studies in the recent years, its pathophysiological...... function has only been poorly understood. The aim of the present study is to establish the significance of ANO1 in PDAC behavior and demarcate its roles in PDAC from those of the volume-regulated anion channel (VRAC). We performed qPCR and Western blot measurements on different PDAC cell lines (Panc-1, Mia...... PaCa 2, Capan-1, AsPC-1, BxPC-3) and compared the results to those obtained in a human pancreatic ductal epithelium (HPDE) cell line. All cancer cell lines showed an upregulation of ANO1 on mRNA and protein levels. Whole-cell patch-clamp recordings identified large Ca2+ and voltage-dependent Cl...

  1. CI- and K+ Channels in Pancreatic Ductal Adenocarcinoma (PDAC)

    DEFF Research Database (Denmark)

    Sauter, Daniel Rafael Peter

    Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival rates of all cancers with >95% of the affected dying from it. Despite of intensive efforts to develop new therapeutic strategies, only few drugs (e.g. gemcitabine, erlotinib) are currently approved for treatment, all exhibit only...... moderate survival benefits. Therefore, novel targets are urgently needed. Cl- and K+ channels play integral roles in the regulation of critical cellular processes such as proliferation, apoptosis and migration. These processes are commonly perturbed in tumor cells. A phenotypic hallmark of cancer is its...... altered pH and Ca2+ homeostasis; a fact that is of particular relevance to tumor biology as many ion channels are regulated by these stimuli. Thus, the aim of this thesis was to elucidate the role of Ca2+-activated and pH – regulated channels in PDAC progression. Patch-clamp recordings from several...

  2. Ductal adenocarcinoma of the prostate: immunohistochemical findings and clinical significance

    Directory of Open Access Journals (Sweden)

    Sha JJ

    2013-10-01

    Full Text Available Jianjun Sha,1,2 Juanjie Bo,1 Jiahua Pan,1 Lianhua Zhang,1 Hanqing Xuan,1 Wei Chen,1 Dong Li,1 Zhaoliang Wang,1 Dongming Liu,1 Yiran Huang1,2 1Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 2School of Biomedical Engineering, Shanghai Jiaotong University, Shanghai, People's Republic of China Introduction: To investigate the clinical features, diagnosis, treatment, and prognosis of ductal adenocarcinoma of the prostate. Methods: The clinicopathological and immunohistochemical data of seven patients with ductal adenocarcinoma of the prostate were retrospectively analyzed. All patients underwent physical examination, magnetic resonance imaging (MRI, bone scan, cystoscopy, and computed tomography (CT scan. The level of prostate-specific antigen (PSA before and after surgery was assessed. Different prostate cancer markers were used for immunohistochemical staining. Results: The mean age of the seven patients diagnosed with prostatic ductal adenocarcinoma in this study was 76.2 years (range 57–88. Five patients presented with intermittent and painless gross hematuria, one patient with progressive dysuria, and one patient with elevated serum PSA on routine health examination. The level of PSA before surgery ranged from 1.3 to 45.0 ng/mL. Immunohistochemical staining results of the prostatic ductal adenocarcinoma confirmed positivity for PSA, prostatic acid phosphatase, androgen receptor, and alpha-methyacyl co-enzyme A (CoA-reductase markers. Two of the patients underwent bilateral orchiectomy combined with anti-androgen therapy, three underwent transurethral resection of prostate, one received radical prostatectomy, and one received medical castration therapy. The clinical outcomes of all patients were satisfactory, based on follow-up data. The symptoms of hematuria and dysuria were ameliorated well, and the postoperative PSA level decreased below 4.0 ng/mL. Recurrence or metastasis of disease was

  3. miRNA-181b increases the sensitivity of pancreatic ductal adenocarcinoma cells to gemcitabine in vitro and in nude mice by targeting BCL-2.

    Science.gov (United States)

    Cai, Baobao; An, Yong; Lv, Nan; Chen, Jianmin; Tu, Min; Sun, Jie; Wu, Pengfei; Wei, Jishu; Jiang, Kuirong; Miao, Yi

    2013-05-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease and is usually resistant to chemotherapy. MicroRNA‑181b (miR-181b) has been reported to be associated with chemoresistance in various types of cancer. In this study, we investigated the effects of miR-181b on the chemosensitivity of PDAC cells to gemcitabine and the underlying molecular events. miR-181b mimics and inhibitors were synthesized for transient gene transfection in vitro. Lentivirus carrying miR-181b mimics were used to infect PDAC cells for nude mouse xenograft assays by implanting infected PDAC cells into recipient mice. Cell viability was determined by MTT assays, while gene expression was assessed using qRT-PCR, western blot analysis and enzyme-linked immunosorbent assay (ELISA). miR-181b targeting BCL-2 expression was assessed by a dual-luciferase activity assay. The data showed that miRNA-181b expression sensitized PDAC cells to gemcitabine treatment. Although gemcitabine-resistant PDAC cell sublines (SW1990/GR and CFPAC-1/GR) expressed higher levels of miRNA-181b, gemcitabine induced higher levels of apoptosis in PDAC cells transfected with miRNA-181b mimics. The nude mouse xenograft assay data showed that miR-181b transfection also sensitized the cells to gemcitabine treatment in vivo. Molecularly, bioinformatics data predicted that miR-181b was able to bind to BCL-2 mRNA 3'UTR. The dual luciferase activity assay revealed that miRNA-181b downregulated BCL-2 expression. The results from western blot analysis showed a reduced BCL-2 expression following miR-181b transfection but an enhanced caspase-3 activity in miRNA-181b mimic-transfected PDAC cells. This study demonstrates that miRNA-181b sensitizes PDAC cells to gemcitabine by targeting BCL-2.

  4. Epithelial-to-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma and Pancreatic Tumor Cell Lines: The Role of Neutrophils and Neutrophil-Derived Elastase

    Directory of Open Access Journals (Sweden)

    Thomas Große-Steffen

    2012-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN and the tumor cell transition, biopsies of patients with PDAC (n=115 were analysed with regard to PMN infiltration and nuclear expression of β-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation of β-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated, β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMT in vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and—by implication—to tumor progression is possible.

  5. Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    O'Connor, Kate; Li-Chang, Hector H; Kalloger, Steven E; Peixoto, Renata D; Webber, Douglas L; Owen, David A; Driman, David K; Kirsch, Richard; Serra, Stefano; Scudamore, Charles H; Renouf, Daniel J; Schaeffer, David F

    2015-04-01

    Tumor budding is a well-established adverse prognostic factor in colorectal cancer. However, the significance and diagnostic reproducibility of budding in pancreatic carcinoma requires further study. We aimed to assess the prognostic significance of tumor budding in pancreatic ductal adenocarcinoma, determine its relationship with other clinicopathologic features, and assess interobserver variability in its diagnosis. Tumor budding was assessed in 192 archival cases of pancreatic ductal adenocarcinoma using hematoxylin and eosin (H&E) sections; tumor buds were defined as single cells or nonglandular clusters composed of <5 cells. The presence of budding was determined through assessment of all tumor-containing slides, and associations with clinicopathologic features and outcomes were analyzed. Six gastrointestinal pathologists participated in an interobserver variability study of 120 images of consecutive tumor slides stained with H&E and cytokeratin. Budding was present in 168 of 192 cases and was associated with decreased overall survival (P=0.001). On multivariable analysis, tumor budding was prognostically significantly independent of stage, grade, tumor size, nodal status, lymphovascular invasion, and perineural invasion. There was substantial agreement among pathologists in assessing the presence of tumor budding using both H&E (K=0.63) and cytokeratin (K=0.63) stains. The presence of tumor budding is an independent adverse prognostic factor in pancreatic ductal carcinoma. The assessment of budding with H&E is reliable and could be used to better risk stratify patients with pancreatic ductal adenocarcinoma.

  6. Circulating IL-35 in pancreatic ductal adenocarcinoma patients.

    Science.gov (United States)

    Jin, Peng; Ren, He; Sun, Wei; Xin, Wen; Zhang, Huan; Hao, Jihui

    2014-01-01

    IL-35 is a novel inhibitory cytokine that is mainly produced by regulatory T-cells (Tregs) and is required for Treg-mediated immunosuppression. However, the plasma levels of IL-35 in patients with pancreatic ductal adenocarcinoma (PDAC) have never been investigated. In this study, we found that plasma IL-35 levels more significantly increased in PDAC patients than in normal controls (134.53 ± 92.45 pg/mL vs. 14.26 ± 6.56 pg/mL). IL-35 mRNA levels were positively correlated with plasma IL-35 levels (EBI3, R = 0.925, pIL-35 expression levels were associated with lymph node metastasis (p = 0.001) and late tumor stage (p = 0.002). For the resected patients, high IL-35 expression levels were associated with large tumor size (pIL-35 in PDAC patients significantly increased, suggesting that regulating the expression of IL-35 may provide a new possible target for the treatment of PDAC patients, especially for the resectable ones.

  7. Perioperative cancer cell dissemination detected with a real-time RT-PCR assay for EpCAM is not associated with worse prognosis in pancreatic ductal adenocarcinoma

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    Houtmeyers François

    2011-01-01

    Full Text Available Abstract Background Epithelial cell adhesion molecule (EpCAM has been used as surrogate marker for the quantification of circulating tumour cells (CTC. Our aim was to prospectively study the value of a real-time RT-PCR assay for EpCAM detection in the peripheral blood and peritoneal cavity of patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma (PDAC. Methods From 48 patients with PDAC (40 resectable, 8 unresectable and 10 patients with chronic pancreatitis undergoing pancreatectomy 10 ml of venous blood was drawn preoperatively (PB and postoperatively (POB, day 1 (D1B, day 7 (D7B and after 6 weeks (6WB. Of all patients undergoing pancreatectomy, 40 ml peritoneal lavage fluid was taken preoperatively and postoperatively. A real-time RT-PCR assay (TaqMan, ABI Prism 7700 was developed for the detection of EpCAM mRNA. To discriminate between EpCAM-positive and negative samples a cut-off was applied. Median postoperative follow-up was 24.0 months (range: 0.7 - 41.3. Results PB was EpCAM-positive (+ in 25% of patients versus 65% of patients in POB (p At none of the time-points, an association was found between EpCAM positivity in blood and/or peritoneal cavity and cancer-specific or disease-free survival. Also, no significant associations were found between clinicopathological variables and perioperative EpCAM positivity. Conclusions Despite a significant increase in EpCAM counts in postoperative blood and peritoneal lavage fluid this was not associated with worse prognosis after pancreatectomy for PDAC. Trial registration Clinicaltrials.gov NCT00495924

  8. Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Riazy, Maziar; Kalloger, Steve E; Sheffield, Brandon S; Peixoto, Renata D; Li-Chang, Hector H; Scudamore, Charles H; Renouf, Daniel J; Schaeffer, David F

    2015-10-01

    Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable disease-specific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables (P≤0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repair-deficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts (P=0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repair-deficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective

  9. A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics

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    Ozhan Ocal

    2015-10-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDA is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48Cre;LSL-KrasG12D;Cdkn2af/f mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR signaling activates Kras. Regulators of G-protein signaling (RGS proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC transgenic mice with KIC mice and show that the Rgs16::GFP transgene is a KrasG12D-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drug screens, we find that weanling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane plus inhibitors of Axl signaling

  10. Bisphosphonates Inhibit Stellate Cell Activity and Enhance Antitumor Effects of Nanoparticle Albumin Bound-Paclitaxel in Pancreatic Ductal Adenocarcinoma

    Science.gov (United States)

    Gonzalez-Villasana, Vianey; Rodriguez-Aguayo, Cristian; Arumugam, Thiruvengadam; Cruz-Monserrate, Zobeida; Fuentes-Mattei, Enrique; Deng, Defeng; Hwang, Rosa F.; Wang, Huamin; Ivan, Cristina; Garza, Raul Joshua; Cohen, Evan; Gao, Hui; Armaiz-Pena, Guillermo N.; Monroig-Bosque, Paloma del C.; Philip, Bincy; Rashed, Mohammed H.; Aslan, Burcu; Erdogan, Mumin Alper; Gutierrez-Puente, Yolanda; Ozpolat, Bulent; Reuben, James M.; Sood, Anil K.; Logsdon, Craig; Lopez-Berestein, Gabriel

    2014-01-01

    Pancreatic stellate cells (PSCs) have been recognized as the principal cells responsible for the production of fibrosis in PDAC. Recently PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBPs) [pamidronate (Pam) or zoledronic acid (ZA)], which are potent MML cell inhibitors. In addition, we tested NBPs treatment combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to enhance antitumor activity. In vitro we observed that PSCs possess α-naphthyl butyrate esterase (ANBE) enzyme activity, a specific marker of MML cells. Moreover NBPs inhibited PSCs proliferation, activation, release of macrophage chemoattractant protein-1 (MCP-1) and type I collagen expression. NBPs also induced PSC apoptosis and cell cycle arrest in the G1 phase. In vivo, NBPs inactivated PSCs; reduced fibrosis; inhibited tumor volume, tumor weight, peritoneal dissemination, angiogenesis, and cell proliferation; and increased apoptosis in an orthotopic murine model of PDAC. These in vivo antitumor effects were enhanced when NBPs were combined with nab-paclitaxel but not gemcitabine (Gem). Our study suggests that targeting PSCs and tumor cells with NBPs in combination with nab-paclitaxel may be a novel therapeutic approach to PDAC. PMID:25193509

  11. Relevant infrastructural alterations in invasive pancreatic ductal adenocarcinoma.

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    Constantin, Vlad Denis; Mirancea, Gabriel Valeriu; Moroşanu, Ana Maria; Mirancea, Nicolae

    2015-01-01

    In this study, we focus our interest on some peculiar infrastructural abnormalities detected in a pancreatic cancer case. Our electron microscopic observations underline the high plasticity of the pancreatic parenchyma cells. Tumor pancreatic exocrine lesions are represented by putative ductal and acinar cells, which proliferate and grow in a haphazard pattern, detrimental to endocrine counterpart. The tumor cells do not exhibit neither a pure ductular or ductal nor a pure acinar phenotype, but tumor lesions represented by neoplastic ductal cells with invasive growth are by far prevalently. In our pancreatic cancer case, electron microscopic investigation clearly shows that a plethora of the epithelial cells from the tumor lesions contain large areas of autophagy leading to the pleomorphic inclusions represented by fibrillary÷filamentous inclusions frequently associated with hyaline-amorphous material, and secondary lysosomes. One of the mostly striking and important finding in this report for a case of pancreatic cancer is the high fragility (extensive dissolutions) of plasma membrane of tumor cells leading to pseudo-syncytia formation. Desmosomal junctions are severely altered, almost missing. Plasma membranes showed shedding membrane vesicles. Extravasated inflammatory cells contribute to the dramatic and extensive destructive areas of epithelial cells as well as tumor-stroma counterpart, including the basement membrane. All above severe infrastructural abnormalities, especially down regulation of cell-cell and cell-extracellular matrix adhesions might result in aberrant cell behavior and, consequently, much care should be taken for the postoperatory patient evolution.

  12. Lipocalin2 promotes invasion, tumorigenicity and gemcitabine resistance in pancreatic ductal adenocarcinoma.

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    Lisa Leung

    Full Text Available Lipocalin 2 (LCN2 is a small secreted protein and its elevated expression has been observed in pancreatic as well as other cancer types. LCN2 has been reported to promote resistance to drug-induced apoptosis, enhance invasion through its physical association with matrix metalloproteinase-9, and promote in vivo tumor growth. LCN2 was found to be commonly expressed in patient PDAC samples and its pattern of immunohistochemical staining intensified with increasing severity in high-grade precursor lesions. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II with high LCN2 expression significantly reduced attachment, invasion, and tumour growth in vivo, but not proliferation or motility. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II with high expression significantly reduced attachment, invasion, and tumour growth in vivo. In contrast, LCN2 overexpression in PANC1, with low endogenous expression, significantly increased invasion, attachment, and enhanced tumor growth. Suppression of LCN2 in BxPC3 and HPAF-II cells increased their sensitivity to gemcitabine in vitro, and in vivo when BxPC3 was tested. Furthermore, LCN2 promotes expression of VEGF and HIF1A which contribute to enhanced vascularity. These overall results demonstrate that LCN2 plays an important role in the malignant progression of pancreatic ductal carcinoma and is a potential therapeutic target for this disease.

  13. Lipocalin2 promotes invasion, tumorigenicity and gemcitabine resistance in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Leung, Lisa; Radulovich, Nikolina; Zhu, Chang-Qi; Organ, Shawna; Bandarchi, Bizhan; Pintilie, Melania; To, Christine; Panchal, Devang; Tsao, Ming Sound

    2012-01-01

    Lipocalin 2 (LCN2) is a small secreted protein and its elevated expression has been observed in pancreatic as well as other cancer types. LCN2 has been reported to promote resistance to drug-induced apoptosis, enhance invasion through its physical association with matrix metalloproteinase-9, and promote in vivo tumor growth. LCN2 was found to be commonly expressed in patient PDAC samples and its pattern of immunohistochemical staining intensified with increasing severity in high-grade precursor lesions. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II) with high LCN2 expression significantly reduced attachment, invasion, and tumour growth in vivo, but not proliferation or motility. Downregulation of LCN2 in two pancreatic ductal adenocarcinoma cell lines (BxPC3 and HPAF-II) with high expression significantly reduced attachment, invasion, and tumour growth in vivo. In contrast, LCN2 overexpression in PANC1, with low endogenous expression, significantly increased invasion, attachment, and enhanced tumor growth. Suppression of LCN2 in BxPC3 and HPAF-II cells increased their sensitivity to gemcitabine in vitro, and in vivo when BxPC3 was tested. Furthermore, LCN2 promotes expression of VEGF and HIF1A which contribute to enhanced vascularity. These overall results demonstrate that LCN2 plays an important role in the malignant progression of pancreatic ductal carcinoma and is a potential therapeutic target for this disease.

  14. Nuclear Position and Shape Deformation of Chromosome 8 Territories in Pancreatic Ductal Adenocarcinoma

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    Sylvia Timme

    2011-01-01

    Full Text Available Cell type specific radial positioning of chromosome territories (CTs and their sub-domains in the interphase seem to have functional relevance in non-neoplastic human nuclei, while much less is known about nuclear architecture in carcinoma cells and its development during tumor progression. We analyzed the 3D-architecture of the chromosome 8 territory (CT8 in carcinoma and corresponding non-neoplastic ductal pancreatic epithelium. Fluorescence-in-situ-hybridization (FISH with whole chromosome painting (WCP probes on sections from formalin-fixed, paraffin wax-embedded tissues from six patients with ductal adenocarcinoma of the pancreas was used. Radial positions and shape parameters of CT8 were analyzed by 3D-microscopy. None of the parameters showed significant inter-individual changes. CT8 was localized in the nuclear periphery in carcinoma cells and normal ductal epithelial cells. Normalized volume and surface of CT8 did not differ significantly. In contrast, the normalized roundness was significantly lower in carcinoma cells, implying an elongation of neoplastic cell nuclei. Unexpectedly, radial positioning of CT8, a dominant parameter of nuclear architecture, did not change significantly when comparing neoplastic with non-neoplastic cells. A significant deformation of CT8, however, accompanies nuclear atypia of carcinoma cells. This decreased roundness of CTs may reflect the genomic and transcriptional alterations in carcinoma.

  15. MicroRNA Expression Analyses in Preoperative Pancreatic Juice Samples of Pancreatic Ductal Adenocarcinoma

    OpenAIRE

    Yoshihiko Sadakari; Takao Ohtsuka; Kenoki Ohuchida; Kosuke Tsutsumi; Shunichi Takahata; Masafumi Nakamura; Kazuhiro Mizumoto; Masao Tanaka

    2010-01-01

    Context Cytological assessment of pancreatic juice is commonly used to diagnose pancreatic ductal adenocarcinoma; however, the sensitivity of cytological assessment has been reported to be low. MicroRNAs are small RNAs regulating various cellular processes and have recently been identified as possible markers of malignant diseases including pancreatic ductal adenocarcinoma. Objective The purposes of this study were to prove the existence of microRNAs in pancreatic juice and to determine w...

  16. Utilization of CDX2 expression in diagnosing pancreatic ductal adenocarcinoma and predicting prognosis.

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    Wenbin Xiao

    Full Text Available CDX2, a master transcriptional regulator of intestinal cell differentiation and survival, has been used as a marker to indicate colorectal lineage in adenocarcinomas of unknown origin. Pancreatic ductal adenocarcinoma (PDAC is one of the most common causes for adenocarcinomas of unknown origin, but CDX2 expression in pancreatic disease remains unclear. In this study, we systemically and extensively investigated the expression and role of CDX2 in PDAC. We reported that CDX2 expression is weak and heterogeneous is all normal pancreas and chronic pancreatitis. It is largely expressed in epithelial-lining cells of pancreatic ducts including main ducts, inter-lobular ducts, intra-lobular ducts, intercalated ducts and centroacinar cells, but not in acinar cells or islet cells. CDX2 expression is down regulated during the transformation process from PanIN to PDAC. Only one third of PDACs retain some degree of CDX2 expression, and this group of PDACs have reduced median survival time compared to that of CDX2 negative group (308 days vs. 586 days, p = 0.0065. Metastatic PDACs remain similar expression pattern to that of the primary sites. Our study clearly demonstrates CDX2 expression in pancreatic diseases including PDAC, which is practically important when CDX2 is used to establish the primary sites of adenocarcinomas of unknown origin. In addition, our study also provides CDX2 as a prognostic marker for PDAC and implicates an important role of CDX2 in the development of normal pancreas and PDAC.

  17. MicroRNA in pancreatic ductal adenocarcinoma and itsprecursor lesions

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the 4thdeadliest cancer in the United States, due to its aggressivenature, late detection, and resistance tochemotherapy. The majority of PDAC develops from3 precursor lesions, pancreatic intraepithelial lesions(PanIN), intraductual papillary mucinous neoplasm(IPMN), and mucinous cystic neoplasm. Early detectionand surgical resection can increase PDAC 5-year survivalrate from 6% for Stage Ⅳ to 50% for Stage Ⅰ. To date,there are no reliable biomarkers that can detect PDAC.MicroRNAs (miRNA) are small noncoding RNAs (18-25nucleotides) that regulate gene expression by affectingtranslation of messenger RNA (mRNA). A large bodyof evidence suggests that miRNAs are dysregulated invarious types of cancers. MiRNA has been profiled as apotential biomarker in pancreatic tumor tissue, blood,cyst fluid, stool, and saliva. Four miRNA biomarkers(miR-21, miR-155, miR-196, and miR-210) have beenconsistently dysregulated in PDAC. MiR-21, miR-155, andmiR-196 have also been dysregulated in IPMN and PanINlesions suggesting their use as early biomarkers of thisdisease. In this review, we explore current knowledge ofmiRNA sampling, miRNA dysregulation in PDAC and itsprecursor lesions, and advances that have been made inusing miRNA as a biomarker for PDAC and its precursorlesions.

  18. MicroRNA Expression Analyses in Preoperative Pancreatic Juice Samples of Pancreatic Ductal Adenocarcinoma

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    Yoshihiko Sadakari

    2010-11-01

    Full Text Available Context Cytological assessment of pancreatic juice is commonly used to diagnose pancreatic ductal adenocarcinoma; however, the sensitivity of cytological assessment has been reported to be low. MicroRNAs are small RNAs regulating various cellular processes and have recently been identified as possible markers of malignant diseases including pancreatic ductal adenocarcinoma. Objective The purposes of this study were to prove the existence of microRNAs in pancreatic juice and to determine whether specific microRNAs in pancreatic juice could be used for detecting pancreatic ductal adenocarcinoma. Methods Relative expression levels of microRNA-21 and microRNA-155 in formalin-fixed paraffin-embedded tissues of resected specimens (no. 13 and pancreatic juice samples collected using preoperative endoscopic retrograde cholangiopancreatography (no. 21 were quantified and their expression levels were then compared to pancreatic ductal adenocarcinoma and chronic pancreatitis. Results Relative expression levels of microRNA-21 in tissue and pancreatic juice samples were significantly higher in pancreatic ductal adenocarcinoma than those in chronic pancreatitis (P=0.009 and P=0.021, respectively. The same results were obtained in the expression levels of microRNA-155 in tissue and pancreatic juice between pancreatic ductal adenocarcinoma and chronic pancreatitis (P=0.014 and P=0.021, respectively. Expression levels of microRNA-21 and microRNA-155 did not correlate with the preoperative cytological results of pancreatic juice. Conclusion MicroRNA-21 and microRNA-155 in pancreatic juice have the potential of becoming biomarkers for diagnosing pancreatic ductal adenocarcinoma.

  19. Prostatic intraepithelial neoplasia-like ductal prostatic adenocarcinoma: A case suitable for active surveillance?

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    Soroush Rais-Bahrami

    2017-01-01

    Full Text Available In contrast to typical prostatic ductal adenocarcinoma, prostatic intraepithelial neoplasia (PIN-like ductal adenocarcinoma is a rare variant of prostate cancer with low-grade clinical behavior. We report a case of a 66-year-old African-American male with an elevated serum prostate-specific antigen who underwent multiparametric prostate magnetic resonance imaging (MRI and MRI/ultrasound fusion-guided biopsies. Pathology demonstrated low-volume Gleason score 3 + 3 = 6 (Grade Group 1, acinar adenocarcinoma involving one core and PIN-like ductal adenocarcinoma on a separate core. Herein, we discuss the potential role of active surveillance for patients with this rare variant of prostate cancer found in the era of advanced imaging with multiparametric MRI for prostate cancer.

  20. Novel Drug Targets Based on Association between Inflammation and Pancreatic Ductal Adenocarcinoma

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    Muhammad Wasif Saif

    2010-07-01

    Full Text Available Dear Sir We read with great interest the editorial published by Uomo et al. in the 2010 May issue of JOP. J Pancreas (Online titled: “Inflammation and Pancreatic Ductal Adenocarcinoma: A Potential Scenario for Novel Drug Targets” [1]. There is a growing amount of evidence that inflammation plays a contributory role in the pathogenesis of cancer, including pancreatic carcinogenesis. Inflammatory states are characterized by the formation of reactive oxygen species and the induction of cell cycling for tissue growth and repair [1, 2, 3]. The initiation, promotion and expansion of tumors may be influenced by numerous components that also function in the inflammatory response. Recognized risk factors for pancreatic cancer include cigarette smoking, chronic/hereditary pancreatitis, obesity and type II diabetes. Each risk factor is linked by the fact that the inflammatory state significantly drives its pathology. We agree with the authors that multiple links between inflammation and pancreatic adenocarcinoma has led to development of novel targeted therapy which is under evaluation both in vivo and in vitro studies to fight against pancreatic adenocarcinoma. Pancreatic cancer is one of the leading causes of cancer mortality in the United States. Current therapy for pancreatic cancer involves surgery, chemotherapy, and radiation therapy; however, the 5-year survival rate remains less than 5%. Therefore, developments of novel agents, in particular based on the pathogenesis of pancreatic adenocarcinoma are urgently indicated.

  1. Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis.

    Science.gov (United States)

    Besmer, Dahlia M; Curry, Jennifer M; Roy, Lopamudra D; Tinder, Teresa L; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y; Gendler, Sandra J; Mukherjee, Pinku

    2011-07-01

    MUC1 is overexpressed and aberrantly glycosylated in more than 60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In this study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared with both KC and KCM. Cell lines derived from KCKO tumors have significantly less tumorigenic capacity compared with cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared with mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor, platelet-derived growth factor, or matrix metalloproteinase 9. Further, significantly less KCKO cells entered the G(2)-M phase of the cell cycle compared with the KCM cells. Proteomics and Western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of mitogen-activated protein kinase (MAPK), as well as a significant decrease in nestin and tubulin-α2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro.

  2. Overexpression of PD2 leads to increased tumorigenicity and metastasis in pancreatic ductal adenocarcinoma

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    Vaz, Arokia Priyanka; Deb, Shonali; Rachagani, Satyanarayana; Dey, Parama; Muniyan, Sakthivel; Lakshmanan, Imayavaramban; Karmakar, Saswati; Smith, Lynette; Johansson, Sonny; Lele, Subodh; Ouellette, Michel; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2016-01-01

    Pancreatic differentiation 2 (PD2), an important subunit of the human PAF complex, was identified after differential screening analysis of 19q13 amplicon, and its overexpression induces oncogenic transformation of NIH3T3 cells, hence raising the possibility of a role for PD2 in tumorigenesis and metastasis. To test this hypothesis, we analyzed here the functional role and clinical significance of PD2 in pancreatic ductal adenocarcinoma (PDAC) and its pathogenesis. Using immunohistochemical analysis, we found that PD2 is detected in the acini but not in the ducts in the normal pancreas. In human PDAC specimens, PD2 was instead primarily detected in the ducts (12/48 patients 25%; p-value < 0.0001), thereby showing that PDAC correlates with increased ductal expression of PD2. Consistently, PD2 expression was increased in telomerase-immortalized human pancreatic ductal cells (HPNE cells) modified to express the HPV16 E6 and E7 proteins, whose respective functions are to block p53 and RB. In addition, ectopic expression of PD2 in PDAC cells (Capan-1 and SW1990) led to increased clonogenicity and migration in vitro, and tumor growth and metastasis in vivo. Interestingly, PD2 overexpression also resulted in enrichment of cancer stem cells (CSCs) and upregulation of oncogenes such as c-Myc and cell cycle progression marker, cyclin D1. Taken together, our results support that PD2 is overexpressed in the ducts of PDAC tissues, and results in tumorigenesis and metastasis via upregulation of oncogenes such as c-Myc and cyclin hence D1 implicating PD2 upregulation in pancreatic oncogenesis with targeted therapeutic potential. PMID:26689992

  3. BAG3 promotes pancreatic ductal adenocarcinoma growth by activating stromal macrophages

    Science.gov (United States)

    Rosati, Alessandra; Basile, Anna; D'Auria, Raffaella; d'Avenia, Morena; De Marco, Margot; Falco, Antonia; Festa, Michelina; Guerriero, Luana; Iorio, Vittoria; Parente, Roberto; Pascale, Maria; Marzullo, Liberato; Franco, Renato; Arra, Claudio; Barbieri, Antonio; Rea, Domenica; Menichini, Giulio; Hahne, Michael; Bijlsma, Maarten; Barcaroli, Daniela; Sala, Gianluca; di Mola, Fabio Francesco; di Sebastiano, Pierluigi; Todoric, Jelena; Antonucci, Laura; Corvest, Vincent; Jawhari, Anass; Firpo, Matthew A; Tuveson, David A; Capunzo, Mario; Karin, Michael; De Laurenzi, Vincenzo; Turco, Maria Caterina

    2015-01-01

    The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential. PMID:26522614

  4. Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine.

    Science.gov (United States)

    Knudsen, Erik S; O'Reilly, Eileen M; Brody, Jonathan R; Witkiewicz, Agnieszka K

    2016-01-01

    Patients with pancreatic ductal adenocarcinoma (PDA) have a poor prognosis despite new treatments; approximately 7% survive for 5 years. Although there have been advances in systemic, primarily cytotoxic, therapies, it has been a challenge to treat patients with PDA using targeted therapies. Sequence analyses have provided a wealth of information about the genetic features of PDA and have identified potential therapeutic targets. Preclinical and early-phase clinical studies have found specific pathways could be rationally targeted; it might also be possible to take advantage of the genetic diversity of PDAs to develop therapeutic agents. The genetic diversity and instability of PDA cells have long been thought of as obstacles to treatment, but are now considered exploitable features. We review the latest findings in pancreatic cancer genetics and the promise of targeted approaches in PDA therapy.

  5. [Ductal adenocarcinoma of the prostate: case report and review of the literature].

    Science.gov (United States)

    Moufid, Kamal; Joual, Abdenbi; Bennani, Saad; El Mrini, Mohamed; El Attar, Hicham

    2004-06-01

    Ductal adenocarcinoma is a histological variant of prostate cancer. The authors report the case of a 53-year-old man, in whom the tumour was revealed by acute urinary retention and haematuria. In the light of this case and a review of the recent literature, the authors discuss the histological, clinical and therapeutic aspects of this rare entity.

  6. Outcomes of Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma in the Netherlands: A Nationwide Retrospective Analysis

    NARCIS (Netherlands)

    Rooij, T. de; Tol, J.A.; Eijck, C.H. van; Boerma, D.; Bonsing, B.A.; Bosscha, K.; Dam, R.M. van; Dijkgraaf, M.G.; Gerhards, M.F.; Goor, H. van; Harst, E. van der; Hingh, I.H. de; Kazemier, G.; Klaase, J.M.; Molenaar, I.Q.; Patijn, G.A.; Santvoort, H.C. van; Scheepers, J.J.; Schelling, G.P. van der; Sieders, E.; Busch, O.R.; Besselink, M.G.

    2016-01-01

    BACKGROUND: Large multicenter series on outcomes and predictors of survival after distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC) are scarce. METHODS: Adults who underwent DP for PDAC in 17 Dutch pancreatic centers between January 2005 and September 2013 were analyzed retrospe

  7. Ductal adenocarcinoma of the prostate: increased mortality risk and decreased PSA secretion

    Science.gov (United States)

    Morgan, Todd M; Welty, Christopher J; Vakar-Lopez, Funda; Lin, Daniel W; Wright, Jonathan L

    2011-01-01

    Introduction and Objectives The clinical significance of ductal prostatic carcinoma has not been well defined. We utilized a population-based cancer registry to identify a large group of ductal carcinoma cases to characterize the impact of the ductal subtype on the presentation and survival of men with prostate cancer. Methods A national cancer registry was used to identify incident cases of ductal and acinar adenocarcinomas from 1996–2006. Clinicopathologic variables were analyzed and Cox multivariate survival analysis performed. PSA values were available for the years 2004–2006, and these were used to assess for differences in Gleason grade and serum PSA levels between ductal and acinar cancers at the time of diagnosis. Results A total of 442,881 acinar cases and 371 ductal cases were identified. Ductal cases were more likely to present with distant disease (12% vs. 4%, p<0.001) and to be poorly differentiated (50% vs. 32%; p<0.001). Ductal histology was associated with a 30% lowering of the geometric mean PSA (adjusted coeff.=0.7, 95% CI 0.6–0.8) and a more than two-fold increased odds of having a PSA<4.0 ng/ml (OR 2.4, 95% CI 1.4–4.0) independent of other clinicopathologic variables. For those with non-distant disease at diagnosis, ductal histology was associated with a 2.4-fold (CI 1.5–3.8) increased disease-specific mortality. Conclusions In the largest series of this histologic subtype, ductal cancers were more likely to present with advanced stage cancer and a lower PSA, suggesting that timely detection of the disease is a significant challenge. In addition, those with loco regional disease were more likely to die of their disease. PMID:20952027

  8. MUC16 contributes to the metastasis of pancreatic ductal adenocarcinoma through focal adhesion mediated signaling mechanism

    Science.gov (United States)

    Chugh, Seema; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Gupta, Suprit; Seshacharyulu, Parthasarathy; Smith, Lynette M.; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2016-01-01

    MUC16, a heavily glycosylated type-I transmembrane mucin is overexpressed in several cancers including pancreatic ductal adenocarcinoma (PDAC). Previously, we have shown that MUC16 is significantly overexpressed in human PDAC tissues. However, the functional consequences and its role in PDAC is poorly understood. Here, we show that MUC16 knockdown decreases PDAC cell proliferation, colony formation and migration in vitro. Also, MUC16 knockdown decreases the tumor formation and metastasis in orthotopic xenograft mouse model. Mechanistically, immunoprecipitation and immunofluorescence analyses confirms MUC16 interaction with galectin-3 and mesothelin in PDAC cells. Adhesion assay displayed decreased cell attachment of MUC16 knockdown cells with recombinant galectin-1 and galectin-3 protein. Further, CRISPR/Cas9-mediated MUC16 knockout cells show decreased tumor-associated carbohydrate antigens (T and Tn) in PDAC cells. Importantly, carbohydrate antigens were decreased in the region that corresponds to MUC16 and suggests for the decreased MUC16-galectin interactions. Co-immunoprecipitation also revealed a novel interaction between MUC16 and FAK in PDAC cells. Interestingly, we observed decreased expression of mesenchymal and increased expression of epithelial markers in MUC16-silenced cells. Additionally, MUC16 loss showed a decreased FAK-mediated Akt and ERK/MAPK activation. Altogether, these findings suggest that MUC16-focal adhesion signaling may play a critical role in facilitating PDAC growth and metastasis. PMID:27382435

  9. Differential roles of cyclin D1 and D3 in pancreatic ductal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Leung Lisa

    2010-02-01

    Full Text Available Abstract Background The cyclin D1 (CCND1 and cyclin D3 (CCND3 are frequently co-overexpressed in pancreatic ductal adenocarcinoma (PDAC. Here we examine their differential roles in PDAC. Results CCND1 and CCND3 expression were selectively suppressed by shRNA in PDAC cell lines with expression levels of equal CCND1 and CCND3 (BxPC3, enhanced CCND1 (HPAC or enhanced CCND3 (PANC1. Suppression of cell proliferation was greater with CCND3 than CCND1 downregulation. CCND3 suppression led to a reduced level of phosphorylated retinoblastoma protein (Ser795p-Rb/p110 and resulted in decreased levels of cyclin A mRNA and protein. A global gene expression analysis identified deregulated genes in D1- or D3-cyclin siRNA-treated PANC1 cells. The downregulated gene targets in CCND3 suppressed cells were significantly enriched in cell cycle associated processes (p Conclusions Our results suggest that CCND3 is the primary driver of the cell cycle, in cooperation with CCND1 that integrates extracellular mitogenic signaling. We also present evidence that CCND1 plays a role in tumor cell migration. The results provide novel insights for common and differential targets of CCND1 and CCND3 overexpression during pancreatic duct cell carcinogenesis.

  10. Disclosure of Erlotinib as a Multikinase Inhibitor in Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Laura Conradt

    2011-11-01

    Full Text Available A placebo-controlled phase 3 trial demonstrated that the epidermal growth factor receptor (EGFR inhibitor erlotinib in combination with gemcitabine was especially efficient in a pancreatic ductal adenocarcinoma (PDAC subgroup of patients developing skin toxicity. However, EGFR expression was not predictive for response, and markers to characterize an erlotinib-responding PDAC group are currently missing. In this work, we observed high erlotinib IC50 values in a panel of human and murine PDAC cell lines. Using EGFR small interfering RNA, we detected that the erlotinib response was marginally influenced by EGFR. To find novel EGFR targets, we used an unbiased chemical proteomics approach for target identification and quality-controlled target affinity determination combined with quantitative mass spectrometry based on stable isotope labeling by amino acids in cell culture. In contrast to gefitinib, we observed a broad target profile of erlotinib in PDAC cells by quantitative proteomics. Six protein kinases bind to erlotinib with similar or higher affinity (Kd = 0.09-0.358 μM than the EGFR (Kd 0.434 μM. We provide evidence that one of the novel erlotinib targets, ARG, contributes in part to the erlotinib response in a PDAC cell line. Our data show that erlotinib is a multikinase inhibitor, which can act independent of EGFR in PDAC. These findings may help to monitor future erlotinib trials in the clinic.

  11. A Cholecystokinin B Receptor-Specific DNA Aptamer for Targeting Pancreatic Ductal Adenocarcinoma

    Science.gov (United States)

    Abraham, Thomas; Pan, Weihua; Tang, Xiaomeng; Linton, Samuel S.; McGovern, Christopher O.; Loc, Welley S.; Smith, Jill P.; Butler, Peter J.; Kester, Mark; Adair, James H.; Matters, Gail L.

    2017-01-01

    Pancreatic ductal adenocarcinomas (PDACs) constitutively express the G-protein-coupled cholecystokinin B receptor (CCKBR). In this study, we identified DNA aptamers (APs) that bind to the CCKBR and describe their characterization and targeting efficacy. Using dual SELEX selection against “exposed” CCKBR peptides and CCKBR-expressing PDAC cells, a pool of DNA APs was identified. Further downselection was based on predicted structures and properties, and we selected eight APs for initial characterizations. The APs bound specifically to the CCKBR, and we showed not only that they did not stimulate proliferation of PDAC cell lines but rather inhibited their proliferation. We chose one AP, termed AP1153, for further binding and localization studies. We found that AP1153 did not activate CCKBR signaling pathways, and three-dimensional Confocal microscopy showed that AP1153 was internalized by PDAC cells in a receptor-mediated manner. AP1153 showed a binding affinity of 15 pM. Bioconjugation of AP1153 to the surface of fluorescent NPs greatly facilitated delivery of NPs to PDAC tumors in vivo. The selectivity of this AP-targeted NP delivery system holds promise for enhanced early detection of PDAC lesions as well as improved chemotherapeutic treatments for PDAC patients. PMID:27754762

  12. CCR7 regulates Twist to induce the epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Li, Kexin; Xu, Baofeng; Xu, Guangying; Liu, Rui

    2016-01-01

    As reported, the CC chemokine receptor 7 (CCR7) trigger a series of signaling cascades in the epithelial-mesenchymal transition (EMT) of some malignancies. Meanwhile, Twist promotes EMT in pancreatic ductal adenocarcinoma (PDAC) progression. Here, effects of Twist on CCR7-induced EMT in the PDAC were investigated in detail. The immunohistochemistry was used to detect the expression of Twist, and then, in vitro assays were applied. The expression rate of Twist was 72.0 % in PDAC samples and closely correlated with tumor-node-metastasis (TNM) stage and invasion. When PDAC cell line PANC1 was subjected to CCL19 stimulation, the expression of p-ERK, p-AKT, Twist, N-cadherin, MMP9, and α-smooth muscle actin (α-SMA) was induced, while the GSK1120212, BEZ235, and MK2206 prohibited the increase of Twist and EMT biomarkers. For another thing, the si-Twist treatment attenuated CCL19-stimulated EMT occurrence, migration, and invasion phenotypes of PANC1 cells. In conclusion, CCR7 pathway up-regulates Twist expression via ERK and PI3K/AKT signaling to manage the EMT of PDAC. Our work allows for clinical gene or protein-targeted regimen of PDAC patients in the near future.

  13. Expression of Ki-67, p53, and K-ras in chronic pancreatitis and pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Seok Jeong; Young Bae Kim; Don Haeng Lee; Jung Il Lee; Jin-Woo Lee; Kye Sook Kwon; Pum-Soo Kim; Hyung Gil Kim; Yong Woon Shin; Young Soo Kim

    2005-01-01

    AIM: To examine surgical specimens of pancreas with either chronic pancreatitis or pancreatic cancer in order to study whether ductal hyperplasia and dysplasia in pancreas represent precursor lesions for pancreatic cancer.METHODS: We examined expression of Ki-67, CEA,p53, and K-ras, in the surgical specimens of pancreas with adenocarcinomas (n = 11) and chronic pancreatitis (n = 12). Cellular proliferation was assessed by Ki-67proliferation index using the proliferation marker Ki-67.In specimens with pancreas cancer, we divided pancreas epithelium into normal (n=7), ductal hyperplasia (n=3), dysplasia (n=4), and cancerous lesion (n=11) after hematoxylin and eosin staining, Ki-67, and CEA immunohistochemical staining. In cases with chronic pancreatitis, the specimen was pathologically examined as in cases with pancreas cancer, and they were also determined as normal (n=10), ductal hyperplasia (n=4), or dysplasia (n= 5). p53 and K-ras expression were also studied by immunohistochemical staining.RESULTS: In pancreatic cancer, the Ki-67 index was 3.73±3.58 in normal site, 6.62±4.39 in ductalhyperplasia, 13.47±4.02 in dysplasia and 37.03±10.05in cancer tissue, respectively. Overall, p53 was positive in normal ducts, ductal hyperplasia, dysplasia, and carcinoma cells in 0 of 14 (0%), 0 of 7 (0%), 7 of 9 (78%),and 10 of 11 (91%), respectively, and K-ras was positive in 0 of 8 (0%), 1 of 3 (33%), 4 of 6 (67%), 4 of 5 (80%),respectively.CONCLUSION: Our results favorably support the hypothesis that ductal hyperplasia and dysplasia of the pancreas might be precursor lesions for pancreas cancer.Further evaluation of oncogenes by the molecular study is needed.

  14. Context-dependent function of the deubiquitinating enzyme USP9X in pancreatic ductal adenocarcinoma.

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    Cox, Jesse L; Wilder, Phillip J; Wuebben, Erin L; Ouellette, Michel M; Hollingsworth, Michael A; Rizzino, Angie

    2014-08-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly malignancies. Recently, the deubiquitinating protease USP9X has been shown to behave as an oncogene in a number of neoplasms, including those of breast, brain, colon, esophagus and lung, as well as KRAS wild-type PDAC. However, other studies suggest that USP9X may function as a tumor-suppressor in a murine PDAC model when USP9X expression is depleted during early pancreatic development. To address the conflicting findings surrounding the role of USP9X in PDAC, we examined the effects of knocking down USP9X in five human PDAC cell lines (BxPC3, Capan1, CD18, Hs766T, and S2-013). We demonstrate that knocking down USP9X in each of the PDAC cell lines reduces their anchorage-dependent growth. Using an inducible shRNA system to knock down USP9X in both BxPC3 and Capan1 cells, we also determined that USP9X is necessary for the anchorage-independent growth. In addition, knockdown of USP9X alters the cell cycle profile of BxPC3 cells and increases their invasive capacity. Finally, we show that an inhibitor of deubiquitinating proteases, WP1130, induces significant cytotoxicity in each of the five PDAC cell lines tested. Overall, our work and the work of others indicate that the function and role of USP9X is highly context-dependent. Although USP9X may function as a tumor-suppressor during the establishment of PDAC, data presented here argue that USP9X promotes cell growth in advanced PDAC cells when PDAC is typically diagnosed. Hence, USP9X may be a promising therapeutic target for the treatment of advanced PDAC.

  15. Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Wu, Yanhua; Wei, Youheng; Fang, Yuan; Han, Xu; Li, Jianang; Zhou, Ping; Yi, Qing; Maitra, Anirban; Liu, Jun O; Tuveson, David A.; Lou, Wenhui; Yu, Long

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a nearly lethal neoplasm. It is a remarkably stroma-rich, vascular-poor, hypoperfused tumor, which prevents efficient drug delivery. Paradoxically, the neoplastic cells have robust glucose uptake, suggesting the microvasculature has adopted an alternative method for nutrient uptake and cellular trafficking. Using an adapted thick tumor section immunostaining and 3-dimensional (3D) construction imaging method in human tissue samples, we identified an undiscovered feature of the mature and angiostatic microvasculature in advanced PDAC tumors; long, “hairy”-like projections on the basal surface of microvessels that we refer to as “basal microvilli”. Functionally, these basal microvilli have an actin-rich cytoskeleton, endocytic and exocytic properties, and they contain glucose transporter-1 (GLUT-1) positive vesicles. Clinically, as was demonstrated by PET-CT, the tumor microvasculature with the longest and the most abundant basal microvilli positively correlated with the high glucose uptake of the PDAC tumor itself. In addition, these basal microvilli were found in regions of the tumor with low GLUT-1 expression, suggesting their presence could be dependent upon the glucose concentrations in the tumor milieu. Altogether, these basal microvilli mark a novel, pathological feature of the PDAC tumor microvasculature. Because these basal microvilli are pathological features with endo- and exocytic properties, they may provide a non-conventional method for cellular trafficking in PDAC tumors. PMID:25561062

  16. Detection of Pancreatic Ductal Adenocarcinoma in Mice by Ultrasound Imaging of Thymocyte Differentiation Antigen 1

    Science.gov (United States)

    Foygel, Kira; Wang, Huaijun; Machtaler, Steven; Lutz, Amelie M.; Chen, Ru; Pysz, Marybeth; Lowe, Anson W.; Tian, Lu; Carrigan, Tricia; Brentnall, Teresa A.; Willmann, Jürgen K.

    2013-01-01

    BACKGROUND & AIMS Early detection of pancreatic ductal adenocarcinoma (PDAC) allows for surgical resection and increases patient survival times. Imaging agents that bind and amplify the signal of neovascular proteins in neoplasms can be detected by ultrasound, enabling accurate detection of small lesions. We searched for new markers of neovasculature in PDAC and assessed their potential for tumor detection by ultrasound molecular imaging. METHODS Thymocyte Differentiation Antigen 1 (Thy1) was identified as a specific biomarker of PDAC neovasculature by proteomic analysis. Upregulation in PDAC was validated by immunohistochemical analysis of pancreatic tissue samples from 28 healthy individuals, 15 with primary chronic pancreatitis tissues, and 196 with PDAC. Binding of Thy1-targeted contrast microbubbles was assessed in cultured cells, in mice with orthotopic PDAC xenograft tumors expressing human Thy1 on the neovasculature, and on the neovasculature of a genetic mouse model of PDAC. RESULTS Based on immunohistochemical analyses, levels of Thy1 were significantly higher in the vascular of human PDAC than chronic pancreatitis (P=.007) or normal tissue samples (P<.0001). In mice, ultrasound imaging accurately detected human Thy1-positive PDAC xenografts, as well as PDACs that express endogenous Thy1 in genetic mouse models of PDAC. CONCLUSION We have identified and validated Thy1 as a marker of PDAC that can be detected by ultrasound molecular imaging in mice. The development of a specific imaging agent and identification of Thy1 as a new biomarker could aid in the diagnosis of this cancer and management of patients. PMID:23791701

  17. Untargeted LC-HRMS-Based Metabolomics for Searching New Biomarkers of Pancreatic Ductal Adenocarcinoma: A Pilot Study.

    Science.gov (United States)

    Ríos Peces, Sandra; Díaz Navarro, Caridad; Márquez López, Cristina; Caba, Octavio; Jiménez-Luna, Cristina; Melguizo, Consolación; Prados, José Carlos; Genilloud, Olga; Vicente Pérez, Francisca; Pérez Del Palacio, José

    2017-04-01

    Pancreatic ductal adenocarcinoma is one of the most lethal tumors since it is usually detected at an advanced stage in which surgery and/or current chemotherapy have limited efficacy. The lack of sensitive and specific markers for diagnosis leads to a dismal prognosis. The purpose of this study is to identify metabolites in serum of pancreatic ductal adenocarcinoma patients that could be used as diagnostic biomarkers of this pathology. We used liquid chromatography-high-resolution mass spectrometry for a nontargeted metabolomics approach with serum samples from 28 individuals, including 16 patients with pancreatic ductal adenocarcinoma and 12 healthy controls. Multivariate statistical analysis, which included principal component analysis and partial least squares, revealed clear separation between the patient and control groups analyzed by liquid chromatography-high-resolution mass spectrometry using a nontargeted metabolomics approach. The metabolic analysis showed significantly lower levels of phospholipids in the serum from patients with pancreatic ductal adenocarcinoma compared with serum from controls. Our results suggest that the liquid chromatography-high-resolution mass spectrometry-based metabolomics approach provides a potent and promising tool for the diagnosis of pancreatic ductal adenocarcinoma patients using the specific metabolites identified as novel biomarkers that could be used for an earlier detection and treatment of these patients.

  18. E-cadherin expression in obesity-associated, Kras-initiated pancreatic ductal adenocarcinoma in mice.

    Science.gov (United States)

    Stark, Alexander P; Chang, Hui-Hua; Jung, Xiaoman; Moro, Aune; Hertzer, Kathleen; Xu, Mu; Schmidt, Andrea; Hines, O Joe; Eibl, Guido

    2015-12-01

    The epithelial-mesenchymal transition (EMT) is critical in the development of invasive epithelial malignancies. EMT is accelerated by inflammation and results in decreased E-cadherin expression. Diet-induced obesity is an inflammatory state that accelerates pancreatic carcinogenesis; its effect on EMT and E-cadherin expression in the development of pancreatic ductal adenocarcinoma is unclear. Conditional Kras(G12D) mice were fed a control diet or a high-fat, high-calorie diet for 3 or 9 months (n = 10 each). Immunohistochemistry with anti-E-cadherin antibody was performed. E-cadherin expression was characterized by staining intensity, location, and proportion of positive cells. In vitro expression of E-cadherin and Slug in primary pancreatic intraepithelial neoplasia (PanIN) and cancer cells was determined by Western blot. The HFCD led to increased weight gain in both 3- (15.8 vs 5.6 g, P cancer, E-cadherin expression was aberrant, with loss of membranous staining and prominent cytoplasmic staining, associated with strong, cytoplasmic expression of β-catenin. In vitro expression of E-cadherin was greatest in primary PanIN cells, accompanied by absent Slug expression. Cancer cell lines demonstrated significantly decreased E-cadherin expression in the presence of upregulated Slug. Despite increased pancreatic inflammation and accelerated carcinogenesis, the high-fat, high-calorie diet did not induce changes in E-cadherin expression in PanIN lesions of all stages. Invasive lesions demonstrated aberrant cytoplasmic E-cadherin staining. Loss of normal membranous localization may reflect a functional loss of E-cadherin. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Pancreatic Ductal Adenocarcinoma (PDA) mice lacking Mucin 1 have a profound defect in tumor growth and metastasis

    Science.gov (United States)

    Besmer, Dahlia M.; Curry, Jennifer M.; Roy, Lopamudra D.; Tinder, Teresa L.; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y.; Gendler, Sandra J.; Mukherjee, Pinku

    2011-01-01

    MUC1 is over expressed and aberrantly glycosolated in >60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In the present study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared to both KC and KCM. Cell lines derived from KCKO tumors have significantly lower tumorigenic capacity compared to cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared to mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or matrix metalloproteinase-9 (MMP9). Further, significantly fewer KCKO cells entered the G2M phase of the cell cycle compared to the KCM cells. Proteomics and western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of MAPK, as well as a significant decrease in Nestin and Tubulin α-2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse in order to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. PMID:21558393

  20. High expression of interleukin-22 and its receptor predicts poor prognosis in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Wen, Zhang; Liao, Quan; Zhao, Jianguo; Hu, Ya; You, Lei; Lu, Zhaohui; Jia, Congwei; Wei, Yingxin; Zhao, Yupei

    2014-01-01

    The cytokine interleukin-22 (IL-22) and its receptor are present in the tumor microenvironment. Their function in pancreatic ductal adenocarcinoma (PDAC) remains largely unknown. The goal of the present study was to measure the expression of IL-22 and IL-22R in PDAC and assess their relationship with clinicopathological features and prognosis. The expression of IL-22 and IL-22R was evaluated by immunohistochemistry in PDAC tissues from 57 patients and by Western blotting in six tumors and adjacent nontumor tissues. A statistical analysis was conducted to assess the relationship between levels of expression, clinicopathological factors, and overall survival. In addition, the relationship between the expression of IL-22 and IL-22R and invasion was assessed by Western blotting and transwell assay with the PDAC cell lines PANC1 and BxPC3. Positive IL-22 staining was detected in PDAC tissues and adjacent nontumor tissues. Positive IL-22R staining was detected in PDAC cells. High expression of IL-22 and IL-22R correlated significantly with lymph node involvement. IL-22 increased the phosphorylation of signal transducer and activator of transcription3, the expression of matrix metalloproteinase 9, and the invasion in PANC1 and BxPC3 cells in vitro while silencing of IL-22R RNA caused opposite effects. Most importantly, overall survival was significantly poorer in patients with high expression of IL-22 and IL-22R than in those with low expression. These findings reveal the positive role of IL-22 and IL-22R in invasion and metastasis in human PDAC. IL-22 and IL-22R may be suitable independent prognostic markers in PDAC.

  1. A benign presentation of primary ductal adenocarcinoma of lacrimal gland: A rare malignancy

    Directory of Open Access Journals (Sweden)

    Lindfay Laura Lau

    2015-01-01

    Full Text Available A 34-year-old patient with a swelling over the upper eyelid for nearly 1 year was seen in our clinic. The history, examination and investigations were suggestive of a benign lacrimal gland tumor. The tumor and lacrimal gland were resected. Subsequent histopathological examination revealed the tumor was a primary ductal adenocarcinoma of the lacrimal gland. This is a very rare tumor with less than half a dozen cases reported so far. This case report is being presented to highlight an unusual presentation of this rare malignancy.

  2. pH Regulatory Transporters in Pancreatic Ductal Adenocarcinoma

    DEFF Research Database (Denmark)

    Kong, Su Chii

    -ATPases. MCT isoforms 1 to -4 are the only proton-coupled isoforms transporting monocarboxylates such as L-lactate. We show that MCT1 and MCT4 are robustly expressed in all PDAC cell lines studied. These transporters were found localized on the plasma membrane of PDAC cells, colocalizing with MCT chaperone...... protein basigin. Lactate influx capacity was reduced upon siRNA-mediated silencing and pharmacological inhibition of MCT1 and/or MCT4. PDAC cell migration was not significantly affected by MCT1 inhibition with AR-C155858 and MCT1 silencing, yet was inhibited by the general MCT inhibitor 4-CIN...... in the generation of tumour microenvironmental acidosis has recently emerged and have been implicated in the promotion of tumour aggressive phenotypes. In present study, substantial up-regulation of subunit a3 was detected in a panel of PDAC cells tested as compared to non-cancerous control HPDE. Silencing...

  3. pH Regulatory Transporters in Pancreatic Ductal Adenocarcinoma

    DEFF Research Database (Denmark)

    Kong, Su Chii

    The abnormal features of hypoxia and altered metabolisms in solid tumours lead to an increased glycolysis that is uncoupled from oxidative phosphorylation in the TCA cycle. Tumoural cells often exhibit dysregulated expressions and activities of various membrane pH regulatory transporters to cope...... with the elevated acid production from this glycolysis, as well as from cellular ATP hydrolysis, sequentially creating a favourable intracellular pH and hostile acidic tumour microenvironment, fortify the tumour cells with highly invasive, metastatic and drug resistant phenotype. In current work, we study...... proliferation was found to be decreased while apoptosis was increased with concanamycin A treatment, indicative of V-ATPases being involved in PDAC cell survival mechanisms as well. Comprehending pH regulation in tumour cells might provide insights in preventing tumourigenesis by pH disruptions. Data presented...

  4. ECM Composition and Rheology Regulate Growth, Motility, and Response to Photodynamic Therapy in 3D Models of Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Cramer, Gwendolyn M; Jones, Dustin P; El-Hamidi, Hamid; Celli, Jonathan P

    2017-01-01

    Pancreatic ductal adenocarcinoma is characterized by prominent stromal involvement, which plays complex roles in regulating tumor growth and therapeutic response. The extracellular matrix (ECM)-rich stroma associated with this disease has been implicated as a barrier to drug penetration, although stromal depletion strategies have had mixed clinical success. It remains less clear how interactions with ECM, acting as a biophysical regulator of phenotype, not only a barrier to drug perfusion, regulate susceptibilities and resistance to specific therapies. In this context, an integrative approach is used to evaluate invasive behavior and motility in rheologically characterized ECM as determinants of chemotherapy and photodynamic therapy (PDT) responses. We show that in 3D cultures with ECM conditions that promote invasive progression, response to PDT is markedly enhanced in the most motile ECM-infiltrating populations, whereas the same cells exhibit chemoresistance. Conversely, drug-resistant sublines with enhanced invasive potential were generated to compare differential treatment response in identical ECM conditions, monitored by particle tracking microrheology measurements of matrix remodeling. In both scenarios, ECM-infiltrating cell populations exhibit increased sensitivity to PDT, whether invasion is consequent to selection of chemoresistance, or whether chemoresistance is correlated with acquisition of invasive behavior. However, while ECM-invading, chemoresistant cells exhibit mesenchymal phenotype, induction of EMT in monolayers without ECM was not sufficient to enhance PDT sensitivity, yet does impart chemoresistance as expected. In addition to containing platform development with broader applicability to inform microenvironment-dependent therapeutics, these results reveal the efficacy of PDT for targeting the most aggressive, chemoresistant, invasive pancreatic ductal adenocarcinoma associated with dismal outcomes for this disease. ECM-infiltrating and

  5. Management and therapeutic response of a prostate ductal adenocarcinoma: a still unknown tumour?

    Science.gov (United States)

    Martorana, Eugenio; Micali, Salvatore; Pirola, Giacomo Maria; Reggiani Bonetti, Luca; Clò, Vera; Ghaith, Ahmed; Bianchi, Giampaolo

    2016-09-26

    Ductal adenocarcinoma is a rare subtype of prostate cancer with a worse prognosis.Histologically, it is characterized by the presence of tall, pseudostratified columnar epithelium with abundant cytoplasm organized in a papillary or cribriform-papillary pattern. Several clinical differences distinguish this subtype of prostate cancer by the conventional acinar adenocarcinoma: exophytic growth into the prostatic urethra, different clinical presentation, different sites of metastasis and more aggressiveness. The rarity of this tumour forced to base our knowledge on small case series or on individual case reports, and does not help to establish appropriate guidelines. Therefore, the diagnosis of this tumour masks clinical implications that are still not well-understood.We report the case of a 69-year-old Caucasian man with a diagnosis of pure prostate ductal adenocarcinoma that early developed multiple metastases after radical prostatectomy. The patient started hormonal therapy with a fast biochemical and radiologic (positron emission tomography-computed tomography, PET-CT) hormonal escape. Therefore, we took the decision to perform chemotherapy with Taxotere along with prednisolone with a relative stability of prostate-specific antigen (PSA) level, but a new PET-CT scan showed a further progression of the disease. Finally, the patient underwent therapy with Abiraterone acetate that did not stop the cancer progression.No therapeutic options available showed a good control of disease progression. PSA proved to be a poor marker while, on the contrary, PET-CT scan has proved to be particularly useful in the management of the disease progression. More efforts are required to add new knowledge about this tumour and assess what is known until now.

  6. MSX2 in pancreatic tumor development and its clinical application for the diagnosis of pancreatic ductal adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Kennichi eSatoh

    2012-11-01

    Full Text Available MSX2, a member of the homeobox genes family, is demonstrated to be the downstream target for ras signaling pathway and is expressed in a variety of carcinoma cells, suggesting its relevance to the development of ductal pancreatic tumors since pancreatic ductal adenocarcinoma (PDAC and intraductal papillary-mucinous neoplasia (IPMN harbor frequent K-ras gene mutations. Recent studies revealed the roles of MSX2 in the development of carcinoma of various origins including pancreas. Among gastrointestinal tumors, PDAC is one of the most malignant. PDAC progresses rapidly to develop metastatic lesions, frequently by the time of diagnosis, and these tumors are usually resistant to conventional chemotherapy and radiation therapy. The molecular mechanisms regulating the aggressive behavior of PDAC still remain to be clarified. On the other hand, IPMN of the pancreas is distinct from PDAC because of its intraductal growth in the main pancreatic duct or secondary branches with rare invasion and metastasis to distant organs. However, recent evidence indicated that once IPMN showed stromal invasion, it progresses like PDAC. Therefore, it is important to determin how IPMN progresses to malignant phenotype. In this review, we focus on the involvement of MSX2 in the enhancement of malignant behavior in PDAC and IPMN, and further highlight the clinical approach to differentiate PDAC from chronic pancreatitis by evaluating MSX2 expression level.

  7. Role of anti-stromal polypharmacy in increasing survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Samuel; J; Tingle; John; A; Moir; Steven; A; White

    2015-01-01

    AIM: To investigate the survival impact of common pharmaceuticals, which target stromal interactions, following a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. METHODS: Data was collected retrospectively for 164 patients who underwent a pancreaticoduodenectomy for pancreatic ductal adenocarcinoma(PDAC). Survival analysis was performed on patients receiving the following medications: angiotensin-converting enzyme inhibitors(ACEI)/angiotensin Ⅱ receptor blockers(ARB), calcium channel blockers(CCB), aspirin, and statins. Statistical analysis included Kaplan-meier survival estimates and cox multivariate regression; the latter of which allowed for any differences in a range of prognostic indicators between groups. Medications showing a significant survival benefit were investigated in combination with other medications to evaluate synergistic effects.RESULTS: No survival benefit was observed with respect to ACEI/ARB(n = 41), aspirin or statins on individual drug analysis(n = 39). However, the entire CCB group(n = 26) showed a significant survival benefit on multivariate cox regression; hazard ratio(HR) of 0.475(CI = 0.250-0.902, P = 0.023). Further analysis revealed that this was influenced by a group of patients who were taking aspirin in combination with CCB; median survival was significantly higher in the CCB + aspirin group(n = 15) compared with the group taking neither drug(n = 98); 1414 d vs 601 d(P = 0.029, logrank test). Multivariate cox regression revealed neither aspirin nor CCB had a statistically significant impact on survival when given alone, however in combination the survival benefit was significant; HR = 0.332(CI = 0.126-0.870, P = 0.025). None of the other medications showed a survival benefit in any combination.CONCLUSION: Aspirin + CCB in combination appears to increase survival in patients with PDAC, highlighting the potential clinical use of combination therapy to target stromal interactions in pancreatic cancer.

  8. Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Aboukameel, Amro; Muqbil, Irfana; Senapedis, William; Baloglu, Erkan; Landesman, Yosef; Shacham, Sharon; Kauffman, Michael; Philip, Philip A; Mohammad, Ramzi M; Azmi, Asfar S

    2017-01-01

    The p21-activated kinase 4 (PAK4) is a key downstream effector of the Rho family GTPases and is found to be overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells but not in normal human pancreatic ductal epithelia (HPDE). Gene copy number amplification studies in PDAC patient cohorts confirmed PAK4 amplification making it an attractive therapeutic target in PDAC. We investigated the antitumor activity of novel PAK4 allosteric modulators (PAM) on a panel of PDAC cell lines and chemotherapy-resistant flow-sorted PDAC cancer stem cells (CSC). The toxicity and efficacy of PAMs were evaluated in multiple subcutaneous mouse models of PDAC. PAMs (KPT-7523, KPT-7189, KPT-8752, KPT-9307, and KPT-9274) show antiproliferative activity in vitro against different PDAC cell lines while sparing normal HPDE. Cell growth inhibition was concurrent with apoptosis induction and suppression of colony formation in PDAC. PAMs inhibited proliferation and antiapoptotic signals downstream of PAK4. Co-immunoprecipitation experiments showed disruption of PAK4 complexes containing vimentin. PAMs disrupted CSC spheroid formation through suppression of PAK4. Moreover, PAMs synergize with gemcitabine and oxaliplatin in vitro KPT-9274, currently in a phase I clinical trial (clinicaltrials.gov; NCT02702492), possesses desirable pharmacokinetic properties and is well tolerated in mice with the absence of any signs of toxicity when 200 mg/kg daily is administered either intravenously or orally. KPT-9274 as a single agent showed remarkable antitumor activity in subcutaneous xenograft models of PDAC cell lines and CSCs. These proof-of-concept studies demonstrated the antiproliferative effects of novel PAMs in PDAC and warrant further clinical investigations. Mol Cancer Ther; 16(1); 76-87. ©2016 AACR.

  9. Total Pancreatectomy and Islet Auto-Transplantation as Treatment for Ampullary Adenocarcinoma in the Setting of Pancreatic Ductal Disruption Secondary to Acute Necrotizing Pancreatitis. A Case Report

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    Uroghupatei P Iyegha

    2012-03-01

    Full Text Available Context Ampullary adenocarcinoma is the third most common periampullary malignancy. Obstruction of the main pancreatic duct is linked with an increased incidence of acute pancreatitis. Acute necrotizing pancreatitis leading to pancreatic duct disruption carries significant morbidity. When these conditions occur in combination, the treatment can be drastically limited as pancreaticoduodenectomy is not a viable option in the setting of friable ductal tissue, which precludes pancreatic ductal anastomosis and can lead to the complications of leak or stricture. Case report Our patient is a 72-year-old woman who developed pancreatic ductal disruption and splenic vein thrombosis as a result of acute necrotizing pancreatitis. Concurrently, she was found to have an ampullary adenoma with high-grade dysplasia. Her treatment options were limited, as she was neither a candidate for pancreaticoduodenectomy given the ductal disruption nor total pancreatectomy, which would render her a brittle diabetic. She was successfully treated with total pancreatectomy and islet auto-transplantation thereby resecting her ampullary lesion while both avoiding a pancreatic anastomosis and preserving pancreatic endocrine beta-cell function. Conclusion We report a case where total pancreatectomy and islet auto-transplantation can be considered as a viable option for treatment of ampullary lesions in a setting where standard surgical options are suboptimal.

  10. Assessment and optimization of electroporation-assisted tumoral nanoparticle uptake in a nude mouse model of pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    West, Derek Lamont; White, Sarah B; Zhang, Zhouli; Larson, Andrew C; Omary, Reed A

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal form of cancer. In 2012, the incidence of PDAC was 43,920. Five-year survival for patients with PDAC is around 6%, regardless of staging, making PDAC one of the deadliest forms of cancer. One reason for this dismal prognosis is chemoresistance to the current first-line therapy, gemcitabine. There are multiple factors that contribute to the chemoresistance observed in pancreatic cancer. Among them, desmoplasia has been increasingly seen as a significant contributor to chemoresistance. To overcome desmoplastic chemoresistance, several novel methods of treatment have been developed. Electroporation is one such novel treatment. High electrical fields are applied to cells to create pores that increase cell permeability. It has been previously demonstrated that electroporation enhances the therapeutic efficacy of anticancer drugs in pancreatic tumor models. Nanoparticle-based drug delivery systems constitute a second novel method to overcome desmoplastic chemoresistance. Due to their intrinsic design advantages, nanoparticles have been shown to increase the effectiveness of chemotherapeutic agents, while further reducing or even eliminating side effects. To date, there have been no studies evaluating the cumulative effect of combining both nanoparticle and electroporation strategies to overcome chemoresistance in PDAC. Our preliminary studies assessed the in vitro and in vivo uptake of doxorubicin-loaded iron oxide nanoparticles as a function of electroporation voltage and timing of administration in pancreatic adenocarcinoma cells. Our studies demonstrated that addition of electroporation to administration of nanoparticles significantly increased the amount of intracellular iron oxide nanoparticle uptake by a PANC-1 cell line in an athymic nude mouse model of PDAC. Further, electroporation-assisted nanoparticle uptake could be significantly altered by changing the timing of application of electroporation.

  11. Ductal adenocarcinoma and unusual differential diagnosis; Duktales Adenokarzinom und ungewoehnliche Differenzialdiagnosen

    Energy Technology Data Exchange (ETDEWEB)

    Haage, P.; Schwartz, C.A.; Scharwaechter, C. [Universitaet Witten/Herdecke, Zentrum fuer Radiologie HELIOS Universitaetsklinikum Wuppertal, Wuppertal (Germany)

    2016-04-15

    Ductal pancreatic adenocarcinoma is by far the most common solid tumor of the pancreas. It has a very poor prognosis, especially in the more advanced stages which are no longer locally confined. Due to mostly unspecific symptoms, imaging is key in the diagnostic process. Because of the widespread use of imaging techniques, incidental findings are to a greater extent discovered in the pancreas, which subsequently entail further work-up. Ductal pancreatic adenocarcinoma can be mimicked by a large number of different lesions, such as anatomical variants, peripancreatic structures and tumors, rarer primary solid pancreatic tumors, cystic tumors, metastases or different variants of pancreatitis. Additionally, a number of precursor lesions can be differentiated. The correct classification is thus important as an early diagnosis of ductal pancreatic adenocarcinoma is relevant for the prognosis and because the possibly avoidable treatment is very invasive. All major imaging techniques are principally suitable for pancreatic imaging. In addition to sonography of the abdomen, usually the baseline diagnostic tool, computed tomography (CT) with its superior spatial resolution, magnetic resonance imaging (MRI) with its good soft tissue differentiation capabilities, possibly in combination with MR cholangiopancreatography (MRCP), endosonography with its extraordinary spatial resolution, conceivably with additional endoscopic retrograde CP or the option of direct biopsy and finally positron emission tomography CT (PET-CT) as a molecular imaging tool are all particularly useful modalities. The various techniques all have its advantages and disadvantages; depending on the individual situation they may need to be combined. (orig.) [German] Das duktale Adenokarzinom ist der weitaus haeufigste solide Tumor des Pankreas. Die Prognose ist sehr schlecht, insbesondere bei fortgeschrittenen, nicht mehr lokal begrenzten Tumoren. Bei meist unspezifischen geringen Beschwerden kommt der

  12. Orphan nuclear receptor Nurr1 as a potential novel marker for progression in human pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Ji, Li; Gong, Chen; Ge, Liangyu; Song, Linping; Chen, Fenfen; Jin, Chunjing; Zhu, Hongyan; Zhou, Guoxiong

    2017-01-01

    Nuclear receptor related-1 protein (Nurr1) is a novel orphan member of the nuclear receptor superfamily (the NR4A family) involved in tumorigenesis. The aim of the present study was to investigate the expression and possible function of Nurr1 in pancreatic ductal adenocarcinoma (PDAC). The expression pattern of Nurr1 protein was determined using immunohistochemical staining in 138 patients with PDAC. Elevated Nurr1 expression was more commonly observed in PDAC tissues and cell lines compared with healthy controls. Elevated expression was significantly associated with histological differentiation (P=0.041), lymph node metastasis (P=0.021), TNM classification of malignant tumors stage (P=0.031) and poor survival (P=0.001). Further experiments demonstrated that suppression of endogenous Nurr1 expression attenuated cell proliferation, migration and invasion, and induced apoptosis of PDAC cells. In conclusion, these results suggest that Nurr1 has an important role in the progression of PDAC and may be used as a novel marker for therapeutic targets.

  13. Prostatic ductal adenocarcinoma: an aggressive tumour variant unrecognized on T2 weighted magnetic resonance imaging (MRI)

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    Schieda, Nicola; Coffey, Niamh; Al-Dandan, Omran; Shabana, Wael [The University of Ottawa, Department of Medical Imaging, The Ottawa Hospital, Ottawa, Ontario (Canada); Gulavita, Previn; Flood, Trevor A. [The University of Ottawa, Department of Anatomical Pathology, The Ottawa Hospital, Ottawa (Canada)

    2014-06-15

    Prostatic ductal adenocarcinoma (DCa) is an aggressive variant. The purpose of this study was to determine if T2 signal intensity (SI) differs from conventional adenocarcinoma (CCa). A retrospective study of patients who underwent preoperative MRI and prostatectomy between 2009 and 2012 was performed. T2 SI ratios (SIR) for tumour (T) to obturator internus muscle (M) and normal peripheral zone (PZ) were compared. Two radiologists evaluated the central gland/PZ to detect tumours and compared diagnostic accuracy. T2 SIR for DCa were 3.60 (T/M), 0.66 (T/PZ); 2.68 (T/M), 0.47 (T/PZ) for Gleason 9; 2.50 (T/M), 0.47 (T/PZ) for Gleason 7/8 and 3.95 (T/M), 0.73 (T/PZ) for Gleason 6 tumours. There was a difference in T2 T/M and T/PZ SIR between DCa and Gleason 9 (p = 0.003, p = 0.004) and Gleason 7/8 (p = 0.006, p = 0.002), but no difference in SIR between DCa and Gleason 6 tumours. The sensitivity for tumour detection was 0-27 % for DCa, 64-82 % for Gleason 9, 44-88 % for Gleason 7-8 and 0-20 % for Gleason 6. There was a difference in the sensitivity of detecting Gleason 9 and 7/8 tumours when compared to DCa (p = 0.004, p = 0.001). DCa resembles Gleason score 6 tumour at T2-weighted MRI, which underestimates tumour grade and renders the tumour occult. (orig.)

  14. Can the new RCP R0/R1 classification predict the clinical outcome in ductal adenocarcinoma of the pancreatic head?

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    Janot, M S; Kersting, S; Belyaev, O; Matuschek, A; Chromik, A M; Suelberg, D; Uhl, W; Tannapfel, A; Bergmann, U

    2012-08-01

    According to the International Union Against Cancer (UICC), R1 is defined as the microscopic presence of tumor cells at the surface of the resection margin (RM). In contrast, the Royal College of Pathologists (RCP) suggested to declare R1 already when tumor cells are found within 1 mm of the RM. The aim of this study was to determine the significance of the RM concerning the prognosis of pancreatic ductal adenocarcinoma (PDAC). From 2007 to 2009, 62 patients underwent a curative operation for PDAC of the pancreatic head. The relevance of R status on cumulative overall survival (OS) was assessed on univariate and multivariate analysis for both the classic R classification (UICC) and the suggestion of the RCP. Following the UICC criteria, a positive RM was detected in 8 %. Along with grading and lymph node ratio, R status revealed a significant impact on OS on univariate and multivariate analysis. Applying the suggestion of the RCP, R1 rate rose to 26 % resulting in no significant impact on OS in univariate analysis. Our study has shown that the RCP suggestion for R status has no impact on the prognosis of PDAC. In contrast, our data confirmed the UICC R classification of RM as well as N category, grading, and lymph node ratio as significant prognostic factors.

  15. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.

    Science.gov (United States)

    Saloman, Jami L; Albers, Kathryn M; Li, Dongjun; Hartman, Douglas J; Crawford, Howard C; Muha, Emily A; Rhim, Andrew D; Davis, Brian M

    2016-03-15

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

  16. Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Ju, Huai-Qiang; Ying, Haoqiang; Tian, Tian; Ling, Jianhua; Fu, Jie; Lu, Yu; Wu, Min; Yang, Lifeng; Achreja, Abhinav; Chen, Gang; Zhuang, Zhuonan; Wang, Huamin; Nagrath, Deepak; Yao, Jun; Hung, Mien-Chie; DePinho, Ronald A.; Huang, Peng; Xu, Rui-Hua; Chiao, Paul J.

    2017-01-01

    Kras activation and p16 inactivation are required to develop pancreatic ductal adenocarcinoma (PDAC). However, the biochemical mechanisms underlying these double alterations remain unclear. Here we discover that NAD(P)H oxidase 4 (NOX4), an enzyme known to catalyse the oxidation of NAD(P)H, is upregulated when p16 is inactivated by looking at gene expression profiling studies. Activation of NOX4 requires catalytic subunit p22phox, which is upregulated following Kras activation. Both alterations are also detectable in PDAC cell lines and patient specimens. Furthermore, we show that elevated NOX4 activity accelerates oxidation of NADH and supports increased glycolysis by generating NAD+, a substrate for GAPDH-mediated glycolytic reaction, promoting PDAC cell growth. Mechanistically, NOX4 was induced through p16-Rb-regulated E2F and p22phox was induced by KrasG12V-activated NF-κB. In conclusion, we provide a biochemical explanation for the cooperation between p16 inactivation and Kras activation in PDAC development and suggest that NOX4 is a potential therapeutic target for PDAC. PMID:28232723

  17. Tumor Microenvironment Modulation by Cyclopamine Improved Photothermal Therapy of Biomimetic Gold Nanorods for Pancreatic Ductal Adenocarcinomas.

    Science.gov (United States)

    Jiang, Ting; Zhang, Bo; Shen, Shun; Tuo, Yanyan; Luo, Zimiao; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

    2017-09-20

    Due to the rich stroma content and poor blood perfusion, pancreatic ductal adenocarcinoma (PDA) is a tough cancer that can hardly be effectively treated by chemotherapeutic drugs. Tumor microenvironment modulation or advanced design of nanomedicine to achieve better therapeutic benefits for PDA treatment was widely advocated by many reviews. In the present study, a new photothermal therapy strategy of PDA was developed by combination of tumor microenvironment modulation and advanced design of biomimetic gold nanorods. On one hand, biomimetic gold nanorods were developed by coating gold nanorods (GNRs) with erythrocyte membrane (MGNRs). It was shown that MGNRs exhibited significantly higher colloidal stability in vitro, stronger photothermal therapeutic efficacy in vitro, and longer circulation in vivo than GNRs. On the other hand, tumor microenvironment modulation by cyclopamine treatment successfully disrupted the extracellular matrix of PDA and improved tumor blood perfusion. Moreover, cyclopamine treatment significantly increased the accumulation of MGNRs in tumors by 1.8-fold and therefore produced higher photothermal efficiency in vivo than the control group. Finally, cyclopamine treatment combined with photothermal MGNRs achieved the most significant shrinkage of Capan-2 tumor xenografts among all the treatment groups. Therefore, with the integrated advantages of tumor microenvironment regulation and long-circulation biomimetic MGNRs, effective photothermal therapy of PDA was achieved. In general, this new strategy of combining tumor microenvironment modulation and advanced design of biomimetic nanoparticles might have great potential in PDA therapy.

  18. The use of Multidimensional Data to Identify the Molecular Biomarker for Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Liwei Zhuang

    2013-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is a lethal disease, and the patient has an extremely poor overall survival with a less than 5% 5-year survival rate. Development of potential biomarkers provides a critical foundation for the diagnosis of PDAC. In this project, we have adopted an integrative approach to simultaneously identify biomarker and generate testable hypothesis from multidimensional omics data. We first examine genes for which expression levels are correlated with survival data. The gene list was screened with TF regulation, predicted miRNA targets information, and KEGG pathways. We identified that 273 candidate genes are correlated with patient survival data. 12 TF regulation gene sets, 11 miRNAs targets gene sets, and 15 KEGG pathways are enriched with these survival genes. Notably, CEBPA/miRNA32/PER2 signaling to the clock rhythm qualifies this pathway as a suitable target for therapeutic intervention in PDAC. PER2 expression was highly associated with survival data, thus representing a novel biomarker for earlier detection of PDAC.

  19. The Clinical and Pathological Significance of Nectin-2 and DDX3 Expression in Pancreatic Ductal Adenocarcinomas.

    Science.gov (United States)

    Liang, Shan; Yang, Zhulin; Li, Daiqiang; Miao, Xiongying; Yang, Leping; Zou, Qiong; Yuan, Yuan

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease, but the genetic basis of PDAC is still unclear. In this study, Nectin-2 and DDX3 expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic lesions, and 13 normal pancreatic tissues were measured by immunohistochemical methods. Results showed that the percentage of positive Nectin-2 and DDX3 expression was significantly higher in PDAC tumors than in peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P DDX3 expression was significantly lower in PDAC patients without lymph node metastasis and invasion and having TNM stage I/II disease than in patients with lymph node metastasis, invasion, and TNM stage III/IV disease (P DDX3 expression is associated with poor differentiation of PDAC. Kaplan-Meier survival analysis showed that positive Nectin-2 and DDX3 expression were significantly associated with survival in PDAC patients (P DDX3 expression were independent poor prognosis factors in PDAC patients. In conclusion, positive Nectin-2 and DDX3 expression are associated with the progression and poor prognosis in PDAC patients.

  20. The Clinical and Pathological Significance of Nectin-2 and DDX3 Expression in Pancreatic Ductal Adenocarcinomas

    Directory of Open Access Journals (Sweden)

    Shan Liang

    2015-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is a highly malignant disease, but the genetic basis of PDAC is still unclear. In this study, Nectin-2 and DDX3 expression in 106 PDAC, 35 peritumoral tissues, 55 benign pancreatic lesions, and 13 normal pancreatic tissues were measured by immunohistochemical methods. Results showed that the percentage of positive Nectin-2 and DDX3 expression was significantly higher in PDAC tumors than in peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (P<0.01. The percentage of cases with positive Nectin-2 and DDX3 expression was significantly lower in PDAC patients without lymph node metastasis and invasion and having TNM stage I/II disease than in patients with lymph node metastasis, invasion, and TNM stage III/IV disease (P<0.05 or P<0.01. Positive DDX3 expression is associated with poor differentiation of PDAC. Kaplan-Meier survival analysis showed that positive Nectin-2 and DDX3 expression were significantly associated with survival in PDAC patients (P<0.001. Cox multivariate analysis revealed that positive Nectin-2 and DDX3 expression were independent poor prognosis factors in PDAC patients. In conclusion, positive Nectin-2 and DDX3 expression are associated with the progression and poor prognosis in PDAC patients.

  1. A Multicenter Trial Defining a Serum Protein Signature Associated with Pancreatic Ductal Adenocarcinoma

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    Anna S. Gerdtsson

    2015-01-01

    Full Text Available Background. Pancreatic ductal adenocarcinoma (PDAC is an aggressive disease with rapid tumor progression and poor prognosis. This study was motivated by the lack of sensitive and specific PDAC biomarkers and aimed to identify a diagnostic, serum protein signature for PDAC. Methods. To mimic a real life test situation, a multicenter trial comprising a serum sample cohort, including 338 patients with either PDAC or other pancreatic diseases (OPD and controls with nonpancreatic conditions (NPC, was analyzed on 293-plex recombinant antibody microarrays targeting immunoregulatory and cancer-associated antigens. Results. Serum samples collected from different hospitals were analyzed and showed that (i sampling from five different hospitals could not be identified as a preanalytical variable and (ii a multiplexed biomarker signature could be identified, utilizing up to 10 serum markers that could discriminate PDAC from controls, with sensitivities and specificities in the 91–100% range. The first protein profiles associated with the location of the primary tumor in the pancreas could also be identified. Conclusions. The results demonstrate that robust enough serum signatures could be identified in a multicenter trial, potentially contributing to the development of a multiplexed biomarker immunoassay for improved PDAC diagnosis.

  2. Proteomic identification of potential prognostic biomarkers in resectable pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Iuga, Cristina; Seicean, Andrada; Iancu, Cornel; Buiga, Rareş; Sappa, Praveen K; Völker, Uwe; Hammer, Elke

    2014-04-01

    Pancreatic cancer is a devastating disease with a mortality rate almost identical with its incidence. In this context, the investigation of the pancreatic cancer proteome has gained considerable attention because profiles of proteins may be able to identify disease states and progression more accurately. Therefore, our objective was to investigate the changes in the proteome of patients suffering from pancreatic ductal adenocarcinoma (PDAC) by a comprehensive quantitative approach. Comparative proteomic profiling by label-free LC-MS/MS analysis of nine matched pairs of tumor and nontumor pancreas samples was used to identify differences in protein levels characteristic for PDAC. In this analysis, 488 proteins were quantified by at least two peptides of which 99 proteins displayed altered levels in PDAC (p 1.3). Screening of data revealed a number of molecules that had already been related to PDAC such as galectin-1 (LEG1), major vault protein, adenylyl cyclase-associated protein 1 (CAP1), but also a potential new prognostic biomarker prolargin (PRELP). The Kaplan-Meier survival analysis revealed a significant correlation of protein abundance of PRELP with postoperative survival of patients with PDAC. For selected proteins the findings were verified by targeted proteomics (SRM), validated by immunohistochemistry and Western blotting and their value as candidate biomarkers is discussed.

  3. CYP1B1 polymorphisms and k-ras mutations in patients with pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Crous-Bou, Marta; De Vivo, Immaculata; Porta, Miquel; Pumarega, José A; López, Tomàs; Alguacil, Joan; Morales, Eva; Malats, Núria; Rifà, Juli; Hunter, David J; Real, Francisco X

    2008-05-01

    The frequency of CYP1B1 polymorphisms in pancreatic cancer has never been reported. There is also no evidence on the relationship between CYP1B1 variants and mutations in ras genes (K-, H- or N-ras) in any human neoplasm. We analyzed the following CYP1B1 polymorphisms in 129 incident cases of pancreatic ductal adenocarcinoma (PDA): the m1 allele (Val to Leu at codon 432) and the m2 allele (Asn to Ser at codon 453). The calculated frequencies for the m1 Val and m2 Asn alleles were 0.45 and 0.68, respectively. CYP1B1 genotypes were out of Hardy-Weinberg equilibrium; this was largely due to K-ras mutated PDA cases. The Val/Val genotype was over five times more frequent in PDA cases with a K-ras mutation than in wild-type cases (OR = 5.25; P = 0.121). In PDA, polymorphisms in CYP1B1 might be related with K-ras activation pathways.

  4. Low Expression of TBX4 Predicts Poor Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma

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    Meijuan Zong

    2011-08-01

    Full Text Available This study was designed to investigate the expression of the T-box transcription factor 4 (TBX4, a tumor biomarker that was previously identified by proteomics, in pancreatic ductal adenocarcinoma (PDAC and evaluate its clinical utility as a potential prognostic biomarkers for PDAC. The expression of TBX4 was detected in 77 stage II PDAC tumors by immunohistochemistry, and the results were analyzed with regard to clinicopathological characteristics and overall survival. Moreover, Tbx4 promoter methylation status in primary PDAC tumors and normal adjacent pancreas tissues was measured by bisulfite sequencing. Among 77 stage II PDAC tumors, 48 cases (62.3% expressed TBX4 at a high level. No significant correlation between TBX4 expression and other clinicopathological parameters, except tumor grade and liver metastasis recurrence, was found. The survival of patients with TBX4-high expression was significantly longer than those with TBX4-low expression (P = 0.010. In multivariate analysis, low TBX4 expression was an independent prognostic factor for overall survival in patients with stage II PDAC. TBX4 promoter methylation status was frequently observed in both PDAC and normal adjacent pancreas. We conclude that a low level of TBX4 expression suggests a worse prognosis for patients with stage II PDAC. Down-regulation of the TBX4 gene in pancreas is less likely to be regulated by DNA methylation.

  5. Low expression of nucleus accumbens-associated protein 1 predicts poor prognosis for patients with pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Nishi, Takeshi; Maruyama, Riruke; Urano, Takeshi; Nakayama, Naomi; Kawabata, Yasunari; Yano, Seiji; Yoshida, Manabu; Nakayama, Kentaro; Miyazaki, Kohji; Takenaga, Keizo; Tanaka, Tsuneo; Tajima, Yoshitsugu

    2012-12-01

    Nucleus accumbens-associated protein 1 (NAC1) is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. High expression of NAC1 is considered to have adverse effects on prognosis through negative regulation of growth arrest and DNA-damage-inducible 45-γ interacting protein 1 (GADD45GIP1) in ovarian and cervical carcinomas. In the present study, the expression of NAC1 in pancreatic ductal adenocarcinoma (PDA) was measured using immunohistochemistry and computer-assisted image analysis in order to investigate its correlation with various clinicopathological parameters and prognosis. Patients with low-NAC1 PDA had worse overall survival (P = 0.0010) and a shorter disease-free survival (P = 0.0036) than patients with high-NAC1 PDA. This was a clinical effect opposite to that reported in ovarian and cervical carcinomas. Furthermore, knockdown of NAC1 in pancreatic carcinoma cell lines did not increase expression of the GADD45GIP1 protein. These results indicate that the gene(s) regulated by NAC1 vary depending on the types of carcinoma or originating tissue, and that low expression of NAC1 predicts poor prognosis for patients with PDA.

  6. Role of epithelial mesenchymal transition (EMT in pancreatic ductal adenocarcinoma (PDAC: is tumor budding the missing link?

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    Eva eKaramitopoulou

    2013-09-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC ranks as the fourth commonest cause of cancer death while its incidence is increasing worldwide. For all stages, survival at 5 years is <5%. The lethal nature of pancreatic cancer is attributed to its high metastatic potential to the lymphatic system and distant organs. Lack of effective therapeutic options contributes to the high mortality rates of PDAC. Recent evidence suggests that epithelial-mesenchymal transition (EMT plays an important role to the disease progression and development of drug resistance in PDAC. Tumor budding is thought to reflect the process of epithelial-mesenchymal transition (EMT which allows neoplastic epithelial cells to acquire a mesenchymal phenotype thus increasing their capacity for migration and invasion and help them become resistant to apoptotic signals. In a recent study by our own group the presence and prognostic significance of tumor budding in PDAC were investigated and an association between high-grade budding and aggressive clinicopathological features of the tumors as well as worse outcome of the patients was found. The identification of EMT phenotypic targets may help identifying new molecules so that future therapeutic strategies directed specifically against them could potentially have an impact on drug resistance and invasiveness and hence improve the prognosis of PDAC patients. The aim of this short review is to present an insight on the morphological and molecular aspects of EMT and on the factors that are involved in the induction of EMT in PDAC.

  7. Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Grace, Shane A; Meeks, Marshall W; Chen, Yongxin; Cornwell, Mona; Ding, Xianzhong; Hou, Ping; Rutgers, Joanne K; Crawford, Susan E; Lai, Jin-Ping

    2017-02-01

    Obesity is an established risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). However, the pathophysiology of how increased adiposity increases the risk for PDAC has not been fully elucidated. Adipose triglyceride lipase (ATGL) is a lipase that catabolizes triglyceride hydrolysis and has been implicated in the development of breast cancer. We hypothesized that overweight patients with PDAC would demonstrate higher tumor ATGL expression compared to non-overweight patients with PDAC. Immunohistochemical analysis for ATGL expression was performed on PDAC tissues from 44 patients after Whipple procedure or distal pancreatectomy. Correlation of ATGL expression with clinicopathological features was evaluated. A total of 23/44 (52.2%) PDACs showed low level ATGL immunoreactivity, while 21/44 (47.8%) showed a high level, with moderate to strong positive ATGL immunoreactivity in more than 50% of the tumor cells. Chi-squared testing revealed a statistically significant association between high ATGL expression and both BMI >25 kg/m(2) (χ(2)=5.74, p=0.017) and increased tumor stroma (χ(2)=19.14, pobesity increases the risk of PDAC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  8. Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Zhou, G; Yu, J; Wang, A; Liu, S-H; Sinnett-Smith, J; Wu, J; Sanchez, R; Nemunaitis, J; Ricordi, C; Rozengurt, E; Brunicardi, F C

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most potent and perilous diseases known, with a median survival rate of 3-5 months due to the combination of only advanced stage diagnosis and ineffective therapeutic options. Metformin (1,1-Dimethylbiguanide hydrochloride), the leading drug used for type 2 diabetes mellitus, emerges as a potential therapy for PDAC and other human cancers. Metformin exerts its anticancer action via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)- dependent and/or AMPK-independent mechanisms. We present data here showing that metformin downregulated pancreatic transcription factor pancreatic duodenal homeobox-1 (PDX-1), suggesting a potential novel mechanism by which metformin exerts its anticancer action. Metformin inhibited PDX-1 expression at both protein and mRNA levels and PDX-1 transactivity as well in PDAC cells. Extracellular signal-regulated kinase (ERK) was identified as a PDX-1-interacting protein by antibody array screening in GFP-PDX-1 stable HEK293 cells. Co-transfection of ERK1 with PDX-1 resulted in an enhanced PDX-1 expression in HEK293 cells in a dose-dependent manner. Immunoprecipitation/Western blotting analysis confirmed the ERK-PDX-1 interaction in PANC-1 cells stimulated by epidermal growth factor (EGF). EGF induced an enhanced PDX-1 expression in PANC-1 cells and this stimulation was inhibited by MEK inhibitor PD0325901. Metformin inhibited EGF-stimulated PDX-1 expression with an accompanied inhibition of ERK kinase activation in PANC- 1 cells. Taken together, our studies show that PDX-1 is a potential novel target for metformin in PDAC cells and that metformin may exert its anticancer action in PDAC by down-regulating PDX-1 via a mechanism involving inhibition of ERK signaling.

  9. Reduced Expression of Histone Methyltransferases KMT2C and KMT2D Correlates with Improved Outcome in Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Dawkins, Joshua B N; Wang, Jun; Maniati, Eleni; Heward, James A; Koniali, Lola; Kocher, Hemant M; Martin, Sarah A; Chelala, Claude; Balkwill, Frances R; Fitzgibbon, Jude; Grose, Richard P

    2016-08-15

    Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.2 months (P = 0.029) and 19.9 versus 11.8 months (P = 0.001), respectively. Experiments with eight human pancreatic cell lines showed attenuated cell proliferation when these methyltransferases were depleted, suggesting that this improved outcome may reflect a cell-cycle block with diminished progression from G0-G1 RNA-seq analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes, respectively, with 19 genes in common. Gene-set enrichment analysis revealed significant downregulation of genes related to cell-cycle and growth. These data were corroborated independently by examining KMT2C/D signatures extracted from the International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Furthermore, these experiments highlighted a potential role for NCAPD3, a condensin II complex subunit, as an outcome predictor in PDAC using existing gene expression series. Kmt2d depletion in KC/KPC cell lines also led to an increased response to the nucleoside analogue 5-fluorouracil, suggesting that lower levels of this methyltransferase may mediate the sensitivity of PDAC to particular treatments. Therefore, it may also be therapeutically beneficial to target these methyltransferases in PDAC, especially in those patients demonstrating higher KTM2C/D expression. Cancer Res; 76(16); 4861-71. ©2016 AACR.

  10. Reduced Expression of Histone Methyltransferases KMT2C and KMT2D Correlates with Improved Outcome in Pancreatic Ductal Adenocarcinoma

    Science.gov (United States)

    Dawkins, Joshua B.N.; Wang, Jun; Maniati, Eleni; Heward, James A.; Koniali, Lola; Kocher, Hemant M.; Martin, Sarah A.; Chelala, Claude; Balkwill, Frances R.; Fitzgibbon, Jude; Grose, Richard P.

    2017-01-01

    Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.2 months (P = 0.029) and 19.9 versus 11.8 months (P = 0.001), respectively. Experiments with eight human pancreatic cell lines showed attenuated cell proliferation when these methyltransferases were depleted, suggesting that this improved outcome may reflect a cell-cycle block with diminished progression from G0–G1. RNA-seq analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes, respectively, with 19 genes in common. Gene-set enrichment analysis revealed significant downregulation of genes related to cell-cycle and growth. These data were corroborated independently by examining KMT2C/D signatures extracted from the International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Furthermore, these experiments highlighted a potential role for NCAPD3, a condensin II complex subunit, as an outcome predictor in PDAC using existing gene expression series. Kmt2d depletion in KC/KPC cell lines also led to an increased response to the nucleoside analogue 5-fluorouracil, suggesting that lower levels of this methyltransferase may mediate the sensitivity of PDAC to particular treatments. Therefore, it may also be therapeutically beneficial to target these methyltransferases in PDAC, especially in those patients demonstrating higher KTM2C/D expression. PMID:27280393

  11. Diagnostic value of immunohistochemical IMP3 expression in core needle biopsies of pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Wachter, David Lukas; Schlabrakowski, Anne; Hoegel, Josef; Kristiansen, Glen; Hartmann, Arndt; Riener, Marc-Oliver

    2011-06-01

    The oncofetal protein, insulin-like growth factor II messenger ribonucleic acid-binding protein 3 (IMP3), has been analyzed in many different tumors. Various studies have found that IMP3 is a marker for malignancy and is correlated with increased tumor aggressiveness and reduced overall survival. The diagnosis of pancreatic ductal adenocarcinoma (PDAC) in core needle biopsies can be challenging, and immunohistochemical markers are needed. We studied IMP3 expression in 177 core needle biopsies of the pancreas, including 112 PDACs, 55 cases with chronic sclerosing pancreatitis, and 10 biopsies with tumor-free pancreatic tissue without inflammation. An additional 18 biopsies of PDAC metastases (16 liver biopsies and 2 lymph node biopsies) were analyzed. To study IMP3 expression in large tissue sections, 45 pancreatic resection specimens (26 with PDAC and 19 with chronic sclerosing pancreatitis) were investigated. In contrast to normal or inflamed pancreatic tissue, which was negative in 47 of 65 (72.3%) cases and weakly positive in 15 of 65 (23.1%) cases, strong IMP3 expression was found in 99 of 112 (88.4%) PDACs. Therefore, sensitivity and specificity of IMP3 expression in the differential diagnosis of PDAC and chronic sclerosing pancreatitis using core needle biopsies were found to be 88.4% and 94.6%, respectively. These results were confirmed in the pancreas resection specimens. Furthermore, strong IMP3 expression was found in 17 of 18 (94.4%) of the PDAC metastases that were analyzed. Our study shows that IMP3 is an easy to use and potentially new immunohistochemical marker for the diagnosis of PDAC in core needle biopsies.

  12. X-ray phase-contrast CT of a pancreatic ductal adenocarcinoma mouse model.

    Directory of Open Access Journals (Sweden)

    Arne Tapfer

    Full Text Available To explore the potential of grating-based x-ray phase-contrast computed tomography (CT for preclinical research, a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC was investigated. One ex-vivo mouse specimen was scanned with different grating-based phase-contrast CT imaging setups covering two different settings: i high-resolution synchrotron radiation (SR imaging and ii dose-reduced imaging using either synchrotron radiation or a conventional x-ray tube source. These experimental settings were chosen to assess the potential of phase-contrast imaging for two different types of application: i high-performance imaging for virtual microscopy applications and ii biomedical imaging with increased soft-tissue contrast for in-vivo applications. For validation and as a reference, histological slicing and magnetic resonance imaging (MRI were performed on the same mouse specimen. For each x-ray imaging setup, attenuation and phase-contrast images were compared visually with regard to contrast in general, and specifically concerning the recognizability of lesions and cancerous tissue. To quantitatively assess contrast, the contrast-to-noise ratios (CNR of selected regions of interest (ROI in the attenuation images and the phase images were analyzed and compared. It was found that both for virtual microscopy and for in-vivo applications, there is great potential for phase-contrast imaging: in the SR-based benchmarking data, fine details about tissue composition are accessible in the phase images and the visibility of solid tumor tissue under dose-reduced conditions is markedly superior in the phase images. The present study hence demonstrates improved diagnostic value with phase-contrast CT in a mouse model of a complex endogenous cancer, promoting the use and further development of grating-based phase-contrast CT for biomedical imaging applications.

  13. Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Chen, Ru; Pan, Sheng; Ottenhof, NIki A.; de Wilde, Roeland F.; Wolfgang, Christopher L.; Lane, Zhaoli; Post, Jane; Bronner, Mary P.; Willmann, Jürgen K.; Maitra, Anirban; Brentnall, Teresa A.

    2012-01-01

    The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival. PMID:22785208

  14. Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma: A retrospective cohort study.

    Science.gov (United States)

    Ninomiya, Go; Fujii, Tsutomu; Yamada, Suguru; Yabusaki, Norimitsu; Suzuki, Kojiro; Iwata, Naoki; Kanda, Mitsuro; Hayashi, Masamichi; Tanaka, Chie; Nakayama, Goro; Sugimoto, Hiroyuki; Koike, Masahiko; Fujiwara, Michitaka; Kodera, Yasuhiro

    2017-03-01

    To investigate the impact of the body composition such as skeletal muscle, visceral fat and body mass index (BMI) on patients with resected pancreatic ductal adenocarcinoma (PDAC). A total of 265 patients who underwent curative surgery for PDAC were examined in this study. The total skeletal muscle and fat tissue areas were evaluated in a single image obtained at the third lumber vertebra during a preoperative computed tomography (CT) scan. The patients were assigned to either the sarcopenia or non-sarcopenia group based on their skeletal muscle index (SMI) and classified into high visceral fat area (H-VFA) or low VFA (L-VFA) groups. The association of clinicopathological features and prognosis with the body composition were statistically analyzed. There were 170 patients (64.2%) with sarcopenia. The median survival time (MST) was 23.7 months for sarcopenia patients and 25.8 months for patients without sarcopenia. The MST was 24.4 months for H-VFA patients and 25.8 months for L-VFA patients. However, sarcopenia patients with BMI ≥22 exhibited significantly poorer survival than patients without sarcopenia (MST: 19.2 vs. 35.4 months, P = 0.025). There was a significant difference between patients with and without sarcopenia who did not receive chemotherapy (5-year survival rate: 0% vs. 68.3%, P = 0.003). The multivariate analysis revealed that tumor size, positive dissected peripancreatic tissue margin, and sarcopenia were independent prognostic factors. Sarcopenia is an independent prognostic factor in PDAC patients with a BMI ≥22. Therefore, evaluating skeletal muscle mass may be a simple and useful approach for predicting patient prognosis. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

  15. Texture analysis for survival prediction of pancreatic ductal adenocarcinoma patients with neoadjuvant chemotherapy

    Science.gov (United States)

    Chakraborty, Jayasree; Langdon-Embry, Liana; Escalon, Joanna G.; Allen, Peter J.; Lowery, Maeve A.; O'Reilly, Eileen M.; Do, Richard K. G.; Simpson, Amber L.

    2016-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States. The five-year survival rate for all stages is approximately 6%, and approximately 2% when presenting with distant disease.1 Only 10-20% of all patients present with resectable disease, but recurrence rates are high with only 5 to 15% remaining free of disease at 5 years. At this time, we are unable to distinguish between resectable PDAC patients with occult metastatic disease from those with potentially curable disease. Early classification of these tumor types may eventually lead to changes in initial management including the use of neoadjuvant chemotherapy or radiation, or in the choice of postoperative adjuvant treatments. Texture analysis is an emerging methodology in oncologic imaging for quantitatively assessing tumor heterogeneity that could potentially aid in the stratification of these patients. The present study derives several texture-based features from CT images of PDAC patients, acquired prior to neoadjuvant chemotherapy, and analyzes their performance, individually as well as in combination, as prognostic markers. A fuzzy minimum redundancy maximum relevance method with leave-one-image-out technique is included to select discriminating features from the set of extracted features. With a naive Bayes classifier, the proposed method predicts the 5-year overall survival of PDAC patients prior to neoadjuvant therapy and achieves the best results in terms of the area under the receiver operating characteristic curve of 0:858 and accuracy of 83:0% with four-fold cross-validation techniques.

  16. Missed pancreatic ductal adenocarcinoma: Assessment of early imaging findings on prediagnostic magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Kyung Mi; Kim, Seong Hyun, E-mail: sh6453.kim@samsung.com; Kim, Young Kon; Song, Kyoung Doo; Lee, Soon Jin; Choi, Dongil

    2015-08-15

    Highlights: • MR imaging was superior to CT for the detection of early PDAC. • A focal lesion with no MPD interruption is common MR finding of early PDAC. • A mean volume doubling time of early PDAC was about five months. - Abstract: Objective: To investigate the early imaging findings and growth rate of pancreatic ductal adenocarcinoma (PDAC), and to assess whether MR imaging detects early PDAC better than CT. Materials and methods: The institutional review board approved this retrospective study and waived the requirement for informed consent. Twenty-two patients were included, and two radiologists, by consensus, assessed the presence of focal lesions, interruption of the main pancreatic duct (MPD), MPD dilatation, and pancreatitis, volume doubling time (VDT) of PDAC on prediagnostic MR imaging. Two other observers independently reviewed three image sets (CT images, unenhanced MR images, and unenhanced and contrast-enhanced MR images) for the detection of early PDAC. Paired Wilcoxon signed rank test and receiver operating characteristic (ROC) curve analysis were used for statistical analyses. Results: In 20 (90.9%) patients, prediagnostic MR exams showed abnormality, and all of them showed focal lesions on the first abnormal prediagnostic MR exams. Thirteen lesions (65%) showed no MPD interruption and one lesion (5%) was accompanied by pancreatitis. The mean VDT of PDAC was 151.7 days (range, 18.3–417.8 days). Diagnostic performance of unenhanced MR images (Az, 0.971–0.989) and combined unenhanced and contrast-enhanced MR images (Az, 0.956–0.963) was significantly better than that of CT images (Az, 0.565–0.583; p < 0.01) for both observers, Conclusion: The most common early imaging finding of PDAC on prediagnostic MR exams was a focal lesion with no MPD interruption with a mean volume doubling time of five months. MR imaging was superior to CT for the detection of early PDAC.

  17. MicroRNA Profiling Implies New Markers of Gemcitabine Chemoresistance in Mutant p53 Pancreatic Ductal Adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Sameer A Dhayat

    Full Text Available No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma (PDAC. MicroRNAs (miR are epigenetic gene regulators with tumorsuppressive or oncogenic roles in various carcinomas. This study assesses chemoresistant PDAC for its specific miR expression pattern.Gemcitabine-resistant variants of two mutant p53 human PDAC cell lines were established. Survival rates were analyzed by cytotoxicity and apoptosis assays. Expression of 1733 human miRs was investigated by microarray and validated by qRT-PCR. After in-silico analysis of specific target genes and proteins of dysregulated miRs, expression of MRP-1, Bcl-2, mutant p53, and CDK1 was quantified by Western blot.Both established PDAC clones showed a significant resistance to gemcitabine (p<0.02 with low apoptosis rate (p<0.001 vs. parental cells. MiR-screening revealed significantly upregulated (miR-21, miR-99a, miR-100, miR-125b, miR-138, miR-210 and downregulated miRs (miR-31*, miR-330, miR-378 in chemoresistant PDAC (p<0.05. Bioinformatic analysis suggested involvement of these miRs in pathways controlling cell death and cycle. MRP-1 (p<0.02 and Bcl-2 (p<0.003 were significantly overexpressed in both resistant cell clones and mutant p53 (p = 0.023 in one clone.Consistent miR expression profiles, in part regulated by mutant TP53 gene, were identified in gemcitabine-resistant PDAC with significant MRP-1 and Bcl-2 overexpression. These results provide a basis for further elucidation of chemoresistance mechanisms and therapeutic approaches to overcome chemoresistance in PDAC.

  18. CEACAM6 Cross-linking Induces Caveolin-1-dependent, Src-mediated Focal Adhesion Kinase Phosphorylation in BxPC3 Pancreatic Adenocarcinoma Cells

    National Research Council Canada - National Science Library

    Mark S. Duxbury; Hiromichi Ito; Stanley W. Ashley; Edward E. Whang

    2004-01-01

    .... We examined the effects of antibody-mediated cross-linking of CEACAM6 on intracellular signaling events and anchorage-independent survival of the CEACAM6-overexpressing pancreatic ductal adenocarcinoma cell line, BxPC3...

  19. Pancreatic Ductal Adenocarcinoma With High Radiotracer Uptake in 68Ga-Prostate-Specific Membrane Antigen PET/CT.

    Science.gov (United States)

    Sahbai, Samine; Rieping, Petra; Pfannenberg, Christina; la Fougére, Christian; Reimold, Matthias

    2017-09-01

    Prostate-specific membrane antigen imaging with PET/CT is increasingly used in prostate cancer and was shown to have a high diagnostic performance. We report a clinical case of a 67-year-old man with previous history of operated prostate cancer and increasing prostate-specific antigen blood level. Ga-HBED-CC prostate-specific membrane antigen PET/CT imaging was indicated for the assessment of local recurrence and lymph node metastases of prostate cancer. In addition, a soft tissue mass in the body of the pancreas with high radiotracer uptake was detected. Histopathology confirmed a pancreatic ductal adenocarcinoma.

  20. hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Lastraioli, E; Perrone, G; Sette, A; Fiore, A; Crociani, O; Manoli, S; D'Amico, M; Masselli, M; Iorio, J; Callea, M; Borzomati, D; Nappo, G; Bartolozzi, F; Santini, D; Bencini, L; Farsi, M; Boni, L; Di Costanzo, F; Schwab, A; Onetti Muda, A; Coppola, R; Arcangeli, A

    2015-01-01

    Background: hERG1 channels are aberrantly expressed in human cancers. The expression, functional role and clinical significance of hERG1 channels in pancreatic ductal adenocarcinoma (PDAC) is lacking. Methods: hERG1 expression was tested in PDAC primary samples assembled as tissue microarray by immunohistochemistry using an anti-hERG1 monoclonal antibody (α-hERG1-MoAb). The functional role of hERG1 was studied in PDAC cell lines and primary cultures. ERG1 expression during PDAC progression was studied in Pdx-1-Cre,LSL-KrasG12D/+,LSL-Trp53R175H/+ transgenic (KPC) mice. ERG1 expression in vivo was determined by optical imaging using Alexa-680-labelled α-hERG1-MoAb. Results: (i) hERG1 was expressed at high levels in 59% of primary PDAC; (ii) hERG1 blockade decreased PDAC cell growth and migration; (iii) hERG1 was physically and functionally linked to the Epidermal Growth Factor-Receptor pathway; (iv) in transgenic mice, ERG1 was expressed in PanIN lesions, reaching high expression levels in PDAC; (v) PDAC patients whose primary tumour showed high hERG1 expression had a worse prognosis; (vi) the α-hERG1-MoAb could detect PDAC in vivo. Conclusions: hERG1 regulates PDAC malignancy and its expression, once validated in a larger cohort also comprising of late-stage, non-surgically resected cases, may be exploited for diagnostic and prognostic purposes in PDAC either ex vivo or in vivo. PMID:25719829

  1. Coexpression of EGFR and CXCR4 predicts poor prognosis in resected pancreatic ductal adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Huanwen Wu

    Full Text Available Epidermal growth factor receptor (EGFR is highly expressed in pancreatic ductal adenocarcinoma (PDAC and is involved in tumorigenesis and development. However, EGFR expression alone has limited clinical and prognostic significance. Recently, the cross-talk between EGFR and G-protein-coupled chemokine receptor CXCR4 has become increasingly recognized.In the present study, immunohistochemical staining of EGFR and CXCR4 was performed on paraffin-embedded specimens from 131 patients with surgically resected PDAC. Subsequently, the associations between EGFR expression, CXCR4 expression, EGFR/CXCR4 coexpression and clinicopathologic factors were assessed, and survival analyses were performed.In total, 64 (48.9% patients expressed EGFR, 68 (51.9% expressed CXCR4, and 33 (25.2% coexpressed EGFR and CXCR4. No significant association between EGFR and CXCR4 expression was observed (P = 0.938. EGFR expression significantly correlated with tumor differentiation (P = 0.031, whereas CXCR4 expression significantly correlated with lymph node metastasis (P = 0.001. EGFR/CXCR4 coexpression was significantly associated with lymph node metastasis (P = 0.026, TNM stage (P = 0.048, and poor tumor differentiation (P = 0.004. By univariate survival analysis, both CXCR4 expression and EGFR/CXCR4 coexpression were significant prognostic factors for poor disease-free survival (DFS and overall survival (OS. Moreover, EGFR/CXCR4 coexpression significantly increased the hazard ratio for both recurrence and death compared with EGFR or CXCR4 protein expression alone. Multivariate survival analysis demonstrated that EGFR/CXCR4 coexpression was an independent prognostic factor for DFS (HR = 2.33, P<0.001 and OS (HR = 2.48, P = 0.001.In conclusion, our data indicate that although EGFR expression alone has limited clinical and prognostic significance, EGFR/CXCR4 coexpression identified a subset of PDAC patients with more aggressive tumor characteristics and a significantly worse

  2. Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Elisabetta Ceni; Tommaso Mello; Mirko Tarocchi; David W Crabb; Anna Caldini; Pietro Invernizzi; Calogero Surrenti; Stefano Milani; Andrea Galli

    2005-01-01

    AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study,we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma.METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay.Expression of PPARγ was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARγ activity was evaluated by transient reporter gene assay. Flow cytometry and DNA fragmentationassay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot.RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate.CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.

  3. Ductal Adenocarcinoma of the Prostate With a Rare Clinical Presentation; Late Gastric Metastasis

    Directory of Open Access Journals (Sweden)

    Hasan Huseyin Tavukcu

    2016-07-01

    Full Text Available A 67 year male had robotic prostatectomy whose pathology revealed mixed type prostate cancer composed of 55% ductal and 45% acinar components. The patient was then admitted to hospital with sudden health problems including ascites and serious vomiting attacks in the 46th month after prostatectomy and the PSA test was 4565 ng/mL. Gastroscopic biopsy was reported and proved immunhistochemically undifferentiated ductal prostate cancer metastasis. This is the first report of late gastric metastasis of ductal prostate cancer.

  4. Contrast enhanced ultrasound with quantitative perfusion analysis for objective characterization of pancreatic ductal adenocarcinoma: A feasibility study.

    Science.gov (United States)

    D'Onofrio, Mirko; Canestrini, Stefano; Crosara, Stefano; De Robertis, Riccardo; Pozzi Mucelli, Roberto

    2014-03-28

    The aim of this study was to determine whether contrast enhanced ultrasound (CEUS) quantitative perfusion analysis allows an objective characterization of ductal adenocarcinoma (ADK) of the pancreas. Patients with pancreatic ADK underwent CEUS. All examinations were performed on an Acuson S2000 system (Siemens, Erlangen, Germany) after the iv administration of 2.4 mL contrast agent (SonoVue(®), Bracco, Milan, Italy). All lesions were pathologically proved. An operator manually drew different regions of interest within the tumor and the adjacent parenchyma to allow the quantitative perfusion analysis. The mean values of peak of enhancement, time to peak and ascending curve were calculated and compared using the Student's t test. The quantitative perfusion analysis was possible in all lesions. The mean values of the peak of enhancement, time to peak and ascending curve were 17.19%, 7.97 s and 159.52% s within the tumor and 33.57%, 8.89 s and 355.29% s within the adjacent parenchyma. The peak of enhancement and the ascending curve values were significantly different within the tumor and the adjacent parenchyma. Thus, CEUS allows the quantitative perfusion analysis of pancreatic ductal adenocarcinoma.

  5. Ductal Adenocarcinoma of the Prostate With a Rare Clinical Presentation; Late Gastric Metastasis

    OpenAIRE

    Hasan Huseyin Tavukcu; Omer Aytac; Fatma Aktepe; Fatih Atug; Levent Erdem; Coskun Tecimer

    2016-01-01

    A 67 year male had robotic prostatectomy whose pathology revealed mixed type prostate cancer composed of 55% ductal and 45% acinar components. The patient was then admitted to hospital with sudden health problems including ascites and serious vomiting attacks in the 46th month after prostatectomy and the PSA test was 4565 ng/mL. Gastroscopic biopsy was reported and proved immunhistochemically undifferentiated ductal prostate cancer metastasis. This is the first report of late gastric metastas...

  6. Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions.

    Science.gov (United States)

    Laeseke, Paul F; Chen, Ru; Jeffrey, R Brooke; Brentnall, Teresa A; Willmann, Jürgen K

    2015-12-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. (©) RSNA, 2015.

  7. Numb Chin Syndrome Leading to a Diagnosis of Salivary Ductal Adenocarcinoma: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Lei Wu

    2017-07-01

    Full Text Available Numb chin syndrome (NCS refers to a rare sensory neuropathy characterized by numbness of the chin within the distribution of the mental or inferior alveolar nerve. Although NCS is usually caused by a benign process, it should not be underestimated and a thorough diagnostic evaluation for a new or known progressive malignancy should always be performed. Here, we report a case of salivary ductal adenocarcinoma that mimicked a pulpitis and periodontitis in its early presentation accompanied by numbness of chin. The course and diagnosis of this case are discussed, and a brief review of the literature is presented. It is hoped for clinicians to keep the malignant possibility of NCS in mind and take a thorough examination.

  8. Inflammatory response related scoring systems in assessing the prognosis of patients with pancreatic ductal adenocarcinoma:a systematic review

    Institute of Scientific and Technical Information of China (English)

    Jawad Ahmad; Nathan Grimes; Shahid Farid; Gareth Morris-Stiff

    2014-01-01

    BACKGROUND: Various scoring systems based on assessment of the systemic inflammatory response help assessing the prognosis of patients with pancreatic ductal adenocarcinoma. In the present systematic review we evaluated the validity of four pre-intervention scoring systems: Glasgow prognostic score (GPS) and its modified version (mGPS), platelet lymphocyte ratio (PLR), neutrophil lymphocyte ratio (NLR), and prognostic nutrition index (PNI). DATA SOURCES: MOOSE guidelines were followed and EMBASE and MEDLINE databases were searched for all published studies until September 2013 using comprehensive text word and MeSH terms. All identified studies were analyzed, and relevant studies were included in the systematic review. RESULTS: Six studies were identified for GPS/mGPS with 3 reporting statistical significance for GPS/mGPS on both univariate analysis (UVA) and multivariate analysis (MVA). Two studies suggested prognostic significance on UVA but not MVA, and in the final study UVA failed to show significance. Eleven studies evaluated the prognostic value of NLR. Six of them reported prognostic significance for NLR on UVA that persisted at MVA in 4 studies, and in the remaining 2 studies NLR was the only significant factor on UVA. In the remaining 5 studies, all in patients undergoing resection, there was no significance on UVA. Seven studies evaluated PLR, with only one study demonstrated its prognostic significance on both UVA and MVA, the rest did not show the significance on UVA. Of the two studies identified for PNI, one demonstrated a statistically significant difference in survival on both UVA and MVA, and the other reported no significance for PNI on UVA. CONCLUSIONS: Both GPS/mGPS and NLR may be useful but further better-designed studies are required to confirm their value. PLR might be little useful, and there are at present inadequate data to assess the prognostic value of PNI. At present, no scoring system is reliable enough to be accepted into routine use

  9. Extracellular Ca2+ Sensing in Salivary Ductal Cells*

    Science.gov (United States)

    Bandyopadhyay, Bidhan C.; Swaim, William D.; Sarkar, Ankana; Liu, Xibao; Ambudkar, Indu S.

    2012-01-01

    Ca2+ is secreted from the salivary acinar cells as an ionic constituent of primary saliva. Ions such as Na+ and Cl− get reabsorbed whereas primary saliva flows through the salivary ductal system. Although earlier studies have shown that salivary [Ca2+] decreases as it flows down the ductal tree into the oral cavity, ductal reabsorption of Ca2+ remains enigmatic. Here we report a potential role for the G protein-coupled receptor, calcium-sensing receptor (CSR), in the regulation of Ca2+ reabsorption by salivary gland ducts. Our data show that CSR is present in the apical region of ductal cells where it is co-localized with transient receptor potential canonical 3 (TRPC3). CSR is activated in isolated salivary gland ducts as well as a ductal cell line (SMIE) by altering extracellular [Ca2+] or by aromatic amino acid, l-phenylalanine (l-Phe, endogenous component of saliva), as well as neomycin. CSR activation leads to Ca2+ influx that, in polarized cells grown on a filter support, is initiated in the luminal region. We show that TRPC3 contributes to Ca2+ entry triggered by CSR activation. Further, stimulation of CSR in SMIE cells enhances the CSR-TRPC3 association as well as surface expression of TRPC3. Together our findings suggest that CSR could serve as a Ca2+ sensor in the luminal membrane of salivary gland ducts and regulate reabsorption of [Ca2+] from the saliva via TRPC3, thus contributing to maintenance of salivary [Ca2+]. CSR could therefore be a potentially important protective mechanism against formation of salivary gland stones (sialolithiasis) and infection (sialoadenitis). PMID:22778254

  10. TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells.

    Science.gov (United States)

    Liu, Jun; Akanuma, Naoki; Liu, Chengyang; Naji, Ali; Halff, Glenn A; Washburn, William K; Sun, Luzhe; Wang, Pei

    2016-08-03

    Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.

  11. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3 overexpression in pancreatic ductal adenocarcinoma correlates with poor survival

    Directory of Open Access Journals (Sweden)

    Scudamore Charles H

    2010-02-01

    Full Text Available Abstract Background Pancreatic ductal adenocarcinoma is a lethal disease with a 5-year survival rate of 4% and typically presents in an advanced stage. In this setting, prognostic markers identifying the more agrressive tumors could aid in managment decisions. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3, also known as IMP3 or KOC is an oncofetal RNA-binding protein that regulates targets such as insulin-like growth factor-2 (IGF-2 and ACTB (beta-actin. Methods We evaluated the expression of IGF2BP3 by immunohistochemistry using a tissue microarray of 127 pancreatic ductal adenocarcinomas with tumor grade 1, 2 and 3 according to WHO criteria, and the prognostic value of IGF2BP3 expression. Results IGF2BP3 was found to be selectively overexpressed in pancreatic ductal adenocarcinoma tissues but not in benign pancreatic tissues. Nine (38% patient samples of tumor grade 1 (n = 24 and 27 (44% of tumor grade 2 (n = 61 showed expression of IGF2BP3. The highest rate of expression was seen in poorly differentiated specimen (grade 3, n = 42 with 26 (62% positive samples. Overall survival was found to be significantly shorter in patients with IGF2BP3 expressing tumors (P = 0.024; RR 2.3, 95% CI 1.2-4.8. Conclusions Our data suggest that IGF2BP3 overexpression identifies a subset of pancreatic ductal adenocarcinomas with an extremely poor outcome and supports the rationale for developing therapies to target the IGF pathway in this cancer.

  12. Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites

    OpenAIRE

    Allaway, Robert J.; Fischer, Dawn A.; de Abreu, Francine B.; Gardner, Timothy B.; Gordon, Stuart R.; Barth, Richard J.; Colacchio, Thomas A.; Wood, Matthew; Kacsoh, Balint Z.; Bouley, Stephanie J.; Cui, Jingxuan; Hamilton, Joanna; Choi, Jungbin A.; Lange, Joshua T.; Peterson, Jason D.

    2016-01-01

    N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activatin...

  13. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

    DEFF Research Database (Denmark)

    Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W

    2016-01-01

    by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were......Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop...... stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression...

  14. Distinction of Invasive Carcinoma Derived From Intraductal Papillary Mucinous Neoplasms From Concomitant Ductal Adenocarcinoma of the Pancreas Using Molecular Biomarkers.

    Science.gov (United States)

    Tamura, Koji; Ohtsuka, Takao; Date, Kenjiro; Fujimoto, Takaaki; Matsunaga, Taketo; Kimura, Hideyo; Watanabe, Yusuke; Miyazaki, Tetsuyuki; Ohuchida, Kenoki; Takahata, Shunichi; Ishigami, Kousei; Oda, Yoshinao; Mizumoto, Kazuhiro; Nakamura, Masafumi; Tanaka, Masao

    2016-07-01

    To clarify the usefulness of molecular biomarkers for distinguishing invasive carcinoma derived from intraductal papillary mucinous neoplasms (IPMNs [Inv-IPMN]) from concomitant pancreatic ductal adenocarcinoma (PDAC). Data from 19 patients with resected concomitant PDAC were retrospectively reviewed. KRAS/GNAS mutations and immunohistochemical (IHC) expression of p53 and p16/CDKN2A were assessed in both IPMN and distinct PDAC. As controls, KRAS/GNAS mutations and IHC labeling were assessed between invasive and noninvasive components in 1 lesion of 22 independent patients. KRAS/GNAS mutation status of invasive and noninvasive components in Inv-IPMN was consistent in 18 (86%) of 21 patients. Conversely, mutational patterns in IPMN and distinct PDAC in the same pancreas differed from each other in 17 (89%) of 19. There were 10 (53%) and 8 (42%) of 19 patients who showed the same p53 and p16/CDKN2A staining between concomitant PDAC and distinct IPMN. In the Inv-IPMN cohort, 19 (86%) of 22 patients showed the same IHC expression pattern between the noninvasive and invasive components. It may be possible to distinguish Inv-IPMN from concomitant PDAC by assessing these molecular biomarkers. More precise distinction of Inv-IPMN and concomitant PDAC will lead to adequate recognition of the natural history of IPMNs and hence optimal management.

  15. Effect of CCR7, CXCR4 and VEGF-C on the lymph node metastasis of human pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Guo, Jinghui; Lou, Wenhui; Ji, Yuan; Zhang, Shuncai

    2013-05-01

    The aim of the present study was to investigate the association between the expression of chemokine receptors CCR7 and CXCR4 and vascular endothelial growth factor (VEGF)-C and the lymph node metastasis of pancreatic ductal adenocarcinoma (PDAC). The mRNA transcription levels of CCR7, CXCR4 and VEGF-C were measured in 24 specimens by real-time reverse transcription (RT)-PCR, while the protein expression levels were measured in 65 specimens by immuohistochemistry. Professional software for pathological image manipulation (Image Pro Plus 6.0) was used to quantitate the results of the immunohistochemical staining. The mRNA and protein expression levels of CCR7, CXCR4 and VEGF-C were all significantly higher in the cancer samples compared with those in the adjacent normal tissue. The CCR7 and VEGF-C mRNA and protein expression levels were significantly higher in the patients with cancer types exhibiting lymph node metastasis and an advanced International Union Against Cancer (UICC) stage (PCCR7 expression (PCCR7 and VEGF-C (P0.05), however the strong positive expression of CCR7 and VEGF-C was significantly associated with the lymph node metastasis of PDAC.

  16. Seven-Signal Proteomic Signature for Detection of Operable Pancreatic Ductal Adenocarcinoma and Their Discrimination from Autoimmune Pancreatitis

    Directory of Open Access Journals (Sweden)

    Kiyoshi Yanagisawa

    2012-01-01

    Full Text Available There is urgent need for biomarkers that provide early detection of pancreatic ductal adenocarcinoma (PDAC as well as discrimination of autoimmune pancreatitis, as current clinical approaches are not suitably accurate for precise diagnosis. We used mass spectrometry to analyze protein profiles of more than 300 plasma specimens obtained from PDAC, noncancerous pancreatic diseases including autoimmune pancreatitis patients and healthy subjects. We obtained 1063 proteomic signals from 160 plasma samples in the training cohort. A proteomic signature consisting of 7 mass spectrometry signals was used for construction of a proteomic model for detection of PDAC patients. Using the test cohort, we confirmed that this proteomic model had discrimination power equal to that observed with the training cohort. The overall sensitivity and specificity for detection of cancer patients were 82.6% and 90.9%, respectively. Notably, 62.5% of the stage I and II cases were detected by our proteomic model. We also found that 100% of autoimmune pancreatitis patients were correctly assigned as noncancerous individuals. In the present paper, we developed a proteomic model that was shown able to detect early-stage PDAC patients. In addition, our model appeared capable of discriminating patients with autoimmune pancreatitis from those with PDAC.

  17. Microvessel Landscape Assessment in Pancreatic Ductal Adenocarcinoma: Unclear Value of Targeting Endoglin (CD105) as Prognostic Factor of Clinical Outcome.

    Science.gov (United States)

    Lytras, Dimitrios; Leontara, Vassileia; Kefala, Maria; Foukas, Periklis G; Giannakou, Niki; Pouliakis, Abraham; Dervenis, Christos; Panayiotides, Ioannis G; Karakitsos, Petros

    2015-01-01

    Tumor angiogenesis based on microvessel density assessment has been associated with poor prognosis in several studies of patients with pancreatic ductal adenocarcinoma (PDAC). Expression of endoglin (CD105), a tumor-induced vascularization marker, has been found to represent a negative prognostic factor in many malignant tumors. The aim of our study was to assess the value of tumoral microvascularity both with pan-endothelial markers and endoglin as well, in correlation with the clinical outcome of patients with PDAC. Fifty-eight patients with PDAC, 36 males and 22 females, with a mean (SD) age of 65.4 (10.0) years were included in the study. Deparaffinized sections from formalin-fixed areas both from the center and periphery (invasion front) of the tumors were immunostained for CD105 as well as for the endothelial markers CD31 and CD34. Tumoral angiogenesis was assessed on the basis of microvessel density (number of vessels per square millimeter) and on microvascular area (square micrometers) as well. High intratumoral microvascular area, in endoglin-stained sections, was found to be of marginal prognostic significance for recurrence (log rank, P 0.05). Survival was also marginally associated with CD31 intratumoral microvascular area (log rank, P 0.05). Further studies are needed before endoglin replaces the conventional angiogenesis markers in PDCA.

  18. Cancer Antigen 125 (CA125, MUC16) Protein Expression in the Diagnosis and Progression of Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Jiang, Kun; Tan, Elaine; Sayegh, Zena; Centeno, Barbara; Malafa, Mokenge; Coppola, Domenico

    2016-04-16

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive carcinoma, with most patients diagnosed at an advanced stage, with a 5-year survival rate of around 5%. An urgent need exists for identifying better diagnostic, prognostic, and therapeutic markers for this lethal disease. Recently, CA125 has been identified in PDAC, and the aim of this research is to study the changes in CA125 expression during the progression of benign pancreatic tissue (BPT) to PDAC and to assess its value as a biomarker of tumor growth. To address these questions, the cellular levels of CA125 in BPT and PDAC were measured using immunohistochemistry and compared on the basis of tumor staging, and the tissue microarray technology were constructed using resected pancreatic tissues. The staining reactions for each case were evaluated semiquantitatively using the histologic score system. Our investigation demonstrates a consistent and significant upregulation of CA125 during the transition from BPT to PDAC. We also found a direct correlation between CA125 immunohistochemistry score and tumor stage (P=0.02). In conclusion, our data indicate that CA125 plays a direct role in pancreatic carcinogenesis and suggests that it may eventually be used as a diagnostic and/or prognostic biomarker of pancreatic cancer. Prospective studies are recommended to evaluate further the diagnostic and prognostic capabilities of CA125 in PDAC, and further studies are warranted to assess the use of CA125 as a therapeutic marker.

  19. Multidetector CT of pancreatic ductal adenocarcinoma: Effect of tube voltage and iodine load on tumour conspicuity and image quality

    Energy Technology Data Exchange (ETDEWEB)

    Loizou, L.; Leidner, B.; Axelsson, E.; Fischer, M.A.; Grigoriadis, A.; Kartalis, N. [Karolinska Institutet, Division of Medical Imaging and Technology, Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden); C1-46 Karolinska University Hospital Huddinge, Department of Radiology, Stockholm (Sweden); Albiin, N. [Karolinska Institutet, Division of Medical Imaging and Technology, Department of Clinical Science, Intervention and Technology (CLINTEC), Stockholm (Sweden); Ersta Hospital, Department of Radiology, Stockholm (Sweden); Del Chiaro, M.; Segersvaerd, R. [Karolinska University Hospital Huddinge, Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Center for Digestive Diseases, Stockholm (Sweden); Verbeke, C. [Karolinska Institutet and Karolinska University Hospital Huddinge, Division of Pathology, Department of Laboratory Medicine, Stockholm (Sweden); Sundin, A. [Uppsala University Hospital, Department of Surgical Sciences, Division of Radiology, Uppsala University and Department of Radiology, Uppsala (Sweden)

    2016-11-15

    To compare a low-tube-voltage with or without high-iodine-load multidetector CT (MDCT) protocol with a normal-tube-voltage, normal-iodine-load (standard) protocol in patients with pancreatic ductal adenocarcinoma (PDAC) with respect to tumour conspicuity and image quality. Thirty consecutive patients (mean age: 66 years, men/women: 14/16) preoperatively underwent triple-phase 64-channel MDCT examinations twice according to: (i) 120-kV standard protocol (PS; 0.75 g iodine (I)/kg body weight, n = 30) and (ii) 80-kV protocol A (PA; 0.75 g I/kg, n = 14) or protocol B (PB; 1 g I/kg, n = 16). Two independent readers evaluated tumour delineation and image quality blindly for all protocols. A third reader estimated the pancreas-to-tumour contrast-to-noise ratio (CNR). Statistical analysis was performed with the Chi-square test. Tumour delineation was significantly better in PB and PA compared with PS (P = 0.02). The evaluation of image quality was similar for the three protocols (all, P > 0.05). The highest CNR was observed with PB and was significantly better compared to PA (P = 0.02) and PS (P = 0.0002). In patients with PDAC, a low-tube-voltage, high-iodine-load protocol improves tumour delineation and CNR leading to higher tumour conspicuity compared to standard protocol MDCT. (orig.)

  20. Myoepithelial cell differentiation markers in ductal carcinoma in situ progression.

    Science.gov (United States)

    Russell, Tanya D; Jindal, Sonali; Agunbiade, Samiat; Gao, Dexiang; Troxell, Megan; Borges, Virginia F; Schedin, Pepper

    2015-11-01

    We describe a preclinical model that investigates progression of early-stage ductal carcinoma in situ (DCIS) and report that compromised myoepithelial cell differentiation occurs before transition to invasive disease. Human breast cancer MCF10DCIS.com cells were delivered into the mouse mammary teat by intraductal injection in the absence of surgical manipulations and accompanying wound-healing confounders. DCIS-like lesions developed throughout the mammary ducts with full representation of human DCIS histologic patterns. Tumor cells were incorporated into the normal mammary epithelium, developed ductal intraepithelial neoplasia and DCIS, and progressed to invasive carcinoma, suggesting the model provides a rigorous approach to study early stages of breast cancer progression. Mammary glands were evaluated for myoepithelium integrity with immunohistochemical assays. Progressive loss of the myoepithelial cell differentiation markers p63, calponin, and α-smooth muscle actin was observed in the mouse myoepithelium surrounding DCIS-involved ducts. p63 loss was an early indicator, calponin loss intermediate, and α-smooth muscle actin a later indicator of compromised myoepithelium. Loss of myoepithelial calponin was specifically associated with gain of the basal marker p63 in adjacent tumor cells. In single time point biopsies obtained from 16 women diagnosed with pure DCIS, a similar loss in myoepithelial cell markers was observed. These results suggest that further research is warranted into the role of myoepithelial cell p63 and calponin expression on DCIS progression to invasive disease.

  1. Upstream and Downstream Co-inhibition of Mitogen-Activated Protein Kinase and PI3K/Akt/mTOR Pathways in Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Matthew H. Wong

    2016-07-01

    Full Text Available BACKGROUND: Extensive cross talk exists between PI3K/Akt/mTOR and mitogen-activated protein kinase (MAPK pathways, and both are upregulated in pancreatic ductal adenocarcinoma (PDAC. Our previous study suggested that epidermal growth factor receptor inhibitor erlotinib which acts upstream of these pathways acts synergistically with PI3K inhibitors in PDAC. Horizontal combined blockade upstream and downstream of these two pathways is therefore explored. METHODS: Erlotinib paired with PI3K inhibitor (BYL719 was tested against erlotinib plus dual PI3K/mTOR inhibitor BEZ-235, and MEK inhibitor (PD98059 plus BEZ235, on five primary PDAC cell lines and on two pairs of parent and erlotinib-resistant (ER cell lines. A range of in vitro assays including cell proliferation, Western blotting, migration, clonogenic, cell cycle, and apopotic assays was used to test for the efficacy of combined blockade. RESULTS: Dual downstream blockade of the MAPK and PAM pathways was more effective in attenuating downstream molecular signals. Synergy was demonstrated for erlotinib and BEZ235 and for PD-98059 and BEZ-235. This resulted in a trend of increased growth cell cycle arrest, apoptosis, cell proliferation, and colony and migration suppression. This combination showed more efficacy in cell lines with acquired resistance to erlotinib. CONCLUSIONS: The additional mTOR blockade provided by BEZ235 in combined blockade resulted in increased anticancer effect. The hypersensitivity of ER cell lines to additional mTOR blockade suggested PAM pathway oncogenic dependence via mTOR. Dual downstream combined blockade of MAPK and PAM pathways with MEK and PI3K/mTOR inhibitor appeared most effective and represents an attractive therapeutic strategy against pancreatic cancer and its associated drug resistance.

  2. MicroRNA-181b-5p, ETS1, and the c-Met pathway exacerbate the prognosis of pancreatic ductal adenocarcinoma after radiation therapy.

    Science.gov (United States)

    Tomihara, Hideo; Yamada, Daisaku; Eguchi, Hidetoshi; Iwagami, Yoshifumi; Noda, Takehiro; Asaoka, Tadafumi; Wada, Hiroshi; Kawamoto, Koichi; Gotoh, Kunihito; Takeda, Yutaka; Tanemura, Masahiro; Mori, Masaki; Doki, Yuichiro

    2017-03-01

    Preoperative chemoradiation therapy (CRT) for pancreatic ductal adenocarcinoma (PDAC) has emerged as a reasonable strategy that shows good prognostic impact. However, after preoperative CRT, resected specimens show remnant tumor cells, which indicate that some tumor cells had acquired or were selected for resistance to CRT. Recently, two oncological mechanisms, the EMT and the presence of CSCs, were reported to be associated with resistance in various cancers. Previous reports showed that HGF could induce EMT in PDAC cells; moreover, the HGF receptor, c-Met, was identified as a dominant pancreatic CSC marker. However, the clinical significance of c-Met expression remains unclear. So, we hypothesized that remnant PDAC tissue after CRT might harbor cells with high c-Met expression, and these cells may exacerbate patients' prognosis. In the immunohistochemical analysis, we showed that preoperative CRT was significantly associated with high c-Met expression; moreover, high c-Met expression was a significant marker of a dismal prognosis. Next, we investigated mechanisms of c-Met upregulation in PDAC cells. We established GEM-resistant and radioresistant PDAC cells to analyze the transcriptome involved in c-Met expression. The microarray data for the established radiation-resistant PDAC cells indicated miR-181b-5p downregulation, which targets ETS1, one of the transcription factors for c-Met, and it was shown that radiation exposure induced c-Met expression through ETS1 increase by the suppression of miR-181b-5p. These results suggested that targeting these mechanisms may promote the development of a novel multidisciplinary treatment strategy for improving preoperative CRT efficiency.

  3. Reduced expression of argininosuccinate synthetase 1 has a negative prognostic impact in patients with pancreatic ductal adenocarcinoma

    Science.gov (United States)

    Liu, Qingqing; Stewart, John; Wang, Hua; Rashid, Asif; Zhao, Jun; Katz, Matthew H.; Lee, Jeffrey E.; Fleming, Jason B.; Maitra, Anirban; Wolff, Robert A.; Varadhachary, Gauri R.; Krishnan, Sunil; Wang, Huamin

    2017-01-01

    Argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme for arginine biosynthesis, is expressed in many types of human malignancies. Recent studies showed that ASS1 may have tumor suppressor function and that ASS1 deficiency is associated with clinical aggressiveness in nasopharyngeal carcinoma, myxofibrosarcomas and bladder cancer. The goal of this study was to evaluate the prognostic impact of ASS1 expression in patients with pancreatic ductal adenocarcinoma (PDAC). Our study included two independent cohorts: untreated cohort, which was comprised of 135 patients with PDAC who underwent pancreatoduodenectomy (PD) without pre-operative neoadjuvant therapy, and treated cohort, which was comprised of 122 patients with PDAC who have completed neoadjuvant therapy and PD. The expression level of ASS1 was evaluated by immunohistochemistry and the results were correlated with clinicopathologic parameters and survival using SPSS statistics. Our study showed that 12% of PDAC in untreated cohort and 15% of PDAC in treated cohort has low expression of ASS1 (ASS1-low). ASS1-low was associated with higher recurrence (p = 0.045), shorter disease-free survival (DFS, 4.8 ± 1.6 months vs 15.3 ± 2.2 months, p = 0.001) and shorter overall survival (OS, 14.6 ± 6.4 months vs 26.5 ± 3.5 months, p = 0.005) in untreated cohort and shorter OS in treated cohort compared to ASS1-high tumors. In multivariate analysis, ASS1-low (HR: 0.45, 95% CI: 0.26–0.79, p = 0.005) was an independent prognostic factor for DFS in untreated cohort and an independent prognostic factor for OS (HR: 0.56, 95% CI: 0.32–0.97, p = 0.04) in treated cohort. Our results provide supporting evidence for future clinical trial using arginine deprivation agents either alone or in combination with conventional chemotherapy in treating pancreatic cancer. PMID:28187218

  4. Resected pancreatic ductal adenocarcinomas with recurrence limited in lung have a significantly better prognosis than those with other recurrence patterns

    Science.gov (United States)

    Wangjam, Tamna; Zhang, Zhe; Zhou, Xian Chong; Lyer, Laxmi; Faisal, Farzana; Soares, Kevin C.; Fishman, Elliott; Hruban, Ralph H.; Herman, Joseph M.; Laheru, Daniel; Weiss, Matthew; Li, Min; De Jesus-Acosta, Ana; Wolfgang, Christopher L.; Zheng, Lei

    2015-01-01

    The majority of patients with curative resection of pancreatic ductal adenocarcinoma recur within 5 years of resection. However, the prognosis associated with different patterns of recurrence has not been well studied. A retrospective review of patients who underwent curative surgical resection of pancreatic cancer was performed. Of the 209 patients, 174 patients developed recurrent disease. Of these 174, 28(16.1%) had recurrent disease limited to lung metastases, 20(11.5%) had recurrence in the lung plus one or more other sites excluding the liver, 73(42.0%) had liver metastasis alone or liver metastasis with any other site except lung, 28(16.1%) local recurrence only, and 25(14.3%) peritoneal recurrence alone or together with local recurrence. Patients with recurrence limited to lung had a 8.5 months(Mo) median survival from recurrence to death, which was significantly better than the survival associated with recurrence in the liver(5.1Mo), in the peritoneum(2.3Mo) or locally(5.1Mo) in multivariable analyses. Among all groups, the time from surgery to the diagnosis of recurrence in patients who recurred in only in the lung was also the longest. However, 75% of patients were found to have indeterminate lung nodules on their surveillance CT scans prior to the diagnosis of recurrence in lung. This delayed diagnosis of lung recurrence may have a negative impact on survival after recurrence. In conclusion, pancreatic cancer with lung recurrence has a significantly better prognosis than recurrence in other sites. Further studies are needed to investigate how different diagnostic and treatment modalities affect the survival of this unique subpopulation of pancreatic cancer patients. PMID:26372811

  5. A comprehensive examination of Smad4, Smad6 and Smad7 mRNA expression in pancreatic ductal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    P Singh

    2011-01-01

    Full Text Available Background: Smad4, Smad6 and Smad7 are important molecules in TGF-beta pathway, which plays an important role in pancreatic ductal adenocarcinoma (PDAC biology. Aims : This study examined the expression profiles of Smad4, Smad6 and Smad7 mRNA in patient samples of PDAC and their relationship to Smad protein expression, SMAD4 gene mutations, clinicopathological parameters and patient survival. Settings and Design: Surgically resected, paired normal and tumor tissues of 25 patients of PDAC were studied. Materials and Methods: Protein and mRNA levels were assessed by immunohistochemistry and RT-PCR, respectively. Statistical Methods: Statistical analysis was done using Student′s t-test, Pearson′s chi-square test, Spearman′s Rank Correlation, Pearson′s Correlation test and Kaplan-Meier Logrank test. Results: While there was a highly significant difference in the protein levels of all three Smads in tumor as compared to normal samples, mRNA levels were significantly different only for Smad4. Protein levels did not correlate significantly with mRNA levels for any of the three Smads. The mRNA levels of Smad4 and Smad6, Smad4 and Smad7, and Smad6 and Smad7 in tumor samples showed a significant positive correlation. The relationship of Smad4 mRNA expression to SMAD4 gene status and Smad4 protein expression was discordant and there was no significant correlation between mRNA expression and clinicopathological parameters and patient survival. Conclusion : The absence of concordance between SMAD4 gene status, mRNA expression and Smad4 protein expression suggests the presence of other regulatory mechanisms in Smad4 transcription and translation in PDAC.

  6. Sonoporation with Acoustic Cluster Therapy (ACT®) induces transient tumour volume reduction in a subcutaneous xenograft model of pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Kotopoulis, Spiros; Stigen, Endre; Popa, Mihaela; Safont, Mireia Mayoral; Healey, Andrew; Kvåle, Svein; Sontum, Per; Gjertsen, Bjørn Tore; Gilja, Odd Helge; McCormack, Emmet

    2017-01-10

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with survival averaging only 3months if untreated following diagnosis. A major limitation in effectively treating PDAC using conventional and targeted chemotherapeutic agents, is inadequate drug delivery to the target location, predominantly due to a poorly vascularised, desmoplastic tumour microenvironment. Ultrasound in combination with ultrasound contrast agents, i.e., microbubbles, that flow through the vasculature and capillaries can be used to disrupt such mechanical barriers, potentially allowing for a greater therapeutic efficacy. This phenomenon is commonly referred to as sonoporation. In an attempt to improve the efficacy of sonoporation, novel microbubble formulations are being developed to address the limitation of commercially produced clinical diagnostic ultrasound contrast agents. In our work here we evaluate the ability of a novel formulation; namely Acoustic Cluster Therapy (ACT®) to improve the therapeutic efficacy of the chemotherapeutic agent paclitaxel, longitudinally in a xenograft model of PDAC. Results indicated that ACT® bubbles alone demonstrated no observable toxic effects, whilst ACT® in combination with paclitaxel can transiently reduce tumour volumes significantly, three days posttreatment (p=0.0347-0.0458). Quantitative 3D ultrasound validated the calliper measurements. Power Doppler ultrasound imaging indicated that ACT® in combination with paclitaxel was able to transiently sustain peak vasculature percentages as observed in the initial stages of tumour development. Nevertheless, there was no significant difference in tumour vasculature percentage at the end of treatment. The high vascular percentage correlated to the transient decrease and overall inhibition of the tumour volumes. In conclusion, ACT® improves the therapeutic efficacy of paclitaxel in a PDAC xenograft model allowing for transient tumour volume reduction and sustained tumour vasculature

  7. Contrast-enhanced CT and diffusion-weighted MR imaging: Performance as a prognostic factor in patients with pancreatic ductal adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Fukukura, Yoshihiko, E-mail: fukukura@m.kufm.kagoshima-u.ac.jp [Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan); Takumi, Koji [Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan); Higashi, Michiyo [Department of Human Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan); Shinchi, Hiroyuki [Department of Surgical Oncology and Digestive Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan); Kamimura, Kiyohisa; Yoneyama, Tomohide; Tateyama, Akihiro [Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima City 890-8544 (Japan)

    2014-04-15

    Objective: To determine whether contrast enhancement of CT and apparent diffusion coefficient on diffusion-weighted MR imaging are important parameters that can predict outcomes for patients with pancreatic ductal adenocarcinoma. Materials and methods: Ninety-two patients with histologically confirmed pancreatic ductal adenocarcinoma who underwent quadriphasic CT (including unenhanced, pancreatic parenchymal, portal venous and delayed phases) and fat-suppressed single-shot echo-planar diffusion-weighted MR imaging at 3.0 T were retrospectively analyzed to investigate prognostic factors. Overall survival curves were drawn using the Kaplan–Meier method. Effects on survival of variables including age, sex, tumor location, tumor size, TNM stage, carbohydrate antigen 19-9, carcinoembryonic antigen, treatment, tumor contrast enhancement and apparent diffusion coefficient values were analyzed in univariate analysis using the log-rank test. Variables were analyzed in multivariate analyses using the Cox proportional hazards regression model. Results: Median survival for the entire patient population was 18.2 months. Higher contrast enhancement during all phases was associated with significantly longer overall survival (P < 0.001 for all phases). The difference in overall survival between groups divided by median apparent diffusion coefficient value was not significant (P = 0.672). TNM stage (P = 0.026) and tumor contrast enhancement on CT (P = 0.027) were significantly related to survival in multivariate analysis. Conclusions: Poor enhancement of pancreatic adenocarcinomas on enhanced CT is associated with reduced patient survival.

  8. Alteraciones epigenéticas en el Adenocarcinoma Ductal de Páncreas. Impacto clínico-patológico

    OpenAIRE

    Evgenyeva, Elena

    2012-01-01

    Introducción: El adenocarcinoma ductal de páncreas (ADP) es una neoplasia bien conocida por su conducta agresiva, mala evolución y una supervivencia media de unos 6 meses, inclusivo en casos de enfermedad no avanzada que se somete a tratamiento quirúrgico, quimioterapia y radioterapia. El cáncer se considera como una enfermedad genética, descubriéndose cada vez más alteraciones en genes implicados en ciclo celular, reparación, apoptosis…etc.. Sin embargo, estos datos no han aportado avances s...

  9. HER2/neu Expression and Gene Alterations in Pancreatic Ductal Adenocarcinoma: A Comparative mmunohistochemistry and Chromogenic in Situ Hybridization Study Based on Tissue Microarrays and Computerized Image Analysis

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    Evangelos Tsiambas

    2006-05-01

    Full Text Available Context: HER2/neu overexpression is observed in many cancers including pancreatic ductal adenocarcinoma. Although immunohistochemistry remains the basic method for evaluating HER2/neu protein expression, significant information regarding gene status cannot be assessed. Design: Using tissue microarray technology, fifty histologically confirmed pancreatic ductal adenocarcinomas were cored twice and re-embedded in one paraffin block. Immunohistochemistry (clone TAB 250 and chromogenic (HER2/neu amplification Spot Light kit in situ hybridization protocols were performed. The immunostained slides were evaluated by conventional eye microscopy and digital image analysis. The chi square test and the kappa statistic were applied by running the SPSS package. Main outcome measures :The levels of staining intensity were estimated by the performance of a semi automated image analysis system. Results :HER2/neu gene amplification was detected in 8/50 cases (16%. Chromosome 17 aneuploidy was detected in 19 cases (38%. Significant improvement in interobserver agreement (kappa=0.76 vs. 0.94 was achieved correlating the immunohistochemical results obtained by conventional eye and digital microscopy, especially in the cases of overexpression (2+, 3+. Finally, 29 (58%, 11 (22%, 6 (12% and 4 (8% cases were characterized as 0, 1+, 2+ and 3+, respectively. HER2/neu protein expression was significantly associated with grade (P=0.019, but not with stage (P=0.466. in addition, chromosome 17 and gene status were not correlated with stage and grade.. Conclusion :Our results indicate that a subset of pancreatic ductal adenocarcinomas is characterized by HER2/neu gene amplification. In contrast to breast cancer, protein overexpression does not predict this specific gene deregulation mechanism. This event may reflect the different biological role of the molecule in those two solid tumours, affecting the response to novel targeted agents, such as monoclonal anti-HER2/neu

  10. Prorenin receptor acts as a potential molecular target for pancreatic ductal adenocarcinoma diagnosis.

    Science.gov (United States)

    Arundhathi, Arivajiagane; Chuang, Wen-Han; Chen, Jen-Kun; Wang, Shin-E; Shyr, Yi-Ming; Chen, Jiun-Yu; Liao, Wei-Neng; Chen, Hsin-Wei; Teng, Yi-Min; Pai, Chiao-Chih; Wang, Chih-Hong

    2016-07-13

    Recent studies have implicated the prorenin receptor (PRR) is associated with pancreatic tumorigenesis. We therefore investigated the role of PRR in pancreatic tumorigenesis and assessed whether PRR can serve as a target for imaging diagnosis at early stages of PDAC. Here we show that aberrant expression of PRR in premalignant PanIN lesions, and human PDAC samples, and PDAC cell lines, particularly in Panc-1 cells. Interestingly, PRR expression was positively associated with PDAC progression. Moreover, overexpression of human PRR resulted in increased cell proliferation and decreased apoptosis, while knockdown of human PRR caused decreased cell proliferation and enhanced apoptosis in pancreatic cancer cells. We also observed that overexpression of human PRR enhanced MAPK and PI3K/Akt signaling pathways in PDAC cells, while knockdown of human PRR suppressed both of pathways. The confocal imaging analysis showed that human PRR was highly expressed in Panc-1, ASPC, and Miapaca cells, whereas BXPC-3, and HPAC cells had a significantly lower fluorescent signals. Consistently, the single-photon emission computed tomography (SPET/CT) showed that the uptake of anti-PRR labelled with 125I was higher in Panc-1 and ASPC tumors-bearing mice after 96 hours injection. Importantly, tumors in pancreas of Pdx1-cre; LSL-KrasG12D mice had a significant increased PRR expression and accumulation of radioactivity at 96 h after injection. These data suggest that 125I-anti-PRR can detect the orthotopic tumors in Pdx1-cre; LSL-KrasG12D mice. Therefore, anti-PRR labelled with 125I is a promising radiotracer for imaging diagnosis at early stages of pancreatic cancer.

  11. Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling.

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    Nones, Katia; Waddell, Nic; Song, Sarah; Patch, Ann-Marie; Miller, David; Johns, Amber; Wu, Jianmin; Kassahn, Karin S; Wood, David; Bailey, Peter; Fink, Lynn; Manning, Suzanne; Christ, Angelika N; Nourse, Craig; Kazakoff, Stephen; Taylor, Darrin; Leonard, Conrad; Chang, David K; Jones, Marc D; Thomas, Michelle; Watson, Clare; Pinese, Mark; Cowley, Mark; Rooman, Ilse; Pajic, Marina; Butturini, Giovanni; Malpaga, Anna; Corbo, Vincenzo; Crippa, Stefano; Falconi, Massimo; Zamboni, Giuseppe; Castelli, Paola; Lawlor, Rita T; Gill, Anthony J; Scarpa, Aldo; Pearson, John V; Biankin, Andrew V; Grimmond, Sean M

    2014-09-01

    The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome-wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high-density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non-malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5' region of genes (including the proximal promoter, 5'UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF-β, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT-ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite amplicon deep sequencing and qRT-PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT-ROBO signaling and up-regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.

  12. The Canonical Wnt Pathway Regulates the Metastasis-Promoting Mucin MUC4 in Pancreatic Ductal Adenocarcinoma

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    Pai, Priya; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Macha, Muzafar A; Sheinin, Yuri; Smith, Lynette M.; Ponnusamy, Moorthy P.; Batra, Surinder K.

    2015-01-01

    Aberrant Wnt signaling frequently occurs in pancreatic cancer (PC) and contributes to disease progression/metastases. Likewise, the transmembrane-mucin MUC4 is expressed de novo in early pancreatic intraepithelial neoplasia (PanINs) and incrementally increases with PC progression, contributing to metastasis. To determine the mechanism of MUC4 upregulation in PC, we examined factors deregulated in early PC progression, such as Wnt/β-catenin signaling. MUC4 promoter analysis revealed the presence of three putative TCF/LEF-binding sites, leading us to hypothesize that MUC4 can be regulated by β-catenin. Immunohistochemical (IHC) analysis of rapid autopsy PC tissues showed a correlation between MUC4 and cytosolic/nuclear β-catenin expression. Knock down (KD) of β-catenin in CD18/HPAF and T3M4 cell lines resulted in decreased MUC4 transcript and protein. Three MUC4 promoter luciferase constructs, p3778, p3000, and p2700, were generated. The construct p3778, encompassing the entire MUC4 promoter, elicited increased luciferase activity in the presence of stabilized β-catenin. Mutation of the TCF/LEF site closest to the transcription start site (i.e., −2629/−2612) and furthest from the start site (i.e., −3425/−3408) reduced MUC4 promoter luciferase activity. Transfection with dominant negative TCF4 decreased MUC4 transcript and protein levels. Chromatin immunoprecipitation confirmed enrichment of β-catenin on −2629/−2612 and −3425/−3408 of the MUC4 promoter in CD18/HPAF. Functionally, CD18/HPAF and T3M4 β-catenin KD cells showed decreased migration and decreased Vimentin, N-cadherin, and pERK1/2 expression. Tumorigenicity studies in athymic nude mice showed CD18/HPAF β-catenin KD cells significantly reduced primary tumor sizes and metastases compared to scrambled control cells. We show for the first time that β-catenin directly governs MUC4 in PC. PMID:26526617

  13. Survival variability of controls and definition of imaging endpoints for longitudinal follow-up of pancreatic ductal adenocarcinoma in rats.

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    Akladios, Cherif; Ignat, Mihaela; Mutter, Didier; Aprahamian, Marc

    2017-01-01

    The 3Rs guideline is the gold standard for ethics in animal experimentation. Two of those rules, namely refinement and reduction, require further improvement. The objective of this study was to define pathways to better compliance with these prerequisites. Two methods which move us in this direction are: (1) using small animal imaging techniques for pancreatic ductal adenocarcinoma (PDAC) follow-up and (2) reduction of the number of control animals included in a study of PDAC progression under treatment. Firstly, we used MicroCT scan to diagnose events showing PDAC progression prior to any clinical symptoms to thereby define more humane endpoints identifiable before any painful phenomenon is observed. Secondly, in order to test the hypothesis of using a reference control group in all preclinical studies of a new treatment of PDAC, we investigated the stability of the results obtained with the control groups in three successive identical studies comparing placebo and gemcitabine in tumor-bearing Lewis rats. Two imaging endpoints were found. The first was the observation of a liver metastasis assessing PDAC diffusion and, earlier than liver metastasis, the presence of bands of fluid along the flanks, with more or less a medial displacement of bowel and solid viscera, reflecting a peritoneal ascites. Results of the longitudinal follow-up of rats in the gemcitabine study revealed heterogeneity in the survival rate in the three control groups, as opposed to the survival rate in the three treated groups which did not differ statistically. As a result, the significance of improved survival with chemotherapy varied greatly according to the control group used for the comparison, ranging from no impact to a highly significant effect. The early detection by the means of animal imaging of one or more signs indicating the onset of a critical step in the development of the disease (e.g., ascites or/and metastasis) allows the researcher to prevent the occurrence of animal pain

  14. Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma

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    Vidhya Kumar

    2016-10-01

    Full Text Available PURPOSE: Losartan, an angiotensin II receptor blocker, can reduce desmoplasia and enhance drug delivery and efficacy through improving interstitial transport and vascular perfusion in pancreatic ductal adenocarcinoma (PDAC models in mice. The purpose of this study was to determine whether magnetic resonance imaging (MRI of magnetic iron oxide nanoparticles (MNPs and micro–positron emission tomography (PET measurements could respectively detect improvements in tumor vascular parameters and drug uptake in orthotopic PDAC in mice treated with losartan. METHOD AND MATERIALS: All experiments were approved by the local Institutional Animal Care and Use Committee. FVB mice with orthotopic PDAC were treated daily with an i.p. injection of losartan (70 mg/kg or saline (control vehicle for 5 days. In order to calculate the fractional blood volume, vessel size index, and vessel density index, MRI was performed at 4.7 T following the injection of 3 mg/kg iron ferumoxytol (i.v.. Dynamic PET images were also acquired for 60 minutes using an 18F-5FU tracer dose of 200 μCi and analyzed for time activity curves normalized to muscle. Statistical analyses compared both cohorts using an unpaired two-tailed t test. RESULTS: In comparison to the control treatment, the losartan administration significantly increased the fractional blood volume (mean ± SEM [12.1 ± 1.7 (n = 19 vs 6.7 ± 1.1 (n = 20; P < .02] and vessel size index (128.2 ± 35.6 vs 57.5 ± 18; P < .05. Losartan also induced a significant increase in the intratumoral uptake of 18F-5FU by 53% (P < .0001. CONCLUSION: MRI using FDA-approved MNPs provides a noninvasive, translatable means of assaying microvascular parameters induced by losartan in pancreatic cancer. PET measurements demonstrated that losartan significantly increased the uptake of 18F-5FU.

  15. Association between genetic subgroups of pancreatic ductal adenocarcinoma defined by high density 500 K SNP-arrays and tumor histopathology.

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    María Laura Gutiérrez

    Full Text Available The specific genes and genetic pathways associated with pancreatic ductal adenocarcinoma are still largely unknown partially due to the low resolution of the techniques applied so far to their study. Here we used high-density 500 K single nucleotide polymorphism (SNP-arrays to define those chromosomal regions which most commonly harbour copy number (CN alterations and loss of heterozygozity (LOH in a series of 20 PDAC tumors and we correlated the corresponding genetic profiles with the most relevant clinical and histopathological features of the disease. Overall our results showed that primary PDAC frequently display (>70% extensive gains of chromosomes 1q, 7q, 8q and 20q, together with losses of chromosomes 1p, 9p, 12q, 17p and 18q, such chromosomal regions harboring multiple cancer- and PDAC-associated genes. Interestingly, these alterations clustered into two distinct genetic profiles characterized by gains of the 2q14.2, 3q22.1, 5q32, 10q26.13, 10q26.3, 11q13.1, 11q13.3, 11q13.4, 16q24.1, 16q24.3, 22q13.1, 22q13.31 and 22q13.32 chromosomal regions (group 1; n = 9 versus gains at 1q21.1 and losses of the 1p36.11, 6q25.2, 9p22.1, 9p24.3, 17p13.3 and Xp22.33 chromosomal regions (group 2; n = 11. From the clinical and histopathological point of view, group 1 cases were associated with smaller and well/moderately-differentiated grade I/II PDAC tumors, whereas and group 2 PDAC displayed a larger size and they mainly consisted of poorly-differentiated grade III carcinomas. These findings confirm the cytogenetic complexity and heterozygozity of PDAC and provide evidence for the association between tumor cytogenetics and its histopathological features. In addition, we also show that the altered regions identified harbor multiple cancer associate genes that deserve further investigation to determine their relevance in the pathogenesis of PDAC.

  16. The combination of a nuclear HMGB1-positive and HMGB2-negative expression is potentially associated with a shortened survival in patients with pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Takeda, Toru; Izumi, Hiroto; Kitada, Shohei; Uramoto, Hidetaka; Tasaki, Takashi; Zhi, Li; Guo, Xin; Kawatsu, Yuichiro; Kimura, Tomoko; Horie, Seichi; Nabeshima, Atsunori; Noguchi, Hirotsugu; Wang, Ke-Yong; Sasaguri, Yasuyuki; Kohno, Kimitoshi; Yamada, Sohsuke

    2014-10-01

    High-mobility group box (HMGB) proteins are ubiquitous, abundant nuclear non-histone chromosomal proteins that play a critical role in binding to distorted DNA structures and subsequently regulating DNA transcription, replication, repair, and recombination. Both HMGB1 and HMGB2 exhibit a high expression in several human cancers and are closely associated with tumor progression and a poor prognosis. However, the expression patterns of these molecules in pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. As most cases of postoperative relapse of PDAC occur within the first 2 years, the clinical significance of accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical HMGB1 and HMGB2 expression and the clinicopathological characteristics and prognosis using 62 paraffin-embedded tumor samples obtained from patients with surgically resected PDAC. The HMGB1/2 expression was considered to be positive when 10 % or more of the cancer cells showed positive nuclear, not merely cytoplasmic, staining. Consequently, the expression of HMGB1/2 was observed in 54 (87.1 %) and 31 (50.0 %) patients, respectively. Unexpectedly, a positive HMGB1 expression was found to have a significantly close relationship with a negative HMGB2 expression. The univariate and multivariate analyses demonstrated that the patients with a HMGB1+ and HMGB2- status had markedly lower disease-specific survival rates, especially within the first 2 years postoperatively, whereas those with a HMGB1+ status alone did not. Therefore, the combination of a HMGB1+ and HMGB2- expression potentially predicts a poor prognosis in patients with PDAC, and these new biomarkers may be useful parameters for clinical management in the early postoperative phase.

  17. Three-year and five-year outcomes of surgical resection for pancreatic ductal adenocarcinoma: Long-term experiences in one medical center.

    Science.gov (United States)

    Hsu, Chih-Po; Hsu, Jun-Te; Liao, Chien-Hung; Kang, Shih-Ching; Lin, Being-Chuan; Hsu, Yu-Pao; Yeh, Chun-Nan; Yeh, Ta-Sen; Hwang, Tsann-Long

    2016-12-20

    Pancreatic ductal adenocarcinoma is one of the most malignant types of cancer. This study evaluated the 3-year and 5-year surgical outcomes associated with the cancer and determined whether statistically identified factors can be used to predict survival. This retrospective review was conducted from 1995 to 2010. Patients who had resectable pancreatic ductal adenocarcinoma and received surgical treatment were included. Cases of hospital mortality were excluded. The relationships between several clinicopathological factors and the survival rate were analyzed. A total of 223 patients were included in this study. The 3-year and 5-year survival rates were 21.4% and 10.1%, respectively, and the median survival was 16.1 months. Tumor size, N status, and resection margins were independent predictive factors for 3-year survival. Tumor size independently predicted 5-year survival. Tumor size is the most important independent prognostic factor for 3-year and 5-year survival. Lymph node status and the resection margins also independently affected the 3-year survival. These patient outcomes might be improved by early diagnosis and radical resection. Future studies should focus on the tumor biology of this aggressive cancer. Copyright © 2016. Published by Elsevier Taiwan.

  18. Development and histopathological characterization of tumorgraft models of pancreatic ductal adenocarcinoma.

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    Patrick L Garcia

    Full Text Available Pancreatic cancer is the one of the deadliest of all malignancies. The five year survival rate for patients with this disease is 3-5%. Thus, there is a compelling need for novel therapeutic strategies to improve the clinical outcome for patients with pancreatic cancer.  Several groups have demonstrated for other types of solid tumors that early passage human tumor xenograft models can be used to define some genetic and molecular characteristics of specific human tumors. Published studies also suggest that murine tumorgraft models (early passage xenografts derived from direct implantation of primary tumor specimens may be useful in identifying compounds with efficacy against specific tumor types.  Because pancreatic cancer is a fatal disease and few well-characterized model systems are available for translational research, we developed and characterized a panel of pancreatic tumorgraft models for biological evaluation and therapeutic drug testing.  Of the 41 primary tumor specimens implanted subcutaneously into mice, 35 produced viable tumorgraft models.  We document the fidelity of histological and morphological characteristics and of KRAS mutation status among primary (F0, F1, and F2 tumors for the twenty models that have progressed to the F3 generation.  Importantly, our procedures produced a take rate of 85%, higher than any reported in the literature. Primary tumor specimens that failed to produce tumorgrafts were those that either contained <10% tumor cells or that were obtained from significantly smaller primary tumors. In view of the fidelity of characteristics of primary tumor specimens through at least the F2 generation in mice, we propose that these tumorgraft models represent a useful tool for identifying critical characteristics of pancreatic tumors and for evaluating potential therapies. 

  19. β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells.

    Science.gov (United States)

    Corritore, Elisa; Lee, Yong-Syu; Sokal, Etienne M; Lysy, Philippe A

    2016-08-01

    Thorough research on the capacity of human islet transplantation to cure type 1 diabetes led to the achievement of 3- to 5-year-long insulin independence in nearly half of transplanted patients. Yet, translation of this technique to clinical routine is limited by organ shortage and the need for long-term immunosuppression, restricting its use to adults with unstable disease. The production of new bona fide β cells in vitro was thus investigated and finally achieved with human pluripotent stem cells (PSCs). Besides ethical concerns about the use of human embryos, studies are now evaluating the possibility of circumventing the spontaneous tumor formation associated with transplantation of PSCs. These issues fueled the search for cell candidates for β-cell engineering with safe profiles for clinical translation. In vivo studies revealed the regeneration capacity of the exocrine pancreas after injury that depends at least partially on facultative progenitors in the ductal compartment. These stimulated subpopulations of pancreatic ductal cells (PDCs) underwent β-cell transdifferentiation through reactivation of embryonic signaling pathways. In vitro models for expansion and differentiation of purified PDCs toward insulin-producing cells were described using cocktails of growth factors, extracellular-matrix proteins and transcription factor overexpression. In this review, we will describe the latest findings in pancreatic β-cell mass regeneration due to adult ductal progenitor cells. We will further describe recent advances in human PDC transdifferentiation to insulin-producing cells with potential for clinical translational studies.

  20. Effect of anthralin on cell viability in human prostate adenocarcinoma.

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    Raevskaya, A A; Gorbunova, S L; Savvateeva, M V; Severin, S E; Kirpichnikov, M P

    2012-07-01

    The study revealed the key role of serine protease hepsin activity in transition of in situ prostate adenocarcinoma into the metastasizing form. Inhibition of hepsin activity suppresses the invasive growth of the tumor. Hepsin is an convenient target for pharmacological agents, so the study of its inhibitory mechanisms is a promising avenue in drug development. Assay of proteolytic activity in various tumor cell lines in vitro showed that this activity in prostate adenocarcinoma cells significantly surpasses proteolytic activity in other examined tumor cell lines. Selective cytotoxic action of anthralin, an inhibitor of hepsin activity, on human adenocarcinoma cells was demonstrated in comparison with other tumor cell lines.

  1. Differentiating Pancreatic Ductal Adenocarcinoma from Pancreatic Serous Cystadenoma, Mucinous Cystadenoma, and a Pseudocyst with Detailed Analysis of Cystic Features on CT Scans: a Preliminary Study

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    Lv, Peijie; Mahyoub, Radfan; Lin, Xiaozhu; Chen, Kemin; Chai, Weimin; Xie, Jing [Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai (China)

    2011-04-15

    To determine whether or not detailed cystic feature analysis on CT scans can assist in the differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) from serous cystadenoma (SCN), mucinous cystadenoma (MCN), and a pseudocyst. This study received Institutional Review Board approval and informed patient consent was waived. Electronic radiology and pathology databases were searched to identify patients with PDAC (n = 19), SCN (n = 26), MCN (n = 20) and a pseudocyst (n = 23) who underwent pancreatic CT imaging. The number, size, location, and contents of cysts, and the contour of the lesions were reviewed, in addition to the wall thickness, enhancement patterns, and other signs of pancreatic and peripancreatic involvement. Diagnosis was based on lesion resection (n = 82) or on a combination of cytological findings, biochemical markers, and tumor markers (n = 6). Fisher's exact test was used to analyze the results. A combination of the CT findings including irregular contour, multiple cysts, mural nodes, and localized thickening, had a relatively high sensitivity (74%) and specificity (75%) for differentiating PDAC from SCN, MCN, and pseudocysts (p < 0.05). Other CT findings such as location, greatest dimension, or the presence of calcification were not significantly different. The CT findings for PDAC are non-specific, but perhaps helpful for differentiation. PDAC should be included in the general differential diagnosis of pancreatic cystic neoplasms

  2. A study of Smad4, Smad6 and Smad7 in Surgically Resected Samples of Pancreatic Ductal Adenocarcinoma and Their Correlation with Clinicopathological Parameters and Patient Survival

    Directory of Open Access Journals (Sweden)

    Singh Puneet

    2011-12-01

    Full Text Available Abstract Background Smad4 is the common mediator of the tumor suppressive functions of TGF-beta. Smad6 and Smad7 are the antagonists of the TGF-beta pathway. This study investigates the differential protein expressions of Smad4, Smad6 and Smad7 in tumor as compared to normal tissue of pancreatic ductal adenocarcinoma (PDAC and compares them with clinicopathological parameters and patient survival. Results There was a significant difference in protein expressions of Smad4 (p = 0.0001, Smad6 (p = 0.0015 and Smad7 (p = 0.0005 protein in tumor as compared to paired normal samples. Loss of Smad7 expression correlated significantly with tumor size (r = 0.421, p Conclusion Loss of Smad4 significantly correlated with poor survival of PDAC patients. In the cases where Smad4 is expressed, Smad6 inhibition is possibly a novel mechanism for Smad4 inactivation. Smad7 has a role in pathobiology of PDAC. Further investigation in the roles of Smad6 and Smad7 would help in the identification of novel therapeutic targets for PDAC.

  3. Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population

    Institute of Scientific and Technical Information of China (English)

    Hong-Li Xu; Jia-Rong Cheng; Wei Zhang; Jing Wang; Herbert Yu; Quan-Xing Ni; Harvey A. Risch; Yu-Tang Gao

    2014-01-01

    Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genome-wide association study (GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population-based case-control study involving 256 patients with pathologicaly confirmed pancreatic ductal adenocarcinoma (PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C alele of rs505922 had an increased cancer risk [adjusted odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.02-1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk (adjusted OR = 1.58, 95% CI: 1.17-2.14; adjusted OR = 1.51, 95% CI: 1.09-2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interaction with cancer risk using a multifactor dimensionality reduction (MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC (adjusted OR = 1.46, 95% CI: 1.12-1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population.

  4. Quantitative and Qualitative Comparison of Single-Source Dual-Energy Computed Tomography and 120-kVp Computed Tomography for the Assessment of Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Bhosale, Priya; Le, Ott; Balachandran, Aprana; Fox, Patricia; Paulson, Eric; Tamm, Eric

    2015-01-01

    The aim of this study was to compare contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) between pancreatic-phase dual-energy computed tomography (DECT) and 120-kVp CT for pancreatic ductal adenocarcinoma (PDA). Seventy-eight patients underwent multiphasic pancreatic imaging protocols for PDA (40, DECT; 38, 120-kVp CT [control]). Using pancreatic phase, CNR and SNR for PDA were obtained for DECT at monochromatic energies 50 through 80 keV, iodine material density images, and 120-kVp images. Using a 5-point scale (1, excellent; 5, markedly limited), images were qualitatively assessed by 2 radiologists in consensus for PDA detection, extension, vascular involvement, and noise. Wilcoxon signed rank and 2-sample tests were used to compare the qualitative measures, CNR and SNR, for DECT and 120-kVp images. Bonferroni correction was applied. Iodine material density image had significantly higher CNR and SNR for PDA than any monochromatic energy images (P Qualitatively, 70-keV images were rated highest in the categories of tumor extension and vascular invasion and were similar to 120-kVp images. Our results indicate that DECT improves PDA lesion conspicuity compared with routine 120-kVp CT, which may allow for better detection of PDA.

  5. Does a family history of pancreatic ductal adenocarcinoma and cyst size influence the follow-up strategy for intraductal papillary mucinous neoplasms of the pancreas?

    Science.gov (United States)

    Mandai, Koichiro; Uno, Koji; Yasuda, Kenjiro

    2014-08-01

    This study aimed to evaluate the relationship between pancreatic ductal adenocarcinoma (PDAC) family history and PDAC development in patients followed up for intraductal papillary mucinous neoplasms (IPMNs) and to assess the cyst size relevance in determining follow-up strategies. We analyzed 300 patients with branch duct and mixed-type IPMN who were followed up at our facility. Among the patients aged 70 years or older, the frequency of PDAC did not differ significantly between those with 1 first-degree relative with PDAC and those without a family history. Although patients with IPMNs of greater than or equal to 30 mm were followed up for a significantly shorter duration than those patients with IPMNs of less than 30 mm, the frequency of IPMN progression and malignant IPMN was significantly greater in the former. The frequency of IPMN progression and pancreatic cancer did not differ significantly according to IPMN size (family history. Special attention should be paid to IPMN progression and malignant transformation in patients with IPMNs of greater than or equal to 30 mm, but cyst size need not be considered when determining follow-up strategies for patients with IPMNs of less than 30 mm without mural nodules.

  6. [Gastric signet ring cell adenocarcinoma: A distinct entity].

    Science.gov (United States)

    Tabouret, Tessa; Dhooge, Marion; Rouquette, Alexandre; Brezault, Catherine; Beuvon, Frédéric; Chaussade, Stanislas; Coriat, Romain

    2014-04-01

    Gastric signet ring cell carcinoma (GSRC) is a distinct entity. Their incidence is increasing. The pathologist plays a central role in the identification of this entity. Diagnosis is based on an adenocarcinoma containing a majority of signet ring cells (above 50 %). The prognosis of GSRC is the same as gastric adenocarcinoma while GSRC appeared more aggressive. Signet ring cells present a low sensitivity to chemotherapy. This review aimed to discuss the histological, the prognostic and the therapeutic aspect of this entity.

  7. Molecular mechanisms of bortezomib resistant adenocarcinoma cells.

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    Erika Suzuki

    Full Text Available Bortezomib (Velcade™ is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM. Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ~30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response.

  8. A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation

    DEFF Research Database (Denmark)

    Shih, Hung Ping; Kopp, Janel L; Sandhu, Manbir

    2012-01-01

    In the pancreas, Notch signaling is thought to prevent cell differentiation, thereby maintaining progenitors in an undifferentiated state. Here, we show that Notch renders progenitors competent to differentiate into ductal and endocrine cells by inducing activators of cell differentiation. Notch...... signaling promotes the expression of Sox9, which cell-autonomously activates the pro-endocrine gene Ngn3. However, at high Notch activity endocrine differentiation is blocked, as Notch also induces expression of the Ngn3 repressor Hes1. At the transition from high to intermediate Notch activity, only Sox9......, but not Hes1, is maintained, thus de-repressing Ngn3 and initiating endocrine differentiation. In the absence of Sox9 activity, endocrine and ductal cells fail to differentiate, resulting in polycystic ducts devoid of primary cilia. Although Sox9 is required for Ngn3 induction, endocrine differentiation...

  9. A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation

    DEFF Research Database (Denmark)

    Shih, Hung Ping; Kopp, Janel L; Sandhu, Manbir

    2012-01-01

    In the pancreas, Notch signaling is thought to prevent cell differentiation, thereby maintaining progenitors in an undifferentiated state. Here, we show that Notch renders progenitors competent to differentiate into ductal and endocrine cells by inducing activators of cell differentiation. Notch...... signaling promotes the expression of Sox9, which cell-autonomously activates the pro-endocrine gene Ngn3. However, at high Notch activity endocrine differentiation is blocked, as Notch also induces expression of the Ngn3 repressor Hes1. At the transition from high to intermediate Notch activity, only Sox9......, but not Hes1, is maintained, thus de-repressing Ngn3 and initiating endocrine differentiation. In the absence of Sox9 activity, endocrine and ductal cells fail to differentiate, resulting in polycystic ducts devoid of primary cilia. Although Sox9 is required for Ngn3 induction, endocrine differentiation...

  10. pT but not pN stage of the 8th TNM classification significantly improves prognostication in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Schlitter, Anna Melissa; Jesinghaus, Moritz; Jäger, Carsten; Konukiewitz, Björn; Muckenhuber, Alexander; Demir, Ihsan Ekin; Bahra, Marcus; Denkert, Carsten; Friess, Helmut; Kloeppel, Günter; Ceyhan, Güralp O; Weichert, Wilko

    2017-08-09

    The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well-characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p < 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061). pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into β cells in mice with reversal of diabetes.

    Science.gov (United States)

    Zhang, Mingfeng; Lin, Qing; Qi, Tong; Wang, Tiankun; Chen, Ching-Cheng; Riggs, Arthur D; Zeng, Defu

    2016-01-19

    We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments β-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of β-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9(+) (Sox9(+)) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing β cells in an in vitro culture. Whether Sox9(+) ductal cells in the adult pancreas can give rise to β cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin- or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9(+) ductal cell differentiation into insulin-producing β cells, and medium hyperglycemia (300-450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting β-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9(+) ductal cell differentiation into β cells in adult mice.

  12. Is stage-specific embryonic antigen 4 a marker for human ductal stem/progenitor cells?

    Science.gov (United States)

    Afrikanova, Ivka; Kayali, Ayse; Lopez, Ana; Hayek, Alberto

    2012-08-01

    The presence of pancreatic stem cells (PnSCs) has not been firmly demonstrated in the human or animal pancreas. Previous reports have suggested that ductal and acinar structures in the exocrine pancreas can be a potential source of progenitor cells. More recently, immature insulin precursors in the periphery of human islets have been found to self-replicate and differentiate to endocrine cells in vitro. Transplantation of these cells under the kidney capsule improves the diabetic state in mice. The controversy surrounding where PnSCs reside could be resolved if a specific marker were to be found that allowed their identification, purification, and directed differentiation to endocrine cells. We have identified in human pancreas cells positive for the stage-specific embryonic antigen 4 (SSEA4), a stem cell marker. These cells also express ductal, pancreatic progenitor, and stem cell protein markers. Interestingly, some of the SSEA4(+) cells scattered in the ducts do not show a ductal cell phenotype. SSEA4(+)-sorted cells formed aggregate-like spheres in culture and robustly differentiated to pancreatic hormone-expressing cells in conditions of high glucose concentration and B27 supplementation. We hypothesize that SSEA4(+) cells or a subpopulation of those cells residing in the pancreatic ducts may be the elusive PnSCs, and in this case, SSEA4 may represent a potential surface antigen marker for human PnSCs. The discovery of specific markers for the identification and purification of human PnSCs would greatly facilitate studies aimed at the expansion of these cells and the development of targeting tools for their potential induction to insulin-producing cells.

  13. Is Stage-Specific Embryonic Antigen 4 a Marker for Human Ductal Stem/Progenitor Cells?

    Science.gov (United States)

    Kayali, Ayse; Lopez, Ana; Hayek, Alberto

    2012-01-01

    Abstract The presence of pancreatic stem cells (PnSCs) has not been firmly demonstrated in the human or animal pancreas. Previous reports have suggested that ductal and acinar structures in the exocrine pancreas can be a potential source of progenitor cells. More recently, immature insulin precursors in the periphery of human islets have been found to self-replicate and differentiate to endocrine cells in vitro. Transplantation of these cells under the kidney capsule improves the diabetic state in mice. The controversy surrounding where PnSCs reside could be resolved if a specific marker were to be found that allowed their identification, purification, and directed differentiation to endocrine cells. We have identified in human pancreas cells positive for the stage-specific embryonic antigen 4 (SSEA4), a stem cell marker. These cells also express ductal, pancreatic progenitor, and stem cell protein markers. Interestingly, some of the SSEA4+ cells scattered in the ducts do not show a ductal cell phenotype. SSEA4+-sorted cells formed aggregate-like spheres in culture and robustly differentiated to pancreatic hormone-expressing cells in conditions of high glucose concentration and B27 supplementation. We hypothesize that SSEA4+ cells or a subpopulation of those cells residing in the pancreatic ducts may be the elusive PnSCs, and in this case, SSEA4 may represent a potential surface antigen marker for human PnSCs. The discovery of specific markers for the identification and purification of human PnSCs would greatly facilitate studies aimed at the expansion of these cells and the development of targeting tools for their potential induction to insulin-producing cells. PMID:23515456

  14. FEATURES OF ISLET-LIKE CLUSTERS GENERATION IN PANCREATIC DUCTAL CELL MOLOLAYER CULTURING

    Directory of Open Access Journals (Sweden)

    L. A. Kirsanova

    2012-01-01

    Full Text Available Newborn rabbit pancreatic cell monolayer was obtained as we described earlier.The cultivated epithelial cells were shown by immunofluorescence to express special ductal marker CK19 and were insulin-and glucagon- negative for 10–15 days. A few fusiforms of nestin-positive cells were found in monolayer. Over 2 weeks in serum-free medium the plaques of epithelial cells became crowded and formed 3-dimentional structures – islet- like clusters. Islet-like clusters contain some insulin- and glucagon-positive cells recognized by immunohysto- chemistry staining. Pancreatic endocrine cell generation in 3-dimentional structures is discussed. 

  15. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids

    Science.gov (United States)

    Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B.; Crawford, Howard C.; Arrowsmith, Cheryl; Kalloger, Steve E.; Renouf, Daniel J.; Connor, Ashton A; Cleary, Sean; Schaeffer, David F.; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K.

    2016-01-01

    There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies. PMID:26501191

  16. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids.

    Science.gov (United States)

    Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B; Crawford, Howard C; Arrowsmith, Cheryl; Kalloger, Steve E; Renouf, Daniel J; Connor, Ashton A; Cleary, Sean; Schaeffer, David F; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K

    2015-11-01

    There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

  17. ABCB2 (TAP1) as the downstream target of SHH signaling enhances pancreatic ductal adenocarcinoma drug resistance.

    Science.gov (United States)

    Xu, Min; Li, Lei; Liu, Zhiqiang; Jiao, Zhijun; Xu, Ping; Kong, Xiangyu; Huang, Haojie; Zhang, Youli

    2013-06-10

    Hedgehog signaling plays critical roles in drug resistance of PDAC. We demonstrate that SHH is highly expressed in PDAC patients and cell lines. SHH signaling protects PDAC cells against gemcitabine induced apoptosis, because either over-expression or knockdown of SHH in PDAC cells affects the sensitivity to gemcitabine. Mechanistic studies show that ABCB2 serves as the downstream target of SHH signaling, leading to the drug resistance of PDAC cells. Combinational treatments with gemcitabine and cyclopamine yield synergistic antitumor effects in vitro and in vivo. Our study suggests that inhibiting SHH signaling or targeting ABCB2 gene improves the efficacy of chemotherapy in patients with PDAC.

  18. In vitro pancreas duodenal homeobox-1 enhances the differentiation of pancreatic ductal epithelial cells into insulin-producing cells

    Science.gov (United States)

    Liu, Tao; Wang, Chun-You; Yu, Feng; Gou, Shan-Miao; Wu, He-Shui; Xiong, Jiong-Xin; Zhou, Feng

    2007-01-01

    AIM: To observe whether pancreatic and duodenal homeobox factor-1 enhances the differentiation of pancreatic ductal epithelial cells into insulin-producing cells in vitro. METHODS: Rat pancreatic tissue was submitted to digestion by collagenase, ductal epithelial cells were separated by density gradient centrifugation and then cultured in RPMI1640 medium with 10% fetal bovine serum. After 3-5 passages, the cells were incubated in a six-well plate for 24 h before transfection of recombination plasmid XlHbox8VP16. Lightcycler quantitative real-time RT-PCR was used to detect the expression of PDX-1 and insulin mRNA in pancreatic epithelial cells. The expression of PDX-1 and insulin protein was analyzed by Western blotting. Insulin secretion was detected by radioimmunoassay. Insulin-producing cells were detected by dithizone-staining. RESULTS: XlHbox8 mRNA was expressed in pancreatic ductal epithelial cells. PDX-1 and insulin mRNA as well as PDX-1 and insulin protein were significantly increased in the transfected group. The production and insulin secretion of insulin-producing cells differentiated from pancreatic ductal epithelial cells were higher than those of the untransfected cells in vitro with a significant difference (1.32 ± 0.43 vs 3.48 ± 0.81, P < 0.01 at 5.6 mmol/L; 4.86 ± 1.15 vs 10.25 ± 1.32, P < 0.01 at 16.7 mmol/L). CONCLUSION: PDX-1 can differentiate rat pancreatic ductal epithelial cells into insulin-producing cells in vitro. In vitro PDX-1 transfection is a valuable strategy for increasing the source of insulin-producing cells. PMID:17876894

  19. In vitro pancreas duodenal homeobox-1 enhances the differentiation of pancreatic ductal epithelial cells into insulin-producing cells

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To observe whether pancreatic and duodenal homeobox factor-1 enhances the differentiation of pancreatic ductal epithelial cells into insulin-producing cells in vitro.METHODS: Rat pancreatic tissue was submitted to digestion by collegenase, ductal epithelial cells were separated by density gradient centrifugation and then cultured in RPMI1640 medium with 10% fetal bovine serum. After 3-5 passages, the cells were incubated in a six-well plate for 24 h before transfection of recombination plasmid XIHbox8VP16. Lightcycler quantitative real-time RT-PCR was used to detect the expression of PDX-1 and insulin mRNA in pancreatic epithelial cells. The expression of PDX-1 and insulin protein was analyzed by Western blotting. Insulin secretion was detected by radioimmunoassay. Insulinproducing cells were detected by dithizone-staining.RESULTS: XIHbox8 mRNA was expressed in pancreatic ductal epithelial cells. PDX-1 and insulin mRNA as well as PDX-1 and insulin protein were significantly increased in the transfected group. The production and insulin secretion of insulin-producing cells differentiated from pancreatic ductal epithelial cells were higher than those of the untransfected cells in vitro with a significant difference (1.32 ± 0.43 vs 3.48 ± 0.81, P < 0.01 at 5.6 mmol/L; 4.86 ± 1.15 vs 10.25 ± 1.32, P < 0.01 at 16.7 mmol/L).CONCLUSION: PDX-1 can differentiate rat pancreatic ductal epithelial cells into insulin-producing cells in vitro.In vitro PDX-1 transfection is a valuable strategy for increasing the source of insulin-producing cells.

  20. Influències clíniques i ambientals en la prevalença de mutacions en l'oncogèn K-ras en pacients amb adenocarcinoma ductal de pàncrees

    OpenAIRE

    Crous Bou, Marta

    2009-01-01

    Descripció del recurs: 27 gener 2010 Antecedents La prevenció primària de l'adenocarcinoma ductal de pàncrees (ADP) està limitada per la falta de coneixement sobre la seva etiologia. El factor de risc més ben establert és el consum de tabac, però explica només una petita proporció de casos. Es discuteix el paper d'altres factors etiològics com els antecedents patològics de diabetis i pancreatitis, la dieta, determinades exposicions ambientals o laborals, i els factors hereditaris. Mutacio...

  1. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting.

    Science.gov (United States)

    Jonckheere, Nicolas; Vasseur, Romain; Van Seuningen, Isabelle

    2017-03-01

    RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence. In this review, we discuss the central role of K-RAS mutations and their tremendous diversity of biological properties by the interconnected regulation of signaling pathways (MAPKs, NF-κB, PI3K, Ral…). In pancreatic ductal adenocarcinoma, transcriptome analysis and preclinical animal models showed that K-RAS mutation alters biological behavior of PDAC cells (promoting proliferation, migration and invasion, evading growth suppressors, regulating mucin pattern, and miRNA expression). K-RAS also impacts tumor microenvironment and PDAC metabolism reprogramming. Finally we discuss therapeutic targeting strategies of K-RAS that have been developed without significant clinical success so far. As K-RAS is considered as the undruggable target, targeting its multiple effectors and target genes should be considered as potential alternatives. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Heterogeneity index evaluated by slope of linear regression on (18)F-FDG PET/CT as a prognostic marker for predicting tumor recurrence in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Kim, Yong-Il; Kim, Yong Joong; Paeng, Jin Chul; Cheon, Gi Jeong; Lee, Dong Soo; Chung, June-Key; Kang, Keon Wook

    2017-06-20

    (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of (18)F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and (18)F-FDG PET/CT parameters. A total of 93 pancreatic ductal adenocarcinoma patients (M:F = 60:33, mean age = 64.2 ± 9.1 years) who underwent preoperative (18)F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each (18)F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and (18)F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence. Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence = 9.4 ± 8.4 months). Comparing the recurrence and no recurrence patients, all of the (18)F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox-regression analyses, MTV (P = 0.013), TLG (P = 0.007), and heterogeneity index-2 (P = 0.027) were significant. Among the clinicopathologic parameters, CA19-9 (P = 0.025) and venous invasion (P = 0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P = 0.005), TLG (P = 0.004), and heterogeneity index-2 (P = 0.016) with venous invasion (P < 0.001, 0.001, and 0

  3. A Phase 1/2 and Biomarker Study of Preoperative Short Course Chemoradiation With Proton Beam Therapy and Capecitabine Followed By Early Surgery for Resectable Pancreatic Ductal Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Theodore S., E-mail: tshong1@partners.org [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Ryan, David P.; Borger, Darrell R.; Blaszkowsky, Lawrence S.; Yeap, Beow Y. [Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Ancukiewicz, Marek [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Deshpande, Vikram; Shinagare, Shweta [Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Wo, Jennifer Y.; Boucher, Yves [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Wadlow, Raymond C.; Kwak, Eunice L.; Allen, Jill N.; Clark, Jeffrey W.; Zhu, Andrew X. [Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Ferrone, Cristina R. [Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Mamon, Harvey J. [Department of Radiation Oncology, Brigham and Women' s Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Adams, Judith; Winrich, Barbara; Grillo, Tarin [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); and others

    2014-07-15

    Purpose: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. Methods and Materials: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. Results: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). Conclusions: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS{sup G12D} status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

  4. Uptake and metabolism of D-glucose in isolated acinar and ductal cells from rat submandibular glands.

    Science.gov (United States)

    Cetik, Sibel; Rzajeva, Aigun; Hupkens, Emeline; Malaisse, Willy J; Sener, Abdullah

    2014-07-01

    The present study deals with the possible effects of selected environmental agents upon the uptake and metabolism of d-glucose in isolated acinar and ductal cells from the rat submandibular salivary gland. In acinar cells, the uptake of d-[U-(14) C]glucose and its non-metabolised analogue 3-O-[(14) C-methyl]-d-glucose was not affected significantly by phloridzin (0.1 mM) or substitution of extracellular NaCl (115 mM) by an equimolar amount of CsCl, whilst cytochalasin B (20 μM) decreased significantly such an uptake. In ductal cells, both phloridzin and cytochalasin B decreased the uptake of d-glucose and 3-O-methyl-d-glucose. Although the intracellular space was comparable in acinar and ductal cells, the catabolism of d-glucose (2.8 or 8.3 mM) was two to four times higher in ductal cells than in acinar cells. Phloridzin (0.1 mM), ouabain (1.0 mM) and cytochalasin B (20 μM) all impaired d-glucose catabolism in ductal cells. Such was also the case in ductal cells incubated in the absence of extracellular Ca(2+) or in media in which NaCl was substituted by CsCl. It is proposed that the ductal cells in the rat submandibular gland are equipped with several systems mediating the insulin-sensitive, cytochalasin B-sensitive and phloridzin-sensitive transport of d-glucose across the plasma membrane.

  5. Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Leshuai W.; McMahon Tobin, Grainne A.; Rouse, Rodney L., E-mail: rodney.rouse@fda.hhs.gov

    2012-10-15

    The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in “on-target” RIN-5mF (islet) cells as well as in “off-target” AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4 mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-L-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. -- Highlights: ► Exenatide did not inhibit islet, acinar or ductal cell proliferation. ► GLP1R protein decreased after glucose stimulation in oleic acid-treated ductal cells. ► Oleic acid treatment altered localization of GLP1R with early and recycling

  6. SMAD4 regulates cell motility through transcription of N-cadherin in human pancreatic ductal epithelium.

    Directory of Open Access Journals (Sweden)

    Ya'an Kang

    Full Text Available Expression of the cellular adhesion protein N-cadherin is a critical event during epithelial-mesenchymal transition (EMT. The SMAD4 protein has been identified as a mediator of transforming growth factor-β (TGF-β superfamily signaling, which regulates EMT, but the mechanisms linking TGF-β signaling to N-cadherin expression remain unclear. When the TGF-β pathway is activated, SMAD proteins, including the common mediator SMAD4, are subsequently translocated into the nucleus, where they influence gene transcription via SMAD binding elements (SBEs. Here we describe a mechanism for control of CDH2, the gene encoding N-cadherin, through the canonical TGFβ-SMAD4 pathway. We first identified four previously undescribed SBEs within the CDH2 promoter. Using telomerase immortalized human pancreatic ductal epithelium, we found that TGF-β stimulation prompted specific SMAD4 binding to all four SBEs. Luciferase reporter and SMAD4-knockdown experiments demonstrated that specific SMAD4 binding to the SBE located at -3790 bp to -3795 bp within the promoter region of CDH2 was necessary for TGF-β-stimulated transcription. Expression of N-cadherin on the surface of epithelial cells facilitates motility and invasion, and we demonstrated that knockdown of SMAD4 causes decreased N-cadherin expression, which results in diminished migration and invasion of human pancreatic ductal epithelial cells. Similar reduction of cell motility was produced after CDH2 knockdown. Together, these findings suggest that SMAD4 is critical for the TGF-β-driven upregulation of N-cadherin and the resultant invasive phenotype of human pancreatic ductal epithelial cells during EMT.

  7. Intercalated duct cell is starting point in development of pancreatic ductal carcinoma?

    Directory of Open Access Journals (Sweden)

    Yamaguchi Toshikazu

    2005-01-01

    Full Text Available Abstract Background Although it is well known that the pancreatic ductal carcinoma may develop having a relationship to the mucous gland hyperplasia (MGH with atypia (PanIN-1B by PanIN system, the starting point of this atypical MGH is unclear. To know it, we examined the pancreas tissue using many methods described below. Methods 1. Twenty-seven surgically resected pancreas tissue specimens, including pancreatic ductal carcinomas (PDC, chronic pancreatitis and normal pancreas, were investigated using immunohistochemical stainings for MUC1, MUC6, 45M1, Ki67 and p53. 2. DNA extraction and analysis of K-ras mutation at codon 12 using microdissection method: The paraffin blocks with 16 regions including the intercalated duct cell (IC adjacant to the atypical MGH were prepared for DNA extraction. Mutation of K-ras codon 12 was analized and compared in enriched polymerase chain reaction-enzyme-linked minisequence assay (PCR-ELMA. Results 1. In the normal pancreas, although no positive cell was seen in 45M1, p53, Ki67, the cytoplasm of IC were always positive for MUC1 and sometimes positive for MUC6. In the pancreas with fibrosis or inflammation, MGH was positive for MUC6 and 45M1. And atypical MGH was positive for MUC1, MUC6 and 45M1. Some IC adjacent to the atypical MGH was positive for Ki67 as well as atypical MGH. The carcinoma cells in all cases of PDC were diffusely positive for MUC1, 45M1, p53 and Ki67, and focally positive for MUC6. 2. In K-ras mutation, we examined the regions including IC adjacent to the atypical MGH, because the immunohistochemical apomucin stainings of these regions resembled those of PDC as decribed above. And K-ras mutation was confirmed in 12 of 16 regions (75%. All mutations were a single mutation, in 6 regions GTT was detected, in 4 regions GAT was detected and in 2 region AGT was detected. Conclusion Some intercalated duct cell may be the starting point of the pancreatic ductal carcinoma, because the exhibitions of

  8. Basal cytokeratin phenotypes of myoepithelial cells indicates the origin of ductal carcinomas in situ of the breast.

    Science.gov (United States)

    Chen, Ling; Yin, Xiaona; Lu, Shanshan; Chen, Guorong; Dong, Lei

    2015-09-01

    Terminal duct lobular unit (TDLU) is widely accepted as the origin of ductal carcinoma in situ of breast. The differentiation states of myoepithelial cells of breast ductal system hint the development of breast hyperplastic lesions. Basal cytokeratin (CK) phenotypes indicate the differentiation of myoepithelial cells. Using antibodies of CK5/6, CK14, and CK17, this study reports the basal CK phenotypes of myoepithelial cells in 20 foci of normal breast, 20 usual ductal hyperplasias, 36 ductal carcinomas in situ (DCIS), and 28 sclerosing adenosis (SA). The results showed that the positive staining of basal CKs of myoepithelial cells in normal ducts were significantly higher than those in normal lobules. The basal CK expression of myoepithelial cells of DCIS and usual ductal hyperplasia was similar to that of normal duct, whereas that of SA was similar to that of normal lobule. We propose a modified model of TDLU origin of intraductal carcinoma that most of DCIS originate from terminal ducts of TDLU, whereas most SA originate from lobules.

  9. Squamoid eccrine ductal carcinoma.

    Science.gov (United States)

    Saraiva, Maria Isabel Ramos; Vieira, Marcella Amaral Horta Barbosa; Portocarrero, Larissa Karine Leite; Fraga, Rafael Cavanellas; Kakizaki, Priscila; Valente, Neusa Yuriko Sakai

    2016-01-01

    Squamoid eccrine ductal carcinoma is an eccrine carcinoma subtype, and only twelve cases have been reported until now. It is a rare tumor and its histopathological diagnosis is difficult. Almost half of patients are misdiagnosed as squamous cell carcinoma by the incisional biopsy. We report the thirteenth case of squamoid eccrine ductal carcinoma. Female patient, 72 years old, in the last 6 months presenting erythematous, keratotic and ulcerated papules on the nose. The incisional biopsy diagnosed squamoid eccrine ductal carcinoma. After excision, histopathology revealed positive margins. A wideningmargins surgery and grafting were performed, which again resulted in positive margins. The patient was then referred for radiotherapy. After 25 sessions, the injury reappeared. After another surgery, although the intraoperative biopsy showed free surgical margins, the product of resection revealed persistent lesion. Distinction between squamoid eccrine ductal carcinoma and squamous cell carcinoma is important because of the more aggressive nature of the first, which requires wider margins surgery to avoid recurrence.

  10. Squamoid eccrine ductal carcinoma*

    Science.gov (United States)

    Saraiva, Maria Isabel Ramos; Vieira, Marcella Amaral Horta Barbosa; Portocarrero, Larissa Karine Leite; Fraga, Rafael Cavanellas; Kakizaki, Priscila; Valente, Neusa Yuriko Sakai

    2016-01-01

    Squamoid eccrine ductal carcinoma is an eccrine carcinoma subtype, and only twelve cases have been reported until now. It is a rare tumor and its histopathological diagnosis is difficult. Almost half of patients are misdiagnosed as squamous cell carcinoma by the incisional biopsy. We report the thirteenth case of squamoid eccrine ductal carcinoma. Female patient, 72 years old, in the last 6 months presenting erythematous, keratotic and ulcerated papules on the nose. The incisional biopsy diagnosed squamoid eccrine ductal carcinoma. After excision, histopathology revealed positive margins. A wideningmargins surgery and grafting were performed, which again resulted in positive margins. The patient was then referred for radiotherapy. After 25 sessions, the injury reappeared. After another surgery, although the intraoperative biopsy showed free surgical margins, the product of resection revealed persistent lesion. Distinction between squamoid eccrine ductal carcinoma and squamous cell carcinoma is important because of the more aggressive nature of the first, which requires wider margins surgery to avoid recurrence. PMID:28099603

  11. In vitro cultivation of human fetal pancreatic ductal stem cells and their differentiation into insulin-producing cells

    Institute of Scientific and Technical Information of China (English)

    Zhong-Xiang Yao; Mao-Lin Qin; Jian-Jun Liu; Xing-Shu Chen; De-Shan Zhou

    2004-01-01

    AIM: To isolate, culture and identify the human fetal pancreatic ductal stem cells in vitro, and to observe the potency of these multipotential cells differentiation into insulin-producing cells.METHODS: The human fetal pancreas was digested by 1 g/L collagease type Ⅳ and then 2.5 g/L trypsin was used to isolate the pancreatic ducta stem cells, followed by culture in serum-free, glucose-free DMEM media with some additional chemical substrates in vitro (according to the different Stage). The cells were induced by glucose-free (control),5 mmol/L, 17.8 mmol/L and 25 mmol/L glucose, respectively.The cell types of differentiated cells were identified using immunocytochemical staining.RESULTS: The shape of human fetal pancreatic ductal stem cells culturedin vitro was firstly fusiform in the first 2 wk,and became monolayer and cobblestone pattern after another 3 to 4 wk. After induced and differentiated by the glucose of different concentrations for another 1 to 2 wk,the cells formed the pancreatic islet-like structures. The identification and potency of these cells were then identified by using the pancreatic ductal stem cell marker, cytokeratin-19 (CK-19), pancreatic β cell marker, insulin and pancreatic α cell marker, glucagons with immunocytochemical staining.At the end of the second week, 95.2% of the cells were positive for CK-19 immunoreactivity. Up to 22.7% of the cells induced by glucose were positive for insulin immunoreactivity, and less than 3.8% of the cells were positive for glucagon immunoreactivity in pancreatic isletlike structures. The positive ratio of immunoreactive staining was dependent on the concentration of glucose, and it was observed that the 17.8 mmol/L glucose stimulated effectively to produce insulin- and glucagons-producing cells.CONCLUSION: The human fetal pancreatic ductal stem cells are capable of proliferation in vitro. These cells have multidifferentiation potential and can be induced by glucose and differentiated into insulin

  12. Diagnosis and Prognostication of Ductal Adenocarcinomas of the Pancreas Based on Genome-Wide DNA Methylation Profiling by Bacterial Artificial Chromosome Array-Based Methylated CpG Island Amplification

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    Masahiro Gotoh

    2011-01-01

    Full Text Available To establish diagnostic criteria for ductal adenocarcinomas of the pancreas (PCs, bacterial artificial chromosome (BAC array-based methylated CpG island amplification was performed using 139 tissue samples. Twelve BAC clones, for which DNA methylation status was able to discriminate cancerous tissue (T from noncancerous pancreatic tissue in the learning cohort with a specificity of 100%, were identified. Using criteria that combined the 12 BAC clones, T-samples were diagnosed as cancers with 100% sensitivity and specificity in both the learning and validation cohorts. DNA methylation status on 11 of the BAC clones, which was able to discriminate patients showing early relapse from those with no relapse in the learning cohort with 100% specificity, was correlated with the recurrence-free and overall survival rates in the validation cohort and was an independent prognostic factor by multivariate analysis. Genome-wide DNA methylation profiling may provide optimal diagnostic markers and prognostic indicators for patients with PCs.

  13. Collision tumor of kidney: A case of renal cell carcinoma with metastases of prostatic adenocarcinoma

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    Monika Vyas

    2013-01-01

    Full Text Available Simultaneous occurrence of prostatic adenocarcinoma and renal cell carcinoma is well documented in the literature. However, metastatic prostatic adenocarcinoma in a kidney harboring a renal cell carcinoma (RCC is quite rare. Although renal cell carcinoma is the most common tumor that can harbor metastasis, metastatic prostatic adenocarcinoma in a kidney harboring a RCC is quite rare. There are four cases in the literature showing metastasis of prostatic adenocarcinoma to RCC. However, as per our knowledge, this is the first case of a collision between RCC and metastatic prostatic adenocarcinoma.

  14. Differentiation of mass-forming focal pancreatitis from pancreatic ductal adenocarcinoma: value of characterizing dynamic enhancement patterns on contrast-enhanced MR images by adding signal intensity color mapping

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Mimi [Hanyang University College of Medicine, Department of Radiology, Hanyang Medical Center, Seoul (Korea, Republic of); Jang, Kyung Mi [Sungkyunkwan University School of Medicine, Department of Radiology, Samsung Medical Center, Seoul (Korea, Republic of); Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Jae-Hun; Jeong, Woo Kyoung; Kim, Seong Hyun; Kang, Tae Wook; Kim, Young Kon; Cha, Dong Ik [Sungkyunkwan University School of Medicine, Department of Radiology, Samsung Medical Center, Seoul (Korea, Republic of); Kim, Kyunga [Samsung Medical Center, Biostatics and Clinical Epidemiology Center, Research Institute for Future Medicine, Seoul (Korea, Republic of)

    2017-04-15

    To evaluate the value of dynamic enhancement patterns on contrast-enhanced MR images by adding signal intensity colour mapping (SICM) to differentiate mass-forming focal pancreatitis (MFFP) from pancreatic ductal adenocarcinoma (PDAC). Forty-one clinicopathologically proven MFFPs and 144 surgically confirmed PDACs were enrolled. Laboratory and MR imaging parameters were used to differentiate MFFP from PDAC. In particular, enhancement patterns on MR images adding SICM were evaluated. By using classification tree analysis (CTA), we determined the predictors for the differentiation of MFFP from PDAC. In the CTA, with all parameters except enhancement pattern on SICM images, ductal obstruction grade and T1 hypointensity grade of the pancreatic lesion were the first and second splitting predictor for differentiation of MFFP from PDAC, in order. By adding an enhancement pattern on the SICM images to CTA, the enhancement pattern was the only splitting predictor to differentiate MFFP from PDAC. The CTA model including enhancement pattern on SICM images has sensitivity of 78.0 %, specificity of 99.3 %, and accuracy of 94.6 % for differentiating MFFP from PDAC. The characterization of enhancement pattern for pancreatic lesions on contrast-enhanced MR images adding SICM would be helpful to differentiate MFFP from PDAC. (orig.)

  15. CYTOKINE-PRODUCING RESERVE OF IMMUNOCOMPETENT CELLS FROM BLOOD AND INVASIVE DUCTAL BREAST CANCER TISSUES: ITS CORRELATION WITH HISTOPATHOLOGICAL AND IMMUNOHISTOCHEMICAL PARAMETERS OF MALIGNANT NEOPLASIA

    Directory of Open Access Journals (Sweden)

    S. A. Arkhipov

    2016-01-01

    Full Text Available The aim of the study was to investigate a relationship between cytokine-producing reserve of invasive ductal cancer cells and its microenvironment, and cytokine-producing reserve of immunocompetent blood cells (IBC, as well as with histopathological and immunohistochemical characteristics of breast cancer. Using ELISA method we investigated the spontaneous and stimulated with polyclonal activators (PA cytokine-producing reserve of IBC and biopsy specimens from invasive ductal cancer (adenocarcinoma in 34 women. Appropriate values were expressed by the Influence Index of polyclonal activators (IIPA upon cytokine production (IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1β, IL-1ra, TNFα, IFNγ, G-CSF, GM-CSF, VEGF-A, MCP-1. In tumor biopsies, we studied expression of VEGF-A, estrogen receptor, progesteron receptor and pro-proliferation marker Ki-67 by means of immunohistochemical method. Activation values of blood IBC in most cases, except of IL-18, IL-1β and MCP-1, were higher than appropriate effects upon cytokine production by tumor tisuues. Meanwhile, the IIPA activation index upon IL-18 (a proinflammatory and prooncogene cytokine production by tumor cells and its microenvironment proved to be elevated, as compared to appropriate IIPA by the blood IBC. Statistical studies showed a direct correlation between IIPA and cytokine production in tumor supernates, IIPA of VEGF-A expression in tumor tissue, with pathohistological parameters and expression of estrogen and progesterone receptors and Ki-67 proliferation marker. A high positive correlation was obtained between IIPA TNFα production by the tumor tissue, and degree of tumor vascularization.We have revealed a negative correlation between IIPA for IL-6, MCP-1 and Ki-67 marker of cell proliferation. A direct correlation was found between IIPA values for IL-1ra/IL-1β production ratios in blood cells, and IIPA for VEGF-A expression in adenocarcinoma tissues, thus indicating to probable

  16. Simultaneous Esophageal Squamous Cell Carcinoma and Adenocarcinoma: A Case Report

    OpenAIRE

    Maleki, Iradj; Shekarriz, Ramin; Nosrati, Anahita; Orang, Elahe

    2015-01-01

    Esophageal squamous cell carcinoma is a rather common cancer in northern Iran. Incidence of adenocarcinoma of esophagus has an increasing trend in Iran. Co-existence of both cancers in one patient is very rare. We report a middle age woman from northern Iran with a typical presentation of esophageal cancer, who was found to have a dual esophageal cancer. The disease was found in the advanced stage with pulmonary metastasis at the presentation. Palliative chemo-radiotherapy induced partial cli...

  17. Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas.

    Science.gov (United States)

    Kopp, Janel L; Dubois, Claire L; Schaffer, Ashleigh E; Hao, Ergeng; Shih, Hung Ping; Seymour, Philip A; Ma, Jenny; Sander, Maike

    2011-02-01

    One major unresolved question in the field of pancreas biology is whether ductal cells have the ability to generate insulin-producing β-cells. Conclusive examination of this question has been limited by the lack of appropriate tools to efficiently and specifically label ductal cells in vivo. We generated Sox9CreER(T2) mice, which, during adulthood, allow for labeling of an average of 70% of pancreatic ductal cells, including terminal duct/centroacinar cells. Fate-mapping studies of the Sox9(+) domain revealed endocrine and acinar cell neogenesis from Sox9(+) cells throughout embryogenesis. Very small numbers of non-β endocrine cells continue to arise from Sox9(+) cells in early postnatal life, but no endocrine or acinar cell neogenesis from Sox9(+) cells occurs during adulthood. In the adult pancreas, pancreatic injury by partial duct ligation (PDL) has been suggested to induce β-cell regeneration from a transient Ngn3(+) endocrine progenitor cell population. Here, we identify ductal cells as a cell of origin for PDL-induced Ngn3(+) cells, but fail to observe β-cell neogenesis from duct-derived cells. Therefore, although PDL leads to activation of Ngn3 expression in ducts, PDL does not induce appropriate cues to allow for completion of the entire β-cell neogenesis program. In conclusion, although endocrine cells arise from the Sox9(+) ductal domain throughout embryogenesis and the early postnatal period, Sox9(+) ductal cells of the adult pancreas no longer give rise to endocrine cells under both normal conditions and in response to PDL.

  18. Difference between intraductal papillary mucinous neoplasms and pancreatic ductal adenocarcinoma%胰腺导管内乳头状黏液性肿瘤与胰腺导管腺癌的差异分析

    Institute of Scientific and Technical Information of China (English)

    徐彬; 楼文晖; 王单松; 靳大勇

    2011-01-01

    Objective To identify difference between intraductal papillary mucinous neoplasms (IPMN) and pancreatic common ductal adenocarcinoma. Methods Between March 2003 and June 2006, 29 patients with pathological diagnosis of IPMN and 46 patients with pancreatic adenocarcinoma in Zhongshan Hospital were retrospectively reviewed. Clinical, biochemical, and histopathologic factors were retrospectively analyzed. Prognosis between two groups were compared by log-rank test.Results The proportion with no symptom visit in IPMN was obviously higher than in pancreatic cancer. Twenty-one of 29 specimens were malignant in IPMN. Stage of the malignant IPMN was significantly earlier than that of the pancreatic adenocarcinoma (P=0.017). Intrapancreatic neural invasion was more common in pancreatic adenocarcinoma than in malignant IPMN (P=0.005). The survival curve of the malignant IPMN was significantly better than that of the pancreatic adenocarcinoma (P=0.014). Conclusion IPMN with less aggressive bionomics can be diagnosed and treated in an earlier stage. So its prognosis is better than that of pancreatic ductal adenocarcinoma. Prognosis of malignant IPMN which is more invasive than stage Ⅱ B is simular to that of common pancreatic cancer. However, this conclusion should be further investigated.%目的 探讨胰腺导管内乳头状黏液性肿瘤(IPMN)与胰腺导管腺癌的差异.方法 回顾性收集2003年3月至2006年6月收治的资料完整的29例IPMN病例和46例胰腺导管腺癌的临床、生化、病理和随访资料,利用单因素及生存分析方法探讨两者的差异.结果 IPMN中无症状就诊比例明显高于胰腺导管腺癌(P<0.05).29例IPMN中21例为恶性,其病理分期明显早于胰腺导管腺癌(P=0.017);肿瘤对胰腺内神经的侵犯较胰腺癌少见(P=0.005).IPMN 患者术后的生存时间长于胰腺导管腺癌,而ⅡB期及以上的恶性IPMN患者术后生存时间与胰腺导管腺癌比较无明显差异.结论 IPMN与胰腺

  19. Procyanidin induces apoptosis of esophageal adenocarcinoma cells via JNK activation of c-Jun. : Procyanidin induces apoptosis of esophageal adenocarcinoma cells via JNK activation of c-Jun.

    NARCIS (Netherlands)

    Connor, Carol A; Adriaens, Michiel; Pierini, Roberto; Johnson, Ian T; Belshaw, Nigel J

    2014-01-01

    Procyanidins are polymeric flavanols found in fruits and vegetables and have shown anticarcinogenic/chemopreventive properties. We previously showed that oligomeric procyanidin extracted from apples induced cell cycle arrest and apoptosis in esophageal adenocarcinoma (OA) cells. To understand the me

  20. Simultaneous large cell neuroendocrine carcinoma and adenocarcinoma of the stomach

    Institute of Scientific and Technical Information of China (English)

    Tadashi Terada; Hirotoshi Maruo

    2011-01-01

    A large cell neuroendocrine carcinoma (LCNEC) of the stomach is very rare. A 76-year-old Japanese man was admitted to our hospital because of epigastralgia and nausea. Endoscopy revealed 2 large tumors in the stomach. He did not have multiple endocrine neoplasia type Ⅰ or Zollinger-Ellison syndrome. Imaging modali-ties, including computed tomography and magnetic resonance imaging, revealed no other tumors. Gas-trectomy, cholecystectomy, and lymph node dissection were performed. The resected stomach had 2 tumors: one was an antral ulcerated type 3 tumor measuring 5 cm x 5 cm, and the other was a polypoid type 1 tumor measuring 6 cm x 6 cm x 3 cm in the fundus. Micro-scopically, the antral ulcerated tumor was a well differ-entiated adenocarcinoma with deep invasion. The fun-dus polypoid tumor was a LCNEC, being composed of malignant large cells arranged in trabecular and nested patterns. The tumor cells were large and the nuclei were vesicular. Nucleoli were frequently present, and there were many mitotic figures, apoptotic bodies, and necrotic areas. Much lymphovascular permeation was seen. Seven out of 29 dissected lymph nodes showed metastatic foci; 6 were from the LCNEC and 1 from the adenocarcinoma. Many intravascular tumor emboli of LCNEC were seen in the peritoneum around the lymph nodes. Mucins were present in the adenocarcinoma but not in the LCNEC. Immunohistochemically, the LCNEC tumor cells were positive for pancytokeratins, synaptophysin (50% positive), chromogranin A (10% positive), Ki-67 (90% labeled), and platelet-derived growth factor-α (80% positive). They were negative for KIT, p53, CD56, and neuron-specific enolase. The non-cancerous stomach showed a normal number of endocrine cells. The patient is now treated with adju-vant chemotherapy.

  1. A case of renal cell carcinoma metastasizing to invasive ductal breast carcinoma

    Directory of Open Access Journals (Sweden)

    Tai-Di Chen

    2014-02-01

    Full Text Available Tumor-to-tumor metastasis is an uncommon but well-documented phenomenon. We present a case of a clear cell renal cell carcinoma (RCC metastasizing to an invasive ductal carcinoma (IDC of the breast. A 74-year-old woman with a past history of clear cell RCC status after radical nephrectomy underwent right modified radical mastectomy for an enlarging breast mass 3 years after nephrectomy. Histological examination revealed a small focus with distinct morphological features similar to clear cell RCC encased in the otherwise typical IDC. Immunohistochemical studies showed that this focus was positive for CD10 and vimentin, in contrast to the surrounding IDC, which was negative for both markers and positive for Her2/neu. Based on the histological and immunohistochemical features, the patient was diagnosed with metastasis of clear cell RCC to the breast IDC. To the best of our knowledge, this is the first reported case of a breast neoplasm as the recipient tumor in tumor-to-tumor metastasis.

  2. TNF-like weak inducer of apoptosis (TWEAK promotes beta cell neogenesis from pancreatic ductal epithelium in adult mice.

    Directory of Open Access Journals (Sweden)

    Fei Wu

    Full Text Available AIM/HYPOTHESIS: The adult mammalian pancreas has limited ability to regenerate in order to restore adequate insulin production from multipotent progenitors, the identity and function of which remain poorly understood. Here we test whether the TNF family member TWEAK (TNF-like weak inducer of apoptosis promotes β-cell neogenesis from proliferating pancreatic ductal epithelium in adult mice. METHODS: C57Bl/6J mice were treated with Fc-TWEAK and pancreas harvested at different time points for analysis by histology and immunohistochemistry. For lineage tracing, 4 week old double transgenic mice CAII-CreER(TM: R26R-eYFP were implanted with tamoxifen pellet, injected with Fc-TWEAK or control Ig twice weekly and analyzed at day 18 for TWEAK-induced duct cell progeny by costaining for insulin and YFP. The effect of TWEAK on pancreatic regeneration was determined by pancytokeratin immunostaining of paraffin embedded sections from wildtype and TWEAK receptor (Fn14 deficient mice after Px. RESULTS: TWEAK stimulates proliferation of ductal epithelial cells through its receptor Fn14, while it has no mitogenic effect on pancreatic α- or β-cells or acinar cells. Importantly, TWEAK induces transient expression of endogenous Ngn3, a master regulator of endocrine cell development, and induces focal ductal structures with characteristics of regeneration foci. In addition, we identify by lineage tracing TWEAK-induced pancreatic β-cells derived from pancreatic duct epithelial cells. Conversely, we show that Fn14 deficiency delays formation of regenerating foci after Px and limits their expansion. CONCLUSIONS/INTERPRETATION: We conclude that TWEAK is a novel factor mediating pancreatic β-cell neogenesis from ductal epithelium in normal adult mice.

  3. Analysis of Immune Cells from Human Mammary Ductal Epithelial Organoids Reveals Vδ2+ T Cells That Efficiently Target Breast Carcinoma Cells in the Presence of Bisphosphonate.

    Science.gov (United States)

    Zumwalde, Nicholas A; Haag, Jill D; Sharma, Deepak; Mirrielees, Jennifer A; Wilke, Lee G; Gould, Michael N; Gumperz, Jenny E

    2016-04-01

    Developing strategies to enhance cancer prevention is a paramount goal, particularly given recent concerns about surgical treatment of preinvasive states such as ductal carcinoma in situ. Promoting effective immunosurveillance by leukocytes that scan for nascent neoplastic transformations represents a potential means to achieve this goal. Because most breast cancers arise within the ductal epithelium, enhancing protective immunosurveillance will likely necessitate targeting one or more of the distinctive lymphocyte types found in these sites under normal conditions. Here, we have characterized the intraepithelial lymphocyte compartment of non-cancerous human breast tissue and identified a subset of T lymphocytes that can be pharmacologically targeted to enhance their responses to breast cancer cells. Specifically, Vδ2(+) γδ T cells were consistently present in preparations of mammary ductal epithelial organoids and they proliferated in response to zoledronic acid, an aminobisphosphonate drug. Vδ2(+) T cells from breast ductal organoids produced the antitumor cytokine IFNγ and efficiently killed bisphosphonate-pulsed breast carcinoma cells. These findings demonstrate the potential for exploiting the ability of Vδ2(+) γδ T cells to respond to FDA-approved bisphosphonate drugs as a novel immunotherapeutic approach to inhibit the outgrowth of breast cancers.

  4. Clear cell adenocarcinoma of a female urethra: A case report and review of the literature

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    Amel Trabelsi

    2009-01-01

    Full Text Available Context : Clear cell adenocarcinoma of the urethra is an extremely rare tumour. Its histogenetic derivation remains controversial. Case report : We report a new case of clear cell adenocarcinoma of the proximal urethra in a 56-year-old woman who presented with grossly hematuria. Urethral cystoscopy revealed a tumour protruding from the posterior urethral wall at the bladder neck. Treatment consisted of urethrocystectomy with pelvic lymph node dissection. Histologically, the neoplasm consisted of clear cell adenocarcinoma of the urethra. Conclusion : It appears that female urethral adenocarcinoma has more than one tissue of origin.

  5. A case with primary signet ring cell adenocarcinoma of the prostate and review of the literature

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    Orcun Celik

    2014-06-01

    Full Text Available Primary signet cell carcinoma of the prostate is a rare histological variant of prostate malignancies. It is commonly originated from the stomach, colon, pancreas, and less commonly in the bladder. Prognosis of the classical type is worse than the adenocarcinoma of the prostate. Primary signet cell adenocarcinoma is diagnosed by eliminating the adenocarcinomas of other organs such as gastrointestinal tract organs. In this case report, we present a case with primary signet cell adenocarcinoma of the prostate who received docetaxel chemotherapy because of short prostate specific antigen doubling time.

  6. Hepatocyte growth factor signaling in intrapancreatic ductal cells drives pancreatic morphogenesis.

    Directory of Open Access Journals (Sweden)

    Ryan M Anderson

    Full Text Available In a forward genetic screen for regulators of pancreas development in zebrafish, we identified donut(s908 , a mutant which exhibits failed outgrowth of the exocrine pancreas. The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and "tip cells" at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis.

  7. Regression analysis of the initial karyometric data on tumor cells in ductal carcinoma and fibroadenoma of the mammary gland.

    Science.gov (United States)

    Kirillov, Vladimir; Akimova, Lydmila

    2010-04-01

    To reveal the differences in the parameters of the second order regression curve with a cluster of experimental points on scattergrams showing the dependence of the perimeter on the area of tumor cell nuclei between ductal carcinoma and fibroadenoma of the mammary gland. Punctate smears taken from patients with ductal carcinoma and fibroadenoma of the mammary gland with coincident histologic and cytologic conclusion were studied and selected. Karyometry of tumor cells was performed with the help of a semiautomatic computer analyzer of digital images. It has been shown that the cluster of experimental points on scattergrams showing the dependence of the perimeter on the area of tumor cell nuclei can be well described by a second order regression curve, which is a parabola. The differences in parabola parameters (coefficients of the parabola equation) characterizing the population of tumor cells in ductal carcinoma and fibroadenoma of the mammary gland were revealed. Boundary values of these parameters in the groups of comparison were ascertained. Parameters of the regression curve to a cluster of experimental points on scattergrams showing the dependence of the perimeter on the area of tumor cell nuclei can be used as an additional diagnostic criterion for breast cancer.

  8. Trefoil factor 3 as a novel biomarker to distinguish between adenocarcinoma and squamous cell carcinoma.

    Science.gov (United States)

    Wang, Xiao-Nan; Wang, Shu-Jing; Pandey, Vijay; Chen, Ping; Li, Qing; Wu, Zheng-Sheng; Wu, Qiang; Lobie, Peter E

    2015-05-01

    In carcinoma, such as of the lung, the histological subtype is important to select an appropriate therapeutic strategy for patients. However, carcinomas with poor differentiation cannot always be distinguished on the basis of morphology alone nor on clinical findings. Hence, delineation of poorly differentiated adenocarcinoma and squamous cell carcinoma, the 2 most common epithelial-origin carcinomas, is pivotal for selection of optimum therapy. Herein, we explored the potential utility of trefoil factor 3 (TFF3) as a biomarker for primary lung adenocarcinoma and extrapulmonary adenocarcinomas derived from different organs. We observed that 90.9% of lung adenocarcinomas were TFF3-positive, whereas no expression of TFF3 was observed in squamous cell carcinomas. The subtype of lung carcinoma was confirmed by four established biomarkers, cytokeratin 7 and thyroid transcription factor 1 for adenocarcinoma and P63 and cytokeratin 5/6 for squamous cell carcinoma. Furthermore, expression of TFF3 mRNA was observed by quantitative PCR in all of 11 human lung adenocarcinoma cell lines and highly correlated with markers of the adenocarcinomatous lineage. In contrast, little or no expression of TFF3 was observed in 4 lung squamous cell carcinoma cell lines. By use of forced expression, or siRNA-mediated depletion of TFF3, we determined that TFF3 appeared to maintain rather than promote glandular differentiation of lung carcinoma cells. In addition, TFF3 expression was also determined in adenocarcinomas from colorectum, stomach, cervix, esophagus, and larynx. Among all these extrapulmonary carcinomas, 93.7% of adenocarcinomas exhibited TFF3 positivity, whereas only 2.9% of squamous cell carcinomas were TFF3-positive. Totally, 92.9% of both pulmonary and extrapulmonary adenocarcinomas exhibited TFF3 positivity, whereas only 1.5% of squamous cell carcinomas were TFF3-positive. In conclusion, TFF3 is preferentially expressed in adenocarcinoma and may function as an additional

  9. Apigenin affects leptin/leptin receptor pathway and induces cell apoptosis in lung adenocarcinoma cell line.

    Science.gov (United States)

    Bruno, Andreina; Siena, Liboria; Gerbino, Stefania; Ferraro, Maria; Chanez, Pascal; Giammanco, Marco; Gjomarkaj, Mark; Pace, Elisabetta

    2011-09-01

    Apigenin, a common edible plant flavonoid, is a well characterised antioxidant. The adipokine leptin exerts proliferative and anti-apoptotic activities in a variety of cell types. In cancer cells, apigenin may induce a pro-apoptotic pathway whereas leptin has an anti-apoptotic role. The purpose of the study is to investigate the role of apigenin and of leptin/leptin receptor pathway on proliferation and on apoptosis in lung adenocarcinoma. Immunocytochemistry, flow cytometry and RT-q-RT PCR, were used to investigate the expression and modulation of leptin receptors on the lung adenocarcinoma cell line A549 in presence or absence of apigenin and of leptin, alone or combined. Clonogenic test to evaluate cell proliferation was assessed. Exogenous leptin binding to its receptors by flow cytometry, reactive oxygen species (ROS) by dichlorofluorescein diacetate analysis, cell death by ethidium bromide and apoptosis by annexin V analysis were assessed. Apoptosis was assessed also in presence of lung adenocarcinoma pleural fluids (PF) (n=6). A549 express leptin/leptin receptor pathway and its expression is upregulated by apigenin. Apigenin alone or combined with leptin significantly decreases cell proliferation and significantly increases the spontaneous release of ROS, with augmented cell death and apoptosis, this latter also in the presence of lung adenocarcinoma PF. Leptin alone significantly increases cell proliferation and significantly decreases cell death. These results strongly suggest the potential utility of the flavonoid apigenin in the complementary therapeutic approach of patients with lung adenocarcinoma. Copyright © 2011 Elsevier Ltd. All rights reserved.

  10. KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis.

    Science.gov (United States)

    Wei, Daoyan; Wang, Liang; Yan, Yongmin; Jia, Zhiliang; Gagea, Mihai; Li, Zhiwei; Zuo, Xiangsheng; Kong, Xiangyu; Huang, Suyun; Xie, Keping

    2016-03-14

    Understanding the molecular mechanisms of tumor initiation has significant impact on early cancer detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma (PDA) initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant Kras(G12D), whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.

  11. Clear Cell Adenocarcinoma of the Urethra: Review of the Literature

    Directory of Open Access Journals (Sweden)

    Anthony Kodzo-Grey Venyo

    2015-01-01

    Full Text Available Background. Clear cell adenocarcinoma of the urethra (CCAU is extremely rare and a number of clinicians may be unfamiliar with its diagnosis and biological behaviour. Aims. To review the literature on CCAU. Methods. Various internet databases were used. Results/Literature Review. (i CCAU occurs in adults and in women in the great majority of cases. (ii It has a particular association with urethral diverticulum, which has been present in 56% of the patients; is indistinguishable from clear cell adenocarcinoma of the female genital tract but is not associated with endometriosis; and probably does not arise by malignant transformation of nephrogenic adenoma. (iii It is usually, readily distinguished from nephrogenic adenoma because of greater cytological a-typicality and mitotic activity and does not stain for prostate-specific antigen or prostatic acid phosphatase. (iv It has been treated by anterior exenteration in women and cystoprostatectomy in men and at times by radiotherapy; chemotherapy has rarely been given. (v CCAU is aggressive with low 5-year survival rates. (vi There is no consensus opinion of treatment options that would improve the prognosis. Conclusions. Few cases of CCAU have been reported. Urologists, gynaecologists, pathologists, and oncologists should report cases of CCAU they encounter and enter them into a multicentric trial to determine the best treatment options that would improve the prognosis.

  12. Prostate Mucinous Adenocarcinoma with Signet Ring Cells: a Case Report and Literature Review

    Institute of Scientific and Technical Information of China (English)

    Yi Wang; Guang Sun; Jiangang Pan; Jiwu Chang; Shumin Zhang; Tao Li; Binghuang Ren

    2006-01-01

    @@ Prostate mucinous adenocarcinoma with signet ring cells(MCSRC)is a rare morphologic variant of prostate cancer,with only 12 cases reported to date.[1] Diagnosis of this carcinoma requires that at least 25% of the tumor tissue should consist of an extracellular mucin pool.[2] In this report, we present a case of prostate prostate mucinous adenocarcinoma with signet ring cells.

  13. Clear-Cell Adenocarcinoma of Vesical Origin: A Case Study of Metastatic Disease Treated with Chemotherapy

    Directory of Open Access Journals (Sweden)

    Carolina Pena Álvarez

    2010-01-01

    Full Text Available Vesical clear cell adenocarcinoma is an uncommon tumour. The description of nearly all published cases focuses on histological issues, providing few clinical particulars and limited followup. The treatment choice is resection. No publications have been found regarding systemic treatments for advanced disease. We present a case of metastatic clear cell adenocarcinoma of the bladder treated with chemotherapy.

  14. Resveratrol engages selective apoptotic signals in gastric adenocarcinoma cells

    Institute of Scientific and Technical Information of China (English)

    William L Riles; Jason Erickson; Sanjay Nayyar; Mary Jo Atten; Bashar M Attar; Oksana Holian

    2006-01-01

    AIM: To investigate the intracellular apoptotic signals engaged by resveratrol in three gastric adenocarcinoma cancer cell lines, two of which (AGS and SNU-1) express p53 and one (KATO-Ⅲ) with deleted p53.METHODS: Nuclear fragmentation was used to quantitate apoptotic cells; caspase activity was determined by photometric detection of cleaved substrates; formation of oxidized cytochrome C was used to measure cytochrome C activity, and Western blot analysis was used to determine protein expression.RESULTS: Gastric cancer cells, irrespective of their p53 status, responded to resveratrol with fragmentation of DNA and cleavage of nuclear lamins A and B and PARP, Resveratrol, however, has no effect on mitochondria-associated apoptotic proteins Bcl-2, Bclxl, Bax, Bid or Smac/Diablo, and did not promote subcellular redistribution of cytochrome C, indicating that resveratrol-induced apoptosis of gastric carcinoma cells does not require breakdown of mitochondrial membrane integrity. Resveratrol up-regulated p53 protein in SNU-1 and AGS cells but there was a difference in response of intracellular apoptotic signals between these cell lines.SNU-1 cells responded to resveratrol treatment with down-regulation of survivin, whereas in AGS and KATO-Ⅲ cells resveratrol stimulated caspase 3 and cytochrome C oxidase activities.CONCLUSION: These findings indicate that even within a specific cancer the intracellular apoptotic signals engaged by resveratrol are cell type dependent and suggest that such differences may be related to differentiation or lack of differentiation of these cells.

  15. A New Surgical Technique of Pancreaticoduodenectomy with Splenic Artery Resection for Ductal Adenocarcinoma of the Pancreatic Head and/or Body Invading Splenic Artery: Impact of the Balance between Surgical Radicality and QOL to Avoid Total Pancreatectomy

    Directory of Open Access Journals (Sweden)

    Ryosuke Desaki

    2014-01-01

    Full Text Available For pancreatic ductal adenocarcinoma (PDAC of the head and/or body invading the splenic artery (SA, we developed a new surgical technique of proximal subtotal pancreatectomy with splenic artery and vein resection, so-called pancreaticoduodenectomy with splenic artery resection (PD-SAR. We retrospectively reviewed a total of 84 patients with curative intent pancreaticoduodenectomy (PD for PDAC of the head and/or body. These 84 patients were classified into the two groups: conventional PD (n=66 and PD-SAR (n=18. Most patients were treated by preoperative chemoradiotherapy (CRT. Postoperative MDCT clearly demonstrated enhancement of the remnant pancreas at 1 and 6 months in all patients examined. Overall survival rates were very similar between PD and PD-SAR (3-year OS: 23.7% versus 23.1%, P=0.538, despite the fact that the tumor size and the percentages of UICC-T4 determined before treatment were higher in PD-SAR. Total daily insulin dose was significantly higher in PD-SAR than in PD at 1 month, while showing no significant differences between the two groups thereafter. PD-SAR with preoperative CRT seems to be promising surgical strategy for PDAC of head and/or body with invasion of the splenic artery, in regard to the balance between operative radicality and postoperative QOL.

  16. The effect of low concentrations of ethanol on gastric adenocarcinoma cell lines

    Directory of Open Access Journals (Sweden)

    Wu Lingjiao

    2013-01-01

    Full Text Available Chronic alcohol consumption was identified as a significant risk factor for cancer in humans. The aim of the study was to analyze the influence of low concentrations of ethanol on gastric adenocarcinoma cell viability, apoptosis, and changes in the expression of alcohol dehydrogenase with ethanol treatment. Gastric adenocarcinoma cell lines (MGC803, MGC823 and SGC7901 were treated with different concentrations of ethanol (0.03125%, 0.0625%, 0.125%, 0.25%, 0.5%, 1%, 2%, and 4%. The MTT (3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay and flow cytometry were used to analyze the effect of ethanol treatment on cell viability and apoptosis. Western blotting was used to analyze the expression of alcohol dehydrogenase in gastric carcinoma cells. Ethanol treatment inhibited cell proliferation in gastric adenocarcinoma cell lines in a significant dose-dependent manner. Ethanol induced apoptosis of gastric adenocarcinoma cells in a dose-dependent manner. The alcohol dehydrogenase activity of gastric adenocarcinoma cells increased with the increase in the concentration of ethanol. Ethanol inhibited cell viability and the growth of gastric adenocarcinoma cell lines. Low concentrations of ethanol also induced apoptosis and increased the expression of alcohol dehydrogenase of the gastric adenocarcinoma cell lines.

  17. The effect of low concentrations of ethanol on gastric adenocarcinoma cell lines

    Directory of Open Access Journals (Sweden)

    Wu Lingjiao

    2014-01-01

    Full Text Available Chronic alcohol consumption has been identified as a significant risk factor for cancer in humans. The aim of the study was to analyze the influence of low concentrations of ethanol on gastric adenocarcinoma cell viability, apoptosis, and changes in the expression of alcohol dehydrogenase with ethanol treatment. Gastric adenocarcinoma cell lines (MGC803, MGC823 and SGC7901 were treated with different concentrations of ethanol (0.03125%, 0.0625%, 0.125%, 0.25%, 0.5%, 1%, 2%, and 4%. An MTT (3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay and flow cytometry were used to analyze the effect of ethanol treatment on cell viability and apoptosis. Western blotting was used to analyze the expression of alcohol dehydrogenase in gastric carcinoma cells. Ethanol treatment inhibited cell proliferation in gastric adenocarcinoma cell lines in a significant dose-dependent manner. Ethanol was also able to induce the apoptosis of gastric adenocarcinoma cells in a dose-dependent manner. Alcohol dehydrogenase activity of gastric adenocarcinoma cells increased with the increase in the concentration of ethanol. Ethanol inhibited cell viability and growth of gastric adenocarcinoma cell lines. Low concentrations of ethanol also induced apoptosis and increased the expression of alcohol dehydrogenase of the gastric adenocarcinoma cell lines.

  18. Classifying the Progression of Ductal Carcinoma from Single-Cell Sampled Data via Integer Linear Programming: A Case Study.

    Science.gov (United States)

    Catanzaro, Daniele; Shackney, Stanley E; Schaffer, Alejandro A; Schwartz, Russell

    2016-01-01

    Ductal Carcinoma In Situ (DCIS) is a precursor lesion of Invasive Ductal Carcinoma (IDC) of the breast. Investigating its temporal progression could provide fundamental new insights for the development of better diagnostic tools to predict which cases of DCIS will progress to IDC. We investigate the problem of reconstructing a plausible progression from single-cell sampled data of an individual with synchronous DCIS and IDC. Specifically, by using a number of assumptions derived from the observation of cellular atypia occurring in IDC, we design a possible predictive model using integer linear programming (ILP). Computational experiments carried out on a preexisting data set of 13 patients with simultaneous DCIS and IDC show that the corresponding predicted progression models are classifiable into categories having specific evolutionary characteristics. The approach provides new insights into mechanisms of clonal progression in breast cancers and helps illustrate the power of the ILP approach for similar problems in reconstructing tumor evolution scenarios under complex sets of constraints.

  19. File list: DNS.Lng.50.AllAg.Lung_adenocarcinoma_cell_lines [Chip-atlas[Archive

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  14. File list: InP.Lng.50.AllAg.Lung_adenocarcinoma_cell_lines [Chip-atlas[Archive

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  9. File list: His.Lng.50.AllAg.Lung_adenocarcinoma_cell_lines [Chip-atlas[Archive

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  10. Nuclear distribution of claudin-2 increases cell proliferation in human lung adenocarcinoma cells.

    Science.gov (United States)

    Ikari, Akira; Watanabe, Ryo; Sato, Tomonari; Taga, Saeko; Shimobaba, Shun; Yamaguchi, Masahiko; Yamazaki, Yasuhiro; Endo, Satoshi; Matsunaga, Toshiyuki; Sugatani, Junko

    2014-09-01

    Claudin-2 is expressed in human lung adenocarcinoma tissue and cell lines, although it is absent in normal lung tissue. However, the role of claudin-2 in cell proliferation and the regulatory mechanism of intracellular distribution remain undefined. Proliferation of human adenocarcinoma A549 cells was decreased by claudin-2 knockdown together with a decrease in the percentage of S phase cells. This knockdown decreased the expression levels of ZONAB and cell cycle regulators. Claudin-2 was distributed in the nucleus in human adenocarcinoma tissues and proliferating A549 cells. The nuclear distribution of ZONAB and percentage of S phase cells were higher in cells exogenously expressing claudin-2 with a nuclear localization signal than in cells expressing claudin-2 with a nuclear export signal. Nuclear claudin-2 formed a complex with ZO-1, ZONAB, and cyclin D1. Nuclear distribution of S208A mutant, a dephosphorylated form of claudin-2, was higher than that of wild type. We suggest that nuclear distribution of claudin-2 is up-regulated by dephosphorylation and claudin-2 serves to retain ZONAB and cyclin D1 in the nucleus, resulting in the enhancement of cell proliferation in lung adenocarcinoma cells.

  11. Identification of distinct phenotypes of locally advanced pancreatic adenocarcinoma.

    LENUS (Irish Health Repository)

    Teo, Minyuen

    2013-03-01

    A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease. Optimal treatment remains controversial. We sought to analyze the clinical course of locally advanced pancreatic adenocarcinoma (LAPC) in order to identify potential distinct clinical phenotypes.

  12. Identification and characterization of SP cells in human lung adenocarcinoma SPC-A1 cells

    Directory of Open Access Journals (Sweden)

    Yanliang ZHU

    2008-10-01

    Full Text Available Background and objective Recently, eloquent studies from some solid tumors have provided proofs that cancers originate from cancer stem cells (CSC. The discovery of CSC has changed our view of carcinogenesis and chemotherapy. The aim of this study is to identify and characterize the CSC population that drives and maintains lung adenocarcinoma growth and metastasis. Methods Side population (SP cell analysis combined with serum-free media (SFM were applied to established human lung adenocarcinoma cell lines. Properties of SP cells were evaluated by their proliferative index, colony-forming efficiency and tumorigenic potential. Results Characteristic SP cells could be detected by FACS in lung adenocarcinoma cell lines. And the proportion of SP cells is greatly increased after serum-free culture.SP cells have a greater proliferative index, a higher colony-forming efficiency and a greater ability to form tumor in vivo .Conclusion SP cells exist in human lung adenocarcinoma cell lines and they could be further enriched by preliminary serum-free culture before FACS sorting.

  13. NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Kai, E-mail: gk161@163.com [Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China); Department of Respiration, 161th Hospital, PLA, Wuhan 430015 (China); Jin, Faguang, E-mail: jinfag@fmmu.edu.cn [Department of Respiration, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China)

    2015-09-25

    The osmoregulated transcription factor nuclear factor of activated T-cells 5(NFAT5), has been found to play important roles in the development of many kinds of human cancers, including breast cancer, colon carcinoma, renal cell carcinoma and melanoma. The aim of the present study was to determine whether NFAT5 is involved in the proliferation and migration of lung adenocarcinoma cells. We found that NFAT5 was upregulated in lung adenocarcinoma cells and knockdown of NFAT5 decreased proliferation and migration of the cells, accompanied by a significant reduction in the expression of AQP5. AQP5 was upregulated in lung adenocarcinoma cells and knockdown of AQP5 also inhibited proliferation and migration of the cells as knockdown of NFAT5 did. Moreover, overexpression of NFAT5 promoted proliferation and migration of lung adenocarcinoma cells, accompanied by a significant increase in the expression of AQP5. These results indicate that NFAT5 plays important roles in proliferation and migration of human lung adenocarcinoma cells through regulating AQP5 expression, providing a new therapeutic option for lung adenocarcinoma therapy. - Highlights: • NFAT5 expression is higher in lung adenocarcinoma cells compared with normal cells. • NFAT5 knockdown decreases proliferation and migration of lung adenocarcinoma cells. • Knockdown of NFAT5 reduces AQP5 expression in human lung adenocarcinoma cells. • Overexpression of NFAT5 promotes proliferation and migration of lung adenocarcinoma cells. • Overexpression of NFAT5 increases AQP5 expression in human lung adenocarcinoma cells.

  14. Identificación de los perfiles de expresión en el adenocarcinoma ductal de páncreas. Implicaciones clínicas

    OpenAIRE

    Gomez Mateo, Maria del Carmen

    2015-01-01

    INTRODUCCIÓN: El cáncer de páncreas es la cuarta causa de muerte por cáncer en el mundo occidental, con una incidencia de 8-10 casos por 100.000 habitantes/año. A pesar de los esfuerzos científicos y el progreso significativo en la comprensión de las bases moleculares del adenocarcinoma de páncreas (ACP), la supervivencia no ha cambiado mucho en los últimos 20 años. El pronóstico de estos pacientes continúa siendo insatisfactorio debido al diagnóstico tardío, las bajas tasas de resecabilid...

  15. Clear Cell Adenocarcinoma Arising from Abdominal Wall Endometriosis

    Directory of Open Access Journals (Sweden)

    Thouraya Achach

    2008-01-01

    Full Text Available Endometriosis is a frequent benign disorder. Malignancy arising in extraovarian endometriosis is a rare event. A 49-year-old woman is presented with a large painful abdominal wall mass. She underwent a myomectomy, 20 years before, for uterus leiomyoma. Computed tomography suggested that this was a desmoid tumor and she underwent surgery. Histological examination showed a clear cell adenocarcinoma associated with endometriosis foci. Pelvic ultrasound, computed tomography, and endometrial curettage did not show any malignancy or endometriosis in the uterus and ovaries. Adjuvant chemotherapy was recommended, but the patient was lost to follow up. Six months later, she returned with a recurrence of the abdominal wall mass. She was given chemotherapy and then she was reoperated.

  16. ADENOVIRUS-MEDIATED WILD-TYPE P53 EXPRESSION SUPPRESSES GROWTH OF LUNG ADENOCARCINOMA CELLS

    Institute of Scientific and Technical Information of China (English)

    Li Jian; Xia Yongjing; Jiang Lei; Li Hongxia; Hu Yajun; Yi Lin; Hu Shixue; Xu Hongji

    1998-01-01

    Objective: To study the growth suppression of lung adenocarcinoma cell by the introduction of wild-type P53gene and explore a gene therapy approach for lung adenocarcinoma. Methods: A replication-deficient adenovirus vector encoding a wild-type P53 was constructed and transfected into the cultured human lung adenocarcinoma cell line GLC-82. The efficiency of gene transfection and expression was detected by immunochemical staining and polymerase chain reaction. The cell growth rate and cell cycle were analysed by cell-counting and flow cytometry. Results: Wild-type P53 gene could be quickly and effectively transfected into the cells by adenovirus vector. Wild-type P53 expression could inhibit GLC-82 cell proliferation and induce apoptosis.Conclusion: The results indicated that recombinant adenovirus expressing wild-type P53 might be useful vector for gene therapy of human lung adenocarcinoma.

  17. Frequencies and prognostic role of KRAS and BRAF mutations in patients with localized pancreatic and ampullary adenocarcinomas

    DEFF Research Database (Denmark)

    Schultz, Nicolai Aagaard; Roslind, Anne; Christensen, Ib J

    2012-01-01

    The frequencies and prognostic role of KRAS and BRAF mutations in patients operated on for pancreatic ductal adenocarcinomas (PDACs) and ampullary adenocarcinomas (A-ACs) are scantily studied.......The frequencies and prognostic role of KRAS and BRAF mutations in patients operated on for pancreatic ductal adenocarcinomas (PDACs) and ampullary adenocarcinomas (A-ACs) are scantily studied....

  18. In Situ Malignant Transformation and Progenitor-Mediated Cell Budding: Two Different Pathways for Breast Ductal and Lobular Tumor Invasion

    Directory of Open Access Journals (Sweden)

    Yan-gao Man, Mina Izadjoo, Guohong Song, Alexander Stojadinovic

    2011-01-01

    Full Text Available The human breast lobular and ductal structures and the derived tumors from these structures differ substantial in their morphology, microenvironment, biological presentation, functions, and clinical prognosis. Based on these differences, we have proposed that pre-invasive lobular tumors may progress to invasive lesions through “in situ malignant transformation”, in which the entire myoepithelial cell layer within a given lobule or lobular clusters undergoes extensive degeneration and disruptions, which allows the entire epithelial cell population associated with these myoepithelial cell layers directly invade the stroma or vascular structures. In contrast, pre-invasive ductal tumors may invade the stroma or vascular structures through “progenitor-mediated cell budding”, in which focal myoepithelial cell degeneration-induced aberrant leukocyte infiltration causes focal disruptions in the tumor capsules, which selectively favor monoclonal proliferation of the overlying tumor stem cells or a biologically more aggressive cell clone. Our current study attempted to provide more direct morphological and immunohistochemical data that are consistent with our hypotheses.

  19. Squamous cell carcinoma of the nipple following radiation therapy for ductal carcinoma in situ: a case report

    Directory of Open Access Journals (Sweden)

    Huang Yajue

    2010-06-01

    Full Text Available Abstract Introduction Radiation-induced nonmelanoma skin cancer was first reported seven years after the discovery of X-rays, but has received relatively little consideration in the literature. Specifically, nonmelanoma skin cancer after conservative surgery and radiation for early stage breast cancer has not been well studied. We report the case of a woman who developed squamous cell carcinoma of the nipple nine years after conservative surgery and radiation for ductal carcinoma in situ of the ipsilateral breast. We also review the relevant literature available to date. Case presentation A 66-year-old African-American woman presented to the hospital with a non-healing ulcer of the right nipple. Her past medical history was significant for right breast ductal carcinoma in situ for which she had undergone lumpectomy and whole breast radiation therapy nine years previously. Mammography and magnetic resonance imaging studies were negative for recurrent breast cancer. However, the latter demonstrated abnormal enhancement in the nipple-areolar region. An incisional biopsy of the lesion demonstrated invasive squamous cell carcinoma. Subsequently, the patient underwent wide excision of the nipple-areolar complex. Sentinel lymph-node biopsy was offered but our patient declined. She was considered to have local disease and hence no further treatment was recommended. Conclusion This case represents the first reported occurrence of squamous cell carcinoma of the nipple to follow conservative surgery and radiation for ductal carcinoma in situ of the ipsilateral breast. It is likely that radiation overexposure resulted in a radiation burn and subsequent radiodermatitis, placing it at risk for squamous cell carcinoma. A diagnosis of squamous cell carcinoma should be considered in a patient with a nipple lesion following radiation therapy for breast cancer.

  20. 25-Hydroxycholesterol promotes migration and invasion of lung adenocarcinoma cells.

    Science.gov (United States)

    Chen, Li; Zhang, Lishan; Xian, Guozhe; Lv, Yinping; Lin, Yanliang; Wang, Yibing

    2017-03-18

    25-hydroxycholesterol (25-HC) is enzymatically produced by cholesterol 25-hydorxylase in various organs and is involved in many processes, including lipid metabolism, inflammation and the immune response. However, the role of 25-HC in the migration and invasion of lung adenocarcinoma (ADC) cells remains largely unknown. In this study, we demonstrated that 0.1 μM 25-HC promoted ADC cell migration and invasion without affecting cell proliferation, especially after coculture with THP1-derived macrophages. Further investigation showed that 0.1 μM 25-HC significantly stimulated interleukin-1β (IL-1β) secretion in a coculture system and increased the expression of LXR and Snail. IL-1β also mimicked the effect of 25-HC. LXR knockdown notably blocked the 25-HC-induced Snail expression, migration and invasion in both the monoculture system and the coculture system, but it did not impact the effect of IL-1β, which suggested that IL-1β functioned in an LXR-independent manner. These results suggested that 25-HC promoted ADC cell migration and invasion in an LXR-dependent manner in the monoculture system but that in the coculture system, the 25-HC-induced IL-1β secretion enhanced the effect of 25-HC in an LXR-independent manner.

  1. Screening for Early Pancreatic Ductal Adenocarcinoma: An Urgent Call! Highlights from the "2009 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 15-17, 2009

    Directory of Open Access Journals (Sweden)

    Michael Xiang Lee

    2009-03-01

    Full Text Available Cancer of the pancreas is the fourth leading cause of cancer mortality in the United States. The annual death rate from the disease almost equals the annual incidence due to the aggressive nature of the cancer as well as to the lack of effective means of screening for it during its early curable stage. Molecular markers and imaging have not proven to be accurate modalities for screening for pancreatic cancer. The diagnosis and management of pancreatic cancer continues to be an overwhelming challenge. The authors discuss the current status of screening for pancreatic cancer and summarize relevant studies presented in the 2009 GI Cancers Symposium: utility of endoscopic ultrasound in screening high risk patients (Abstract #112, diagnostic performance of a highly specific antibody for MUC1 (Abstract #113, use of metabonomics for the early detection of pancreatic adenocarcinoma (Abstract #126, and a report on the potential impact of delay in diagnosis and treatment on pancreatic cancer outcomes at a tertiary care center (Abstract #137.

  2. Novel pancreatic cancer cell lines derived from genetically engineered mouse models of spontaneous pancreatic adenocarcinoma: applications in diagnosis and therapy.

    Directory of Open Access Journals (Sweden)

    María P Torres

    Full Text Available Pancreatic cancer (PC remains one of the most lethal human malignancies with poor prognosis. Despite all advances in preclinical research, there have not been significant translation of novel therapies into the clinics. The development of genetically engineered mouse (GEM models that produce spontaneous pancreatic adenocarcinoma (PDAC have increased our understanding of the pathogenesis of the disease. Although these PDAC mouse models are ideal for studying potential therapies and specific genetic mutations, there is a need for developing syngeneic cell lines from these models. In this study, we describe the successful establishment and characterization of three cell lines derived from two (PDAC mouse models. The cell line UN-KC-6141 was derived from a pancreatic tumor of a Kras(G12D;Pdx1-Cre (KC mouse at 50 weeks of age, whereas UN-KPC-960 and UN-KPC-961 cell lines were derived from pancreatic tumors of Kras(G12D;Trp53(R172H;Pdx1-Cre (KPC mice at 17 weeks of age. The cancer mutations of these parent mice carried over to the daughter cell lines (i.e. Kras(G12D mutation was observed in all three cell lines while Trp53 mutation was observed only in KPC cell lines. The cell lines showed typical cobblestone epithelial morphology in culture, and unlike the previously established mouse PDAC cell line Panc02, expressed the ductal marker CK19. Furthermore, these cell lines expressed the epithelial-mesenchymal markers E-cadherin and N-cadherin, and also, Muc1 and Muc4 mucins. In addition, these cell lines were resistant to the chemotherapeutic drug Gemcitabine. Their implantation in vivo produced subcutaneous as well as tumors in the pancreas (orthotopic. The genetic mutations in these cell lines mimic the genetic compendium of human PDAC, which make them valuable models with a high potential of translational relevance for examining diagnostic markers and therapeutic drugs.

  3. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

    Energy Technology Data Exchange (ETDEWEB)

    Gomez-Casal, Roberto; Bhattacharya, Chitralekha [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Epperly, Michael W. [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Basse, Per H. [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Wang, Hong [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Biostatistics, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Wang, Xinhui [Harvard Medical School, Harvard University, 25 Shattuck Street, Boston, MA 02115 (United States); Proia, David A. [Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421 (United States); Greenberger, Joel S. [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Socinski, Mark A.; Levina, Vera, E-mail: levinav@upmc.edu [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213 (United States)

    2015-05-22

    The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors.

  4. High Expression of HIF1a Is a Predictor of Clinical Outcome in Patients with Pancreatic Ductal Adenocarcinomas and Correlated to PDGFA, VEGF, and bFGF

    Directory of Open Access Journals (Sweden)

    Andreas-Claudius Hoffmann

    2008-07-01

    Full Text Available PURPOSE: Pancreatic cancer still has one of the worst prognoses in gastrointestinal cancers with a 5-year survival rate of 5%, making it necessary to find markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. In this study, we investigated the prognostic values of HIF1a, bFGF, VEGF, and PDGFA gene expressions as well as their interrelationships. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma (age, 65; range, 34–85 years. After laser capture microdissection, direct quantitative real-time reverse transcription-polymerase chain reaction assays were performed in triplicates to determine HIF1a, PDGFA, VEGF, and bFGF gene expression levels. Multivariate Cox proportional hazards regression analysis was used to assess the impact of HIF1a gene expression on prognosis. RESULTS:HIF1a was significantly correlated to every gene we tested: bFGF (P = .04, VEGF (P = .02, and PDGFA (P = .03. Tumor size, P = .04, and high HIF1a mRNA expression (cutoff, 75th percentile had a significant impact on survival, P = .009 (overall model fit, P = .02. High HIF1a expression had a sensitivity of 87.1% and a specificity of 55.6% for the diagnosis short (<6 months versus long (6–60 months survival. CONCLUSIONS: Measuring PDGFA, bFGF, and HIF1a expression may contribute to a better understanding of the prognosis of patients with pancreatic cancer and may even play a crucial role for the distribution of patients to multimodal therapeutic regimens. Larger studies including patients treated with actual chemotherapeutics seem to be warranted.

  5. [A Case of Synchronous Multiple Esophageal Cancers Composed of Squamous Cell Carcinoma and Barrett's Adenocarcinoma].

    Science.gov (United States)

    Kobayashi, Toshiyuki; Shiozaki, Atsushi; Fujiwara, Hitoshi; Konishi, Hirotaka; Arita, Tomohiro; Kosuga, Toshiyuki; Morimura, Ryo; Murayama, Yasutoshi; Komatsu, Shuhei; Kuriu, Yoshiaki; Ikoma, Hisashi; Nakanishi, Masayoshi; Ichikawa, Daisuke; Okamoto, Kazuma; Otsuji, Eigo

    2015-11-01

    A 67-year-old man was admitted to our hospital for treatment for multiple superficial esophageal cancers. Screening upper gastrointestinal endoscopy examination revealed a superficial squamous cell carcinoma (SCC) at the middle thoracic esophagus and Barrett's epithelium and a superficial adenocarcinoma at the abdominal esophagus. We performed a subtotal esophagectomy with gastric tube reconstruction via the retrosternal route. Pathological examination revealed a Barrett's adenocarcinoma at the abdominal esophagus. Esophageal cancer is thought to be a multicentric disease, and we sometimes find multiple esophageal cancers. In Japan, most cases of multiple esophageal cancers are composed of SCCs, and the occurrence of multiple esophageal cancers composed of SCC and Barrett's adenocarcinoma is rare. In contrast, the number of the patients with Barrett's esophagus is increasing, and the number of the patients with Barrett's adenocarcinoma also seems to be on the rise. Therefore, it is important be aware of the possibility of multiple esophageal cancers composed of SCC and Barrett's adenocarcinoma while making diagnoses.

  6. [Short- and long-term results in operable pancreatic ductal adenocarcinomas from a cooperation between two departments gastroenterology-visceral surgery at non-university hospitals benchmarked to results of expert-centers].

    Science.gov (United States)

    Dippold, Wolfgang; Sivanathan, Visvakanth; Statt, Katharina; Roitman, Marc; Link, Karl Heinrich

    2017-02-01

    The only curative approach in pancreatic ductal adenocarcinoma (PDAC) is resection, which is possible only in 15 - 30 % of patients. Local tumor spread or distant metastases are contraindications for resection in the majority of patients. Surgical-oncological quality with short- and long-term results are varying tremendously, so that "expertise/quality" are associated to hospital- or surgeon's volume and/or center formation. The treatment results also depend, to a great extent, on the medical diagnostic quality. With our retrospective study, we aim to compare the results-quality of cooperative pancreatic cancer treatment based on an extensive preoperative diagnostic procedure for staging and risk estimation in a specialized GI-medical department and visceral surgical-oncological expertise in pancreatic cancer surgery at a general hospital with the results-quality of expert centers. Fifty-three patients with PDAC had diagnosis and resection of their cancer between 1/2002 and 12/2009. The 30 day hospital-mortality was 3.8 % and the median survival time after demission from the hospital was 23.1 months. The 5-year-survival rate of R0-resected patients, all of whom had received adjuvant chemotherapy, was high with 31 %. The survival data and the extraordinarily high resection rate of 98.1 % in the patient group, whose primary tumor stage was pT3 in 81 %, reflects the excellent cooperation of high standards in medical diagnostic processes, visceral pancreatic surgery, and adjuvant medical chemotherapy. The results are well comparable to those of "high volume centers". The responsible heads of the two departments have been trained at university expert centers. Expertise in the treatment of pancreatic cancer patients may be successfully transferred from an expert center to a general hospital, if the team has high expertise. © Georg Thieme Verlag KG Stuttgart · New York.

  7. Effects of the Spider Venom on proliferation of Human Lung Adenocarcinoma Cell A549

    Directory of Open Access Journals (Sweden)

    Zengxiang HU

    2010-10-01

    Full Text Available Background and objective The spider venom may inspire new drugs to treat cancer. The aim of this study is to investigate the effects and mechanisms of spider venom on lung adenocarcinoma cell A549. Methods The proliferation of lung adenocarcinoma A549 cells was detected by MTT. The apoptosis rate was observed with MTT assay and flow cytometer. The activity of catalase was detected by colorimetry. The malondialdehyde (MDA content was determined by improved thiobarbituric acid fluorometric method. The expression of P38MAPK protein was analyzed with Western blot. Results Spider venom can remarkably inhibite the proliferation of lung adenocarcinoma A549 cells, increased activity of catalase and MDA content, down-regulated expression of P38MAPK compared with the control group. Conclusion The reduced proliferation of lung adenocarcinoma A549 cells by spider venom is may be associated with the increased of activity of catalase and MDA content and decreased expression of P38MAPK.

  8. The effect of low concentrations of ethanol on gastric adenocarcinoma cell lines

    OpenAIRE

    Wu Lingjiao; Chen Shaohua; Zhang Yu; Pan Hongming

    2014-01-01

    Chronic alcohol consumption has been identified as a significant risk factor for cancer in humans. The aim of the study was to analyze the influence of low concentrations of ethanol on gastric adenocarcinoma cell viability, apoptosis, and changes in the expression of alcohol dehydrogenase with ethanol treatment. Gastric adenocarcinoma cell lines (MGC803, MGC823 and SGC7901) were treated with different concentrations of ethanol (0.03125%, 0.0625%, 0.125%, 0....

  9. Cytomorphological features of ALK-positive lung adenocarcinomas: psammoma bodies and signet ring cells.

    Science.gov (United States)

    Pareja, Fresia; Crapanzano, John P; Mansukhani, Mahesh M; Bulman, William A; Saqi, Anjali

    2015-03-01

    Correlation between histology and genotype has been described in lung adenocarcinomas. For example, studies have demonstrated that adenocarcinomas with an anaplastic lymphoma kinase (ALK) gene rearrangement may have mucinous features. The objective of the current study was to determine whether a similar association can be identified in cytological specimens. A retrospective search for ALK-rearranged cytopathology (CP) and surgical pathology (SP) lung carcinomas was conducted. Additional ALK-negative (-) lung adenocarcinomas served as controls. For CP and SP cases, the clinical data (i.e., age, sex, and smoking history), architecture, nuclear features, presence of mucin-containing cells (including signet ring cells), and any additional salient characteristics were evaluated. The search yielded 20 ALK-positive (+) adenocarcinomas. Compared with patients with ALK(-) lung adenocarcinomas (33 patients; 12 with epidermal growth factor receptor [EGFR]-mutation, 11 with Kristen rat sarcoma [KRAS]-mutation, and 10 wild-type adenocarcinomas), patients with ALK(+) adenocarcinoma presented at a younger age; and there was no correlation noted with sex or smoking status. The most common histological pattern in SP was papillary/micropapillary. Mucinous features were associated with ALK rearrangement in SP specimens. Signet ring cells and psammoma bodies were evident in and significantly associated with ALK(+) SP and CP specimens. However, psammoma bodies were observed in rare adenocarcinomas with an EGFR mutation. Both the ALK(+) and ALK(-) groups had mostly high nuclear grade. Salient features, including signet ring cells and psammoma bodies, were found to be significantly associated with ALK(+) lung adenocarcinomas and are identifiable on CP specimens. Recognizing these may be especially helpful in the molecular triage of scant CP samples. © 2014 American Cancer Society.

  10. CEACAM6 cross-linking induces caveolin-1-dependent, Src-mediated focal adhesion kinase phosphorylation in BxPC3 pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Duxbury, Mark S; Ito, Hiromichi; Ashley, Stanley W; Whang, Edward E

    2004-05-28

    Despite lacking transmembrane or intracellular domains, glycosylphosphatidylinositol-anchored proteins can modulate intracellular signaling events, in many cases through aggregation within membrane "lipid raft" microdomains. CEACAM6 is a glycosylphosphatidylinositol-linked cell surface protein of importance in the anchorage-independent survival and metastasis of pancreatic adenocarcinoma cells. We examined the effects of antibody-mediated cross-linking of CEACAM6 on intracellular signaling events and anchorage-independent survival of the CEACAM6-overexpressing pancreatic ductal adenocarcinoma cell line, BxPC3. CEACAM6 cross-linking increased c-Src activation and induced tyrosine phosphorylation of p125(FAK) focal adhesion kinase. Focal adhesion kinase phosphorylation was dependent on c-Src kinase activation, for which caveolin-1 was required. CEACAM6 cross-linking induced a significant increase in cellular resistance to anoikis. These observations represent the first characterization of the mechanism through which this important cell surface oncoprotein influences intracellular signaling events and hence malignant cellular behavior.

  11. Angiogenesis and mast cell density in invasive pulmonary adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Ehsan Ullah

    2012-01-01

    Conclusion: High angiogenesis and MCD predict poor survival and are positively correlated with each other and with the histological grades in pulmonary adenocarcinoma. High angiogenesis is also associated with advance TNM stage of disease.

  12. Regulation of cholesterol synthesis in four colonic adenocarcinoma cell lines.

    Science.gov (United States)

    Cerda, S R; Wilkinson, J; Broitman, S A

    1995-12-01

    Colon tumor cells, unlike normal human fibroblasts, exhibited an uncoupling of low density lipoprotein (LDL)-derived cholesterol from cellular growth, when endogenous cholesterol synthesis was inhibited by mevinolin, a hydroxymethylglutaryl-CoA reductase (HMG-CoAR) competitive inhibitor [Fabricant, M., and Broitman, S.A. (1990) Cancer Res. 50, 632-636]. Further evaluation of cholesterol metabolism was conducted in two undifferentiated (SW480, SW1417) and two differentiated (HT29, CACO2) colonic adenocarcinoma (adeno-CA) cell lines and an untransformed human fibroblast, AG1519A. Cells grown in monolayer culture to near subconfluency were used to assess endogenous cholesterol synthesis by 14C-acetate incorporation, in response to the following treatments in lipoprotein-deficient serum (LPDS)-supplemented minimum essential medium (MEM): LPDS alone, LDL, mevinolin, mevinolin with LDL, and 25-hydroxy-cholesterol (25-OH-CH). Complete fetal bovine serum (FBS)-supplemented MEM was used as control. All colon tumor lines exhibited similarly high endogenous cholesterol synthesis in both FBS and LPDS relative to the fibroblasts which demonstrated low basal levels in FBS and maximal synthesis in LPDS. LDL treatment did not inhibit cholesterol synthesis in colon tumor cells, but suppressed that in the fibroblast by 70%. Sterol repression of cholesterol synthesis mediated by 25-OH-CH occurred in all cells. Mevinolin caused a reduction in cholesterol synthesis in the colonic cancer cell lines, which was not further decreased by concurrent addition of LDL. In contrast, in mevinolin-treated fibroblasts, LDL further inhibited cholesterol synthesis. When the effect of cell density on cholesterol synthesis regulation was evaluated under conditions of sparse density in SW480 and SW147, results indicated that (i) basal rates of cholesterol synthesis were higher, (ii) LDL inhibited cholesterol synthesis more effectively, and (iii) mevinolin or 25-OH-CH had a more pronounced effect than in

  13. Clear cell adenocarcinoma of the ulterine cervix in a 15 year old girl: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Seung Joon; Kim, Jee Eun; KIm, Hyung Sik; Choi, Hye Young [Dept. of Radiology, Gachon University Gil Hospital, Incheon (Korea, Republic of)

    2013-10-15

    Cervical cancer is rare in the pediatric population. In cases of cervical cancer, adenocarcinoma is predominantly reported. Clear cell adenocarcinoma (CCAC) of the uterine cervix is a very rare tumor and accounts for only 4% of all adenocarcinomas of the uterine cervix. Risk factors and pathogenesis of this disease are not exactly revealed. The intrauterine exposure to diethylstilbestrol (DES) and associated non-steroidal estrogen during pregnancy before 18 weeks is the only known risk factor. This study reports the imaging finding of primary uterine cervical tumor in a 15-year-old girl, who was finally diagnosed with CCAC, with no maternal history of DES exposure in utero.

  14. Ipsilateral synchronous renal pelvic transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    韩平; 魏强; 石明; 杨宇如

    2004-01-01

    @@ Reports of multiple synchronous primary renal neoplasms in the literature are rare. Although primary renal tumors of 2 distinctively dissimilar origins have been sporadically described,1-6 to our knowledge there have been no reported cases of triple primary renal neoplasms in the same kidney. Here we report a very rare case of ipsilateral synchronous renal pelvic transitional cell carcinoma, squamous cell carcinoma and adenocarcinoma with marked hydronephrosis and multiple stones in the same kidney.

  15. Primary mucinous adenocarcinoma of the bladder with signet-ring cells: case report

    Directory of Open Access Journals (Sweden)

    Marcelo Lorenzi Marques

    Full Text Available CONTEXT: Primary adenocarcinomas of the bladder are uncommon and usually occur by contiguity with or hematogenic dissemination of other adenocarcinomas such as colorectal, prostate and gynecological tract carcinomas. Mucinous and signet-ring cell histological patterns are even rarer and it is often difficult to morphologically distinguish them from metastatic colorectal adenocarcinoma. CASE REPORT: We present and discuss a rare case of primary mucinous adenocarcinoma of the bladder with signet-ring cells in a 57-year-old male patient. Other primary sites for the tumor had been excluded and, in the absence of digestive tract tumor and for confirmation that it was a primary bladder tumor, an immunohistochemistry study was performed.

  16. Fluorouracil selectively enriches stem-like cells in the lung adenocarcinoma cell line SPC.

    Science.gov (United States)

    Shi, Mu-mu; Xiong, Yan-lei; Jia, Xin-shan; Li, Xin; Zhang, Li; Li, Xiao-lei; Wang, En-Hua

    2013-06-01

    Most adult stem cells are in the G0 or quiescent phase of the cell cycle and account for only a small percentage of the cells in the tissue. Thus, isolation of stem cells from tissues for further study represents a major challenge. This study sought to enrich cancer stem cells and explore cancer stem-like cell clones using 5-fluorouracil (5-FU) in the lung adenocarcinoma cell line, SPC. Proliferation inhibition was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, according to which half maximal inhibitory concentration values were calculated. Expression levels of stem cell markers after treatment with 5-FU were examined using immunofluorescence and Western blotting. Additionally, side population (SP) cells were sorted using FACS. Properties of SP cells were evaluated by using Transwell, colony-forming assays, and tumor formation experiments. 5-FU greatly inhibits proliferation, especially of cells in S phase. SP cells possess greater invasive potential, higher clone-forming potential, and greater tumor-forming ability than non-SP cells. Treatment with 5-FU enriches the SP cells with stem cell properties in human lung adenocarcinoma cell lines.

  17. Pancreatic intraepithelial neoplasia and ductal adenocarcinoma induced by DMBA in mice: effects of alcohol and caffeine Neoplasia pancreática intraepithelial e adenocarcinoma ductal induzidos pelo DMBA em camundongos: efeitos do álcool e da cafeína

    Directory of Open Access Journals (Sweden)

    Luiz Roberto Wendt

    2007-06-01

    Full Text Available PURPOSE: To evaluate the effects of alcohol and caffeine in a pancreatic carcinogenesis mouse model induced by 7,12-dimethylbenzantracene (DMBA, according to the PanIN classification system. METHODS: 120 male, Mus musculus, CF-1 mice were divided into four groups. Animals received either water or caffeine or alcohol or alcohol + caffeine in their drinking water. In all animals, 1 mg of DMBA was implanted into the head of the pancreas. After 30 days, euthanasia was performed; excised pancreata were then fixed in formalin, stained with hematoxylin-eosin and categorized as follows: normal ducts, reactive hyperplasia, PanIN-1A, PanIN-1B, PanIN-2, PanIN-3 or adenocarcinoma. RESULTS: PanIN lesions were verified in all groups. Adenocarcinoma was detected in 15% of animals in the caffeine group, 16.6% in the water group, 23.8% in the alcohol + caffeine group and 52.9% in the alcohol group (POBJETIVO: Avaliar os efeitos do álcool e da cafeína na carcinogênese pancreática induzida pelo 7,12-dimetilbenzantraceno (DMBA em camundongos, descrevendo as lesões de acordo com a classificação das neoplasias pacreáticas intraepiteliais (PanIN. MÉTODOS: 120 camundogos machos, Mus musculus, CF-1 foram divididos em quatro grupos. Animais receberam água ou cafeína ou álcool ou álcool + cafeína para beber. Em todos animais, 1 mg de DMBA foi implantado na cabeça do pâncreas. Após 30 dias, eutanásia foi realizada, o pâncreas foi removido, fixado em formalina e corado com hematoxilina e eosina sendo classificado em: ductos normais, hiperplasia reativa, PanIN-1A, PanIN-1B, PanIN-2, PanIN-3 ou adenocarcinoma. RESULTADOS: Neoplasias pancreáticas intraepiteliais foram encontradas em todos grupos. Adenocarcinoma foi detectado em 15% dos animais do grupo cafeína, 16,6% do grupo água, 23,8% do grupo álcool + cafeína e 52,9% do grupo álcool (P<0,05. CONCLUSÕES: O modelo experimental de carcinogênese pancreática em camundongos utilizando DMBA induz

  18. Ascl3 expression marks a progenitor population of both acinar and ductal cells in mouse salivary glands.

    Science.gov (United States)

    Bullard, Tara; Koek, Laurie; Roztocil, Elisa; Kingsley, Paul D; Mirels, Lily; Ovitt, Catherine E

    2008-08-01

    Ascl3, also know as Sgn1, is a member of the mammalian achaete scute (Mash) gene family of transcription factors, which have been implicated in cell fate specification and differentiation. In the mouse salivary gland, expression of Ascl3 is restricted to a subset of duct cells. Salivary gland function depends on the secretory acinar cells, which are responsible for saliva formation, and duct cells, which modify the saliva and conduct it to the oral cavity. The salivary gland ducts are also the putative site of progenitor cells in the adult gland. Using a Cre recombinase-mediated reporter system, we followed the fate of Ascl3-expressing cells after the introduction of an EGFP-Cre expression cassette into the Ascl3 locus by homologous recombination. Lineage tracing shows that these cells are progenitors of both acinar and ductal cell types in all three major salivary glands. In the differentiated progeny, expression of Ascl3 is down-regulated. These data directly demonstrate a progenitor-progeny relationship between duct cells and the acinar cell compartment, and identify a population of multipotent progenitor cells, marked by expression of Ascl3, which is capable of generating both gland cell types. We conclude that Ascl3-expressing cells contribute to the maintenance of the adult salivary glands.

  19. Mistaken identity of widely used esophageal adenocarcinoma cell line TE-7.

    Science.gov (United States)

    Boonstra, Jurjen J; van der Velden, Albertina W; Beerens, Erwin C W; van Marion, Ronald; Morita-Fujimura, Yuiko; Matsui, Yasuhisa; Nishihira, Tetsuro; Tselepis, Chris; Hainaut, Pierre; Lowe, Anson W; Beverloo, Berna H; van Dekken, Herman; Tilanus, Hugo W; Dinjens, Winand N M

    2007-09-01

    Cancer of the esophagus is the seventh leading cause of cancer death worldwide. Esophageal carcinoma cell lines are useful models to study the biological and genetic alterations in these tumors. An important prerequisite of cell line research is the authenticity of the used cell lines because the mistaken identity of a cell line may lead to invalid conclusions. Estimates indicate that up to 36% of the cell lines are of a different origin or species than supposed. The TE series, established in late 1970s and early 1980s by Nishihira et al. in Japan, is one of the first esophageal cancer cell line series that was used throughout the world. Fourteen TE cell lines were derived from human esophageal squamous cell carcinomas and one, TE-7, was derived from a primary esophageal adenocarcinoma. In numerous studies, this TE-7 cell line was used as a model for esophageal adenocarcinoma because it is one of the few esophageal adenocarcinoma cell lines existing. We investigated the authenticity of the esophageal adenocarcinoma cell line TE-7 by xenografting, short tandem repeat profiling, mutation analyses, and array-comparative genomic hybridization and showed that cell line TE-7 shared the same genotype as the esophageal squamous cell carcinoma cell lines TE-2, TE-3, TE-12, and TE-13. In addition, for more than a decade, independent TE-7 cultures from Japan, United States, United Kingdom, France, and the Netherlands had the same genotype. Examination of the TE-7 cell line xenograft revealed the histology of a squamous cell carcinoma. We conclude that the TE-7 cell line, used in several laboratories throughout the world, is not an adenocarcinoma, but a squamous cell carcinoma cell line. Furthermore, the cell lines TE-2, TE-3, TE-7, TE-12, and TE-13 should be regarded as one single squamous cell carcinoma cell line.

  20. Absorption spectra of adenocarcinoma and squamous cell carcinoma cervical tissues

    Science.gov (United States)

    Ivashko, Pavlo; Peresunko, Olexander; Zelinska, Natalia; Alonova, Marina

    2014-08-01

    We studied a methods of assessment of a connective tissue of cervix in terms of specific volume of fibrous component and an optical density of staining of connective tissue fibers in the stroma of squamous cancer and cervix adenocarcinoma. An absorption spectra of blood plasma of the patients suffering from squamous cancer and cervix adenocarcinoma both before the surgery and in postsurgical periods were obtained. Linear dichroism measurements transmittance in polarized light at different orientations of the polarization plane relative to the direction of the dominant orientation in the structure of the sample of biotissues of stroma of squamous cancer and cervix adenocarcinoma were carried. Results of the investigation of the tumor tissues showed that the magnitude of the linear dichroism Δ is insignificant in the researched spectral range λ=280-840 nm and specific regularities in its change observed short-wave ranges.

  1. Low-grade ductal carcinoma in situ and invasive mammary carcinoma with columnar cell morphology arising in a complex fibroadenoma in continuity with columnar cell change and flat epithelial atypia.

    Science.gov (United States)

    Petersson, Fredrik; Tan, Puay Hoon; Putti, Thomas Choudary

    2010-10-01

    We describe the clinicopathologic features of a small low-grade invasive mammary carcinoma with cytomorphological columnar cell features arising in a complex fibroadenoma that in addition to sclerosing adenosis, apocrine metaplasia, and usual ductal hyperplasia also displayed columnar cell change with flat epithelial atypia and low-grade ductal carcinoma in situ merging with the invasive carcinoma. There were strong cytomorphological similarities between the invasive carcinoma and the low-grade ductal carcinoma in situ, which also showed significant overlap in the immunohistochemical findings.

  2. Dynamics of regulatory networks in gastrin-treated adenocarcinoma cells.

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    Naresh Doni Jayavelu

    Full Text Available Understanding gene transcription regulatory networks is critical to deciphering the molecular mechanisms of different cellular states. Most studies focus on static transcriptional networks. In the current study, we used the gastrin-regulated system as a model to understand the dynamics of transcriptional networks composed of transcription factors (TFs and target genes (TGs. The hormone gastrin activates and stimulates signaling pathways leading to various cellular states through transcriptional programs. Dysregulation of gastrin can result in cancerous tumors, for example. However, the regulatory networks involving gastrin are highly complex, and the roles of most of the components of these networks are unknown. We used time series microarray data of AR42J adenocarcinoma cells treated with gastrin combined with static TF-TG relationships integrated from different sources, and we reconstructed the dynamic activities of TFs using network component analysis (NCA. Based on the peak expression of TGs and activity of TFs, we created active sub-networks at four time ranges after gastrin treatment, namely immediate-early (IE, mid-early (ME, mid-late (ML and very late (VL. Network analysis revealed that the active sub-networks were topologically different at the early and late time ranges. Gene ontology analysis unveiled that each active sub-network was highly enriched in a particular biological process. Interestingly, network motif patterns were also distinct between the sub-networks. This analysis can be applied to other time series microarray datasets, focusing on smaller sub-networks that are activated in a cascade, allowing better overview of the mechanisms involved at each time range.

  3. Acinar-to-ductal metaplasia accompanies c-myc-induced exocrine pancreatic cancer progression in transgenic rodents.

    Science.gov (United States)

    Grippo, Paul J; Sandgren, Eric P

    2012-09-01

    Several important characteristics of exocrine pancreatic tumor pathogenesis remain incompletely defined, including identification of the cell of origin. Most human pancreatic neoplasms are ductal adenocarcinomas. However, acinar cells have been proposed as the source of some ductal neoplasms through a process of acinar-to-ductal metaplasia. The oncogenic transcription factor c-myc is associated with human pancreatic neoplasms. Transgenic mice overexpressing c-myc under control of acinar cell-specific elastase (Ela) gene regulatory elements not only develop acinar cell carcinomas but also mixed neoplasms that display both acinar-like neoplastic cells and duct-like neoplastic cells. In this report, we demonstrate that, first, c-myc is sufficient to induce acinar hyperplasia, though neoplastic lesions develop focally. Second, cell proliferation remains elevated in the neoplastic duct cell compartment of mixed neoplasms. Third, the proliferation/apoptosis ratio in cells from all lesion types remains constant, suggesting that differential regulation of these processes is not a feature of cancer progression in this model. Fourth, before the development of mixed neoplasms, there is transcriptional activation of the duct cell-specific cytokeratin-19 gene promoter in multicellular foci of amylase-positive acinar neoplasms. This observation provides direct evidence for metaplasia as the mechanism underlying development of ductal neoplastic cells within the context of an acinar neoplasm and suggests that the stimulus for this transformation acts over a multicellular domain or field within a neoplasm. Finally, focal ductal elements develop in some acinar cell carcinomas in Ela-c-myc transgenic rats, indicating that myc-associated acinar-to-ductal metaplasia is not restricted to the mouse.

  4. Clear Cell Adenocarcinoma of the Renal Pelvis in a Male Patient

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    Sarawut Kongkarnka

    2013-01-01

    Full Text Available Carcinoma of the renal pelvis is an uncommon renal neoplasm. Clear cell adenocarcinoma in the urinary tract is rare and has a histomorphology resembling that of the female genital tract. We herein present a case of clear cell adenocarcinoma of the renal pelvis, which is the first example in a male patient to our knowledge. A 54-year-old man presented with right flank pain. The tumor was associated with renal stones and hydronephrosis and invaded into the peripelvic fat tissue with regional lymph node metastasis. The patient died of metastatic disease six months postoperatively. Histologically, the tumor showed complex papillary architecture lined with clear and hobnail cells. Clear cell adenocarcinoma of the renal pelvis may pose a diagnostic challenge on histological grounds, particularly in the distinction from renal cell carcinoma. The immunohistochemical stains could help confirm the diagnosis. Due to its rarity, an effective treatment regimen remains to be determined.

  5. Identification and Characterization of Side Population Cells in Human Lung Adenocarcinoma SPC-A1 Cells

    Institute of Scientific and Technical Information of China (English)

    Yan-liang Zhu; Long-bang Chen; Jing-hua Wang; Xin-yi Xia

    2011-01-01

    Objective: There has been an increasing interest in recent years in the role of stem cells.With an extensive understanding of their biology,a major role for stem cells in the malignant process has been proposed and the existence of cancer stem cells(CSCs) has been confirmed in hematopoietic malignancies and solid organ malignancies including brain cancer,breast,prostate,colon,and pancreatic cancer.Lung cancer is the leading cause of cancer mortality in most large cities of China.It is possible that lung cancer contains cancer stem cells responsible for its malignancy.The aim of this study is to identify,characterize and enrich the CSC population that drives and maintains lung adenocarcinoma growth and metastasis.Methods: Side population(SP) cell analysis and sorting were applied on human lung adenocarcinoma cell line and an attempt to further enrich them by preliminary serum-free culture before fluorescence activated cell sorting (FACS) was done.Stem cell properties of SP cells were evaluated by their proliferative index,colony-forming efficiency,tumorigenic potential,bi-differentiation capacity and the expression of common stem cell surface markers.Results: Lung cancer cells could grow in a serum-free Medium(SFM) as non-adherent spheres similar to neurospheres or mammospheres.The proportion of SP cells in cell spheres was significantly higher than that in cells grown as monolayers.SP cells had a greater proliferative index,a higher colony-forming efficiency and a greater ability to form tumor in vivo.SP cells were both CCA positive and SP-C positive while non-SP cells were only SP-C positive.Flow cytometric analysis of cell phenotype showed that SP cells expressed CD133 and CD44,the common cell surface markers of cancer stem cells,while non-SP cells only expressed CD44.Conclusion: SP cells existed in human lung adenocarcinoma cell lines and they could be further enriched by preliminary serum-free culture before FACS sorting.SP cells possessed the properties of

  6. Identification and Characterization of Side Population Cells in Human Lung Adenocarcinoma SPC-A1 Cells

    Institute of Scientific and Technical Information of China (English)

    Yan-liang Zhu; Long-bang Chen; Jing-hua Wang; Xin-yi Xia

    2010-01-01

    Objective:There has been an increasing interest in recent years in the role of stem cells.With an extensive understanding of their biology,a major role for stem cells in the malignant process has been proposed and the existence of cancer stem cells(CSCs)has been confirmed in hematopoietic malignancies and solid organ malignancies including brain cancer,breast,prostate,colon,and pancreatic cancer.Lung cancer is the leading cause of cancer mortality in most large cities of China.It is possible that lung cancer contains cancer stem cells responsible for its malignancy.The aim of this study is to identify,characterize and enrich the CSC population that drives and maintains lung adenocarcinoma growth and metastasis.Methods:Side population(SP)cell analysis and sorting were applied on human lung adenocarcinoma cell line and an attempt to further enrich them by preliminary serum-free culture before fluorescence activated cell sorting(FACS)was done.Stem cell properties of SP cells were evaluated by their proliferative index,colony-forming efficiency,tumorigenic potential,bi-differentiation capacity and the expression of common stem cell surface markers.Results:Lung cancer cells could grow in a serum-free Medium(SFM)as non-adherent spheres similar to neurospheres or mammospheres.The proportion of SP cells in cell spheres was significantly higher than that in cells grown as monolayers.SP cells had a greater proliferative index,a higher colony-forming efficiency and a greater ability to form tumor in vivo.SP cells were both CCA positive and SP-C positive while non-SP cells were only SP-C positive.Flow cytometric analysis of cell phenotype showed that SP cells expressed CD133 and CD44,the common cell surface markers of cancer stem cells,while non-SP cells only expressed CD44.Conclusion:SP cells existed in human lung adenocarcinoma cell lines and they could be further enriched by preliminary serum-free culture before FACS sorting.SP cells possessed the properties of cancer stem

  7. HBME-1 immunostaining in reactive mesothelial versus metastatic adenocarcinoma cells in serous fluid

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    Alireza Rahmani

    2011-01-01

    Full Text Available Background: The cytological diagnoses of serous effusions are usually made by routine cytomorphology with certainty. However, overlapping cases sometimes exist between reactive mesothelial and adenocarcinoma cells. We tried to evaluate the diagnostic utility of HBME-1 in distinguishing between reactive mesothelial cells and adenocarcinoma in serous effusions. Materials and Methods: Fifty-two cytologic specimens processed by cell-block technique were retrieved from the archive and were assigned to two groups: Group I: 26 effusions containing reactive/benign mesothelial cells; Group II: 26 effusions containing carcinoma cells. Immunostaining with HBME-1 was performed using an Envision technique. The staining intensity of cells, according to proportion of immunoreactive cells, was scored as: 0 (negative, 1+ (<10%, 2+ (10-50%, and 3+ (≥50%; and the predominant staining pattern of positive cells were determined. Statistical analysis and tests of significance were performed using SPSS software. Results: The calculated mean values (in percentile for stained cells in adenocarcinoma and reactive mesothelial cells were 25.57 and 67.88, respectively ( P = 0.001. Thin membranous, thick membranous, thick and thin membranous, cytoplasmic and combined patterns of staining in adenocarcinoma cells were respectively 4 cases (21.1%, 0 case, 0 case, 8 cases (42.1%, and 7 cases (36.8%, and in reactive mesothelial cells, these were 7 cases (26.9%, 1 case (3.8%, 18 cases (69.2%, 0 case, and 0 case, respectively. The intensity of staining in majority (88.5% of reactive mesothelial cells was scored 3+, but the distribution varied in the other group. Conclusions: The staining pattern and intensity for HBME-1 is a useful panel for differentiation of adenocarcinoma and mesothelial cells.

  8. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling.

    Science.gov (United States)

    Hohwieler, Meike; Illing, Anett; Hermann, Patrick C; Mayer, Tobias; Stockmann, Marianne; Perkhofer, Lukas; Eiseler, Tim; Antony, Justin S; Müller, Martin; Renz, Susanne; Kuo, Chao-Chung; Lin, Qiong; Sendler, Matthias; Breunig, Markus; Kleiderman, Susanne M; Lechel, André; Zenker, Martin; Leichsenring, Michael; Rosendahl, Jonas; Zenke, Martin; Sainz, Bruno; Mayerle, Julia; Costa, Ivan G; Seufferlein, Thomas; Kormann, Michael; Wagner, Martin; Liebau, Stefan; Kleger, Alexander

    2017-03-01

    The generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment. We designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny. Extensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro, but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids. Taken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  9. Comparative transcriptomes of adenocarcinomas and squamous cell carcinomas reveal molecular similarities that span classical anatomic boundaries.

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    Eric W Lin

    2017-08-01

    Full Text Available Advances in genomics in recent years have provided key insights into defining cancer subtypes "within-a-tissue"-that is, respecting traditional anatomically driven divisions of medicine. However, there remains a dearth of data regarding molecular profiles that are shared across tissues, an understanding of which could lead to the development of highly versatile, broadly applicable therapies. Using data acquired from The Cancer Genome Atlas (TCGA, we performed a transcriptomics-centered analysis on 1494 patient samples, comparing the two major histological subtypes of solid tumors (adenocarcinomas and squamous cell carcinomas across organs, with a focus on tissues in which both subtypes arise: esophagus, lung, and uterine cervix. Via principal component and hierarchical clustering analysis, we discovered that histology-driven differences accounted for a greater degree of inherent molecular variation in the tumors than did tissue of origin. We then analyzed differential gene expression, DNA methylation, and non-coding RNA expression between adenocarcinomas and squamous cell carcinomas and found 1733 genes, 346 CpG sites, and 42 microRNAs in common between organ sites, indicating specific adenocarcinoma-associated and squamous cell carcinoma-associated molecular patterns that were conserved across tissues. We then identified specific pathways that may be critical to the development of adenocarcinomas and squamous cell carcinomas, including Liver X receptor activation, which was upregulated in adenocarcinomas but downregulated in squamous cell carcinomas, possibly indicating important differences in cancer cell metabolism between these two histological subtypes of cancer. In addition, we highlighted genes that may be common drivers of adenocarcinomas specifically, such as IGF2BP1, which suggests a possible link between embryonic development and tumor subtype. Altogether, we demonstrate the need to consider biological similarities that transcend

  10. Clear cell adenocarcinoma of the colon: A case report and review of literature

    Institute of Scientific and Technical Information of China (English)

    Koichi Soga; Ken-Ichi Mukaisho; Takanori Hattori; Hideyuki Konishi; Natsuko Tatsumi; Chika Konishi; Keimei Nakano; Naold Wakabayashi; Shoji Mitsufuji; Keisho Kataoka; Takeshi Okanoue

    2008-01-01

    A primary clear cell adenocarcinoma of the colon is arare oncologic entity.We herein report a case of such atumor of the sigmoid colon in a 71-year-old woman whowas successfully treated by an endoscopic polypecLomy in our hospital.We also reviewed the published reports regarding cases of primary clear cell tumors in the colon.

  11. NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone.

    Science.gov (United States)

    Moore, Z; Chakrabarti, G; Luo, X; Ali, A; Hu, Z; Fattah, F J; Vemireddy, R; DeBerardinis, R J; Brekken, R A; Boothman, D A

    2015-01-15

    Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (e.g., FK866) target the most active pathway of NAD(+) synthesis in tumor cells, but lack tumor-selectivity for use as a single agent. Reducing NAD(+) pools by inhibiting NAMPT primed pancreatic ductal adenocarcinoma (PDA) cells for poly(ADP ribose) polymerase (PARP1)-dependent cell death induced by the targeted cancer therapeutic, β-lapachone (β-lap, ARQ761), independent of poly(ADP ribose) (PAR) accumulation. β-Lap is bioactivated by NADPH:quinone oxidoreductase 1 (NQO1) in a futile redox cycle that consumes oxygen and generates high levels of reactive oxygen species (ROS) that cause extensive DNA damage and rapid PARP1-mediated NAD(+) consumption. Synergy with FK866+β-lap was tumor-selective, only occurring in NQO1-overexpressing cancer cells, which is noted in a majority (∼85%) of PDA cases. This treatment strategy simultaneously decreases NAD(+) synthesis while increasing NAD(+) consumption, reducing required doses and treatment times for both drugs and increasing potency. These complementary mechanisms caused profound NAD(P)(+) depletion and inhibited glycolysis, driving down adenosine triphosphate levels and preventing recovery normally observed with either agent alone. Cancer cells died through an ROS-induced, μ-calpain-mediated programmed cell death process that kills independent of caspase activation and is not driven by PAR accumulation, which we call NAD(+)-Keresis. Non-overlapping specificities of FK866 for PDA tumors that rely heavily on NAMPT-catalyzed NAD(+) synthesis and β-lap for cancer cells with elevated NQO1 levels affords high tumor-selectivity. The concept of reducing NAD(+) pools in cancer cells to sensitize them to ROS-mediated cell death by β-lap is a novel strategy with potential application for pancreatic and other types of NQO1+ solid tumors.

  12. The effect of low concentrations of ethanol on gastric adenocarcinoma cell lines

    OpenAIRE

    Wu Lingjiao; Chen Shaohua; Zhang Yu; Pan Hongming

    2013-01-01

    Chronic alcohol consumption was identified as a significant risk factor for cancer in humans. The aim of the study was to analyze the influence of low concentrations of ethanol on gastric adenocarcinoma cell viability, apoptosis, and changes in the expression of alcohol dehydrogenase with ethanol treatment. Gastric adenocarcinoma cell lines (MGC803, MGC823 and SGC7901) were treated with different concentrations of ethanol (0.03125%, 0.0625%, 0.125%, 0.25%, 0.5%, 1%, 2%, and 4%). The MTT...

  13. Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma

    Science.gov (United States)

    Che, Keying; Zhao, Yang; Qu, Xiao; Pang, Zhaofei; Ni, Yang; Zhang, Tiehong; Du, Jiajun; Shen, Hongchang

    2017-01-01

    Purpose Gastric carcinoma (GC) is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma. Materials and methods Hematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS) was statistically analyzed. Results Among the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145) of them. Single cell invasion and large cell invasion were observed in 62.8% (186) and 16.9% (50) of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, Ptumor budding and single cell invasion were observed to be independent risk factors for gastric adenocarcinoma (PTumor budding and single cell invasion in gastric adenocarcinoma are associated with an unfavorable prognosis.

  14. Small nuclear ribonucleoprotein associated polypeptide N accelerates cell proliferation in pancreatic adenocarcinoma.

    Science.gov (United States)

    Ma, Jin; Zhang, Zhuo; Wang, Jiancheng

    2015-10-01

    The spliceosome, the large RNA‑protein molecular complex, is crucial for pre‑mRNA splicing. Several antitumor drugs have been found to tightly bind to the components of the spliceosome and mutations in the spliceosome have been reported in several types of cancer. However, the involvement of the spliceosome in pancreatic adenocarcinoma remains unclear. In the present study, small nuclear ribonucleoprotein associated polypeptide N (SNRPN), a key constituent of spliceosomes, was disrupted in BxPC‑3 pancreatic adenocarcinoma cells using lentivirus‑mediated RNA interference (RNAi). It was found that knockdown of SNRPN reduced the proliferation ability of BxPC‑3 cells, as determined by an MTT assay. Furthermore, cell colony formation was impaired in SNRPN depleted adenocarcinoma cells and cell cycle analysis showed that depletion of SNRPN led to S phase cell cycle arrest and apoptosis. These results suggest that SNRPN is a key player in pancreatic adenocarcinoma cell growth, and targeted loss of SNRPN may be a potential therapeutic method for pancreatic cancer.

  15. Aryl hydrocarbon receptor protects lung adenocarcinoma cells against cigarette sidestream smoke particulates-induced oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Ya-Hsin [Graduate Institute of Basic Medical Science, School of Medicine, China Medical University, Taichung 40402, Taiwan, ROC (China); Huang, Su-Chin; Lin, Chun-Ju; Cheng, Li-Chuan [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan, ROC (China); Li, Lih-Ann, E-mail: lihann@nhri.org.tw [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan, ROC (China)

    2012-03-15

    Environmental cigarette smoke has been suggested to promote lung adenocarcinoma progression through aryl hydrocarbon receptor (AhR)-signaled metabolism. However, whether AhR facilitates metabolic activation or detoxification in exposed adenocarcinoma cells remains ambiguous. To address this question, we have modified the expression level of AhR in two human lung adenocarcinoma cell lines and examined their response to an extract of cigarette sidestream smoke particulates (CSSP). We found that overexpression of AhR in the CL1-5 cell line reduced CSSP-induced ROS production and oxidative DNA damage, whereas knockdown of AhR expression increased ROS level in CSSP-exposed H1355 cells. Oxidative stress sensor Nrf2 and its target gene NQO1 were insensitive to AhR expression level and CSSP treatment in human lung adenocarcinoma cells. In contrast, induction of AhR expression concurrently increased mRNA expression of xenobiotic-metabolizing genes CYP1B1, UGT1A8, and UGT1A10 in a ligand-independent manner. It appeared that AhR accelerated xenobiotic clearing and diminished associated oxidative stress by coordinate regulation of a set of phase I and II metabolizing genes. However, the AhR-signaled protection could not shield cells from constant oxidative stress. Prolonged exposure to high concentrations of CSSP induced G0/G1 cell cycle arrest via the p53–p21–Rb1 signaling pathway. Despite no effect on DNA repair rate, AhR facilitated the recovery of cells from growth arrest when CSSP exposure ended. AhR-overexpressing lung adenocarcinoma cells exhibited an increased anchorage-dependent and independent proliferation when recovery from exposure. In summary, our data demonstrated that AhR protected lung adenocarcinoma cells against CSSP-induced oxidative stress and promoted post-exposure clonogenicity. -- Highlights: ► AhR expression level influences cigarette sidestream smoke-induced ROS production. ► AhR reduces oxidative stress by coordinate regulation of

  16. Mechanisms of hepatocyte growth factor-mediated signaling in differentiation of pancreatic ductal epithelial cells into insulin-producing cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xin-Yu; Zhan, Xiao-Rong [Department of Endocrinology, First Hospital of Harbin Medical University, Harbin, Hei Long Jiang Province 150001 (China); Lu, Chong [Department of Neurology, First Hospital of Harbin Medical University, Harbin, Hei Long Jiang Province 150001 (China); Liu, Xiao-Min, E-mail: 13796658016@163.com [Department of Endocrinology, First Hospital of Harbin Medical University, Harbin, Hei Long Jiang Province 150001 (China); Wang, Xiao-Chen [Department of Endocrinology, First Hospital of Harbin Medical University, Harbin, Hei Long Jiang Province 150001 (China)

    2010-07-30

    Research highlights: {yields} A hypothesis that the differentiation of PDEC is through MAPKs or PI3K/AKT pathways. {yields} Determine if kinases (ERK1/2, p38, JNK, and AKT) are activated in these pathways. {yields} Determine signal pathway(s) that may effect on HGF-induced differentiation of PDEC. {yields} PI3K-AKT pathway is involved in the differentiation of PDECs induced by HGF. {yields} MEK-ERK pathway effect on the proliferation of PDECs but not the differentiation. -- Abstract: Pancreatic ductal epithelial cells (PDECs) were induced to differentiate into insulin-producing cells by hepatocyte growth factor (HGF) in our previous study, but the mechanism through which this induction occurs is still unknown. HGF is a ligand that activates a tyrosine kinase encoded by the c-Met proto-oncogene. This activation is followed by indirect activation of multiple downstream signal transduction pathways (including MAPKs and the PI3K/AKT signaling pathways) that initiate various biological effects. Therefore, we speculated that the differentiation of PDECs is through either the MAPK signaling pathway or the PI3K/AKT signaling pathway. To test this hypothesis, isolated PDECs from adult rats were stimulated by adding HGF to their medium for 28 days. Then, the expression levels of several protein kinases, including MAPKs (ERK1/2, p38, and JNK) and AKT, were determined by Western blotting to determine if specific protein kinases are activated in these pathways. Subsequently, re-isolated from adult rats and cultured PDECs were pre-treated with specific inhibitors of proteins shown to be activated in these signaling pathways; these cells were then induced to differentiate by the addition of HGF. The expression levels of protein kinases were determined by Western blotting, and the differentiation rate of insulin-positive cells was determined by flow cytometry. The change of PDEC differentiation rates were compared between the groups in which cells with or without inhibitors

  17. Gremlin is overexpressed in lung adenocarcinoma and increases cell growth and proliferation in normal lung cells.

    Directory of Open Access Journals (Sweden)

    Michael S Mulvihill

    Full Text Available BACKGROUND: Gremlin, a member of the Dan family of BMP antagonists, is a glycosylated extracellular protein. Previously Gremlin has been shown to play a role in dorsal-ventral patterning, in tissue remodeling, and recently in angiogenesis. Evidence has previously been presented showing both over- and under-expression of Gremlin in different tumor tissues. Here, we sought to quantify expression of Gremlin in cancers of the lung and performed in vitro experiments to check whether Gremlin promotes cell growth and proliferation. METHODOLOGY/PRINCIPAL FINDINGS: Expression of Gremlin in 161 matched tumor and normal lung cancer specimens is quantified by quantitative real-time PCR and protein level is measured by immunohistochemistry. GREM1 was transfected into lung fibroblast and epithelial cell lines to assess the impact of overexpression of Gremlin in vitro. RESULTS: Lung adenocarcinoma but not squamous cell carcinoma shows a significant increase in Gremlin expression by mRNA and protein level. Lung fibroblast and epithelial cell lines transfected with GREM1 show significantly increased cell proliferation. CONCLUSIONS/SIGNIFICANCE: Our data suggest that Gremlin acts in an oncogenic manner in lung adenocarcinoma and could hold promise as a new diagnostic marker or potential therapeutic target in lung AD or general thoracic malignancies.

  18. Cell division cycle 20 overexpression predicts poor prognosis for patients with lung adenocarcinoma.

    Science.gov (United States)

    Shi, Run; Sun, Qi; Sun, Jing; Wang, Xin; Xia, Wenjie; Dong, Gaochao; Wang, Anpeng; Jiang, Feng; Xu, Lin

    2017-03-01

    The cell division cycle 20, a key component of spindle assembly checkpoint, is an essential activator of the anaphase-promoting complex. Aberrant expression of cell division cycle 20 has been detected in various human cancers. However, its clinical significance has never been deeply investigated in non-small-cell lung cancer. By analyzing The Cancer Genome Atlas database and using some certain online databases, we validated overexpression of cell division cycle 20 in both messenger RNA and protein levels, explored its clinical significance, and evaluated the prognostic role of cell division cycle 20 in non-small-cell lung cancer. Cell division cycle 20 expression was significantly correlated with sex (p = 0.003), histological classification (p cell lung cancer patients. In lung adenocarcinoma patients, overexpression of cell division cycle 20 was significantly associated with bigger primary tumor size (p = 0.0023), higher MKI67 level (r = 0.7618, p cell carcinoma patients, no significant association of cell division cycle 20 expression was observed with any clinical parameter or prognosis. Overexpression of cell division cycle 20 is associated with poor prognosis in lung adenocarcinoma patients, and its overexpression can also be used to identify high-risk groups. In conclusion, cell division cycle 20 might serve as a potential biomarker for lung adenocarcinoma patients.

  19. miR let-7家族在胰腺导管腺癌发生发展中的作用%The Mechanism of miR let-7 Family in Pancreatic Ductal Adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    曾玮; 刘孟刚; 刘宏鸣; 谢斌; 袁涛; 杨俊涛; 蓝翔; 陈平

    2014-01-01

    目的:在大规模表达谱芯片中寻找与胰腺导管腺癌( PDAC)相关的RNA分子,并探讨其分子机制。方法基于RNA的表达谱数据,构建“转录因子-miRNA-mRNA”调控关系网络,挖掘与PDAC相关的mRNA及miRNA。结果6个miR let-7家族miRNA成员( hsa-let-7i、hsa-let-7d、hsa-let-7b、hsa-let-7g、hsa-let-7c、hsa-let-7e)参与一个核心调控网络,其网络中涉及的基因和其他miRNA均为与PDAC发生发展相关的分子。其中处于网络核心位置的基因ALDH1A1、ZEB1、HMGA2、EGR1和TGFB1,与PDAC的发展及预后直接相关。网络中的hsa-mir-200b、hsa-mir-200a可与ZEB1基因相互调控,通过Notch信号通路影响PDAC的发展及转移。结论 miR let-7家族miRNA分子可能与ALDH1A1、ZEB1与HMGA2等分子相互调控,并与PDAC的发生发展密切相关。%Objective To identify candidate molecules related to pancreatic ductal adenocarcinoma ( PDAC) and investi-gate the molecular mechanism of the candidate molecule by large-scale expression profiles .Methods miRNA and mRNA expres-sion of PDAC was used to construct the molecular regulatory network by the interaction of ‘transcription factor target miRNA ’ and‘mRNA target gene ’ ,and identify some candidate genes and miRNAs related to PDAC .Results There were 6 kinds of miR let-7(hsa-let-7i、hsa-let-7d、hsa-let-7b、hsa-let-7g、hsa-let-7c、hsa-let-7e),all genes and miRNA were related to PDAC development . ALDH1A1、ZEB1、HMGA2、EGR1 and TGFB1 were directly related to PDAC development and prognosis .has-mir-200b and has-mir-200a interacted with ZEB1,and influenced the prognosis of PDAC through Notch signaling pathway .Conclusion miR let-7 family may interact with ALDH1A1、ZEB1、HMGA2,and are related the PDAC development .

  20. 胰腺导管腺癌不同靶区勾画方法的稳定性研究%Stabilities of Different Strategies for Target Volume Delineation in Pancreatic Ductal Adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    李丹明; 穆庆霞; 孙新臣; 王沛沛

    2014-01-01

    Objective To compare the four various strategies [Radiation Therapy Oncology Group(RTOG),Oxford,Michigan and Selective Chemoradiation in Advanced Localized Pancreatic Cancer(SCALOP)]for target volume delineation in pancreatic ductal adenocarcinoma(PDAC). Methods Enhanced CT scanning was performed in 9 patients with pathologically proved PDAC, and planning target volumes(PTVs)were independently outlined by five radiotherapists according to the four different guidelines for target volume delineation.The size of PTVs,coefficient of vari-ance(COV),concordance index and Vintersection were compared quantificationally.Results The size of PTVs,Vintersection and concordance index were not significantly different between Ox-ford guideline and RTOG guideline(P>0.05),but were significantly different between RTOG or Oxford guidelines and Michigan or SCALOP guidelines(P0.05).Conclu-sion SCALOP and Michigan guidelines have better stability than RTOG and Oxford guidelines for target volume delineation in patients with PDAC.There are obvious differences in size of PTVs among the four various strategies.Further clinical evidence-based medical evidence is essen-tial to support the guideline that is beneficial for improving the survival of PDAC patients.%目的:研究4种[放射治疗肿瘤学组(RTOG)、牛津(Oxford)、密歇根(Michigan)和选择性放化疗协作组(SCALOP)]不同胰腺导管腺癌(PDAC)靶区勾画方法的差异。方法对9例病理确诊为 PDAC术后或未行手术的患者均行CT增强扫描,由5位医师在CT上根据4种不同的靶区定义独立勾画计划靶体积(PTVs)。比较9例患者的 RTOG、Oxford、Michigan和 SCALOP靶区勾画方法的 PTVs 情况,并以协方差(COV)、一致性指数(con-cordance index)和交集体积百分比(Vintersection)定量比较不同靶区勾画方法的勾画的稳定性。结果9例患者的 RTOG靶区勾画方法PTVs、Vintersection和 concordance index值与 Oxford

  1. Conversion of Prostate Adenocarcinoma to Small Cell Carcinoma-Like by Reprogramming.

    Science.gov (United States)

    Borges, Gisely T; Vêncio, Eneida F; Quek, Sue-Ing; Chen, Adeline; Salvanha, Diego M; Vêncio, Ricardo Z N; Nguyen, Holly M; Vessella, Robert L; Cavanaugh, Christopher; Ware, Carol B; Troisch, Pamela; Liu, Alvin Y

    2016-09-01

    The lineage relationship between prostate adenocarcinoma and small cell carcinoma was studied by using the LuCaP family of xenografts established from primary neoplasm to metastasis. Expression of four stem cell transcription factor (TF) genes, LIN28A, NANOG, POU5F1, SOX2, were analyzed in the LuCaP lines. These genes, when force expressed in differentiated cells, can reprogram the recipients into stem-like induced pluripotent stem (iPS) cells. Most LuCaP lines expressed POU5F1, while LuCaP 145.1, representative of small cell carcinoma, expressed all four. Through transcriptome database query, many small cell carcinoma genes were also found in stem cells. To test the hypothesis that prostate cancer progression from "differentiated" adenocarcinoma to "undifferentiated" small cell carcinoma could involve re-expression of stem cell genes, the four TF genes were transduced via lentiviral vectors into five adenocarcinoma LuCaP lines-70CR, 73CR, 86.2, 92, 105CR-as done in iPS cell reprogramming. The resultant cells from these five transductions displayed a morphology of small size and dark appearing unlike the parentals. Transcriptome analysis of LuCaP 70CR* ("*" to denote transfected progeny) revealed a unique gene expression close to that of LuCaP 145.1. In a prostate principal components analysis space based on cell-type transcriptomes, the different LuCaP transcriptome datapoints were aligned to suggest a possible ordered sequence of expression changes from the differentiated luminal-like adenocarcinoma cell types to the less differentiated, more stem-like small cell carcinoma types, and LuCaP 70CR*. Prostate cancer progression can thus be molecularly characterized by loss of differentiation with re-expression of stem cell genes. J. Cell. Physiol. 231: 2040-2047, 2016. © 2016 Wiley Periodicals, Inc.

  2. NR4A2 is regulated by gastrin and influences cellular responses of gastric adenocarcinoma cells.

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    Kristine Misund

    Full Text Available The peptide hormone gastrin is known to play a role in differentiation, growth and apoptosis of cells in the gastric mucosa. In this study we demonstrate that gastrin induces Nuclear Receptor 4A2 (NR4A2 expression in the adenocarcinoma cell lines AR42J and AGS-GR, which both possess the gastrin/CCK2 receptor. In vivo, NR4A2 is strongly expressed in the gastrin responsive neuroendocrine ECL cells in normal mucosa, whereas gastric adenocarcinoma tissue reveals a more diffuse and variable expression in tumor cells. We show that NR4A2 is a primary early transient gastrin induced gene in adenocarcinoma cell lines, and that NR4A2 expression is negatively regulated by inducible cAMP early repressor (ICER and zinc finger protein 36, C3H1 type-like 1 (Zfp36l1, suggesting that these gastrin regulated proteins exert a negative feedback control of NR4A2 activated responses. FRAP analyses indicate that gastrin also modifies the nucleus-cytosol shuttling of NR4A2, with more NR4A2 localized to cytoplasm upon gastrin treatment. Knock-down experiments with siRNA targeting NR4A2 increase migration of gastrin treated adenocarcinoma AGS-GR cells, while ectopically expressed NR4A2 increases apoptosis and hampers gastrin induced invasion, indicating a tumor suppressor function of NR4A2. Collectively, our results uncover a role of NR4A2 in gastric adenocarcinoma cells, and suggest that both the level and the localization of NR4A2 protein are of importance regarding the cellular responses of these cells.

  3. Selective loss of TGFbeta Smad-dependent signalling prevents cell cycle arrest and promotes invasion in oesophageal adenocarcinoma cell lines.

    Directory of Open Access Journals (Sweden)

    Benjamin A Onwuegbusi

    Full Text Available In cancer, Transforming Growth Factor beta (TGFbeta increases proliferation and promotes invasion via selective loss of signalling pathways. Oesophageal adenocarcinoma arises from Barrett's oesophagus, progresses rapidly and is usually fatal. The contribution of perturbed TGFbeta signalling in the promotion of metastasis in this disease has not been elucidated. We therefore investigated the role of TGFbeta in Barrett's associated oesophageal adenocarcinoma using a panel of cell lines (OE33, TE7, SEG, BIC, FLO. 4/5 adenocarcinoma cell lines failed to cell cycle arrest, down-regulate c-Myc or induce p21 in response to TGFbeta, and modulation of a Smad3/4 specific promoter was inhibited. These hyperproliferative adenocarcinoma cell lines displayed a TGFbeta induced increase in the expression of the extracellular matrix degrading proteinases, urokinase-type plasminogen activator (uPA and plasminogen activator inhibitor 1 (PAI-1, which correlated with an invasive cell phenotype as measured by in vitro migration, invasion and cell scattering assays. Inhibiting ERK and JNK pathways significantly reduced PAI and uPA induction and inhibited the invasive cell phenotype. These results suggest that TGFbeta Smad-dependent signalling is perturbed in Barrett's carcinogenesis, resulting in failure of growth-arrest. However, TGFbeta can promote PAI and uPA expression and invasion through MAPK pathways. These data would support a dual role for TGFbeta in oesophageal adenocarcinoma.

  4. The different functions and clinical significances of caveolin-1 in human adenocarcinoma and squamous cell carcinoma

    Science.gov (United States)

    Fu, Pin; Chen, Fuchun; Pan, Qi; Zhao, Xianda; Zhao, Chen; Cho, William Chi-Shing; Chen, Honglei

    2017-01-01

    Caveolin-1 (Cav-1), a major structural protein of caveolae, is an integral membrane protein which plays an important role in the progression of carcinoma. However, whether Cav-1 acts as a tumor promoter or a tumor suppressor still remains controversial. For example, the tumor-promoting function of Cav-1 has been found in renal cancer, prostate cancer, tongue squamous cell carcinoma (SCC), lung SCC and bladder SCC. In contrast, Cav-1 also plays an inhibitory role in esophagus adenocarcinoma, lung adenocarcinoma and cutaneous SCC. The role of Cav-1 is still controversial in thyroid cancer, hepatocellular carcinoma, gastric adenocarcinoma, colon adenocarcinoma, breast cancer, pancreas cancer, oral SCC, laryngeal SCC, head and neck SCC, esophageal SCC and cervical SCC. Besides, it has been reported that the loss of stromal Cav-1 might predict poor prognosis in breast cancer, gastric cancer, pancreas cancer, prostate cancer, oral SCC and esophageal SCC. However, the accumulation of stromal Cav-1 has been found to be promoted by the progression of tongue SCC. Taken together, Cav-1 seems playing a different role in different cancer subtypes even of the same organ, as well as acting differently in the same cancer subtype of different organs. Thus, we hereby explore the functions of Cav-1 in human adenocarcinoma and SCC from the perspective of clinical significances and pathogenesis. We envision that novel targets may come with the further investigation of Cav-1 in carcinogenesis. PMID:28243118

  5. Renal adenocarcinoma, hepatocellular carcinoma, and pancreatic islet cell carcinoma in a binturong (Arctictis binturong).

    Science.gov (United States)

    Klaphake, Eric; Shoieb, Ahmed; Ramsay, Ed; Schumacher, Juergen; Craig, Linden

    2005-03-01

    A 19-yr-old binturong (Arctictis binturong) with acute upper respiratory disease was euthanized. Postmortem findings included hepatocellular carcinoma, pancreatic islet cell carcinoma, and renal adenocarcinoma with metastasis to the spleen, pleura, and pericardium. A link between primary hepatic and renal neoplasms has been noted in older humans.

  6. Role of canine basal cells in postnatal prostatic development, induction of hyperplasia, and sex hormone-stimulated growth; and the ductal origin of carcinoma.

    Science.gov (United States)

    Leav, I; Schelling, K H; Adams, J Y; Merk, F B; Alroy, J

    2001-08-01

    The canine prostate has often been proposed as a model for abnormal growth of the human gland. Hyperplasia of the prostate is common in aging men and has been estimated to be present in 100% of old intact dogs. While prostatic carcinoma is common in older men, it appears to be rare in dogs and unlike the disease in humans, it occurs with relatively high frequency in castrated animals. Since basal cells are thought to be key participants in normal and abnormal growth of the human gland, we used immunohistochemistry to investigate the role that they may play in canine prostatic development, the evolution of hyperplasia and carcinoma, and the effects of sex hormones on these cells. Prostate specimens were obtained at autopsy from seven sexually immature dogs, autopsy and biopsy samples from 14 sexually mature intact animals, from four castrates, and from19 dogs with prostatic carcinoma. In addition, we also studied the prostates from two intact dogs treated with 5alpha-dihydrotestosterone (DHT) for 6 months and two castrated dogs that were subsequently treated with 5alpha-androstane-3alpha diol and estradiol-17alpha, as well as specimens from two sexually ablated animals given DHT for 2 weeks. All specimens were immunostained for high molecular weight cytokeratin (HMC), pancytokeratin, androgen receptor (AR), and the proliferative marker KI-67. We find that basal cells are the major proliferative cell type in the neonatal and adult canine prostate and that the expression of HMC staining, which defines these cells, may be regulated by androgens. In the adult gland, ductal basal cells formed a contiguous layer, whereas those lining acini were discontinuous. Populations of both basal cell types were variably AR positive, but while HMC immunostaining was abolished in acinar cells following long-term castration, staining remained in ductal cell counterparts. Paralleling the histological development of hyperplasia, the acinar basal cell population increased with age and

  7. A rare tumoral combination, synchronous lung adenocarcinoma and mantle cell lymphoma of the pleura

    Directory of Open Access Journals (Sweden)

    Foroulis Christophoros N

    2008-12-01

    Full Text Available Abstract Background Coexistence of adenocarcinoma and mantle cell lymphoma in the same or different anatomical sites is extremely rare. We present a case of incidental discovery of primary lung adenocarcinoma and mantle cell lymphoma involving the pleura, during an axillary thoracotomy performed for a benign condition. Case presentation A 73-year old male underwent bullectomy and apical pleurectomy for persistent pneumothorax. A bulla of the lung apex was resected en bloc with a scar-like lesion of the lung, which was located in proximity with the bulla origin, by a wide wedge resection. Histologic examination of the stripped-off parietal pleura and of the bullectomy specimen revealed the synchronous occurrence of two distinct neoplasms, a lymphoma infiltrating the pleura and a primary, early lung adenocarcinoma. Immunohistochemical and fluorescence in situ hybridization assays were performed. The morphologic, immunophenotypic and genetic findings supported the diagnosis of primary lung adenocarcinoma (papillary subtype coexisting with a non-Hodgkin, B-cell lineage, mantle cell lymphoma involving both, visceral and parietal pleura and without mediastinal lymph node involvement. The neoplastic lymphoid cells showed the characteristic immunophenotype of mantle cell lymphoma and the translocation t(11;14. The patient received 6 cycles of chemotherapy, while pulmonary function tests precluded further pulmonary parenchyma resection (lobectomy for his adenocarcinoma. The patient is alive and without clinical and radiological findings of local recurrence or distant relapse from both tumors 14 months later. Conclusion This is the first reported case of a rare tumoral combination involving simultaneously lung and pleura, emphasizing at the incidental discovery of the two coexisting neoplasms during a procedure performed for a benign condition. Any tissue specimen resected during operations performed for non-tumoral conditions should be routinely sent for

  8. Study of mast cells in prostate lesions: Adenocarcinoma compared with hyperplasia

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    Vittal Rakshith

    2016-01-01

    Full Text Available Background: (1 To study and correlate the mast cell numbers in benign prostatic hyperplasia (BPH and prostate carcinoma lesions. (2 To compare mast cell numbers of intratumoral and peritumoral regions in prostate adenocarcinomas. (3 To ascertain a relationship between the number of mast cells and age, prostate-specific antigen (PSA levels, and Gleason Grade. Subjects and Methods: One-hundred cases of prostate lesions, consisting of 75 cases of BPH and 25 cases of prostatic adenocarcinoma, received in the form of transurethral resection of prostate chips in the Department of Pathology, were included in the study. After histopathological diagnosis, the paraffin sections were stained with toluidine blue. Results: The mean value of mast cell count per mm2 in benign and malignant lesion was 37.05 and 92.20, respectively. The difference in mean mast cell count in BPH and prostatic adenocarcinoma was found to be statistically significant (P = 0.001. The correlation between mast cell count and Gleason Grade was found to be statistically significant (P: Grades I–III - 0.043; 0.002; 0.012. However, no correlation was found between mast cell count with age and PSA levels. Conclusion: In this study, an increase in the number of mast cells was observed in patients with prostate cancer than in benign lesions. This suggests a stimulating role of mast cells in the progression of cancer.

  9. Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma

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    Che K

    2017-02-01

    Full Text Available Keying Che,1,* Yang Zhao,2,3,* Xiao Qu,1 Zhaofei Pang,1 Yang Ni,4 Tiehong Zhang,4 Jiajun Du,1,5 Hongchang Shen4 1Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 2Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center of Cancer Medicine, Fudan University Shanghai Cancer Center, 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 4Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, 5Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People’s Republic of China *These authors contributed equally to this work Purpose: Gastric carcinoma (GC is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma.Materials and methods: Hematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS was statistically analyzed.Results: Among the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145 of them. Single cell invasion and large cell invasion were observed in 62.8% (186 and 16.9% (50 of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, P<0

  10. Anti-proliferative role of recombinant lethal toxin of Bacillus anthracis on primary mammary ductal carcinoma cells revealing its therapeutic potential.

    Science.gov (United States)

    Khandia, Rekha; Pattnaik, Bramhadev; Rajukumar, Katherukamem; Pateriya, Atul; Bhatia, Sandeep; Murugkar, Harshad; Prakash, Anil; Pradhan, Hare Krishna; Dhama, Kuldeep; Munjal, Ashok; Joshi, Sunil K

    2017-05-30

    Bacillus anthracis secretes three secretary proteins; lethal factor (LF), protective antigen (PA) and edema factor (EF). The LF has ability to check proliferation of mammary tumors, chiefly depending on mitogen activated protein kinase (MAPK) signaling pathway. Evaluation of therapeutic potential of recombinant LF (rLF), recombinant PA (rPA) and lethal toxin (rLF + rPA = LeTx) on the primary mammary ductal carcinoma cells revealed significant (p role of receptor for LF revealed c-Met receptor showing strongest affinity for LF (H bond = 19; Free energy = -773.96), followed by nerve growth factor receptor (NGFR) and human epidermal growth factor receptor (HER)-1. The study summarizes the use of rLF or LeTx as therapeutic molecule against primary mammary ductal carcinoma cells and also the c-Met as potential alternative receptor for LF to mediate and modulate PA independent signal transduction.

  11. Gemcitabine response in pancreatic adenocarcinoma cells is synergistically enhanced by dithiocarbamate derivatives.

    Science.gov (United States)

    Dalla Pozza, Elisa; Donadelli, Massimo; Costanzo, Chiara; Zaniboni, Tatyana; Dando, Ilaria; Franchini, Marta; Arpicco, Silvia; Scarpa, Aldo; Palmieri, Marta

    2011-04-15

    Pancreatic adenocarcinoma is a common malignancy that remains refractory to all available therapies, including the gold standard drug gemcitabine (GEM). We investigated the effect of the combination of GEM and each of the ionophore compounds pyrrolidine dithiocarbamate (PDTC) and disulfiram [DSF; 1-(diethylthiocarbamoyldisulfanyl)-N,N-diethylmethanethioamide] on p53(-/-) pancreatic adenocarcinoma cell growth. PDTC or DSF synergistically inhibited cell proliferation when used in combination with GEM by inducing apoptotic cell death. This effect was associated with an increased mitochondrial O(2)(•-) production and was further enhanced by zinc ions. Basal levels of mitochondrial O(2)(•-) or manganese superoxide dismutase (MnSOD) strictly correlated with the IC(50) for GEM or the percentage of synergism. Thus, the most relevant values of the antiproliferative synergism were obtained in GEM-resistant pancreatic adenocarcinoma cell lines. Interestingly, the GEM-sensitive T3M4 cells transfected with MnSOD expression vector showed mitochondrial O(2)(•-) and IC(50) for GEM similar to those of resistant cell lines. In vivo experiments performed on nude mice xenotransplanted with the GEM-resistant PaCa44 cell line showed that only the combined treatment with GEM and DSF/Zn completely inhibited the growth of the tumoral masses. These results and the consideration that DSF is already used in clinics strongly support the GEM and DSF/Zn combination as a new approach to overcoming pancreatic cancer resistance to standard chemotherapy.

  12. Combined choriocarcinoma,neuroendocrine cell carcinoma and tubular adenocarcinoma in the stomach

    Institute of Scientific and Technical Information of China (English)

    Yasumitsu Hirano; Takuo Hara; Hiroshi Nozawa; Kaeko Oyama; Naohiro Ohta; Kenji Omura; Go Watanabe; Hideki Niwa

    2008-01-01

    We described a patient with adenocarcinoma of the stomach combined with choriocarcinoma and neuroendocrine cell carcinoma.An 85-year-old man visited our hospital because of appetite loss.Gastric fiborscopy revealed a large tumor occupying the cardial region and anterior wall of the gastric body.The patient underwent total gastrectomy with lymphnode dissection and partial resection of the liver.Choriocarcinoma,small cell carcinoma and tubular adenocarcinoma existed in the gastric tumor.The choriocarcinomatous foci contained cells positive for beta-subunit of human chorionic gonadotropin (B-hCG) and human placental lactogen mainly in syncytiotrophoblastic cells.The small cell carcinomatous loci contained cells positive for synaptophysin,neuron-specific enolase (NSF),and chromogranin A.The prognosis for gastric adenocarcinoma with choriocarcinoma and neuroendocrine cell carcinoma is exceedingly poor.This patient died about 2 mo after the first complaint from hepatic failure.This is the first reported case of gastric cancer with these three pathological features.

  13. Capsaicin-induced cell death in a human gastric adenocarcinoma cell line

    Institute of Scientific and Technical Information of China (English)

    Yi-Ching Lo; Yuan-Chen Yang; I-Chieh Wu; Fu-Chen Kuo; Chi-Ming Liu; Hao-Wei Wang; Chao-Hung Kuo; Jeng-Yi Wu; Deng-Chyang Wu

    2005-01-01

    AIM: Capsaicin, a pungent ingredient found in red pepper,has long been used in spices, food additives, and drugs.Cell death induced by the binding of capsaicin was examined in a human gastric adenocarcinoma cell line (AGS cells).METHODS: By using XTT-based cytotoxicityassay, flow cytometry using the TUNEL method, and quantitation of DNA fragmentation, both cell death and DNA fragmentation were detected in AGS cells treated with capsaicin. By using Western blotting methods, capsaicin reduced the expression of Bcl-2, the antiapoptotic protein, in AGS cells in a concentration-dependent manner.RESULTS: After incubation of AGS cells with capsaicin for 24 h, cell viability decreased significantly in a dose-dependent manner. After incubation of AGS cells with capsaicin for 24 h, apoptotic bodies also significantly increased, and were again correlated with the dose of capsaicin. When the concentration of capsaicin was 1 mmol/L, the amount of DNA fragments also increased. Similar results werealso in the lower traces.CONCLUSION: These results suggest that capsaicininduced cell death might be via a Bcl-2 sensitive apoptotic pathway. Therefore, capsaicin might induce protection from gastric cancer.

  14. Cryptolepine, isolated from Sida acuta, sensitizes human gastric adenocarcinoma cells to TRAIL-induced apoptosis.

    Science.gov (United States)

    Ahmed, Firoj; Toume, Kazufumi; Ohtsuki, Takashi; Rahman, Mahmudur; Sadhu, Samir Kumar; Ishibashi, Masami

    2011-01-01

    Bioassay guided separation of Sida acuta whole plants led to the isolation of an alkaloid, cryptolepine (1), along with two kaempferol glycosides (2-3). Compound 1 showed strong activity in overcoming TRAIL-resistance in human gastric adenocarcinoma (AGS) cells at 1.25, 2.5 and 5 μm. Combined treatment of 1 and TRAIL sensitized AGS cells to TRAIL-induced apoptosis at the aforementioned concentrations. Copyright © 2010 John Wiley & Sons, Ltd.

  15. Analysis of Differential Gel Electrophoresis of Paclitaxol Resistant and Sensitive Lung Adenocarcinoma Cells' Secretome

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    Tianqing CHU

    2009-07-01

    Full Text Available Background and objective Paclitaxol (PTX resistance is one of main factors which affect the outcome of chemotherapy of lung adenocarcinoma. The aim of this study is to compare the secreted protein expression profiles between Paclitaxol (PTX resistant and sensitive lung adenocarcinoma cells by proteomic research method, so as to provide evidence of choosing individual chemotherapy drugs in clinical treatment. Methods Total secreted proteins extracted from a PTX sensitive cell line A549 and a PTX resistant cell line A549-Taxol were separated by fluorscent differential gel electrophoresis (DIGE. High quality 2-DE profiles were obtained and analyzed by Decyder 6.5 analysis software to screen differentially expressed protein spots. Those spots were identified by mass spectrometry. Results 2-DE patterns of lung adenocarcinoma cells with high-resolution and reproducibility were obtained. 76 significantly differentially expressed protein spots were screened, 19 proteins were identified by mass spectrometry. The identified proteins could be classified into different catogories: metabolic enzyme, extracellular matrix (ECM degradation enzyme, cytokine, signal transducer, cell adhesion, and so on. Conclusion Multiple secreted proteins related to chemoresistance of A549-Taxol cells were identified in this study for the first time. The results presented here would provide clues to identify new serologic chemoresistant biomarkers of NSCLC.

  16. CLONING AND IDENTIFICATION OF A GENE RELATED TO THE DIFFERENTIATION OF HUMAN GASTRIC ADENOCARCINOMA CELLS

    Institute of Scientific and Technical Information of China (English)

    王建华; 陈诗书

    2002-01-01

    Objective: To compare the differential expression of mRNA between MKN-28 (highly differentiated) and MKN-45 (poorly differentiated) gastric adenocarcinoma cells and identify genes involved in human gastric adenocarcinoma differentiation. Methods: Differential expression of mRNA between MKN-28 and MKN-45 adenocarcinoma cells was investigated by fluorescent differential display (FDD). Differentially expressed cDNA was analyzed by bio-informatics and confirmed by RT-PCR and Northern-blot. Results: 45 differential fragments were finally attained. One of them (No. 10) was an approximate 750 bp cDNA and highly up-regulated in MKN-45 cells as compared with MKN-28 cells. By using Blastn and UniGene database analysis, we found the fragment was mapped to chromosome 14q11.2(q12 and showed a significant homology to Bcl-2 binding protein gene (BNip3), which was recently identified encoding pro-apoptosis protein located in mitochondrial. Conclusion: The BNip3 induced apoptosis could be suppressed by interacting with bcl-2. The BNip3 gene in tumor cells might be up-regulated by the hypoxia response element through the HIF1a transcription factor, causing death of the hypoxic cells at the center of the tumor where vascularization is usually poor in the process of tumor development.

  17. Roles of histamine on the expression of aldehyde dehydrogenase 1 in endometrioid adenocarcinoma cell line.

    Science.gov (United States)

    Wang, Yi; Jiang, Yang; Ikeda, Jun-Ichiro; Tian, Tian; Sato, Atsushi; Ohtsu, Hiroshi; Morii, Eiichi

    2014-10-01

    Cancer-initiating cells (CICs) are a limited number of cells that are essential for maintenance, recurrence, and metastasis of tumors. Aldehyde dehydrogenase 1 (ALDH1) has been recognized as a marker of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and that ALDH1 high population was more tumorigenic, invasive, and resistant to apoptosis than ALDH1 low population. Histamine plays a critical role in cancer cell proliferation, migration, and invasion. Here, we examined the effect of histamine on ALDH1 expression in endometrioid adenocarcinoma cell line. The addition of histamine increased ALDH1 high population, which was consistent with the result that histamine enhanced the invasive ability and the resistance to anticancer drug. Among 4 types of histamine receptors, histamine H1 and H2 receptor (H1R and H2R) were expressed in endometrioid adenocarcinoma cell line. The addition of H1R agonist but not H2R agonist increased ALDH1. The antagonist H1R but not H2R inhibited the effect of histamine on ALDH1 expression. These results indicated that histamine increased the expression of ALDH1 via H1R but not H2R. These findings may provide the evidence for exploring a new strategy to suppress CICs by inhibiting ALDH1 expression with histamine.

  18. Mammalian mediator 19 mediates H1299 lung adenocarcinoma cell clone conformation, growth, and metastasis.

    Science.gov (United States)

    Xu, Lu-Lu; Guo, Shu-Liang; Ma, Su-Ren; Luo, Yong-Ai

    2012-01-01

    Mammalian mediator (MED) is a multi-protein coactivator that has been identified by several research groups. The involvement of the MED complex subunit 19 (MED 19) in the metastasis of lung adenocarcinoma cell line (H1299), which expresses the MED 19 subunit, was here investigated. When MED 19 expression was decreased by RNA interference H1299 cells demonstrated reduced clone formation, arrest in the S phase of the cell cycle, and lowered metastatic capacity. Thus, MED 19 appears to play important roles in the biological behavior of non-small cell lung carcinoma cells. These findings may be important for the development of novel lung carcinoma treatments.

  19. Pancreatic ductal bicarbonate secretion: challenge of the acinar acid load

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    Peter eHegyi

    2011-07-01

    Full Text Available Acinar and ductal cells of the exocrine pancreas form a close functional unit. Although most studies contain data either on acinar or ductal cells, an increasing number of evidence highlights the importance of the pancreatic acinar-ductal functional unit. One of the best examples for this functional unit is the regulation of luminal pH by both cell types. Protons co-released during exocytosis from acini cause significant acidosis, whereas, bicarbonate secreted by ductal cells cause alkalization in the lumen. This suggests that the first and probably one of the most important role of bicarbonate secretion by pancreatic ductal cells is not only to neutralize the acid chyme entering into the duodenum from the stomach, but to neutralize acidic content secreted by acinar cells. To accomplish this role, it is more than likely that ductal cells have physiological sensing mechanisms which would allow them to regulate luminal pH. To date, four different classes of acid-sensing ion channels have been identified in the gastrointestinal tract (transient receptor potential ion channels, two-pore domain potassium channel, ionotropic purinoceptor and acid-sensing ion channel, however, none of these have been studied in pancreatic ductal cells. In this mini-review, we summarize our current knowledge of these channels and urge scientists to characterize ductal acid-sensing mechanisms and also to investigate the challenge of the acinar acid load on ductal cells.

  20. 生物钟周期基因2与胰腺导管腺癌预后的相关性分析%Correlation analysis between period circadian clock 2 gene and the prognosis of pancreatic ductal adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    曾玮; 刘孟刚; 刘宏鸣; 谢斌; 袁涛; 杨俊涛; 蓝翔; 陈平

    2014-01-01

    Objective To explore the prognosis related genes of pancreatic ductal adenocarcinoma (PDAC)and investigate the molecular regulation mechanism.Methods Gene expression data of 102 PDAC patients with complete clinical survival data were selected from gene expression database of National Center for Biotechnology Information.The 106 transcription regulation gene collection was collected from Transfac database.The 715 microRNA (miRNA)target regulation gene collection was selected according to PicTar and TargetScanS method.Biological pathway data obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG).The known cancer genes were collected from the cancer gene census (CGC) database.Univariate Cox proportional hazards model was used to analyze the correlation between gene expression data and survival time,then obtained survival related candidate genes from the whole genome. Then the enriched genes were analyzed by hypergeometric distribution algorithm from three databases. Multiple correction testing was performed by BH-FDR method (FDR < 0.05 ).Kaplan-Meier was performed for survival curve analysis of PDAC.Results The results of data of 102 PDAC patients analyzed by univariate Cox proportional hazards model indicated that 273 genes were significantly related to the survival time of patients (P <0.000 1 ).After 273 survival genes were enrichment analyzed in 106 transcription factor regulation gene collection,12 survival genes enriched transcription factor target gene sets were found.After 273 survival genes were enrichment analyzed in 715 miRNA target regulation gene collection,11 survival genes enriched miRNAs target sets were discovered.After 273 survival genes were enrichment analyzed in pathway data of KEGG,15 survival genes enriched pathways were obtained. Period circadian clock 2 (PER2 )was regulated by CCAAT/enhancer binding protein (CEBPA)at transcription level and regulated by miRNA-32 after transcription.The prognosis of PDAC was affected by circadian

  1. Direct growth-inhibitory effects of prostaglandin E2 in pancreatic cancer cells in vitro through an EP4/PKA-mediated mechanism.

    Science.gov (United States)

    Schmidt, Andrea; Sinnett-Smith, James; Young, Steven; Chang, Hui-Hua; Hines, O Joe; Dawson, David W; Rozengurt, Enrique; Eibl, Guido

    2017-06-01

    There is strong evidence linking inflammation and the development of pancreatic ductal adenocarcinoma. Cyclooxygenase-2 (COX-2) and COX-2-derived PGE2 are overexpressed in human and murine pancreatic ductal adenocarcinoma. Several studies have demonstrated an important role of COX-2-derived PGE2 in tumor-stroma interactions; however, the direct growth effects of prostaglandin E2 (PGE2) on pancreatic ductal adenocarcinoma cells is less well defined. Our aim was to investigate the effects of PGE2 on pancreatic ductal adenocarcinoma cell growth and to characterize the underlying mechanisms. Human pancreatic ductal adenocarcinoma cell lines, Panc-1 and MIA PaCa-2, were treated with PGE2 in varying doses (0-10 μM). Effects on the phosphorylation of ERK1/2 were evaluated by Western blot. Colony formation was observed for cells treated with PGE2 for 11 days. DNA synthesis was determined by (3H)-thymidine incorporation assay. Gene expression of E-type prostaglandin (EP)2/EP4 receptors and their correlation with survival in patients with pancreatic ductal adenocarcinoma were assessed using the RNA-Seq data set from The Cancer Genome Atlas Research Network. PGE2 decreased the size and number of colonies in Panc-1 but not MIA PaCa-2 cells. In the Panc-1 cells, PGE2 activated PKA/CREB and decreased phosphorylation of ERK1/2, which was reversed by an EP4 receptor antagonist, while an EP2 receptor antagonist had no effect. In contrast, in MIA PaCa-2 cells, PGE2 had no effect on ERK1/2 phosphorylation. Treatment of both Panc-1 and MIA PaCa-2 cells with forskolin/IBMX decreased ERK1/2 phosphorylation. Finally, PGE2 decreased DNA synthesis only in Panc-1 cells, which was reversed by an EP4 receptor antagonist. In human pancreatic ductal adenocarcinoma, high EP2 and low EP4 gene expression was correlated to worse median overall survival (15.6 vs 20.8 months, log-rank P = .017). Our study provides evidence that PGE2 can inhibit directly pancreatic ductal adenocarcinoma

  2. Effect of leptin on cell proliferation and apoptosis of gastric adenocarcinoma cell line-SGC7901 and colon cancer cell line-HT-29

    Institute of Scientific and Technical Information of China (English)

    Chang-Wen Yu; Bi-Sheng Zhu

    2016-01-01

    Objective:To explore effect of leptin on cell proliferation and apoptosis of gastric adenocarcinoma cell line-SGC7901 and colon cancer cell line-HT-29.Methods: MTT and flow cytometry were adopted for detecting the effect of exogenous leptin on cell cycle of gastric adenocarcinoma cell line-SGC7901 and colon cancer cell line-HT-29.Results: Leptin with mass concentration (0 ng/mL, 5 ng/mL, 50 ng/mL, 100 ng/mL, 200 ng/mL) could stimulate the growth of gastric adenocarcinoma cell line-SGC7901 and colon cancer cell line-HT-29; exogenous leptin with mass concentration (5 ng/mL, 50 ng/mL, 100 ng/mL, 200 ng/mL) could inhibit cell growth of gastric adenocarcinoma cell line-SGC7901 and colon cancer cell line-HT-29 after 72 h; among which, inhibiting effects of cell line-SGC7901 and cell line-HT-29 were the most significant under the effect of exogenous leptin with mass concentration-200 ng/mL.Conclusion:Within a certain concentration and action time, exogenous leptin can stimulate the growth of gastric adenocarcinoma cell line and colon cancer cell line, and then promot the tumor cell proliferation and/or inhibit the tumor cell apoptosis.

  3. Primary diffuse large B cell lymphoma developing at the ileocolonic anastomosis site after right hemicolectomy for adenocarcinoma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Hye Yeon; Choi, Seung Joon; Kim, Hyung Sik; Kim, Jeong Ho; Choi, Hye Young [Dept. of Radiology, Gachon University Gil Hospital, Incheon (Korea, Republic of)

    2014-04-15

    Lymphoma is rarely associated with ileocolonic surgery. We report the imaging findings of primary diffuse large B-cell lymphoma arising in an ileocolonic anastomosis site, found five years after a right hemicolectomy for adenocarcinoma in the ascending colon.

  4. Multisystem Langerhans cell histiocytosis coexisting with metastasizing adenocarcinoma of the lung: A case report

    Directory of Open Access Journals (Sweden)

    Lovrenski Aleksandra

    2013-01-01

    Full Text Available Introduction. Langerhans cell histiocytosis (LCH is an uncommon disease of unknown etiology characterized by uncontrolled proliferation and infiltration of various organs by Langerhans cells. Case report. We presented a 54-year-old man, heavy smoker, with dyspnea, cough, hemoptysis, headache and ataxia, who died shortly after admission to our hospital. On the autopsy, tumor was found in the posterior segment of the right upper pulmonary lobe as well as a right-sided occipitoparietal lesion which penetrated into the right ventricle resulting in internal and external hematocephalus. Histologically and immunohistohemically, the diagnosis of primary lung adenocarcinoma with brain metastasis was made (tumor cells showed positivity for CK7 and TTF-1 which confirmed the diagnosis. In the lung parenchyma around the tumor, as well as in brain tissue around the metastatic adenocarcinoma histiocytic lesions were found. Light microscopic examination of the other organs also showed histiocytic lesions involving the pituitary gland, hypothalamus, spleen and mediastinal lymph nodes. Immunohistochemical studies revealed CD68, S-100 and CD1a immunoreactivity within the histiocytes upon which the diagnosis of Langerhans' cells histiocytosis was made. Conclusion. The multisystem form of LCH with extensive organ involvement was an incidental finding, while metastatic lung adenocarcinoma to the brain that led to hematocephalus was the cause of death.

  5. Empirical studies about quercetin increasing chemosensitivity on human lung adenocarcinoma cell line A549

    Institute of Scientific and Technical Information of China (English)

    Xuejun Zhan; Runxiang Zhang; Yanping Xu; Shuhua Yang; Daze Xie; Liwei Tan

    2012-01-01

    Objective: The present study was designed to investigate whether quercetin exerts increasing chemosensitivity on human lung adenocarcinoma cells when quercetin combined with cisplatin (DDP) and vincristine (VCR) in vitro respectively and its possible antitumor mechanism. To provide experimental proof for clinical combination application. Methods: Using intermittent administration of high dose VCR, human lung adenocarcinoma sensitive cell line (A549/S) was induced to VCR-resistant human lung adenocarcinoma cell line (A549/VCR). MTT assay was adapted for examing the 50% inhibition (IC50) value of DDP and VCR on A549/S and A549/VCR when quercetin combined with DDP and VCR respectively. Results: IC50 of DDP on A549/S and A549/VCR was 10.18 and 12.35 mg/L, and the IC50 of VCR on the two cell lines was 1.21 and 12.77 mg/L, respectively. The resistance fold of A549/VCR on VCR and DDP was 10.55 and 1.21, respectively. When quercetin at concentration of 50, 100 and 200 μmol/L in combination with DDP and VCR respectively, the IC50 of DDP and VCR on A549/S and A549/VCR were obvious decreased (P < 0.05 – P < 0.01). Conclusion: The experiment results suggested that quercetin could increase the chemosensitivity and partly revise the resistance of A549/VCR.

  6. Primary Clear Cell Adenocarcinoma of a Urethral Diverticulum Treated with Multidisciplinary Robotic Anterior Pelvic Exenteration

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    Dane Scantling

    2013-01-01

    Full Text Available Primary urethral carcinoma is extremely rare and is marked by a variety of clinical symptoms. Primary carcinoma of a urethral diverticulum is still rarer and clear cell adenocarcinoma of the urethra is particularly uncommon (Swartz et al., 2006. Such infrequency has led to inadequate management guidance in the literature for a disease that is often late in presentation and carries substantial morbidity and mortality. This treatable but grave disease deserves definitive curative treatment. We present the first published instance in which it was treated with robotic anterior exenteration. In our case, a 47-year-old female was referred to the urology service for investigation of recurring urinary tract infections. During the workup, the patient was found to have an advanced clear cell urethral adenocarcinoma originating in a urethral diverticulum. We discuss the natural history of this condition, its consequences, and the first instance of its treatment using robotic anterior pelvic exenteration.

  7. Different maspin functions in the lung adenocarcinoma A549 and SPC-A1 cell lines.

    Science.gov (United States)

    Zhou, Jun; Hualong, Qin; Zhou, Peng; Guo, Feng

    2015-11-01

    Mammary serine protease inhibitor (maspin) is a tumor suppressor gene that is silenced in the majority of cancer cells during metastatic progression by transcriptional and epigenetic mechanisms. The function of maspin in non‑small cell lung cancer cells (NSCLC) has not been clearly defined. In the present study, the expression of maspin in NSCLC cell lines, in particular, the adenocarcinoma cell lines, was heterogeneous. While the expression levels of maspin in PC‑9 and H460 cell lines were intact, the expression of maspin in the A549 and SPC‑A1 cells was hardly detected. Ectopic expression of maspin in A549 cells carrying the K‑ras gene point mutation significantly inhibited cell migration and invasion abilities, which was associated with downregulated expression of matrix metalloproteinase‑2 and integrin β1. Ectopic expression of maspin in SPC‑A1 cells harboring the wild‑type K‑ras gene predominantly affected cell growth via targeting the AKT signaling molecules. Maspin functions differently in lung adenocarcinoma cells, possibly due to the varied molecular characteristics.

  8. Genetic and Epigenetic Determinants of Lung Cancer Subtype: Adenocarcinoma to Small Cell Conversion

    Science.gov (United States)

    2015-08-01

    disease progression in colorectal cancer patients. 5 R01 CA182587-02 (PI: Solit) 1/1/2014 - 12/31/2018 0.60 calendar...patients with muscle invasive and metastatic bladder cancer the prevalence of PI3 kinase alterations, the pattern of co-mutational events, their...AWARD NUMBER: W81XWH-14-1-0223 TITLE: Genetic and Epigenetic Determinants of Lung Cancer Subtype: Adenocarcinoma to Small Cell Conversion

  9. Anal metastasis of rectal cancer-adenocarcinoma of squamous cells: a case report and literature review.

    Science.gov (United States)

    Sasaki, Shun; Sugiyama, Masahiko; Nakaji, Yu; Nakanishi, Ryota; Nakashima, Yuichiro; Saeki, Hiroshi; Oki, Eiji; Oda, Yoshinao; Maehara, Yoshihiko

    2017-12-01

    Anal metastasis of colorectal cancer is very rare and is usually associated with a history of anal disease, including anal fistula, fissure, hemorrhoidectomy, and anastomotic injury. We report a case of rectal cancer with a synchronous anal metastasis consisting of adenocarcinoma of squamous cells without a history of anal disease. A 60-year-old woman had a chief complaint of melena. She had a 1.5-cm anal tumor on the perianal skin, and a Bollman type 2 rectal tumor on the Ra portion was found on colonoscopy. Biopsy of both tumors revealed a similar histology of well- to moderately differentiated adenocarcinoma. There was no sign of metastases in lymph nodes or other organs. For the purpose of diagnosis and treatment, transperineal local resection of the anal tumor was performed, and it was histologically identified as adenocarcinoma of squamous cells with no invasion to muscles, lymph ducts, or microvessels. The pathological margin was free. Then, to achieve radical cure, laparoscopic low anterior resection (LAR) with D3 lymphadenectomy was performed. The histological diagnosis of the anal tumor was adenocarcinoma of squamous cells without invasion to muscles, lymph ducts, or vessels. The surgical margin was completely free. Immunohistochemical analysis of both tumors revealed similar staining patterns, and the final diagnosis was rectal cancer with metastasis to the anal skin. The patient received no postoperative therapy, and no recurrences have been observed 12 months after surgery. We expect that our sphincter-preserving surgical strategy provided a good prognosis for the synchronous rectal cancer and anal metastasis. This is a rare report of a case with an anal metastasis of colorectal cancer on perianal squamous cells without a history of anal disease that was resected while preserving anal function.

  10. A clear cell adenocarcinoma of the gallbladder with hepatoid differentiation: case report and review of literature

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    Zhang C

    2016-09-01

    Full Text Available Chengsheng Zhang,1,2 Wei Zhang,1,2 Dianbin Mu,1 Xuetao Shi,1 Lei Zhao1,2 1Department of Hepatobiliary Surgery, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Science, 2School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong Province, People’s Republic of China Abstract: An 80-year-old male was referred to our department for a gallbladder mass. He denied any history of alcohol consumption or cholecystitis and smoking. Hepatitis B surface antigen test and antihepatitis C antibody test were found to be negative. Serum carbohydrate antigen 19-9 (CA19-9 and carcinoembryonic antigen were elevated (CA19-9 was 59.92 U/mL and carcinoembryonic antigen was 12.64 ng/mL, whereas alpha-fetoprotein was below the normal limit (2.46 ng/mL. Computed tomography scan revealed a solid mass with measurements of 4.6×5.6×7.1 cm, which nearly filled the whole gallbladder space. Radical cholecystectomy, including segments IV B and V of the liver and lymphadenectomy, was performed. The neoplasm in gallbladder was completely resected, and the patient obtained a negative margin. Histological and immunohistochemical profile suggested a clear cell adenocarcinoma of the gallbladder with hepatoid differentiation. After reviewing the literature, we reported that this case is the first identified case of cell adenocarcinoma of the gallbladder with extensive hepatoid differentiation. However, clinical features of clear cell adenocarcinoma with hepatoid differentiation remain unclear due to the extremely rare incidence. There was no indication of adjuvant chemotherapy and no literature has been reported on the application of chemotherapy. This case showed a promising clinical outcome after curative resection, which indicated that surgical treatment could be potentially considered for suitable patients. Keywords: gallbladder, clear cell adenocarcinoma, hepatoid differentiation 

  11. Increased Levels of Erythropoietin in Nipple Aspirate Fluid and in Ductal Cells from Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Ferdinando Mannello

    2008-01-01

    Full Text Available Background: Erythropoietin (Epo is an important regulator of erythropoiesis, and controls proliferation and differentiation of both erythroid and non-erythroid tissues. Epo is actively synthesized by breast cells during lactation, and also plays a role in breast tissues promoting hypoxia-induced cancer initiation. Our aims are to perform an exploratory investigation on the Epo accumulation in breast secretions from healthy and cancer patients and its localization in breast cancer cells.

  12. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Peng Huang; Chun-You Wang; Shan-Miao Gou; He-Shui Wu; Tap Liu; Jiang-Xin Xiong

    2008-01-01

    AIM: To explore the method of isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma cell line PANC-1.METHODS: The PANC-1 cells were cultured in Dulbecco modified eagle medium F12 (1:1 volume)(DMEM-F12) supplemented with 20% fetal bovine serum (FBS).Subpopulation cells with properties of tumor stem cells were isolated from pancreatic adenocarcinoma cell line PANC-1 according to the cell surface markers CD44 and CD24 by flow cytometry.The proliferative capability of these cells in vitro were estimated by 3-[4,5-dimehyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) method.And the tumor growth of different subpopulation cells which were injected into the hypodermisof right and left armpit of nude mice was studied,and expression of CD44 and CD24 of the CD44+CD24+ cell-formed nodules and PANC-1 cells were detected by avidin-biotin-peroxidase complex (ABC) immunohistochemical staining.RESULTS: The 5.1%-17.5% of sorted PANC-1 cells expressed the cell surface marker CD44,57.8% -70.1% expressed CD24,only 2.1%-3.5% of cells were CD44+ CD24+.Compared with CD44-CD24- cells,CD44+CD24+ cells had a lower growth rate in vitro.Implantation of 104 CD44 CD24- cells in nude mice showed no evident tumor growth at wk 12.In contrast,large tumors were found in nude mice implanted with 103 CD44+CD24+ cells at wk 4 (2/8),a 20-fold increase in tumorigenic potential (P<0.05 or P<0.01).There was no obvious histological difference between the cells of the CD44+CD24+ cell-formed nodules and PANC-1 cells.CONCLUSION: CD44 and CD24 may be used as the cell surface markers for isolation of pancreatic cancer stem cells from pancreatic adenocarcinoma cell line PANC-1.Subpopulation cells CD44+CD24+ have properties of tumor stem cells.Because cancer stem cells are thought to be responsible for tumor initiation and its recurrence after an initial response to chemotherapy,it may be a very promising target for new drug development.

  13. Evaluation of the expression of stem cell markers in human breast cancer reveals a correlation with clinical progression and metastatic disease in ductal carcinoma.

    Science.gov (United States)

    Martin, Tracey Amanda; Jiang, Wen Guo

    2014-01-01

    The tumor stem cell theory could explain how patients with metastatic disease show clinical relapse several months after starting treatment due to the survival of a small group of cells with unique characteristics. We examined the distribution and expression of a panel of stem cell markers in human breast cancer primary tumors. Human breast tissues were processed for immunohistochemistry, and RNA was extracted for analysis by quantitative-PCR. Immunohistochemical assay revealed that CD44 was strongly expressed in background endothelia and epithelia. CD133 expression was lost in tumor-associated endothelial cells. Conversely, CD49b was strongly stained in the tumors, associated vessels and ducts but was weakly stained in the background epithelia. q-PCR analysis revealed that CD44 and PSCA were reduced in patients with poor outcome (metastatic disease and death from breast cancer), with a marked reduction in ductal carcinoma, particularly with metastasis to bone although these did not reach significant difference. CD133 was significantly reduced in patients with metastatic disease and was also significantly reduced in patients with ductal carcinoma/bone metastasis. Conversely, CD49F was increased in patients with a poor outcome and those with ductal cancer and bone metastases. This is the first study to determine the distribution and expression pattern of these stem cell markers in human breast cancer. There was a significant association between loss of expression and metastatic disease in patients with breast cancer. Such differential expression may play a part in breast cancer disease progression, and suggests that the current stem cell theory may not hold true for all cancer types.

  14. Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma.

    Science.gov (United States)

    Mainardi, Sara; Mijimolle, Nieves; Francoz, Sarah; Vicente-Dueñas, Carolina; Sánchez-García, Isidro; Barbacid, Mariano

    2014-01-07

    Ubiquitous expression of a resident K-Ras(G12V) oncogene in adult mice revealed that most tissues are resistant to K-Ras oncogenic signals. Indeed, K-Ras(G12V) expression only induced overt tumors in lungs. To identify these transformation-permissive cells, we induced K-Ras(G12V) expression in a very limited number of adult lung cells (0.2%) and monitored their fate by X-Gal staining, a surrogate marker coexpressed with the K-Ras(G12V) oncoprotein. Four weeks later, 30% of these cells had proliferated to form small clusters. However, only SPC(+) alveolar type II (ATII) cells were able to form hyperplastic lesions, some of which progressed to adenomas and adenocarcinomas. In contrast, induction of K-Ras(G12V) expression in lung cells by intratracheal infection with adenoviral-Cre particles generated hyperplasias in all regions except the proximal airways. Bronchiolar and bronchioalveolar duct junction hyperplasias were primarily made of CC10(+) Clara cells. Some of them progressed to form benign adenomas. However, only alveolar hyperplasias, exclusively made up of SPC(+) ATII cells, progressed to yield malignant adenocarcinomas. Adenoviral infection induced inflammatory infiltrates primarily made of T and B cells. This inflammatory response was essential for the development of K-Ras(G12V)-driven bronchiolar hyperplasias and adenomas, but not for the generation of SPC(+) ATII lesions. Finally, activation of K-Ras(G12V) during embryonic development under the control of a Sca1 promoter yielded CC10(+), but not SPC(+), hyperplasias, and adenomas. These results, taken together, illustrate that different types of lung cells can generate benign lesions in response to K-Ras oncogenic signals. However, in adult mice, only SPC(+) ATII cells were able to yield malignant adenocarcinomas.

  15. Characterization of spheres derived from canine mammary gland adenocarcinoma cell lines.

    Science.gov (United States)

    Michishita, Masaki; Akiyoshi, Rui; Yoshimura, Hisashi; Katsumoto, Takuo; Ichikawa, Hitoshi; Ohkusu-Tsukada, Kozo; Nakagawa, Takayuki; Sasaki, Nobuo; Takahashi, Kimimasa

    2011-10-01

    There is increasing evidence for the presence of cancer stem cells in several solid tumors, and these cancer stem cells have a potential role in tumor initiation, aggression, and recurrence. The stem cell-like properties of spheres derived from canine mammary tumors remain largely elusive. We attempted to induce sphere formation using four cell lines of canine mammary adenocarcinoma, and characterized the spheres derived from a CHMp line in vitro and in vivo. The CHMp-derived spheres showed predominantly CD44+CD24- population, higher expression of stem cell-related genes, such as CD133, Notch3 and MDR, and higher resistance to doxorubicin compared with the CHMp-derived adherent cells. Xenograft transplantations in nude mice demonstrated that only 1 × 10(4)sphere cells were sufficient for tumor formation. Use of the sphere assay on these sphere-derived tumors showed that sphere-forming cells were present in the tumors, and were maintained in serial transplantation. We propose that spheres derived from canine mammary adenocarcinoma cell lines possess a potential characteristic of cancer stem cells. Spheres derived from canine mammary tumors could be a powerful tool with which to investigate novel therapeutic drugs and to elucidate the molecular and cellular mechanisms that underlie tumorigenesis.

  16. Barret's adenocarcinomas resemble adenocarcinomas of the gastric cardia in terms of chromosomal copy number changes, but relate to squamous cell carcinomas of the distal oesophagus with respect to the presence of high-level amplifications

    NARCIS (Netherlands)

    M.M. Weiss (Marjan); E.J. Kuipers (Ernst); M.A.J.A. Hermsen (Mario); N.C.T. Grieken (Nicole); G.J.A. Offerhaus (Johan); J.P.A. Baak (Jan); S.G.M. Meuwissen; C.J.L.M. Meijer (Chris)

    2003-01-01

    textabstractThree different cancers predominantly occur at the gastro-oesophageal junction: squamous cell carcinomas of the distal oesophagus, adenocarcinomas of the distal oesophagus (Barrett's carcinomas), and adenocarcinomas of the gastric cardia. The aim of the present study was to investigate

  17. Effects of mifepristone on proliferation of human gastric adenocarcinoma cell line SGC-7901 in vitro

    Institute of Scientific and Technical Information of China (English)

    Da-Qiang Li; Zhi-Biao Wang; Jin Bai; Jie Zhao; Yuan Wang; Kai Hu; Yong-Hong Du

    2004-01-01

    AIM: To explore the effects of mifepristone, a progesterone receptor (PR) antagonist, on the proliferation of human gastric adenocarcinoma cell line SGC-7 901 in vitro and the possible mechanisms involved.METHODS: In situ hybridization was used to detect theexpression of PR mRNA in SGC-7 901 cells. After treatment with various concentrations of mifepristone (2.5, 5, 10,20 μmol/L) at various time intervals, the ultrastructural changes, cell proliferation, cell-cycle phase distribution, and the expression of caspase-3 and Bcl-XL were analyzed using transmission electron microscopy (TEM), tetrazolium blue(MTT) assay, 3H-TdR incorporation, flow cytometry, and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Mifepristone markedly induced apoptosis and inhibited cell proliferation of PR- positive SGC-7 901 cells revealed by TEM, MTT assay and 3H-TdR incorporation, in a dose- and time-dependent manner. The inhibitory rate was increased from 8.98% to 51.29%. Flow cytometric analysis showed mifepristone dose-dependently decreased cells in S and G2/M phases, increased cells in Go/G1 phase,reduced the proliferative index from 57.75% to 22.83%. In addition, mifepristone up-regulated the expression of caspase-3, and down- regulated the Bcl-XL expression, dose-dependently.CONCLUSION: Mifepristone effectively inhibited the proliferation of PR-positive human gastric adenocarcinoma cell line SGC-7 901 in vitro through multiple mechanisms, and may be a beneficial agent against human adenocarcinoma.

  18. Coexistence of Granular Cell Tumor and Invasive Ductal Breast Cancer in Contralateral Breasts: A Case Report

    Directory of Open Access Journals (Sweden)

    Maurizio Di Bonito

    2014-07-01

    Full Text Available Granular cell tumor (GCT is a benign tumor of the breast that can mimic, on breast imaging, invasive carcinomas. Biological evolution of mammary GCT is unknown, especially if it is associated with an invasive carcinoma in the same or contralateral breast. This report details the morphological features of these synchronous lesions highlighting their biological characteristics and suggesting an appropriate follow up.

  19. Goblet cells carcinoid with mucinous adenocarcinoma of the vermiform appendix: a step towards the unitary intestinal stem cell theory?

    Science.gov (United States)

    Gravante, G; Yahia, S; Gopalakrishnan, K; Mathew, G

    2014-06-01

    Associations of various histotypes in appendiceal neoplasms may help elucidate the histogenesis of such uncommon tumors. We present the fourth published case of Goblet Cell Carcinoid (GCC) associated with mucinous adenocarcinoma of the appendix. This association has been described only for GCC and not for classic appendix carcinoids which are thought to originate from neuroendocrine-committed cells. The GCC-mucinous association adds more towards the theory of a pluripotent intestinal stem cell with amphicrine possibilities of differentiation.

  20. Molecular Analysis of Motility in Metastatic Mammary Adenocarcinoma Cells

    Science.gov (United States)

    1996-09-01

    comparisons with the F-actin binding activity of EF1 from Dictyostelium (Edmonds et al., 1995). These conditions are physiological for a free living amoeba ...activity resulting from the appearance of free barbed ends very close to the leading edge of extending lamellipods. Both actin polymerization and...cells demonstrate the massive accumulation of F-actin and EGF-R in ruffles and under the plasma membrane at the free cell edge in colonies of A431 cells

  1. Primary cell culture of human adenocarcinomas--practical considerations.

    Science.gov (United States)

    Lerescu, Lucian; Tucureanu, Cătălin; Caraş, Iuliana; Neagu, Stefan; Melinceanu, Laura; Sălăgeanu, Aurora

    2008-01-01

    Cell culture is one of the major tools for oncology research, being an excellent system in which to study the biochemistry and molecular biology associated with individual cancer types and to understand cancer cell physiology. Progress in understanding the biology of any type of carcinoma has been impeded by the inability to culture adequately malignant cells from most epithelial tissues. The ultimate in vitro tumor model would completely reflect the in vivo tumor microenvironment in function and mechanism. Unfortunately, such a model does not currently exist. Homogeneous cell lines that can be continuously propagated on plastic surfaces have been extensively used as a surrogate for tumor environment; however they are very different from the in vivo tumor cells. Model systems involving primary culture represent the situation most closely related to the original tissue although they have a number of disadvantages over cell lines, such as the limited ability to repeat studies with a well characterized culture system that can be used in multiple laboratories. The primary culture may contain many types of stromal and infiltrating cell types potentially complicating the interpretation of data. Yet, their properties better reflect the cellular interactions present in intact tissue. The present article reviews the critical steps in obtaining, routine maintenance and cryopreservation of primary tumor cell cultures, based on information from literature and personal experience on the subject. The article also includes an updated protocol for primary tumor cell isolation and culture.

  2. Fibroblast Growth Factor 2: An Epithelial Ductal Cell Growth Inhibitor That Drops Out in Breast Cancer

    Science.gov (United States)

    2011-10-01

    analyzed data on tumor progression in these genetically modified animals and completed the staining of different markers of tumor growth (FGF/ FGFR ...H) . Original magnifications: X400 (A-H) 6. FGF, FGFRs and markers differentiating normal and mammary tumor cells We also continued to...oncogene or the absence of FGF2. Figure 5 Immunohistochemistry (IHC) of FGFR in mammary cancer. Staining confirmed the presence of FGFR1

  3. Boletus edulis biologically active biopolymers induce cell cycle arrest in human colon adenocarcinoma cells.

    Science.gov (United States)

    Lemieszek, Marta Kinga; Cardoso, Claudia; Ferreira Milheiro Nunes, Fernando Hermínio; Ramos Novo Amorim de Barros, Ana Isabel; Marques, Guilhermina; Pożarowski, Piotr; Rzeski, Wojciech

    2013-04-25

    The use of biologically active compounds isolated from edible mushrooms against cancer raises global interest. Anticancer properties are mainly attributed to biopolymers including mainly polysaccharides, polysaccharopeptides, polysaccharide proteins, glycoproteins and proteins. In spite of the fact that Boletus edulis is one of the widely occurring and most consumed edible mushrooms, antitumor biopolymers isolated from it have not been exactly defined and studied so far. The present study is an attempt to extend this knowledge on molecular mechanisms of their anticancer action. The mushroom biopolymers (polysaccharides and glycoproteins) were extracted with hot water and purified by anion-exchange chromatography. The antiproliferative activity in human colon adenocarcinoma cells (LS180) was screened by means of MTT and BrdU assays. At the same time fractions' cytotoxicity was examined on the human colon epithelial cells (CCD 841 CoTr) by means of the LDH assay. Flow cytometry and Western blotting were applied to cell cycle analysis and protein expression involved in anticancer activity of the selected biopolymer fraction. In vitro studies have shown that fractions isolated from Boletus edulis were not toxic against normal colon epithelial cells and in the same concentration range elicited a very prominent antiproliferative effect in colon cancer cells. The best results were obtained in the case of the fraction designated as BE3. The tested compound inhibited cancer cell proliferation which was accompanied by cell cycle arrest in the G0/G1-phase. Growth inhibition was associated with modulation of the p16/cyclin D1/CDK4-6/pRb pathway, an aberration of which is a critical step in the development of many human cancers including colon cancer. Our results indicate that a biopolymer BE3 from Boletus edulis possesses anticancer potential and may provide a new therapeutic/preventive option in colon cancer chemoprevention.

  4. THE ROLE OF RECOMBINANT Rb GENE ADENOVIRUS VECTOR IN THE GROWTH OF LUNG ADENOCARCINOMA CELLS

    Institute of Scientific and Technical Information of China (English)

    Li Jian; Jiang Lei; Xia Yongjing; Li Hongxia; Hu Yajun; Hu Shixue; Xu Hongji

    1998-01-01

    Objective:To study the role of the most extensively studied tumor suppressor gene, retinoblastoma (Rb) gene,on the growth of lung adenocarcinoma cell line GLC-82 and explore a gene therapy approach for lung adenocarcinoma. Methods: The recombinant Rb gene adenovirus vector was constructed, the control virus which carries LacZ gene was producted by the same method. Infection effects were detected by biochemical staining of β-gal and immunohistochemical analysis of Rb protein. The Rb cDNA of infected cells were determined by PCR. The cell growth rate and cell cycle were observed by cell-counting and flow cytometry. Results: The constructed recombinant adenovirus vector could infect effectively the cells with high level expression of Rb cDNA and Rb protein. The transfection of wild-type Rb gene could suppress GLC-82 cell proliferation and decrease the cellular DNA synthesis. Conclusions: These results showed the possibility of using recombinant Rb gene adenovirus vector in the gene therapy of cancer to inhibit the growth of cancer.

  5. Mixed Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Spindle Cell and Clear Cell Features in the Extrahepatic Bile Duct

    Directory of Open Access Journals (Sweden)

    John Wysocki

    2014-01-01

    Full Text Available Mixed adenoneuroendocrine carcinomas, spindle cell carcinomas, and clear cell carcinomas are all rare tumors in the biliary tract. We present the first case, to our knowledge, of an extrahepatic bile duct carcinoma composed of all three types. A 65-year-old man with prior cholecystectomy presented with painless jaundice, vomiting, and weight loss. CA19-9 and alpha-fetoprotein (AFP were elevated. Cholangioscopy revealed a friable mass extending from the middle of the common bile duct to the common hepatic duct. A bile duct excision was performed. Gross examination revealed a 3.6 cm intraluminal polypoid tumor. Microscopically, the tumor had foci of conventional adenocarcinoma (CK7-positive and CA19-9-postive surrounded by malignant-appearing spindle cells that were positive for cytokeratins and vimentin. Additionally, there were separate areas of large cell neuroendocrine carcinoma (LCNEC. Foci of clear cell carcinoma merged into both the LCNEC and the adenocarcinoma. Tumor invaded through the bile duct wall with extensive perineural and vascular invasion. Circumferential margins were positive. The patient’s poor performance status precluded adjuvant therapy and he died with recurrent and metastatic disease 5 months after surgery. This is consistent with the reported poor survival rates of biliary mixed adenoneuroendocrine carcinomas.

  6. Does clear cell carcinoma of stomach exist? Clinicopathological and prognostic significance of clear cell changes in gastric adenocarcinomas.

    Science.gov (United States)

    Kim, Joo-Yeon; Park, Do Youn; Kim, Gwang Ha; Jeon, Tae-Yong; Lauwers, Gregory Y

    2014-07-01

    In contrast to clear cell carcinomas developing in other organs (e.g. ovary and uterus), gastric adenocarcinomas with clear cell features are not well characterized. We evaluated a series of 762 gastric adenocarcinomas for the presence of clear cell changes; and investigated the nature of the changes using several histochemical and immunohistochemical markers, their association with various clinicopathological features, and their prognostic significance. Clear cell changes were observed in 8.5% (n = 65) of gastric cancers. Cases with clear cell changes (GCC) were associated significantly with older age, intestinal type histology, body/fundic location, greater depth of invasion, lymph node metastases and lymphovascular invasion. An increasing proportion of clear cell changes indicated a worsening prognosis, and was identified as an independent marker of poor prognosis using the Cox proportional hazard model (hazard ratio, 0.462; P = 0.003). Of 62 GCCs subjected to special staining, 35 cases (55.6%) displayed cytoplasmic accumulation of glycogen, while 21 (33.3%) contained mucin. GCCs showing glycogen accumulation expressed AFP, glypican-3 and CD10 more commonly than those with mucin, which commonly expressed Muc5AC and Muc6. Clear cell gastric adenocarcinoma is a unique subgroup of gastric cancer which, although heterogeneous, has a poor prognosis. © 2014 John Wiley & Sons Ltd.

  7. What is the origin of pancreatic adenocarcinoma?

    Directory of Open Access Journals (Sweden)

    Pandey Krishan K

    2003-01-01

    Full Text Available Abstract The concept of pancreatic cancer origin is controversial. Acinar, ductal or islet cells have been hypothesized as the cell of origin. The pros and cons of each of these hypotheses are discussed. Based on the world literature and recent observations, pancreatic cells seem to have potential for phenotypical transdifferentiation, i.e ductal-islet, ductal-acinar, acinar-ductal, acinar-islet, islet-acinar and islet-ductal cells. Although the possibility is discussed that cancer may arise from either islet, ductal or acinar cells, the circumstances favoring the islet cells as the tumor cell origin include their greater transdifferentiation potency into both pancreatic and extrapancreatic cells, the presence of a variety of carcinogen-metabolizing enzymes, some of which are present exclusively in islet cells and the growth factor-rich environment of islets.

  8. Alterations of tumor suppressor gene p16INK4a in pancreatic ductal carcinoma

    Directory of Open Access Journals (Sweden)

    Radotra Bishan

    2005-06-01

    Full Text Available Abstract Background Cell cycle inhibitor and tumor suppressor gene p16 / MTS-1 has been reported to be altered in a variety of human tumors. The purpose of the study was to evaluate primary pancreatic ductal adenocarcinomas for potentially inactivating p16 alterations. Methods We investigated the status of p16 gene by polymerase chain reaction (PCR, nonradioisotopic single strand conformation polymorphism (SSCP, DNA sequencing and hypermethylation analysis in 25 primary resected ductal adenocarcinomas. In addition, we investigated p16 protein expression in these cases by immunohistochemistry (IHC using a monoclonal antibody clone (MS-887-PO. Results Out of the 25 samples analyzed and compared to normal pancreatic control tissues, the overall frequency of p16 alterations was 80% (20/25. Aberrant promoter methylation was the most common mechanism of gene inactivation present in 52% (13/25 cases, followed by coding sequence mutations in 16% (4/25 cases and presumably homozygous deletion in 12% (3/25 cases. These genetic alterations correlated well with p16 protein expression as complete loss of p16 protein was found in 18 of 25 tumors (72%. Conclusion These findings confirm that loss of p16 function could be involved in pancreatic cancer and may explain at least in part the aggressive behaviour of this tumor type.

  9. Alterations of tumor suppressor gene p16INK4a in pancreatic ductal carcinoma

    Science.gov (United States)

    Attri, Jyotika; Srinivasan, Radhika; Majumdar, Siddhartha; Radotra, Bishan Dass; Wig, Jaidev

    2005-01-01

    Background Cell cycle inhibitor and tumor suppressor gene p16 / MTS-1 has been reported to be altered in a variety of human tumors. The purpose of the study was to evaluate primary pancreatic ductal adenocarcinomas for potentially inactivating p16 alterations. Methods We investigated the status of p16 gene by polymerase chain reaction (PCR), nonradioisotopic single strand conformation polymorphism (SSCP), DNA sequencing and hypermethylation analysis in 25 primary resected ductal adenocarcinomas. In addition, we investigated p16 protein expression in these cases by immunohistochemistry (IHC) using a monoclonal antibody clone (MS-887-PO). Results Out of the 25 samples analyzed and compared to normal pancreatic control tissues, the overall frequency of p16 alterations was 80% (20/25). Aberrant promoter methylation was the most common mechanism of gene inactivation present in 52% (13/25) cases, followed by coding sequence mutations in 16% (4/25) cases and presumably homozygous deletion in 12% (3/25) cases. These genetic alterations correlated well with p16 protein expression as complete loss of p16 protein was found in 18 of 25 tumors (72%). Conclusion These findings confirm that loss of p16 function could be involved in pancreatic cancer and may explain at least in part the aggressive behaviour of this tumor type. PMID:15985168

  10. Metformin inhibits salivary adenocarcinoma growth through cell cycle arrest and apoptosis

    OpenAIRE

    2015-01-01

    The inhibitory effects of metformin have been observed in many types of cancer. However, its effect on human salivary gland carcinoma is unknown. The effect of metformin alone or in combination with pp242 (an mTOR inhibitor) on salivary adenocarcinoma cells growth were determined in vitro and in vivo. We found that metformin suppressed HSY cell growth in vitro in a time and dose dependent manner associated with a reduced expression of MYC onco-protein, and the same inhibitory effect of metfor...

  11. Comparative evaluation of cisplatin and carboplatin sensitivity in endometrial adenocarcinoma cell lines.

    OpenAIRE

    Rantanen, V; Grénman, S.; Kulmala, J; Grénman, R

    1994-01-01

    Platinum analogues are frequently used in the treatment of advanced or recurrent endometrial cancer. To study the sensitivity of endometrial cancer to cisplatin and carboplatin, we tested two long-established (RL95-2, KLE) and six new cell lines (UM-EC-1, UM-EC-2, UM-EC-3, UT-EC-2A, UT-EC-2B, UT-EC-3) using the 96-well-plate clonogenic assay. This assay has proven to be suitable for testing chemosensitivity of both adenocarcinoma and squamous cell carcinoma. The chemosensitivity was expressed...

  12. Downregulation of cytochrome c oxidase subunit 7A1 expression is important in enhancing cell proliferation in adenocarcinoma cells.

    Science.gov (United States)

    Mishra, Nawneet; Timilsina, Uddhav; Ghimire, Dibya; Dubey, Ravi C; Gaur, Ritu

    2017-01-22

    Mitochondrial Dysfunction has been implicated in multiple human diseases, including cancer. Among all cancer, lung cancer is the most common type of cancer worldwide with low survival rates. Mammals possess multiple subunits of the mitochondrial enzyme Cytochrome C oxidase (COX). The COX subunits are expressed in a tissue specific manner and have been implicated in cancer cell metabolism although their molecular and regulatory mechanisms are not clearly understood. In this study, we aimed at identifying novel gene signatures in lung cancer. We performed extensive analysis of seven different Gene Expression Omnibus (GEO) datasets pertaining to different stages of lung adenocarcinoma and identified that multiple subunits of COX genes are differentially expressed in these patients. Amongst all COX genes, the expression of COX7A1 gene was observed to be highly down regulated in these patients. In order to validate the GEO datasets, we looked at the expression of multiple COX genes using quantitative real time PCR (qPCR) using human lung adenocarcinoma cell line A549. Our results confirmed that COX 7A1 gene expression was indeed highly reduced in these cells. Overexpression of COX7A1 in human lung cancer cells led to inhibition of cell proliferation and increase in cell death via apoptosis. These results indicated that low level of COX7A1 gene expression is essential to regulate cell viability and inhibit cell death in lung adenocarcinoma. Our study has identified COX7A1 as a novel gene that might play a crucial role in the etiology of lung adenocarcinoma and can serve as a biomarker for lung cancer disease progression.

  13. [Expression of aquaporins and its significance in human pulmonary adenocarcinoma cell line SPC-A-1].

    Science.gov (United States)

    Chen, Jie; Bai, Chunxue; Zhang, Min; Ren, Zhenyi; Hu, Jie

    2004-06-20

    To investigate the expression of aquaporins in human pulmonary adenocarcinoma cell line SPC-A-1. The expressions of aquaporin 1, aquaporin 3, aquaporin 4, and aquaporin 5 in mRNA level and their locations were determined in cell line SPC-A-1 respectively by RT-PCR and immunohistochemistry. The immunohistochemical stain showed aquaporin 3 and aquaporin 5 located on the membrane of SPC-A-1 cell, but no positive stain of aquaporin 1 and aquaporin 4 was observed. Both aquaporin 3 and aquaporin 5 mRNA expressed in SPC-A-1 cell line, and the expression level of aquaporin 5 mRNA was significantly higher than that of aquaporin 3 mRNA ( P SPC-A-1 cell line. Aquaporin 3 and aquaporin 5 express in SPC-A-1 cell, and their roles in water transport of SPC-A-1 cell should be further investigated.

  14. Immunohistochemical analysis of cancer stem cell markers in invasive breast carcinoma and associated ductal carcinoma in situ: relationships with markers of tumor hypoxia and microvascularity.

    Science.gov (United States)

    Currie, Margaret J; Beardsley, Brooke E; Harris, Gavin C; Gunningham, Sarah P; Dachs, Gabi U; Dijkstra, Birgit; Morrin, Helen R; Wells, J Elisabeth; Robinson, Bridget A

    2013-03-01

    We performed immunohistochemical analysis of 3 cancer stem cell-related markers (CD44(+)/CD24(-/low), aldehyde dehydrogenase [ALDH]-1, CD133) in 94 invasive ductal carcinomas and assessed relationships with markers of hypoxia (carbonic anhydrase IX [CAIX]), tumor microvessel density (CD31), and clinicopathologic variables. Overall, 10% of tumors were CD44(+)/CD24(-/low), 13% were ALDH-1(+), 25% were CD133(+), 35% were immunonegative, and 1 tumor was immunopositive for all 3 markers. Associated ductal carcinoma in situ (DCIS) was present in 48% of tumors. Marker immunopositivity was detected in DCIS in 13% (CD44(+)/CD24(-/low)), 7% (ALDH-1(+)), and 32% (CD133(+)) of these tumors and was more likely present in DCIS when also detected in the invasive compartment (P = .03, P = .001, and P = .009, respectively). CD44(+)/CD24(-/low) cells were more common in progesterone receptor-negative tumors (P breast cancers (P breast cancer and showed that CD44(+)/CD24(-/low) and CD133(+) cells were more frequently observed in hypoxic regions of tumor, whereas ALDH-1(+) cells more commonly colocalized to tumors with high microvessel density.

  15. Transcription Activity of Ectogenic Human Carcinoembryonic Antigen Promoter in Lung Adenocarcinoma Cells A549

    Institute of Scientific and Technical Information of China (English)

    XIONG Weining; FANG Huijuan; XU Yongjian; XIONG Shendao; CAO Yong; SONG Qingfeng; ZENG Daxiong; ZHANG Huilan

    2006-01-01

    The transcription activity of ectogenic human carcinoembryonic antigen (CEA) promoter in lung adenocarcinoma cells A549 was investigated for the further gene-targeting therapy. The reporter gene green fluorescent protein (GFP) driven by CEA promoter and human cytomegalovirus (CMV) promoter were relatively constructed and named plasmid pCEA-EGFP and pCMV-GFP respectively. The intensity of fluorescence was detected by fluorescence microscope and flow cytometry analysis after the pCEA-GFP and pSNAV-GFP plasmids were transfected into A549 cells through liposome respectively. The results showed (4.08±0.63) % of the A549 cells transfected with pCEA-AFP plasmid expressed, significantly lower than that of the A549 cells transfected with pCMV-GFP [(43.27±3.54) %]. It was suggested that ectogenic human CEA promoter in lung adenocarcinoma cells A549 was weakly expressed. The distinct specificity of CEA promoter in CEA high expression cells was regarded as a tool in selective gene therapy, but the transcription activity of ectogenic human CEA promoter was needed to increase in the future.

  16. Aptamers Selected to Postoperative Lung Adenocarcinoma Detect Circulating Tumor Cells in Human Blood

    Science.gov (United States)

    Zamay, Galina S; Kolovskaya, Olga S; Zamay, Tatiana N; Glazyrin, Yury E; Krat, Alexey V; Zubkova, Olga; Spivak, Ekaterina; Wehbe, Mohammed; Gargaun, Ana; Muharemagic, Darija; Komarova, Mariia; Grigorieva, Valentina; Savchenko, Andrey; Modestov, Andrey A; Berezovski, Maxim V; Zamay, Anna S

    2015-01-01

    Circulating tumor cells (CTCs) are rare cells and valuable clinical markers of prognosis of metastasis formation and prediction of patient survival. Most CTC analyses are based on the antibody-based detection of a few epithelial markers; therefore miss an important portion of mesenchymal cancer cells circulating in blood. In this work, we selected and identified DNA aptamers as specific affinity probes that bind to lung adenocarcinoma cells derived from postoperative tissues. The unique feature of our selection strategy is that aptamers are produced for lung cancer cell biomarkers in their native state and conformation without previous knowledge of the biomarkers. The aptamers did not bind to normal lung cells and lymphocytes, and had very low affinity to A549 lung adenocarcinoma culture. We applied these aptamers to detect CTCs, apoptotic bodies, and microemboli in clinical samples of peripheral blood of lung cancer and metastatic lung cancer patients. We identified aptamer-associated protein biomarkers for lung cancer such as vimentin, annexin A2, annexin A5, histone 2B, neutrophil defensin, and clusterin. Tumor-specific aptamers can be produced for individual patients and synthesized many times during anticancer therapy, thereby opening up the possibility of personalized diagnostics. PMID:26061649

  17. In vitro evaluation of curcumin effects on breast adenocarcinoma 2D and 3D cell cultures.

    Science.gov (United States)

    Abuelba, Hussam; Cotrutz, Carmen Elena; Stoica, Bogdan Alexandru; Stoica, Laura; Olinici, DoiniŢa; Petreuş, Tudor

    2015-01-01

    Breast adenocarcinoma cell line MDA-MB-231, even if it expresses low levels of E-cadherin, still readily form multicellular aggregates of cells, namely spheroids. Curcumin is a diarylheptanoid antitumoral drug while it significantly inhibits cell migration, invasion, and colony formation in vitro and reduces tumor growth and liver metastasis in vivo. Curcumin photoactivation may enhance antiapoptotic role against cancer cells. To evaluate the effect of low curcumin concentrations, ranged from 1.9 to 15 μM, with and without photoactivation, using a manufactured 670 nm LED-matrix. A secondary aim was to evaluate the ideal method to produce easy-to-use tumor cell spheroids, comparing two low adherence plate supports. Breast adenocarcinoma cell line MDA-MB-231 were cultured according to 2D monolayer and 3D spheroid models then submitted to normal and photoactivated curcumin in micromolar concentrations. MTT assay was used to evaluate cell viability following curcumin application on cells. On 2D cell cultures, curcumin inhibits cell tumor development and proliferation at concentrations of 15 μM, with a viability of 65.7% at 48 hours incubation time. A decreased viability up to 25% for a concentration of 15 μM was recorded following photoactivation and cytotoxic action on breast cancer tumor cell line continued at concentrations of 7.5 and 3.75 μM. Curcumin photoactivation increases pro-apoptotic effects in both 2D and 3D tumor cell culture models and also responsiveness to curcumin is slightly reduced in spheroid-like structures. Thus, 3D tumor cell culture systems appear to be the ideal environment for in vitro assays regarding anticancer drug effects on cell viability.

  18. Bax is not involved in the resveratrol-induced apoptosis in human lung adenocarcinoma cells

    Science.gov (United States)

    Zhang, Wei-wei; Wang, Zhi-ping; Chen, Tong-sheng

    2010-02-01

    Resveratrol (RV) is a natural plant polyphenol widely present in foods such as grapes, wine, and peanuts. Previous studies indicate that RV has an ability to inhibit various stages of carcinogenesis and eliminate preneoplastic cells in vitro and in vivo. However, little is known about the molecular mechanism of RV-induced apoptosis in human lung adenocarcinoma (ASTC-a-1) cell. In this report, we analyzed whether Bax translocation from cytoplasm to mitochondria during RV-induced apoptosis in single living cell using onfocal microscopey. Cells were transfected with GFP-Bax plasmid. Cell counting kit (CCK-8) assay was used to assess the inhibition of RV on the cells viability. Apoptotic activity of RV was detected by Hoechst 33258 and propidium iodide (PI) staining. Our results showed that RV induced a dose-dependent apoptosis in which Bax did not translocate to mitochondrias.

  19. Antimigratory Effects of the Methanol Extract from Momordica charantia on Human Lung Adenocarcinoma CL1 Cells

    Directory of Open Access Journals (Sweden)

    Hsue-Yin Hsu

    2012-01-01

    Full Text Available Momordica charantia has been found to exhibit anticancer activity, in addition to its well-known therapeutic functions. We have demonstrated that the leaf extract of Momordica charantia (MCME induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. In this study, a different susceptibility to MCME was found in human lung adenocarcinoma CL1 cells with different metastatic ability, leading to the significant difference of cell viability and invasiveness between MCME-treated CL1-0 and CL1-5 cells. MCME was found to upregulate the expression of Wnt-2 and affect the migratory and invasive ability of CL1 cells through suppressed MMP-2 and MMP-9 enzymatic activities. We proposed that MCME mediates inhibition against migration of CL1 cells by reducing the expression and activation of Src and FAK to decrease the expression of downstream Akt, β-catenin, and MMPs.

  20. Expression of C4.4A in precursor lesions of pulmonary adenocarcinoma and squamous cell carcinoma

    DEFF Research Database (Denmark)

    Jacobsen, Benedikte; Santoni-Rugiu, Eric; Illemann, Martin

    2012-01-01

    in precursor lesions of lung squamous cell carcinoma and adenocarcinoma was investigated by stainings with a specific anti-C4.4A antibody. In the transformation from normal bronchial epithelium to squamous cell carcinoma, C4.4A was weakly expressed in basal cell hyperplasia but dramatically increased......The protein C4.4A, a structural homologue of the urokinase-type plasminogen activator receptor, is a potential new biomarker in non-small cell lung cancer, with high levels of expression recently shown to correlate to poor survival of adenocarcinoma patients. In this study, C4.4A immunoreactivity...... finding that C4.4A expression levels do not provide prognostic information on the survival of squamous cell carcinoma patients. In the progression from normal alveolar epithelium to peripheral adenocarcinoma, we observed an unexpected, distinct cytoplasmic staining for C4.4A in a fraction of atypical...

  1. Oleanolic acid-induced apoptosis and its relation with intracellular calcium in human lung adenocarcinoma A549 cells

    Institute of Scientific and Technical Information of China (English)

    Asmitanand; Thakur

    2010-01-01

    Objective To investigate the effect of oleanolic acid (OA) on apoptosis,correlation between apoptosis and intracellular calcium,and its mechanism in human lung adenocarcinoma cell line A549. Methods Human lung adenocarcinoma A549 cells were incubated in vitro and assigned with OA concentrations of 0,10,20 and 40μg/mL. The apoptosis status of A549 cell line was detected with Annexin V-FITC/PI by flow cytometry (FCM); fluorescence intensity (FI) of A549 cells was assessed and the level of intracellular calciu...

  2. Correlation between Gli2, FAK expression in colonic adenocarcinoma tissue with different clinical pathological characteristics and cancer cell proliferation, invasion

    Institute of Scientific and Technical Information of China (English)

    Zhe Su

    2017-01-01

    Objective:To study the correlation between glioma-associated oncogene homologue 2 (Gli2), focal adhesion kinase (FAK) expression in colonic adenocarcinoma tissue with different clinical pathological characteristics and cancer cell proliferation, invasion.Methods: 56 patients with colonic adenocarcinoma who received surgical resection in our hospital between May 2012 and December 2015 were selected, cancer tissue and para-carcinoma tissue were collected respectively, immunohistochemical staining was used to detect the Gli2 and FAK protein-positive rate, and fluorescence quantitative PCR was used to determine the mRNA expression of Gli2 and FAK as well as the proliferation and invasionn genes.Results:Gli2 and FAK mRNA expression and protein-positive rate in colonic adenocarcinoma tissues were significantly higher than those in para-carcinoma tissues (P<0.05); Gli2 and FAK mRNA expression and protein-positive rate in colonic adenocarcinoma tissues with low differentiation, no differentiation, extraserosal infiltration and Dukes stage D were significantly higher than those in colonic adenocarcinoma tissues with high differentiation, medium differentiation, intraserosal infiltration, Dukes stage B-C (P<0.05); CyclinD1, CDK4, c-myc, N-cadherin and vimentin mRNA expression in Gli2- and FAK-positive colonic adenocarcinoma tissues were significantly higher than those in Gli2- and FAK-negative colonic adenocarcinoma tissues (P<0.05).Conclusions:Gli2 and FAK expression are high in colonic adenocarcinoma tissues and associated with the clinical pathological staging of tumor, and highly expressed Gli2 and FAK can promote cell proliferation and invasion.

  3. Sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC-05.

    Science.gov (United States)

    Zhou, Lan; Yao, Qian; Li, Yan; Huang, Yun-Chao; Jiang, Hua; Wang, Chuan-Qiong; Fan, Lei

    2017-01-01

    Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non-smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane-induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL-05) to explore the value of sulforaphane in lung cancer prevention and treatment. Cell growth inhibition was determined by methyl thiazolyl tetrazolium assay; cell morphology and apoptosis were observed under transmission electron microscope; cell cycle and apoptosis rates were detected using flow cytometry; B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) messenger RNA expression were determined by quantitative PCR; and p53, p73, p53 upregulated modulator of apoptosis (PUMA), Bax, Bcl-2, and caspase-9 protein expression were detected by Western blotting. Sulforaphane inhibited XWLC-05 cell growth with inhibitory concentration (IC)50 of 4.04, 3.38, and 3.02 μg/mL at 24, 48, and 72 hours, respectively. Sulforaphane affected the XWLC-05 cell cycle as cells accumulated in the G2/M phase. The proportion of apoptotic cells observed was 27.6%. Compared with the control, the sulforaphane group showed decreased Bcl-2 and p53 expression, and significantly increased p73, PUMA, Bax, and caspase-9 protein expression (P Sulforaphane induces Xuanwei lung adenocarcinoma cell apoptosis. Its possible mechanism may involve the upregulation of p73 expression and its effector target genes PUMA and Bax in lung cancer cells, downregulation of the anti-apoptotic gene B cl -2, and activation of caspase-9. It may also involve downregulation of the mutant p53 protein. © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  4. [Peripheral lung adenocarcinoma versus squamous cell carcinoma: evaluation with first-pass perfusion imaging using 64-detector row CT].

    Science.gov (United States)

    Li, Yuan; Yang, Zhigang; Chen, Tianwu; Yu, Jianqun; Deng, Yuping; Li, Zhenlin

    2009-04-01

    The aim of this study was to elucidate the characteristics of time attenuation curve and CT perfusion parameters for pulmonary adenocarcinomas and squamous cell carcinomas. 58 cases of pulmonary adenocarcinomas and 27 cases of squamous cell carcinomas underwent first pass CT perfusion imaging with 64-row MDCT. Data were analyzed using commercial software to generate time attenuation curve (TAC) and CT perfusion parameters, including perfusion, peak enhanced (PE), time to peak (TTP), and blood volume (BV). For TAC, there were 36.2% of type I and 63.8% of type II in adenocarcinomas, while there were 22.2% of type I and 77.8% of type II in squamous cell carcinomas. There was not significant difference (P>0.05). Perfusion, PE, TTP and BV of adenocarcinomas were 63.2 +/- 45.4 ml x min(-1) x ml(-1), 60.2 +/- 46.6 Hu, 34.8 +/- 10.2 s and 34.3 +/- 23.6 ml x 100 g(-1), respectively, while 54.3 +/- 50.2 ml x min(-1) x ml(-1), 48.5 +/- 34.9 Hu, 36.1 +/- 11.2 s and 27.6 +/- 21.7 ml x 100 g(-1), for squamous cell carcinoma, respectively. No significant differences were found between groups (P>0.05). No significant differences in TAC and CT perfusion parameters were found between adenocarcinomas and squamous cell carcinomas.

  5. Variations of very low-density lipoprotein receptor subtype expression in gastrointestinal adenocarcinoma cells with various differentiations

    Institute of Scientific and Technical Information of China (English)

    Tao Chen; Fan Wu; Feng-Ming Chen; Jun Tian; Shen Qu

    2005-01-01

    AIM: This study is aimed at investigating the expression and possible significances of very low-density lipoprotein receptor (VLDLR) subtypes in gastroenteric adenocarcinoma tissues and cells with various differentiations. METHODS: Thirty-one cases of gastroenteric carcinoma/ adjacent normal tissues were enrolled in the study, which were diagnosed and classified by the clinicopathological diagnosis. The expression of VLDLR subtypes was detected in gastroenteric carcinoma/adjacent normal tissues and three various differentiated human gastric adenocarcinoma cell lines (MKN28, SGC7901 and MKN45) by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis.RE,SULTS: Two VLDLR subtypes, namely, type Ⅱ VLDLR and type Ⅰ VLDLR, were found to express changes in gastroenteric carcinoma tissues, their adjacent normal tissue, and gastric adenocarcinoma cell lines as well. Type Ⅱ VLDLR is predominantly expressed in poorly- or moderately-differentiated gastroenteric carcinoma tissues and gastric adenocarcinoma cell lines, whereas type ⅠVLDLR is mainly detected in well-differentiated intestinal carcinoma tissues and gastric adenocarcinoma cells compared with the adjacent normal tissues. CONCLUSION: The results suggested that the variations of the VLDLR subtype expression might be correlated with the progress and differentiation of gastroenteric carcinoma.

  6. Echinophora platyloba DC (Apiaceae crude extract induces apoptosis in human prostate adenocarcinoma cells (PC 3

    Directory of Open Access Journals (Sweden)

    Fatemeh Zare Shahneh

    2014-10-01

    Full Text Available Background: Prostate cancer is the second leading malignancy worldwide and the second prominent cause of cancer-related deaths among men. Therefore, there is a serious necessity for finding advanced alternative therapeutic measures against this lethal malignancy. In this article, we report the cytotoxicity and the mechanism of cell death of the methanolic extract prepared from Echinophora platyloba DC plant against human prostate adenocarcinoma PC 3 cell line and Human Umbilical Vein Endothelial Cells HUVEC cell line. Methods: Cytotoxicity and viability of the methanolic extract were assessed by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay and dye exclusion assay. Cell death enzyme-linked immunosorbent assay (ELISA was employed to quantify the nucleosome production resulting from nuclear DNA fragmentation during apoptosis and determine whether the mechanism involves induction of apoptosis or necrosis. The cell death was identified as apoptosis using terminal deoxynucleotidyl transferase (TdT-mediated dUTP nick end labeling (TUNEL assay and DNA fragmentation gel electrophoresis. Results: E. platyloba could decrease cell viability in malignant cells in a dose- and time-dependent manner. The IC50 values against PC 3 were determined as 236.136 ± 12.4, 143.400 ± 7.2, and 69.383 ± 1.29 μg/ml after 24, 36, and 48 h, respectively, but there was no significant activity in HUVEC normal cell (IC50 > 800 μg/ml. Morphological characterizations and DNA laddering assay showed that the methanolic extract treated cells displayed marked apoptotic characteristics such as nuclear fragmentation, appearance of apoptotic bodies, and DNA laddering fragment. Increase in an early apoptotic population was observed in a dose-dependent manner. PC 3 cell death elicited by the extract was found to be apoptotic in nature based a clear indication of TUNEL assay and gel electrophoresis DNA fragmentation, which is a hallmark of apoptosis

  7. Infrared light-absorbing gold/gold sulfide nanoparticles induce cell death in esophageal adenocarcinoma

    Science.gov (United States)

    Li, Yan; Gobin, Andre M; Dryden, Gerald W; Kang, Xinqin; Xiao, Deyi; Li, Su Ping; Zhang, Guandong; Martin, Robert CG

    2013-01-01

    Gold nanoparticles and near infrared-absorbing light are each innocuous to tissue but when combined can destroy malignant tissue while leaving healthy tissue unharmed. This study investigated the feasibility of photothermal ablation therapy for esophageal adenocarcinoma using chitosan-coated gold/gold sulfide (CS-GGS) nanoparticles. A rat esophagoduodenal anastomosis model was used for the in vivo ablation study, and three human esophageal cell lines were used to study the response of cancer cells and benign cells to near infrared light after treatment with CS-GGS. The results indicate that both cancerous tissue and cancer cells took up more gold nanoparticles and were completely ablated after exposure to near infrared light. The benign tissue and noncancerous cells showed less uptake of these nanoparticles, and remained viable after exposure to near infrared light. CS-GGS nanoparticles could provide an optimal endoluminal therapeutic option for near infrared light ablation of esophageal cancer. PMID:23818775

  8. A case of clear cell adenocarcinoma arising from the urethral diverticulum: Utility of urinary cytology and immunohistochemistry

    Directory of Open Access Journals (Sweden)

    Shin-ichi Nakatsuka

    2012-01-01

    Full Text Available Carcinomas rarely arise from the urethral diverticulum. In this report, we present a case of clear cell adenocarcinoma arising from the urethral diverticulum. A 42-year-old woman complained of bloody discharge and lower back pain. Imaging studies showed a tumor involving the region surrounding the urethra and cystourethroscopy showed papillary and villous tumors in the urethral diverticula. Cytology of the urine sediment showed papillary or spherical clusters of atypical cells, some of which had clear abundant cytoplasm and formed mirror ball-like clusters, suggesting adenocarcinoma. Although histological diagnosis was indeterminate by biopsy and transurethral resection (TUR because of absence of stromal invasion, surgically resected specimen via cysturethrectomy revealed that the tumor was clear cell carcinoma. Urinary cytological findings and immunohistochemical analysis for CD15, Ki-67, and p53 might be useful for accurate diagnosis of clear cell adenocarcinoma that arises from the urethral diverticulum when sufficient materials are not available by biopsy and TUR.

  9. Chromosomal and Genetic Analysis of a Human Lung Adenocarcinoma Cell Line OM

    Institute of Scientific and Technical Information of China (English)

    Yong-Wu Li; Lin Bai; Lyu-Xia Dai; Xu He; Xian-Ping Zhou

    2016-01-01

    Background: Lung cancer has become the leading cause of death in many regions.Carcinogenesis is caused by the stepwise accumulation of genetic and chromosomal changes.The aim of this study was to investigate the chromosome and gene alterations in the human lung adenocarcinoma cell line OM.Methods: We used Giemsa banding and multiplex fluorescence in situ hybridization focusing on the human lung adenocarcinoma cell line OM to analyze its chromosome alterations.In addition, the gains and losses in the specific chromosome regions were identified by comparative genomic hybridization (CGH) and the amplifications of cancer-related genes were also detected by polymerase chain reaction (PCR).Results: We identified a large number of chromosomal numerical alterations on all chromosomes except chromosome X and 19.Chromosome 10 is the most frequently involved in translocations with six different interchromosomal translocations.CGH revealed the gains on chromosome regions of 3q25.3-28, 5p13, 12q22-23.24, and the losses on 3p25-26, 6p25, 6q26-27, 7q34-36, 8p22-23, 9p21-24, 10q25-26.3, 12p 13.31-13.33 and 17p 13.1-13.3.And PCR showed the amplification of genes: Membrane metalloendopeptidase (MME), sucrase-isomaltase (SI), butyrylcholinesterase (BCHE), and kininogen (KNG).Conclusions: The lung adenocarcinoma cell line OM exhibited multiple complex karyotypes, and chromosome 10 was frequently involved in chromosomal translocation, which may play key roles in tumorigenesis.We speculated that the oncogenes may be located at 3q25.3-28, 5p13, 12q22-23.24, while tumor suppressor genes may exist in 3p25-26, 6p25, 6q26-27, 7q34-36, 8p22-23, 9p21-24, 10q25-26.3, 12p 13.31-13.33, and 17p 13.1-13.3.Moreover, at least four genes (MME, SI, BCHE, and KNG) may be involved in the human lung adenocarcinoma cell line OM.

  10. Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus-Differences in Etiology, Epidemiology and Prevention

    Institute of Scientific and Technical Information of China (English)

    ElfriedeBollschweiler; EvaWolfgarten

    2004-01-01

    In Germany, esophageal carcinoma is one of the ten most frequent causes of death. Normally the disease is found in men over the age of 50. Although squamous cell carcinoma (SCC) of the esophagus has been more commonly diagnosed over the past 30 years, there is increasing incidence of esophageal adenocarcinoma (AC) in Western industrialized countries. For SCC the known etiological risk factors are nicotine and alcohol abuse. For AC, they are moderate nicotine and alcohol consumption as well as gastro-esophageal reflux and obesity.

  11. MicroRNA-449a enhances radiosensitivity in CL1-0 lung adenocarcinoma cells.

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    Yi-Jyun Liu

    Full Text Available Lung cancer is the leading cause of cancer-related mortality worldwide. Radiotherapy is often applied for treating lung cancer, but it often fails because of the relative non-susceptibility of lung cancer cells to radiation. MicroRNAs (miRNAs have been reported to modulate the radiosensitivity of lung cancer cells and have the potential to improve the efficacy of radiotherapy. The purpose of this study was to identify a miRNA that can adjust radiosensitivity in lung adenocarcinoma cells. Two lung adenocarcinoma cell lines (CL1-0 and CL1-5 with different metastatic ability and radiosensitivity were used. In order to understand the regulatory mechanisms of differential radiosensitivity in these isogenic tumor cells, both CL1-0 and CL1-5 were treated with 10 Gy radiation, and were harvested respectively at 0, 1, 4, and 24 h after radiation exposure. The changes in expression of miRNA upon irradiation were examined using Illumina Human microRNA BeadChips. Twenty-six miRNAs were identified as having differential expression post-irradiation in CL1-0 or CL1-5 cells. Among these miRNAs, miR-449a, which was down-regulated in CL1-0 cells at 24 h after irradiation, was chosen for further investigation. Overexpression of miR-449a in CL1-0 cells effectively increased irradiation-induced DNA damage and apoptosis, altered the cell cycle distribution and eventually led to sensitization of CL1-0 to irradiation.

  12. Development of PIN and Prostate Adenocarcinoma Cell Lines: A Model System for Multistage Tumor Progression

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    Colin R. Soares

    2002-01-01

    Full Text Available Existing prostate cancer cell lines have been derived from late stages of human prostate cancer. In this paper, we present two cell lines generated from prostatic intraepithelial neoplasia (PIN, the precursor lesion for prostate adenocarcinoma. Pr-111 and Pr-117 were established from PIN lesions that developed in the C3(1/Tag transgenic model of prostate cancer. Pr-111 and Pr-117 cells express simian virus 40 large T antigen (SV40 Tag and are immortalized in culture, distinguishing them from normal prostate cells. The growth rates of these two cell lines are quite different; with Pr-111 cells growing much more slowly (doubling time approximately 40 hours compared to Pr-117 cells (doubling time approximately 22 hours, and also show significantly different growth rates in different media. Both prostate cell lines express cytokeratin and androgen receptor (AR with Pr-111 cells demonstrating androgen-dependent growth and Pr-117 cells exhibiting androgen-responsive growth characteristics. Athymic nude mice injected with Pr-111 cells either do not develop tumors or develop tumors after a long latency period of 14 weeks. Pr-117 cells, however, develop tumors by 3 to 6 weeks, suggesting that Pr-117 cells represent a later stage of tumor progression. These two novel cell lines will be useful for studying early stages of prostate tumor development and androgen responsiveness.

  13. RAI,one candidate gene associated with differentiation of human lung adenocarcinoma cells

    Institute of Scientific and Technical Information of China (English)

    王雪皎; 张睿; 刘芝华; 王秀琴; 丁芳; 郭明洲; 吴旻

    2000-01-01

    From all-trans retinoic acid (ATRA)-treated human lung adenocarcinoma GLC-82 cells and control, subtractive cDNA library has been constructed using subtractive hybridization technique in our laboratory. The screening of the cDNA subtractive library resulted in identification of a clone containing cDNA fragment of one ATRA-induced gene (RAI) in GLC-82 cells. The positive clone with full-length cDNA of RAI was identified by screening fetal brain cDNA library using colony hybridization technique, and then sequenced. RT-PCR results showed that RAI was expressed in many different human fetal tissues. These results suggest that RAI may be involved in cell differentiation and play an important role in vital activities of cells.

  14. RAI, one candidate gene associated with differentiation of human lung adenocarcinoma cells

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    From all-trans retinoic acid (ATRA)-treated human lung adenocarcinoma GLC-82 cells and control, subtractive cDNA library has been constructed using subtractive hybridization technique in our laboratory. The screening of the cDNA subtractive library resulted in identification of a clone containing cDNA fragment of one ATRA-induced gene (RAI) in GLC-82 cells. The positive clone with full-length cDNA of RAI was identified by screening fetal brain cDNA library using colony hybridization technique, and then sequenced. RT-PCR results showed that RAI was expressed in many different human fetal tissues. These results suggest that RAI may be involved in cell differentiation and play an important role in vital activities of cells.

  15. Effects of EGF and TGF-alpha on invasion and proteinase expression of uterine cervical adenocarcinoma OMC-4 cells.

    Science.gov (United States)

    Ueda, M; Fujii, H; Yoshizawa, K; Terai, Y; Kumagai, K; Ueki, K; Ueki, M

    Uterine cervical adenocarcinoma typically is an aggressive neoplasm with a propensity for early invasion and dissemination; however, the regulatory mechanism of invasive activity of cervical adenocarcinoma cells has not been fully understood. In this study, biological effects of epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha on invasion and proteinase expression of human cervical adenocarcinoma OMC-4 cells were investigated. Tumor cell migration along a gradient of substratum-bound fibronectin and invasion into the reconstituted basement membrane were stimulated by 0.1-10 nM EGF and TGF-alpha in a concentration-dependent manner. Their effects on tumor cell migration were also confirmed by wound assay. The zymography of tumor-conditioned medium showed that the treatment of OMC-4 cells with EGF and TGF-alpha resulted in the increase of matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (uPA). Matrilysin (MMP-7), also secreted by OMC-4 cells, was not affected by these growth factors. These results suggest that EGF and TGF-alpha act as positive regulators on the invasion of cervical adenocarcinoma cells, which may be associated with their stimulatory effects on tumor cell motility and the induction of type IV collagenase and uPA secreted by tumor cells.

  16. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression

    NARCIS (Netherlands)

    Froeling, F.E.; Feig, C.; Chelala, C.; Dobson, R.; Mein, C.E.; Tuveson, D.A.; Clevers, H.; Hart, I.R.; Kocher, H.M.

    2011-01-01

    BACKGROUND & AIMS: Patients with pancreatic ductal adenocarcinoma are deficient in vitamin A, resulting in activation of pancreatic stellate cells (PSCs). We investigated whether restoration of retinol to PSCs restores their quiescence and affects adjacent cancer cells. METHODS: PSCs and cancer cell

  17. DNA Damage in CD133-Positive Cells in Barrett’s Esophagus and Esophageal Adenocarcinoma

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    Raynoo Thanan

    2016-01-01

    Full Text Available Barrett’s esophagus (BE caused by gastroesophageal reflux is a major risk factor of Barrett’s esophageal adenocarcinoma (BEA, an inflammation-related cancer. Chronic inflammation and following tissue damage may activate progenitor cells under reactive oxygen/nitrogen species-rich environment. We previously reported the formation of oxidative/nitrative stress-mediated mutagenic DNA lesions, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG and 8-nitroguanine, in columnar epithelial cells of BE tissues and cancer cells of BEA tissues. We investigated the mechanisms of BEA development in relation to oxidative/nitrative DNA damage and stem cell hypothesis. We examined 8-nitroguanine and 8-oxodG formation and the expression of stem cell marker (CD133 in biopsy specimens of patients with BE and BEA by immunohistochemical analysis in comparison with those of normal subjects. CD133 was detected at apical surface of columnar epithelial cells of BE and BEA tissues, and the cytoplasm and cell membrane of cancer cells in BEA tissues. DNA lesions and CD133 were colocalized in columnar epithelial cells and cancer cells. Their relative staining intensities in these tissues were significantly higher than those in normal subjects. Our results suggest that BE columnar epithelial cells with CD133 expression in apical surface undergo inflammation-mediated DNA damage, and mutated cells acquire the property of cancer stem cells with cytoplasmic CD133 expression.

  18. Multicolor immunofluorescence reveals that p63- and/or K5-positive progenitor cells contribute to normal breast epithelium and usual ductal hyperplasia but not to low-grade intraepithelial neoplasia of the breast.

    Science.gov (United States)

    Boecker, Werner; Stenman, Göran; Schroeder, Tina; Schumacher, Udo; Loening, Thomas; Stahnke, Lisa; Löhnert, Catharina; Siering, Robert Michael; Kuper, Arthur; Samoilova, Vera; Tiemann, Markus; Korsching, Eberhard; Buchwalow, Igor

    2017-03-16

    We contend that knowledge about the cellular composition of normal breast epithelium is a prerequisite for understanding proliferative breast disease. Against this background, we used multicolor immunofluorescence to study normal breast epithelium and two types of intraepithelial proliferative breast lesion for expression of the p63, basal keratin K5, glandular keratin K8/18, SMA, ER-alpha, and Ki67. We studied eight normal breast epithelium samples, 12 cases of usual ductal hyperplasia, and 33 cases of low-grade intraepithelial neoplasia (9 flat epithelial atypia, 14 low-grade ductal carcinoma in situ and 10 cases of lobular neoplasia). Usual ductal hyperplasia showed striking similarity to normal luminal breast epithelium including p63+ and/or K5+ luminal progenitor cells and the full spectrum of luminal progeny cells. In normal breast epithelium and usual ductal hyperplasia, expression of ER-alpha was associated with lack of expression of the proliferation antigen Ki67. In contrast, we found in both types of low-grade intraepithelial neoplasia robust expression of keratin K8/18 and a positive association between ER-alpha and Ki67 expression. However, these lesions were consistently negative for p63 and/or K5. Our observational study supports the view that usual ductal hyperplasia and low-grade intraepithelial neoplasia are different entities rather than part of a spectrum of the same disease. We propose a new operational model of cell differentiation that may serve to better understand correlations between normal breast epithelium and proliferative breast diseases. From our data we conclude that p63+ and/or K5+ progenitor cells contribute to maintenance of normal epithelium and usual ductal hyperplasia, but not to low-grade intraepithelial neoplasia of the breast.

  19. Data for comparative proteomics analysis of the antitumor effect of CIGB-552 peptide in HT-29 colon adenocarcinoma cells

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    Teresa Núñez de Villavicencio-Díaz

    2015-09-01

    Full Text Available CIGB-552 is a second generation antitumor peptide that displays potent cytotoxicity in lung and colon cancer cells. The nuclear subproteome of HT-29 colon adenocarcinoma cells treated with CIGB-552 peptide was identified and analyzed [1]. This data article provides supporting evidence for the above analysis.

  20. Two-stage induced differentiation of OCT4+/Nanog+ stem-like cells in lung adenocarcinoma.

    Science.gov (United States)

    Li, Rong; Huang, Jinsu; Ma, Meili; Lou, Yuqing; Zhang, Yanwei; Wu, Lixia; Chang, David W; Zhao, Picheng; Dong, Qianggang; Wu, Xifeng; Han, Baohui

    2016-10-18

    Stem-like cells in solid tumors are purported to contribute to cancer development and poor treatment outcome. The abilities to self-renew, differentiate, and resist anticancer therapies are hallmarks of these rare cells, and steering them into lineage commitment may be one strategy to curb cancer development or progression. Vitamin D is a prohormone that can alter cell growth and differentiation and may induce the differentiation cancer stem-like cells. In this study, octamer-binding transcription factor 4 (OCT4)-positive/Nanog homeobox (Nanog)- positive lung adenocarcinoma stem-like cells (LACSCs) were enriched from spheroid cultured SPC-A1 cells and differentiated by a two-stage induction (TSI) method, which involved knockdown of hypoxia-inducible factor 1-alpha (HIF1α) expression (first stage) followed by sequential induction with 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3, VD3) and suberoylanilide hydroxamic acid (SAHA) treatment (second stage). The results showed the HIF1α-knockdowned cells displayed diminished cell invasion and clonogenic activities. Moreover, the TSI cells highly expressed tumor suppressor protein p63 (P63) and forkhead box J1 (FOXJ1) and lost stem cell characteristics, including absent expression of OCT4 and Nanog. These cells regained sensitivity to cisplatin in vitro while losing tumorigenic capacity and decreased tumor cell proliferation in vivo. Our results suggest that induced transdifferentiation of LACSCs by vitamin D and SAHA may become novel therapeutic avenue to alter tumor cell phenotypes and improve patient outcome.The development and progression of lung cancer may involve rare population of stem-like cells that have the ability to grow, differentiate, and resist drug treatment. However, current therapeutic strategies have mostly focused on tumor characteristics and neglected the potential source of cells that may contribute to poor clinical outcome. We generated lung adenocarcinoma stem-like cells from spheroid culture and

  1. Comparative proteomic and phosphoproteomic profiling of pancreatic adenocarcinoma cells treated with CB1 or CB2 agonists.

    Science.gov (United States)

    Brandi, Jessica; Dando, Ilaria; Palmieri, Marta; Donadelli, Massimo; Cecconi, Daniela

    2013-05-01

    The pancreatic adenocarcinoma cell line Panc1 was treated with cannabinoid receptor ligands (arachidonylcyclopropylamide or GW405833) in order to elucidate the molecular mechanism of their anticancer effect. A proteomic approach was used to analyze the protein and phosphoprotein profiles. Western blot and functional data mining were also employed in order to validate results, classify proteins, and explore their potential relationships. We demonstrated that the two cannabinoids act through a widely common mechanism involving up- and down-regulation of proteins related to energetic metabolism and cell growth regulation. Overall, the results reported might contribute to the development of a therapy based on cannabinoids for pancreatic adenocarcinoma.

  2. High fluence laser irradiation induces reactive oxygen species generation in human lung adenocarcinoma cells

    Science.gov (United States)

    Wang, Fang; Xing, Da; Chen, Tong-Sheng

    2006-09-01

    Low-power laser irradiation (LPLI) has been used for therapies such as curing spinal cord injury, healing wound et al. Yet, the mechanism of LPLI remains unclear. Our previous study showed that low fluences laser irradiation induces human lung adenocarcinoma cells (ASTC-a-1) proliferation, but high fluences induced apoptosis and caspase-3 activation. In order to study the mechanism of apoptosis induced by high fluences LPLI further, we have measured the dynamics of generation of reactive oxygen species (ROS) using H IIDCFDA fluorescence probes during this process. ASTC-a-1 cells apoptosis was induced by He-Ne laser irradiation at high fluence of 120J/cm2. A confocal laser scanning microscope was used to perform fluorescence imaging. The results demonstrated that high fluence LPLI induced the increase of mitochondria ROS. Our studies contribute to clarify the biological mechanism of high fluence LPLI-induced cell apoptosis.

  3. Layered Double Hydroxide as a Vehicle to Increase Toxicity of Gallate Ions against Adenocarcinoma Cells

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    Jenny Arratia-Quijada

    2016-07-01

    Full Text Available The antineoplasic activity of gallic acid has been reported. This compound induces apoptosis and inhibits the growth of several neoplasic cells. However, this molecule is easily oxidized and degraded in the body. The aim of this work was to intercalate gallate ions into layered double hydroxide (LDH nanoparticles under controlled conditions to reduce oxidation of gallate and to evaluate its toxicity against the A549 adenocarcinoma cell line. An isopropanol medium under nitrogen atmosphere was adequate to intercalate gallate ions with a lesser oxidation degree as detected by electron spin resonance spectroscopy. Concentrations of the hybrid LDH-gallate nanoparticles between 0.39 and 25 µg/mL reduced the cell viability to 67%, while the value reached with the pure gallic acid and LDH was 90% and 78%, respectively, thus proving that the combination of gallate ions with the inorganic nanoparticles increases the toxicity potential within this dose range.

  4. Lacrimal gland ductal carcinomas

    DEFF Research Database (Denmark)

    Andreasen, Simon; Grauslund, Morten; Heegaard, Steffen

    2017-01-01

    HER2 amplification was found in cases 2 and 3. CONCLUSION: This study identified a spectrum of genetic events and pattern of protein expression in DC of the lacrimal gland similar to a subset of carcinomas of the breast and ductal carcinomas of the salivary glands. For therapeutic purposes...

  5. Detection of Merkel cell polyomavirus in cervical squamous cell carcinomas and adenocarcinomas from Japanese patients

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    Imajoh Masayuki

    2012-08-01

    Full Text Available Abstract Background Merkel cell polyomavirus (MCPyV was identified originally in Merkel cell carcinoma (MCC, a rare form of human skin neuroendocrine carcinoma. Evidence of MCPyV existence in other forms of malignancy such as cutaneous squamous cell carcinomas (SCCs is growing. Cervical cancers became the focus of our interest in searching for potentially MCPyV-related tumors because: (i the major histological type of cervical cancer is the SCC; (ii the uterine cervix is a common site of neuroendocrine carcinomas histologically similar to MCCs; and (iii MCPyV might be transmitted during sexual interaction as demonstrated for human papillomavirus (HPV. In this study, we aimed to clarify the possible presence of MCPyV in cervical SCCs from Japanese patients. Cervical adenocarcinomas (ACs were also studied. Results Formalin-fixed paraffin-embedded tissue samples from 48 cervical SCCs and 16 cervical ACs were examined for the presence of the MCPyV genome by polymerase chain reaction (PCR and sequencing analyses. PCR analysis revealed that 9/48 cervical SCCs (19% and 4/16 cervical ACs (25% were positive for MCPyV DNA. MCPyV-specific PCR products were sequenced to compare them with reference sequences. The nucleotide sequences in the MCPyV large T (LT-sequenced region were the same among MCPyV-positive cervical SCCs and AC. Conversely, in the MCPyV viral protein 1 (VP1-sequenced region, two cervical SCCs and three cervical ACs showed several nucleotide substitutions, of which three caused amino acid substitutions. These sequencing results suggested that three MCPyV variants of the VP1 were identified in our cases. Immunohistochemistry showed that the LT antigen was expressed in tumor cells in MCPyV-positive samples. Genotyping of human HPV in the MCPyV-positive samples revealed that infected HPVs were HPV types 16, 31 and 58 for SCCs and HPV types 16 and 18 for ACs. Conclusions This study provides the first observation that MCPyV coexists in a subset

  6. Invasive ductal carcinomas of the breast showing partial reversed cell polarity are associated with lymphatic tumor spread and may represent part of a spectrum of invasive micropapillary carcinoma.

    Science.gov (United States)

    Acs, Geza; Esposito, Nicole N; Rakosy, Zsuzsa; Laronga, Christine; Zhang, Paul J

    2010-11-01

    Invasive micropapillary carcinomas (IMPC) of the breast are aggressive tumors frequently associated with lymphatic invasion and nodal metastasis even when micropapillary (MP) differentiation is very focal within the tumors. We have noticed that some breast carcinomas showing lymphatic spread but lacking histologic features of IMPC have occasional tumor cell clusters reminiscent of those of IMPC without the characteristic prominent retraction artifact. To study the clinicopathologic significance of such features, we prospectively selected 1323 invasive ductal carcinomas and determined the presence and extent of MP differentiation and retraction artifact in the tumors. One representative tumor block per case was used for immunostaining for epithelial membrane antigen (EMA). Partial reverse cell polarity (PRCP) was defined as prominent linear EMA reactivity on at least part of the periphery of tumor cell clusters usually associated with decreased cytoplasmic staining. The clinicopathologic features of carcinomas with PRCP were compared with IMPC and invasive ductal (no special type) carcinomas without this feature. Of the 1323 cases, 96 (7.3%) and 92 (7.0%) showed MP features and the presence of PRCP, respectively. We found that the presence of both PRCP and MP features were strongly associated with decreased cytoplasmic EMA immunoreactivity and the presence of lymphatic invasion and nodal metastasis, even if such features were present only very focally. Our results suggest that breast carcinomas with PRCP may have the same implication as MP differentiation and these tumors may represent part of a spectrum of IMPC. Complete or partial reversal of cell polarity may play a significant role in lymphatic tumor spread.

  7. MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma

    DEFF Research Database (Denmark)

    Schultz, Nicolai A; Werner, Jens; Willenbrock, Hanni;

    2012-01-01

    MicroRNAs have potential as diagnostic cancer biomarkers. The aim of this study was (1) to define microRNA expression patterns in formalin-fixed parafin-embedded tissue from pancreatic ductal adenocarcinoma, ampullary adenocarcinoma, normal pancreas and chronic pancreatitis without using micro......, normal pancreas and duodenal adenocarcinoma. In all, 43 microRNAs had higher and 41 microRNAs reduced expression in pancreatic cancer compared with normal pancreas. In all, 32 microRNAs were differently expressed in pancreatic adenocarcinoma compared with chronic pancreatitis (17 higher; 15 reduced......-dissection and (2) to discover new diagnostic microRNAs and combinations of microRNAs in cancer tissue. The expression of 664 microRNAs in tissue from 170 pancreatic adenocarcinomas and 107 ampullary adenocarcinomas were analyzed using a commercial microRNA assay. Results were compared with chronic pancreatitis...

  8. Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases.

    Science.gov (United States)

    Reid, Michelle D; Basturk, Olca; Shaib, Walid L; Xue, Yue; Balci, Serdar; Choi, Hye-Jeong; Akkas, Gizem; Memis, Bahar; Robinson, Brian S; El-Rayes, Bassel F; Staley, Charles A; Staley, Christopher A; Winer, Joshua H; Russell, Maria C; Knight, Jessica H; Goodman, Michael; Krasinskas, Alyssa M; Adsay, Volkan

    2016-10-01

    High-grade versions of appendiceal goblet cell carcinoids ('adenocarcinoma ex-goblet cell carcinoids') are poorly characterized. We herein document 77 examples. Tumors occurred predominantly in females (74%), mean age 55 years (29-84), most with disseminated abdominal (77% peritoneal, 58% gynecologic tract involvement) and stage IV (65%) disease. Many presented to gynecologic oncologists, and nine had a working diagnosis of ovarian carcinoma. Metastases to liver (n=3) and lung (n=1) were uncommon and none arose in adenomatous lesions. Tumors had various histologic patterns, in variable combinations, most of which were fairly specific, making them recognizable as appendiceal in origin, even at metastatic sites: I: Ordinary goblet cell carcinoid/crypt pattern (rounded, non-luminal acini with well-oriented goblet cells), in variable amounts in all cases. II: Poorly cohesive goblet cell pattern (diffusely infiltrative cords/single files of signet ring-like/goblet cells). III: Poorly cohesive non-mucinous cell (diffuse-infiltrative growth of non-mucinous cells). IV: Microglandular (rosette-like glandular) pattern without goblet cells. V: Mixed 'other' carcinoma foci (including ordinary intestinal/mucinous). VI: goblet cell carcinoid pattern with high-grade morphology (marked nuclear atypia). VII: Solid sheet-like pattern punctuated by goblet cells/microglandular units. Ordinary nested/trabecular ('carcinoid pattern') was very uncommon. In total, 33(52%) died of disease, with median overall survival 38 months and 5-year survival 32%. On multivariate analysis perineural invasion and younger age (tumor progression. In conclusion, 'adenocarcinoma ex-goblet cell carcinoid' is an appendix-specific, high-grade malignant neoplasm with distinctive morphology that is recognizable at metastatic sites and recapitulates crypt cells (appendiceal crypt cell adenocarcinoma). Unlike intestinal-type adenocarcinoma, it occurs predominantly in women, is disguised as gynecologic malignancy

  9. Effects of non-thermal mobile phone radiation on breast adenocarcinoma cells

    Directory of Open Access Journals (Sweden)

    Zen Fourie

    2011-09-01

    Full Text Available Mobile phone usage currently exceeds landline communication in Africa. The extent of this usage has raised concerns about the long-term health effects of the ongoing use of mobile phones. To assess the physiological effects of radiation from mobile phones in vitro, MCF-7 breast adenocarcinoma cells were exposed to 2W/kg non-thermal 900-MHz mobile phone radiation. The effects investigated were those on metabolic activity, cell morphology, cell cycle progression, phosphatidylserine (PS externalisation and the generation of reactive oxygen species and nitrogen species. Statistically insignificant increases in mitochondrial dehydrogenase activity were observed in irradiated cells when compared to controls. Fluorescent detection of F-actin demonstrated an increase in F-actin stress fibre formation in irradiated MCF-7 cells. Cell cycle progression revealed no statistically significant variation. A small increase in early and late apoptotic events in irradiated MCF-7 cells was observed. No statistically significant changes were observed in reactive oxygen and reactive nitrogen species generation. In addition, quantitative and qualitative analyses of cell cycle activity and nuclear and cytosolic changes, respectively, revealed no significant changes. In conclusion, exposure to 1 h of 900-MHz irradiation induced an increase in PS externalisation and an increase in the formation of F-actin stress fibres in MCF-7 cells. Data obtained from this study, and their correlation with other studies, provides intriguing links between radio frequency radiation and cellular events and warrant further investigation.

  10. [Effect of endothelin-1 on the proliferation of human lung adenocarcinoma cell SPC-A1].

    Science.gov (United States)

    Ye, Qianjun; Zhou, Juan; Zhang, Weimin

    2007-02-20

    Endothelin-1 (ET-1) is a potent mitogen involved in tumor cell growth and angiogenesis. The aim of this study is to explore the effect of ET-1 on the proliferation of human lung adenocarcinoma cells SPC-A1. Cell number was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide] assay. Cell cycle was detected by flow cytometry. ET-1 (1×10⁻¹⁵ -1×10⁻⁸ mol/L) enhanced SPC-A1 cell growth in a dose-dependent manner in vitro, with the greatest effect beginning at 1×10⁻¹¹ mol/L. Effect of ET-1 (1×10⁻¹⁰ mol/L) on the proliferation of SPC-A1 cells was completely blocked by BQ123 (1×10⁻⁷ mol/L), a highly selective endothelin receptor A (ETA) antagonist (P SPC-A1 cells (P SPC-A1 cell cycle. ET-1 enhances SPC-A1 cell proliferation by the activation of ETA receptor. Ca(2+) influx from voltage dependent calcium-channel contributes to this process.

  11. Targeting the cell cycle in esophageal adenocarcinoma: an adjunct to anticancer treatment.

    Science.gov (United States)

    Dibb, Martyn; Ang, Yeng S

    2011-04-28

    Esophageal adenocarcinoma is a major cause of cancer death in men in the developed world. Continuing poor outcomes with conventional therapies that predominantly target apoptosis pathways have lead to increasing interest in treatments that target the cell cycle. A large international effort has led to the development of a large number of inhibitors, which target cell cycle kinases, including cyclin-dependent kinases, Aurora kinases and polo-like kinase. Initial phase I/II trials in solid tumors have often demonstrated only modest clinical benefits of monotherapy. This may relate in part to a failure to identify the patient populations that will gain the most clinical benefit. Newer compounds lacking the side effect profile of first-generation compounds may show utility as adjunctive treatments targeted to an individual's predicted response to treatment.

  12. Targeting the cell cycle in esophageal adenocarcinoma: An adjunct to anticancer treatment

    Institute of Scientific and Technical Information of China (English)

    Martyn Dibb; Yeng S Ang

    2011-01-01

    Esophageal adenocarcinoma is a major cause of cancer death in men in the developed world. Continuing poor outcomes with conventional therapies that predomi-nantly target apoptosis pathways have lead to increas-ing interest in treatments that target the cell cycle. A large international effort has led to the development of a large number of inhibitors, which target cell cycle kinases, including cyclin-dependent kinases, Aurora ki-nases and polo-like kinase. Initial phaseⅠ/Ⅱtrials in solid tumors have often demonstrated only modest clinical benefits of monotherapy. This may relate in part to a failure to identify the patient populations that will gain the most clinical benefit. Newer compounds lacking the side effect profile of first-generation compounds may show utility as adjunctive treatments targeted to an in-dividual's predicted response to treatment.

  13. Pulmonary mixed squamous cell and glandular papilloma mimicking adenocarcinoma: a case study and literature review.

    Science.gov (United States)

    Lin, Dongliang; Jiang, Yanxia; Wang, Jigang; Ding, Li; Xin, Fangjie; Zhao, Han; Li, Yujun

    2013-08-01

    Mixed squamous cell and glandular papilloma of the lung is an extremely rare benign neoplasm. Here we present another case of mixed squamous cell and glandular papilloma in a 64-year-old female nonsmoker. Histologically, the tumor was composed of mainly papillary structures covered with squamous, glandular and transitional epithelium. Some glandular structures extending into adjacent bronchiolar and alveolar spaces with mucus were similar to adenocarcinoma. Immunohistochemical analysis showed the different kinds of epithelia had similar immunophenotype. The different components were positive for cytokeratin (CK)7, CK19, CAM5.2, CK5/6, CK34βE12, and TTF-1, but negative for CK20. The transitional morphology and immunohistochemistry indicate the different components likely come from a same kind of progenitor in the bronchiolar wall.

  14. Adenocarcinoma of the rete testis with prominent papillary structure and clear neoplastic cells: Morphologic and immunohistochemical findings and differential diagnosis

    Directory of Open Access Journals (Sweden)

    Pei-Wen Huang

    2015-01-01

    Full Text Available Adenocarcinoma of the rete testis is rare, and its etiology is unknown. The definite diagnosis merely depends on the exclusion of other tumors and histological features. We first describe a 38-year-old man with a carcinoma arising in the rete testis. The tumor was characterized by clear neoplastic cells and branching papillary growth. Focal stromal invasion and transition of normal rete epithelium to neoplastic cells were seen. The neoplastic cells were positive for epithelial membrane antigen, Ber-Ep4, vimentin, renal cell carcinoma marker, and CD10, while negative for Wilms′ tumor 1, thyroid transcription factor-1, estrogen receptor, prostate specific antigen, placental alkaline phosphate, CD117, and alpha-1-fetoprotein. According to the above features, we diagnosed this tumor as adenocarcinoma of the rete testis. To our best knowledge, this is the first reported case of adenocarcinoma of the rete testis with prominently papillary structure and clear neoplastic cells. The rarity of adenocarcinoma of the rete testis and the unique features in our case cause diagnostic pitfalls. A complete clinicopathological study and thorough differential diagnosis are crucial for the correct result.

  15. Effect of caffeic acid esters on carcinogen-induced mutagenicity and human colon adenocarcinoma cell growth.

    Science.gov (United States)

    Rao, C V; Desai, D; Kaul, B; Amin, S; Reddy, B S

    1992-11-16

    Propolis, a honey bee hive product, is thought to exhibit a broad spectrum of activities including antibiotic, antiviral, anti-inflammatory and tumor growth inhibition; some of the observed biological activities may be due to caffeic acid (cinnamic acid) esters that are present in propolis. In the present study we synthesized three caffeic acid esters, namely methyl caffeate (MC), phenylethyl caffeate (PEC) and phenylethyl dimethylcaffeate (PEDMC) and tested them against the 3,2'-dimethyl-4-aminobiphenyl, (DMAB, a colon and mammary carcinogen)-induced mutagenicity in Salmonella typhimurium strains TA 98 and TA 100. Also, the effect of these agents on the growth of human colon adenocarcinoma, HT-29 cells and activities of ornithine decarboxylase (ODC) and protein tyrosine kinase (PTK) was studied. Mutagenicity was induced in Salmonella typhimurium strains TA 98 and TA 100 plus S9 activation using 5 and 10 micrograms DMAB and antimutagenic activities of 0-150 microM MC, 0-60 microM PEC and 0-80 microM PEDMC were determined. The results indicate that MC, PEC and PEDMC were not mutagenic in the Salmonella tester system. DMAB-induced mutagenicity was significantly inhibited with 150 microM MC, 40-60 microM PEC and 40-80 microM PEDMC in both tester systems. Treatment of HT-29 colon adenocarcinoma cells with > 150 microM MC, 30 microM PEC and 20 microM PEDMC significantly inhibited the cell growth and syntheses of RNA, DNA and protein. ODC and PTK activities were also inhibited in HT-29 cells treated with different concentrations of MC, PEC and PEDMC. These results demonstrate that caffeic acid esters which are present in Propolis possess chemopreventive properties when tested in short-term assay systems.

  16. Xanthohumol inhibits the extracellular signal regulated kinase (ERK) signalling pathway and suppresses cell growth of lung adenocarcinoma cells.

    Science.gov (United States)

    Sławińska-Brych, Adrianna; Zdzisińska, Barbara; Dmoszyńska-Graniczka, Magdalena; Jeleniewicz, Witold; Kurzepa, Jacek; Gagoś, Mariusz; Stepulak, Andrzej

    2016-05-16

    Aberrant activation of the Ras/MEK/ERK signaling pathway has been frequently observed in non-small-cell lung carcinoma (NSCLC) and its important role in cancer progression and malignant transformation has been documented. Hence, the ERK1/2 kinase cascade becomes a potential molecular target in cancer treatment. Xanthohumol (XN, a prenylated chalcone derived from hope cones) is known to possess a broad spectrum of chemopreventive and anticancer activities. In our studies, the MTT and BrdU assays revealed that XN demonstrated greater antiproliferative activity against A549 lung adenocarcinoma cells than against the lung adenocarcinoma H1563 cell line. We observed that XN was able to suppress the activities of ERK1/2 and p90RSK kinases, followed by inhibition of phosphorylation and activation of the CREB protein. Additionally, the XN treatment of the cancer cells caused upregulation of key cell cycle regulators p53 and p21 as well as downregulation of cyclin D1. As a result, the cytotoxic effect of XN was attributed to the cell cycle arrest at G1 phase and induction of apoptosis indicated by increased caspase-3 activity. Thus, XN might be a promising anticancer drug candidate against lung carcinomas.

  17. Previous heat shock treatment inhibits Mayaro virus replication in human lung adenocarcinoma (A549) cells.

    Science.gov (United States)

    Virgilio, P L; Godinho-Netto, M C; Carvalho Mda, G

    1997-01-01

    Human lung adenocarcinoma cells (A549) were submitted to mild or severe heat shock (42 degrees C or 44 degrees C) for 1 h, while another group of cells was double-heat-shocked (submitted to 42 degrees C for 1 h, returned to 37 degrees C for 3 h, then exposed to 44 degrees C for 1 h). After each heat treatment, the cells were infected with Mayaro virus for 24 h and incubated at 37 degrees C. The results showed that the double-heat-shocked thermotolerant cells exhibited a 10(4)-fold virus titre inhibition, despite the recovery of protein synthesis and original morphology 24 h post-infection. In contrast, cells submitted to mild or severe heat shock exhibited weaker inhibition of Mayaro virus titre (10(2)-fold). The mildly heat-shocked cells also presented a full recovery in protein synthesis, which was not observed in severely heat-shocked cells. These results indicate that exposure of A549 cells to a mild or to a double heat shock treatment before Mayaro virus infection induces an antiviral state.

  18. Rab27A regulates exosome secretion from lung adenocarcinoma cells A549: involvement of EPI64.

    Science.gov (United States)

    Li, Wenhai; Hu, Yunsheng; Jiang, Tao; Han, Yong; Han, Guoliang; Chen, Jiakuan; Li, Xiaofei

    2014-11-01

    Exosomes are small membrane vesicles secreted into the extracellular compartment by exocytosis. The unique composition of exosomes can be transported to other cells which allow cells to exert biological functions at distant sites. However, in lung cancer, the regulation of exosome secretion was poorly understood. In this study, we employed human lung adenocarcinoma A549 cells to determine the exosome secretion and involved regulation mechanism. We found that Rab27A was expressed in A549 cells and the reduction of Rab27A by Rab27A-specific shRNA could significantly decrease the secretion of exosome by A549 cells. EPI64, a candidate GAP that is specific for Rab27, was also detected in A549 cells. By pull-down assay, we found that EPI64 participated in the exosome secretion of A549 cells by acting as a specific GAP for Rab27A, not Rab27B. Overexpression of EPI64 enhanced exosome secretion. Taken together, in A549 cells, EPI64 could regulate the exosome secretion by functioning as a GAP specific for Rab27A.

  19. Cytotoxic and apoptotic effects of chalcone derivatives of 2-acetyl thiophene on human colon adenocarcinoma cells.

    Science.gov (United States)

    de Vasconcelos, Alana; Campos, Vinicius Farias; Nedel, Fernanda; Seixas, Fabiana Kömmling; Dellagostin, Odir A; Smith, Kevin R; de Pereira, Cláudio Martin Pereira; Stefanello, Francieli Moro; Collares, Tiago; Barschak, Alethéa Gatto

    2013-06-01

    Recent studies report that chalcones exhibit cytotoxicity to human cancer cell lines. Typically, the form of cell death induced by these compounds is apoptosis. In the context of the discovery of new anticancer agents and in light of the antitumour potential of several chalcone derivatives, in the present study, we synthesized and tested the cytotoxicity of six chalcone derivatives on human colon adenocarcinoma cells. Six derivatives of 3-phenyl-1-(thiophen-2-yl) prop-2-en-1-one were prepared and characterized on the basis of their (1) H and (13) C NMR spectra. HT-29 cells were treated with synthesized chalcones on two concentrations by three different incubation times. Cells were evaluated by cell morphology, Tetrazolium dye (MTT) colorimetric assay, live/dead, flow cytometry (annexin V) and gene expression analyses to determine the cytotoxic way. Chalcones 3-(4-bromophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (C06) and 3-(2-nitrophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (C09) demonstrated higher cytotoxicity than other chalcones as shown by cell morphology, live/dead and MTT assays. In addition, C06 induced apoptosis on flow cytometry annexin V assay. These data were confirmed by a decreased expression of anti-apoptotic genes and increased pro-apoptotic genes. Our findings indicate in summary that the cytotoxic activity of chalcone C06 on colorectal carcinoma cells occurs by apoptosis.

  20. Doxorubicin delivery enhanced by electroporation to gastrointestinal adenocarcinoma cells with P-gp overexpression.

    Science.gov (United States)

    Kulbacka, Julita; Daczewska, Małgorzata; Dubińska-Magiera, Magda; Choromańska, Anna; Rembiałkowska, Nina; Surowiak, Paweł; Kulbacki, Marek; Kotulska, Małgorzata; Saczko, Jolanta

    2014-12-01

    Electroporation (EP) can effectively support the penetration of macromolecules from the extracellular space into cells. Electropores induced by the influence of electromagnetic field generate additional paths of transport for macromolecules. The aim of this study was evaluation of the electroporation effect on doxorubicin transport efficiency to human colon (LoVo and LoVo/DX) and gastric (EPG85-257/P and EPG85-257/RDB) adenocarcinoma cells with overexpression of P-glycoprotein and murine macrophage cell line (P388/D1). In our EP experiments cells were placed into a cuvette with aluminum electrodes and pulsed with five square electric pulses of 1300 V/cm and duration of 50 μs each. Cells were also treated with low doxorubicin concentration ([DOX]=1.7 μM). The ultrastructure (TEM) and changes of P-glycoprotein expression of tumor cells subjected to electric field were monitored. The mitochondrial cell function and trypan blue staining were evaluated after 24h. Our results indicate the most pronounced effect of EP with DOX and disturbed ultrastructure in resistant gastric and colon cells with decrease of P-gp expression. Electroporation may be an attractive delivery method of cytostatic drugs in chemotherapy, enabling reduction of drug dose, exposure time and side effects.

  1. Mechanism of arctigenin-mediated specific cytotoxicity against human lung adenocarcinoma cell lines.

    Science.gov (United States)

    Susanti, Siti; Iwasaki, Hironori; Inafuku, Masashi; Taira, Naoyuki; Oku, Hirosuke

    2013-12-15

    The lignan arctigenin (ARG) from the herb Arctium lappa L. possesses anti-cancer activity, however the mechanism of action of ARG has been found to vary among tissues and types of cancer cells. The current study aims to gain insight into the ARG mediated mechanism of action involved in inhibiting proliferation and inducing apoptosis in lung adenocarcinoma cells. This study also delineates the cancer cell specificity of ARG by comparison with its effects on various normal cell lines. ARG selectively arrested the proliferation of cancer cells at the G0/G1 phase through the down-regulation of NPAT protein expression. This down-regulation occurred via the suppression of either cyclin E/CDK2 or cyclin H/CDK7, while apoptosis was induced through the modulation of the Akt-1-related signaling pathway. Furthermore, a GSH synthase inhibitor specifically enhanced the cytotoxicity of ARG against cancer cells, suggesting that the intracellular GSH content was another factor influencing the susceptibility of cancer cells to ARG. These findings suggest that specific cytotoxicity of ARG against lung cancer cells was explained by its selective modulation of the expression of NPAT, which is involved in histone biosynthesis. The cytotoxicity of ARG appeared to be dependent on the intracellular GSH level.

  2. Gene expression changes associated with Barrett's esophagus and Barrett's-associated adenocarcinoma cell lines after acid or bile salt exposure

    Directory of Open Access Journals (Sweden)

    Sahbaie Peyman

    2007-06-01

    Full Text Available Abstract Background Esophageal reflux and Barrett's esophagus represent two major risk factors for the development of esophageal adenocarcinoma. Previous studies have shown that brief exposure of the Barrett's-associated adenocarcinoma cell line, SEG-1, or primary cultures of Barrett's esophageal tissues to acid or bile results in changes consistent with cell proliferation. In this study, we determined whether similar exposure to acid or bile salts results in gene expression changes that provide insights into malignant transformation. Methods Using previously published methods, Barrett's-associated esophageal adenocarcinoma cell lines and primary cultures of Barrett's esophageal tissue were exposed to short pulses of acid or bile salts followed by incubation in culture media at pH 7.4. A genome-wide assessment of gene expression was then determined for the samples using cDNA microarrays. Subsequent analysis evaluated for statistical differences in gene expression with and without treatment. Results The SEG-1 cell line showed changes in gene expression that was dependent on the length of exposure to pH 3.5. Further analysis using the Gene Ontology, however, showed that representation by genes associated with cell proliferation is not enhanced by acid exposure. The changes in gene expression also did not involve genes known to be differentially expressed in esophageal adenocarcinoma. Similar experiments using short-term primary cultures of Barrett's esophagus also did not result in detectable changes in gene expression with either acid or bile salt exposure. Conclusion Short-term exposure of esophageal adenocarcinoma SEG-1 cells or primary cultures of Barrett's esophagus does not result in gene expression changes that are consistent with enhanced cell proliferation. Thus other model systems are needed that may reflect the impact of acid and bile salt exposure on the esophagus in vivo.

  3. SMAD4 loss enables EGF, TGFβ1 and S100A8/A9 induced activation of critical pathways to invasion in human pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Moz, Stefania; Basso, Daniela; Bozzato, Dania; Galozzi, Paola; Navaglia, Filippo; Negm, Ola H; Arrigoni, Giorgio; Zambon, Carlo-Federico; Padoan, Andrea; Tighe, Paddy; Todd, Ian; Franchin, Cinzia; Pedrazzoli, Sergio; Punzi, Leonardo; Plebani, Mario

    2016-10-25

    Epidermal Growth Factor (EGF) receptor overexpression, KRAS, TP53, CDKN2A and SMAD4 mutations characterize pancreatic ductal adenocarcinoma. This mutational landscape might influence cancer cells response to EGF, Transforming Growth Factor β1 (TGFβ1) and stromal inflammatory calcium binding proteins S100A8/A9. We investigated whether chronic exposure to EGF modifies in a SMAD4-dependent manner pancreatic cancer cell signalling, proliferation and invasion in response to EGF, TGFβ1 and S100A8/A9. BxPC3, homozigously deleted (HD) for SMAD4, and BxPC3-SMAD4+ cells were or not stimulated with EGF (100 ng/mL) for three days. EGF pre-treated and non pretreated cells were stimulated with a single dose of EGF (100 ng/mL), TGFβ1 (0,02 ng/mL), S100A8/A9 (10 nM). Signalling pathways (Reverse Phase Protein Array and western blot), cell migration (Matrigel) and cell proliferation (XTT) were evaluated. SMAD4 HD constitutively activated ERK and Wnt/β-catenin, while inhibiting PI3K/AKT pathways. These effects were antagonized by chronic EGF, which increased p-BAD (anti-apoptotic) in response to combined TGFβ1 and S100A8/A9 stimulation. SMAD4 HD underlied the inhibition of NF-κB and PI3K/AKT in response to TGFβ1 and S100A8/A9, which also induced cell migration. Chronic EGF exposure enhanced cell migration of both BxPC3 and BxPC3-SMAD4+, rendering the cells less sensitive to the other inflammatory stimuli. In conclusion, SMAD4 HD is associated with the constitutive activation of the ERK and Wnt/β-catenin signalling pathways, and favors the EGF-induced activation of multiple signalling pathways critical to cancer proliferation and invasion. TGFβ1 and S100A8/A9 mainly inhibit NF-κB and PI3K/AKT pathways and, when combined, sinergize with EGF in enhancing anti-apoptotic p-BAD in a SMAD4-dependent manner.

  4. A comparative analysis by SAGE of gene expression profiles of esophageal adenocarcinoma and esophageal squamous cell carcinoma

    NARCIS (Netherlands)

    van Baal, Jantine W. P. M.; Milana, Francesco; Rygiel, Agnieszka M.; Sondermeijer, Carine M. T.; Spek, C. Arnold; Bergman, Jacques J. G. H. M.; Peppelenbosch, Maikel P.; Krishnadath, Kausilia K.

    2008-01-01

    Esophageal adenocarcinoma (EA) and esophageal squamous cell carcinoma (ESCC) are the two main types of esophageal cancer. Despite extensive research the exact molecular basis of these cancers is unclear. Therefore we evaluated the transcriptome of EA in comparison to non-dysplastic Barrett's esophag

  5. Stratified epithelium in prostatic adenocarcinoma: a mimic of high-grade prostatic intraepithelial neoplasia.

    Science.gov (United States)

    Hameed, Omar; Humphrey, Peter A

    2006-07-01

    Typically glands of prostatic adenocarcinoma have a single cell lining, although stratification can be seen in invasive carcinomas with a cribriform architecture, including ductal carcinoma. The presence and diagnostic significance of stratified cells within non-cribriform carcinomatous prostatic glands has not been well addressed. The histomorphological features and immunohistochemical profile of cases of non-cribriform prostatic adenocarcinoma with stratified malignant glandular epithelium were analyzed. These cases were identified from needle biopsy cases from the consultation files of one of the authors and from a review of 150 consecutive in-house needle biopsy cases of prostatic adenocarcinoma. Immunohistochemistry was performed utilizing antibodies reactive against high molecular weight cytokeratin (34betaE12), p63 and alpha-methylacyl-coenzyme-A racemase (AMACR). A total of 8 cases were identified, including 2 from the 150 consecutive in-house cases (1.3%). In 4 cases, the focus with glands having stratified epithelium was the sole carcinomatous component in the biopsy, while such a component represented 5-30% of the invasive carcinoma seen elsewhere in the remaining cases. The main attribute in all these foci was the presence of glandular profiles lined by several layers of epithelial cells with cytological and architectural features resembling flat or tufted high-grade prostatic intraepithelial neoplasia, but lacking basal cells as confirmed by negative 34betaE12 and/or p63 immunostains in all cases. The AMACR staining profile of the stratified foci was variable, with 4 foci showing positivity, and 3 foci being negative, including two cases that displayed AMACR positivity in adjacent non-stratified prostatic adenocarcinoma. Prostatic adenocarcinoma with stratified malignant glandular epithelium can be identified in prostate needle biopsy samples harboring non-cribriform prostatic adenocarcinoma and resembles glands with high-grade prostatic

  6. The Polycomb group protein RING1B is overexpressed in ductal breast carcinoma and is required to sustain FAK steady state levels in breast cancer epithelial cells

    Science.gov (United States)

    Bosch, Almudena; Panoutsopoulou, Konstantina; Corominas, Josep Maria; Gimeno, Ramón; Moreno-Bueno, Gema; Martín-Caballero, Juan; Morales, Saleta; Lobato, Tania; Martínez-Romero, Carles; Farias, Eduardo F.; Mayol, Xavier; Cano, Amparo; Hernández-Muáoz, Inmaculada

    2014-01-01

    In early stages of metastasis malignant cells must acquire phenotypic changes to enhance their migratory behavior and their ability to breach the matrix surrounding tumors and blood vessel walls. Epigenetic regulation of gene expression allows the acquisition of these features that, once tumoral cells have escape from the primary tumor, can be reverted. Here we report that the expression of the Polycomb epigenetic repressor Ring1B is enhanced in tumoral cells that invade the stroma in human ductal breast carcinoma and its expression is coincident with that of Fak in these tumors. Ring1B knockdown in breast cancer cell lines revealed that Ring1B is required to sustain Fak expression in basal conditions as well as in Tgfβ-treated cells. Functionally, endogenous Ring1B is required for cell migration and invasion in vitro and for in vivo invasion of the mammary fat pad by tumoral cells. Finally we identify p63 as a target of Ring1B to regulate Fak expression: Ring1B depletion results in enhanced p63 expression, which in turns represses Fak expression. Importantly, Fak downregulation upon Ring1B depletion is dependent on p63 expression. Our findings provide new insights in the biology of the breast carcinoma and open new avenues for breast cancer prognosis and therapy. PMID:24742605

  7. Apocrine adenocarcinoma of the vulva

    Directory of Open Access Journals (Sweden)

    Babita Kajal

    2013-09-01

    Full Text Available Cutaneous vulvar carcinomas are predominantly of squamous cell carcinoma type. Primary vulvar adenocarcinomas are rare with a poorly understood histogenesis. They are classified into extramammary Paget’s disease, sweat gland carcinomas, and breast-like adenocarcinomas of the vulva. Adenocarcinomas, originating from Bartholin glands, can also present as vulvar adenocarcinoma. Rare adenocarcinomas with apocrine features have been described in the literature. The origin of these neoplasms from the native apocrine sweat glands or from anogenital mammary-like glands is still debatable. We report herein a case of a 67 year old female with a rare primary apocrine carcinoma of the vulva.

  8. Second cancers after squamous cell carcinoma and adenocarcinoma of the cervix

    DEFF Research Database (Denmark)

    Chaturvedi, Anil K; Kleinerman, Ruth A; Hildesheim, Allan;

    2008-01-01

    PURPOSE: Although cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) are both caused by human papillomavirus (HPV) infection, they differ in cofactors such as cigarette smoking. We assessed whether these cofactor differences translate into differences in second cancer risk. PATIENTS...... AND METHODS: We assessed second cancer risk among 85,109 cervical SCC and 10,280 AC survivors reported to population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States. Risks compared to the general population were assessed using standardized incidence ratios (SIR). RESULTS......: Overall cancer risk was significantly increased among both cervical SCC survivors (n = 10,559 second cancers; SIR, 1.31; 95% CI, 1.29 to 1.34) and AC survivors (n = 920 second cancers; SIR, 1.29; 95% CI, 1.22 to 1.38). Risks of HPV-related and radiation-related cancers were increased to a similar extent...

  9. Double Primary Tumors-Renal Cell Carcinoma and Duodenal Mucinous Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Dejan Vuckovic

    2012-12-01

    Full Text Available A 59-year old patient was admited to the Gastroenterology Clinic with the signs of gastrointestinal bleeding. Computerized tomography (CT and a barium-meal radiography revealed a circumferential nodular wall narrowing and incomplete stricture at the D2 part of the duodenum. CT also showed a poorly demarcated mass in the upper and lower poles of the left kidney. During the operation, the whole kidney together with the tumor was removed and also a part of the duodenum. Morphological features of both tumors were typical and distinctive enough to set the diagnosis of two independent primary tumors. The possibility of one being the metastasis of the other was excluded. The diagnosis of double primary malignant neoplasms - renal cell carcinoma and duodenal mucinous adenocarcinoma was made.

  10. Apoptosis signal-regulating kinase 1 mediates denbinobin-induced apoptosis in human lung adenocarcinoma cells

    Directory of Open Access Journals (Sweden)

    Pan Shiow-Lin

    2009-05-01

    Full Text Available Abstract In the present study, we explore the role of apoptosis signal-regulating kinase 1 (ASK1 in denbinobin-induced apoptosis in human lung adenocarcinoma (A549 cells. Denbinobin-induced cell apoptosis was attenuated by an ASK1 dominant-negative mutant (ASK1DN, two antioxidants (N-acetyl-L-cysteine (NAC and glutathione (GSH, a c-Jun N-terminal kinase (JNK inhibitor (SP600125, and an activator protein-1 (AP-1 inhibitor (curcumin. Treatment of A549 cells with denbinobin caused increases in ASK1 activity and reactive oxygen species (ROS production, and these effects were inhibited by NAC and GSH. Stimulation of A549 cells with denbinobin caused JNK activation; this effect was markedly inhibited by NAC, GSH, and ASK1DN. Denbinobin induced c-Jun phosphorylation, the formation of an AP-1-specific DNA-protein complex, and Bim expression. Bim knockdown using a bim short interfering RNA strategy also reduced denbinobin-induced A549 cell apoptosis. The denbinobin-mediated increases in c-Jun phosphorylation and Bim expression were inhibited by NAC, GSH, SP600125, ASK1DN, JNK1DN, and JNK2DN. These results suggest that denbinobin might activate ASK1 through ROS production to cause JNK/AP-1 activation, which in turn induces Bim expression, and ultimately results in A549 cell apoptosis.

  11. DNA damage response signaling in lung adenocarcinoma A549 cells following gamma and carbon beam irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, Somnath [Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India); Narang, Himanshi, E-mail: himinarang@gmail.com [Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India); Sarma, Asitikantha [Radiation Biology Laboratory, Inter University Accelerator Centre, Aruna Asaf Ali Marg, New Delhi 110 067 (India); Krishna, Malini [Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India)

    2011-11-01

    Carbon beams (5.16 MeV/u, LET = 290 keV/{mu}m) are high linear energy transfer (LET) radiation characterized by higher relative biological effectiveness than low LET radiation. The aim of the current study was to determine the signaling differences between {gamma}-rays and carbon ion-irradiation. A549 cells were irradiated with 1 Gy carbon or {gamma}-rays. Carbon beam was found to be three times more cytotoxic than {gamma}-rays despite the fact that the numbers of {gamma}-H2AX foci were same. Percentage of cells showing ATM/ATR foci were more with {gamma}-rays however number of foci per cell were more in case of carbon irradiation. Large BRCA1 foci were found in all carbon irradiated cells unlike {gamma}-rays irradiated cells and prosurvival ERK pathway was activated after {gamma}-rays irradiation but not carbon. The noteworthy finding of this study is the early phase apoptosis induction by carbon ions. In the present study in A549 lung adenocarcinoma, authors conclude that despite activation of same repair molecules such as ATM and BRCA1, differences in low and high LET damage responses might be due to their distinct macromolecular complexes rather than their individual activation and the activation of cytoplasmic pathways such as ERK, whether it applies to all the cell lines need to be further explored.

  12. Phospholipid flippase associates with cisplatin resistance in plasma membrane of lung adenocarcinoma A549 cells

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The fusion of the liposomes containing N-(7-nitro-2, 1, 3-benzoxadiazol-4-yl)-i ,2-hexadecanoylSn-glycero-3-1abeled phosphatidylethanolamine (NBD-PE) with A549 and A549/DDP cells was performed, and the activity of the phospholipid flippase in the plasma membrane of the cells was measured by fluorescence intensity change of NBDPE in the outer membrane. When A549 or A549/DDP cells containing N BD-PE were incubated at 37 C for 0, 30, 60 and 90 min, the fluorescence intensities in the outer membrane of the cells were 0%, 1.4%, 2.9% and 7.8% for A59cells, and 0%, 10.5 %, 15. 5 % and 18.3 % for A549/DDP cells respectively, demonstrating that the phospholipid flippase was distributed in the plasma membrane of As49 cells, but its activity in the drug-resistant A549/DDP cells was much higher than that in the A549 cells. When the A549/DDP cells were incubated with a multidrug resistance reverse agent, verapamil, for 60 min at 37C, the results showed that the NBD-PE in outer membrane decreased by 25.0% compared with the control's. Furthermore, when A549/DDP cells were incubated with 25 μmol/L cisplatin, which is a specific anticancer drug, the flippase activity decreased by 31.6%, and it further decreased with the increase of cisplatin concentration, suggesting that phospholipid flippase in the membrane might be related to the cisplatin-resistance of human lung adenocarcinoma cancer cells.

  13. Inhibition of Prostaglandin Reductase 2, a Putative Oncogene Overexpressed in Human Pancreatic Adenocarcinoma, Induces Oxidative Stress-Mediated Cell Death Involving xCT and CTH Gene Expressions through 15-Keto-PGE2.

    Directory of Open Access Journals (Sweden)

    Emily Yun-Chia Chang

    Full Text Available Prostaglandin reductase 2 (PTGR2 is the enzyme that catalyzes 15-keto-PGE2, an endogenous PPARγ ligand, into 13,14-dihydro-15-keto-PGE2. Previously, we have reported a novel oncogenic role of PTGR2 in gastric cancer, where PTGR2 was discovered to modulate ROS-mediated cell death and tumor transformation. In the present study, we demonstrated the oncogenic potency of PTGR2 in pancreatic cancer. First, we observed that the majority of the human pancreatic ductal adenocarcinoma tissues was stained positive for PTGR2 expression but not in the adjacent normal parts. In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2. Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT and cystathionine gamma-lyase (CTH, two important providers of intracellular cysteine for the generation of glutathione (GSH, which is widely accepted as the first-line antioxidative defense. The oxidative stress-mediated cell death after silencing of PTGR2 or addition of 15-keto-PGE2 was further abolished after restoring intracellular GSH concentrations and cysteine supply by N-acetyl-L-cysteine and 2-Mercaptomethanol. Our data highlight the therapeutic potential of targeting PTGR2/15-keto-PGE2 for pancreatic cancer.

  14. Radiation induced esophageal adenocarcinoma in a woman previously treated for breast cancer and renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Raissouni Soundouss

    2012-08-01

    Full Text Available Abstract Background Secondary radiation-induced cancers are rare but well-documented as long-term side effects of radiation in large populations of breast cancer survivors. Multiple neoplasms are rare. We report a case of esophageal adenocarcinoma in a patient treated previously for breast cancer and clear cell carcinoma of the kidney. Case presentation A 56 year-old non smoking woman, with no alcohol intake and no familial history of cancer; followed in the National Institute of Oncology of Rabat Morocco since 1999 for breast carcinoma, presented on consultation on January 2011 with dysphagia. Breast cancer was treated with modified radical mastectomy, 6 courses of chemotherapy based on CMF regimen and radiotherapy to breast, inner mammary chain and to pelvis as castration. Less than a year later, a renal right mass was discovered incidentally. Enlarged nephrectomy realized and showed renal cell carcinoma. A local and metastatic breast cancer recurrence occurred in 2007. Patient had 2 lines of chemotherapy and 2 lines of hormonotherapy with Letrozole and Tamoxifen assuring a stable disease. On January 2011, the patient presented dysphagia. Oesogastric endoscopy showed middle esophagus stenosing mass. Biopsy revealed adenocarcinoma. No evidence of metastasis was noticed on computed tomography and breast disease was controlled. Palliative brachytherapy to esophagus was delivered. Patient presented dysphagia due to progressive disease 4 months later. Jejunostomy was proposed but the patient refused any treatment. She died on July 2011. Conclusion We present here a multiple neoplasm in a patient with no known family history of cancers. Esophageal carcinoma is most likely induced by radiation. However the presence of a third malignancy suggests the presence of genetic disorders.

  15. Effects of NVP-BEZ235 on the proliferation, migration, apoptosis and autophagy in HT-29 human colorectal adenocarcinoma cells.

    Science.gov (United States)

    Yu, Yang; Yu, Xiaofeng; Ma, Jianxia; Tong, Yili; Yao, Jianfeng

    2016-07-01

    The phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) pathway plays a significant role in colorectal adenocarcinoma. NVP-BEZ235 (dactolisib) is a novel dual inhibitor of PI3K/mTOR. The effects of NVP-BEZ235 in human colorectal adenocarcinoma are still unclear. In the present study, we aimed to explore the proliferation, migration, apoptosis and autophagy in HT-29 human colorectal adenocarcinoma cells. HT-29 human colorectal adenocarcinoma cells were treated with NVP-BEZ235 (0, 0.001, 0.01, 0.1, 1 and 3 µM) for 24 and 48 h, respectively. Cells were also treated with NVP-BEZ235 (0.1 µM), DDP (100, 300 and 1,000 µM), and NVP-BEZ235 (0.1 µM) combined with DDP (100, 300 and 1,000 µM) respectively, and cultured for 24 h after treatment. MTT assay was utilized to evaluate the effects of NVP-BEZ235 alone or NVP-BEZ235 combined with cis-diamminedichloroplatinum (DDP) on proliferation of HT-29 cells. Cell wound-scratch assay was used detect cell migration. In addition, expression of microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B and LC3B) in HT-29 cells was detected by immunofluorescence at 48 h after NVP-BEZ235 (1 µM) treatment. Expression of proteins involved in cell cycle and proliferation (p-Akt, p-mTOR and cyclin D1), apoptosis (cleaved caspase-3), and autophagy (cleaved LC3B and Beclin-1) were detected by western blot analysis. NVP-BEZ235 inhibited the proliferation and migration of HT-29 human colorectal adenocarcinoma cells. NVP-BEZ235 decreased protein expression of p-Akt, p-mTOR and cyclin D1, and increased protein expression of cleaved caspase-3, cleaved LC3B and Beclin-1 as the concentrations and the incubation time of NVP-BEZ235 increased. In addition, NVP-BEZ235 and DDP had synergic effects in inhibiting cell proliferation and migration. The expression of protein involved in apoptosis (cleaved caspase-3) was higher in drug combination group compared to the NVP-BEZ235 single treatment group. NVP-BEZ235

  16. Fibroadenoma with "immature-like" type of usual ductal hyperplasia.

    Science.gov (United States)

    Bezić, Joško; Karaman, Ivana; Kunac, Nenad

    2016-01-01

    We herein report a case of the breast fibroadenoma with foci of so-called immature variant of the conventional ductal hyperplasia. This type of usual ductal hyperplasia is histologically characterised by encircling intraductal proliferation of large cells with pale to amphophilic cytoplasm and large nuclei which vary in shape and in staining quality of the chromatin. We showed here, using the cytokeratin immunohistochemistry, that the proliferating cells were not of immature but rather mature immunohistochemical phenotype. Because of the presented discordance between immature histology and mature immunohistological profile we suggest that this rare type of usual ductal hyperplasia should be called "immature-like".

  17. [Ultrastructural organization of the epithelial layers and surface morphological characteristics of cells in adenocarcinomas of the cervix uteri].

    Science.gov (United States)

    Chernyĭ, A P

    1984-08-01

    The cell interrelations, and cellular attachment to the stroma in normal columnar epithelium and adenocarcinoma of the cervix uteri were examined by transmission and scanning electron microscopy. The application of rapid enzymatic digestion technique allows to visualize the topography of cell membranes, otherwise disguised in ordinary conditions. Four types of disordered epithelial sheets characterized by different apical, lateral and basal cell surface changes are described. Various alterations in morphology of the basement membrane and adjacent conjunctive tissue are associated with the tumor appearance. Marked deviations in cell-stroma contact may lead to the inversion of cell polarity revealed in cervical adenocarcinoma: cellular parts adjoining to stroma acquire characteristic features of the apical pole.

  18. Annexin A4 is involved in proliferation, chemo-resistance and migration and invasion in ovarian clear cell adenocarcinoma cells.

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    Tae Mogami

    Full Text Available Ovarian clear cell adenocarcinoma (CCC is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca(++-binding annexin A4 (ANXA4 protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.

  19. Annexin A4 is involved in proliferation, chemo-resistance and migration and invasion in ovarian clear cell adenocarcinoma cells.

    Science.gov (United States)

    Mogami, Tae; Yokota, Naho; Asai-Sato, Mikiko; Yamada, Roppei; Koizume, Shiro; Sakuma, Yuji; Yoshihara, Mitsuyo; Nakamura, Yoshiyasu; Takano, Yasuo; Hirahara, Fumiki; Miyagi, Yohei; Miyagi, Etsuko

    2013-01-01

    Ovarian clear cell adenocarcinoma (CCC) is the second most common subtype of ovarian cancer after high-grade serous adenocarcinomas. CCC tends to develop resistance to the standard platinum-based chemotherapy, and has a poor prognosis when diagnosed in advanced stages. The ANXA4 gene, along with its product, a Ca(++)-binding annexin A4 (ANXA4) protein, has been identified as the CCC signature gene. We reported two subtypes of ANXA4 with different isoelectric points (IEPs) that are upregulated in CCC cell lines. Although several in vitro investigations have shown ANXA4 to be involved in cancer cell proliferation, chemoresistance, and migration, these studies were generally based on its overexpression in cells other than CCC. To elucidate the function of the ANXA4 in CCC cells, we established CCC cell lines whose ANXA4 expressions are stably knocked down. Two parental cells were used: OVTOKO contains almost exclusively an acidic subtype of ANXA4, and OVISE contains predominantly a basic subtype but also a detectable acidic subtype. ANXA4 knockdown (KO) resulted in significant growth retardation and greater sensitivity to carboplatin in OVTOKO cells. ANXA4-KO caused significant loss of migration and invasion capability in OVISE cells, but this effect was not seen in OVTOKO cells. We failed to find the cause of the different IEPs of ANXA4, but confirmed that the two subtypes are found in clinical CCC samples in ratios that vary by patient. Further investigation to clarify the mechanism that produces the subtypes is needed to clarify the function of ANXA4 in CCC, and might allow stratification and improved treatment strategies for patients with CCC.

  20. 1-MT Enhances Potency of Tumor Cell Lysate-pulsed Dendritic Cells against Pancreatic Adenocarcinoma by Downregulating the Percentage of Tregs

    Institute of Scientific and Technical Information of China (English)

    李元栋; 徐钧; 邹浩军; 王春友

    2010-01-01

    This study examined whether 1-methyl-tryptophan [1-MT,an indoleamine 2,3-dioxygenase(IDO) inhibitor] could reduce CD4+CD25+ regulatory T cells(Tregs) proliferation and improve the anti-tumor efficacy of dendritic cells(DCs) pulsed with tumor cell lysate in the mice bearing pancreatic adenocarcinoma.The models of pancreatic adenocarcinoma were established in C57BL/6 mice by subcutaneous injection of Pan02 cells.Eight mice which were subcutaneously injected with PBS served as control.The expression of IDO was...

  1. Effects of Spinach Powder Fat-Soluble Extract on Proliferation of Human Gastric Adenocarcinoma Cells

    Institute of Scientific and Technical Information of China (English)

    HE TAo; HUANG CHENG-YU; CHEN HAl; HOU YUN-HUA

    1999-01-01

    Four kinds of assays were used to study the effect of a fat-soluble extract of spinach powder(SPFE) on the proliferation of human gastric adenocarcinoma cell line (SGC-7901) in vitro.These studies included: ( i ) cell growth assay, ( ii ) colony forming assay, ( iii ) MTT colorimetric assay, and ( iv ) 3H-TdR incorporation assay. The concentrations of SPFE expressed as the level of β-carotene in the medium were 2 × 10-s, 2 × 10-7 and 2 × 10-6 mol/L β-carotene in assays ( i ) ~ ( iii ), but 4 × 10-8, 4 × 10-7 and 4 × 10-6 mol/L β-carotene in assay ( iV ) respectively. The results indicated that SPFE inhibited the proliferation and colony forming ability of SGC-7901 cells. And in MTT assay, SPFE inhibited the viability of SGC-7901 cells, but no inhibitory effect of SPFE was observed on the viability of lymphocytes in peripheral blood of healthy people. Finally, in the 3H-TdR incorporation test, both SPFE and β-carotene showed significant inhibitory effects on DNA synthesis in SGC-7901 cells, but SPFE was more effective than 3-carotene.

  2. TROP2 overexpression promotes proliferation and invasion of lung adenocarcinoma cells

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    Li, Zanhua [Medical School of Nanchang University (China); The Chest Hospital of Jiangxi Province Department of Respiration (China); Jiang, Xunsheng [Department of Respiration, Medical School of Nanchang University (China); Zhang, Wei, E-mail: weizhangncu@gmail.com [Department of Respiration, The First Affiliated Hospital of Nanchang University (China)

    2016-01-29

    Recent studies suggest that the human trophoblast cell-surface antigen TROP2 is highly expressed in a number of tumours and is correlated with poor prognosis. However, its role in non-small cell lung carcinoma (NSCLC) remains largely unknown. Here we examined TROP2 expression by immunohistochemistry in a series of 68 patients with adenocarcinoma (ADC). We found significantly elevated TROP2 expression in ADC tissues compared with normal lung tissues (P < 0.05), and TROP2 overexpression was significantly associated with TNM (tumour, node, metastasis) stage (P = 0.012), lymph node metastasis (P = 0.038), and histologic grade (P = 0.013). Kaplan–Meier survival analysis revealed that high TROP2 expression correlated with poor prognosis (P = 0.046). Multivariate analysis revealed that TROP2 expression was an independent prognostic marker for overall survival of ADC patients. Moreover, TROP2 overexpression enhanced cell proliferation, migration, and invasion in the NSCLC cell line A549, whereas knockdown of TROP2 induced apoptosis and impaired proliferation, migration, and invasion in the PC-9 cells. Altogether, our data suggest that TROP2 plays an important role in promoting ADC and may represent a novel prognostic biomarker and therapeutic target for the disease.

  3. Proapoptotic effects of new pentabromobenzylisothiouronium salts in a human prostate adenocarcinoma cell line.

    Science.gov (United States)

    Koronkiewicz, Mirosława; Kazimierczuk, Zygmunt; Szarpak, Kinga; Chilmonczyk, Zdzisław

    2012-01-01

    Prostate cancer is the second most common cancer in elderly men worldwide and its incidence rate is rising continuously. Agents capable of inducing apoptosis in prostate cancer cells seem a promising approach to treat this malignancy. In this study we describe the synthesis of a number of novel N- and N,N'-substituted S-2,3,4,5,6-pentabromobenzylisothiouronium bromides and their activity against the human prostate adenocarcinoma PC3 cell line. All the compounds produced changes in mitochondrial transmembrane potential and cell cycle progression, showed a cytostatic effect and induced apoptosis in the tested cancer line in a concentration- and time-dependent manner. The most effective compounds ZKK-3, ZKK-9 and ZKK-13 produced, at 20 microM concentration, apoptosis in 42, 46, and 66% of the cells, respectively, after 48 h incubation. Two selected S-2,3,4,5,6-pentabromobenzylisothiouronium bromides (ZKK-3, ZKK-9) showed also a synergic proapoptotic effect with the new casein kinase II inhibitor 2-(4-methylpiperazin-1-yl)-4,5,6,7-tetrabromo-1H-benzimidazole (TBIPIP) in the PC3 cell line.

  4. Cytoplasmic Overexpression of CD95L in Esophageal Adenocarcinoma Cells Overcomes Resistance to CD95-Mediated Apoptosis

    Directory of Open Access Journals (Sweden)

    Gregory A. Watson

    2011-03-01

    Full Text Available Introduction: The CD95/CD95L pathway plays a critical role in tissue homeostasis and immune system regulation; however, the function of this pathway in malignancy remains poorly understood. We hypothesized that CD95L expression in esophageal adenocarcinoma confers advantages to the neoplasm other than immune privilege. Methods: CD95L expression was characterized in immortalized squamous esophagus (HET-1A and Barrett esophagus (BAR-T cells; adenocarcinoma cell lines FLO-1, SEG-1, and BIC-1, and MDA468 (- control; and KFL cells (+ control. Analyses included reverse transcription-polymerase chain reaction, immunoblots of whole cell and secretory vesicle lysates, FACScan analysis, laser scanning confocal microscopy of native proteins and fluorescent constructs, and assessment of apoptosis and ERK1/2 pathways. Results: Cleaved, soluble CD95L is expressed at both the RNA and protein levels in these cell lines derived from esophageal adenocarcinoma and other human tissues. CD95L was neither trafficked to the cell membrane nor secreted into the media or within vesicles, rather the protein seems to be sequestered in the cytoplasm. CD95 and CD95L colocalize by immunofluorescence, but an interaction was not proven by immunoprecipitation. Overexpression of CD95L in the adenocarcinoma cell lines induced robust apoptosis and, under conditions of pan-caspase inhibition, resulted in activation of ERK signaling. Conclusions: CD95L localization in EA cells is inconsistent with the conference of immune privilege and is more consistent with a function that promotes tumor growth through alternative CD95 signaling. Reduced cell surface expression of CD95 affects cell sensitivity to extracellular apoptotic signals more significantly than alterations in downstream modulators of apoptosis.

  5. Hypoxia and prostaglandin E receptor 4 signalling pathways synergise to promote endometrial adenocarcinoma cell proliferation and tumour growth.

    Directory of Open Access Journals (Sweden)

    Rob D Catalano

    Full Text Available The prostaglandin endoperoxide synthase (PTGS pathway is a potent driver of tumour development in humans by enhancing the biosynthesis and signalling of prostaglandin (PG E(2. PTGS2 expression and PGE(2 biosynthesis is elevated in endometrial adenocarcinoma, however the mechanism whereby PTGS and PGE(2 regulate endometrial tumour growth is unknown. Here we investigated (a the expression profile of the PGE synthase enzymes (PTGES, PTGES-2, PTGES-3 and PGE receptors (PTGER1-4 in endometrial adenocarcinomas compared with normal endometrium and (b the role of PTGER4 in endometrial tumorigenesis in vivo. We found elevated expression of PTGES2 and PTGER4 and suppression of PTGER1 and PTGER3 in endometrial adenocarcinomas compared with normal endometrium. Using WT Ishikawa endometrial adenocarcinoma cells and Ishikawa cells stably transfected with the full length PTGER4 cDNA (PTGER4 cells xenografted in the dorsal flanks of nude mice, we show that PTGER4 rapidly and significantly enhances tumour growth rate. Coincident with enhanced PTGER4-mediated tumour growth we found elevated expression of PTGS2 in PTGER4 xenografts compared with WT xenografts. Furthermore we found that the augmented growth rate of the PTGER4 xenografts was not due to enhanced angiogenesis, but regulated by an increased proliferation index and hypoxia. In vitro, we found that PGE(2 and hypoxia independently induce expression of PTGER4 indicating two independent pathways regulating prostanoid receptor expression. Finally we have shown that PGE(2 and hypoxia synergise to promote cellular proliferation of endometrial adenocarcinoma cells.

  6. Sensitivity of gastric adenocarcinoma and normal cell lines against combined or conjugated antimetabolites.

    Science.gov (United States)

    Weinreich, Jürgen; Struller, Florian; Küper, Markus; Hack, Anita; Königsrainer, Alfred; Schott, Timm C

    2013-04-01

    The in-vitro growth inhibition of cancer and normal cell lines caused by mixed or covalently linked antimetabolites should clarify whether the conjugation of antimetabolites influences cell sensitivity and growth inhibition in a manner that differs from an equimolar mixture of the same antimetabolites or not. Growth inhibition of the human gastric adenocarcinoma cell lines 23132/87 and MKN-45 in comparison with normal gastric intestinal CCL-241 and the dermal fibroblast cell line NHDF was evaluated using CASY technology. The cell lines were incubated with an equimolar mixture of 5-fluoro-2'-deoxyuridine (5FdU)+3'-C-ethynylcytidine (ECyd) or the covalently linked duplex drug 5FdU(5'→5')ECyd. The drug and metabolites of the assays and medium were determined semiquantitatively using high-performance liquid chromatography. The sensitivity of cancer and nonmalignant cell lines was clearly different against the duplex drug. A measure of 0.65 µmol/l 5FdU(5'→5')ECyd, for example, reduced the growth of MKN-45 or 23132/87 gastric cancer cells from 100% on day 0 to about 50 or 20% on day 10, respectively. However, under the same conditions, the growth of the nonmalignant NHDF and CCL-241 cell lines was not markedly inhibited. The cytostatic activity of the duplex drug is based on the active metabolites in and outside the cell formed by the degradation of 5FdU(5'→5')ECyd. The sensitivity of cell lines against the duplex drug depended on its ability to metabolize the duplex drug. 5FdU(5'→5')ECyd should be more advantageous for specific and efficient polychemotherapy of gastric cancer than the corresponding equimolar mixture of 5FdU+ECyd or a standard combination regime of single drugs.

  7. Sulforaphane‐induced apoptosis in Xuanwei lung adenocarcinoma cell line XWLC‐05

    Science.gov (United States)

    Zhou, Lan; Yao, Qian; Huang, Yun‐chao; Jiang, Hua; Wang, Chuan‐qiong; Fan, Lei

    2016-01-01

    Background Xuanwei district in Yunnan Province has the highest incidence of lung cancer in China, especially among non‐smoking women. Cruciferous vegetables can reduce lung cancer risk by prompting a protective mechanism against respiratory tract inflammation caused by air pollution, and are rich in sulforaphane, which can induce changes in gene expression. We investigated the effect of sulforaphane‐induced apoptosis in Xuanwei lung adenocarcinoma cell line (XWCL‐05) to explore the value of sulforaphane in lung cancer prevention and treatment. Methods Cell growth inhibition was determined by methyl thiazolyl tetrazolium assay; cell morphology and apoptosis were observed under transmission electron microscope; cell cycle and apoptosis rates were detected using flow cytometry; B‐cell lymphoma 2 (Bcl‐2) and Bcl‐2‐like protein 4 (Bax) messenger RNA expression were determined by quantitative PCR; and p53, p73, p53 upregulated modulator of apoptosis (PUMA), Bax, Bcl‐2, and caspase‐9 protein expression were detected by Western blotting. Results Sulforaphane inhibited XWLC‐05 cell growth with inhibitory concentration (IC)50 of 4.04, 3.38, and 3.02 μg/mL at 24, 48, and 72 hours, respectively. Sulforaphane affected the XWLC‐05 cell cycle as cells accumulated in the G2/M phase. The proportion of apoptotic cells observed was 27.6%. Compared with the control, the sulforaphane group showed decreased Bcl‐2 and p53 expression, and significantly increased p73, PUMA, Bax, and caspase‐9 protein expression (P cancer cells, downregulation of the anti‐apoptotic gene B cl ‐2, and activation of caspase‐9. It may also involve downregulation of the mutant p53 protein. PMID:27878984

  8. In vitro antiproliferative characteristics of flavonoids and diazepam on SNU-C4 colorectal adenocarcinoma cells.

    Science.gov (United States)

    Lee, Sang-Woo; Lee, Jae-Tae; Lee, Maan-Gee; Lee, Ho Won; Ahn, Sohn Joo; Lee, Yong Jin; Lee, You La; Yoo, Jeongsoo; Ahn, Byeong-Cheol; Ha, Jeoung-Hee

    2009-04-01

    The need for beneficial use of sedatives in oncologic patients is increasing. Therefore, in this study, antiproliferative characteristics of herbal and synthetic sedatives were examined in vitro in SNU-C4 human colorectal adenocarcinoma cells. Apigenin (50% inhibition concentration, IC(50) = 1.8 +/- 0.5 microM) and diazepam (IC(50) = 7.0 +/- 0.5 microM) showed concentration-dependent inhibition of SNU-C4 cancer cell survival. Efficacy of cancer cell survival inhibition by apigenin and diazepam was much lower than that of 5-fluorouracil (5-FU), a known chemotherapeutic drug. However, 10(-6) M concentration of apigenin and diazepam potentiated 5-FU-induced cytotoxicity. In SNU-C4 cells, 10(-6) M concentrations of diazepam, flumazenil (Ro15-1788), Ro5-4864, or PK11195, all ligands for central- or peripheral-type benzodiazepine (BZD) receptors, inhibited cell survival like the flavonoid apigenin (4',5,7-trihydroxyflavone) and fisetin (3,7,3',4'-tetrahydroxyflavone). Also like the plant flavonoids, treatment with 10(-6) M concentration of diazepam for 3 days hardly affect the peripheral-type BZD receptor (PBR) messenger RNA (mRNA) expression and inhibited glucose utilization of SNU-C4 cells. Treatment with flavonoids or diazepam for 6 days upregulated PBR mRNA expression and cell cytotoxicity of SNU-C4 cells. Furthermore, treatment with 10(-6) M concentration of apigenin, a natural sedative material originating from traditional herbs, positively modulated BZD-induced antiproliferative cytotoxicity in SNU-C4 cells. Overall, the in vitro antiproliferative activity on SNU-C4 cancer cells of herbal sedatives, such as apigenin, plus additive enhancement of synthetic BZD- and 5-FU-induced antiproliferative activities, were shown. In conclusion, this study provides experimental basis for advanced trial in the future.

  9. Astragalus saponins induce apoptosis in human gastric adenocarcinoma cells via a caspase 3-dependent pathway

    Institute of Scientific and Technical Information of China (English)

    JOSHUA K S Ko; Kathy K W Auyeung

    2008-01-01

    Objective Many Asian countriea including China, Japan and Korea have very high incidence of gastric cancer, in which about 42 % cases occur in mainland China. The precise targets and underlying mechanisms are not well understood. Our previous study revealed that Astragalus saponins (AST) showed promising effects on the suppression of the growth of HT-29 human colon cancer cells and tumor xenograft by inhibiting cell proliferation and promoting apoptosis. In the present study, we investigated the anti-carcinogenic effects of AST in AGS human gastric adenocarcinoma cells and attempted to elucidate the underlying mechanisms. Methods Growth inhibition of AGS cells was determined by using the MTT viability test. Involvement of different members of the apoptotic cascade and other growth-related factors was explored by assessment of their protein expression using Western blot analysis. Distribution of cells in different phases of the cell cycle was assessed by flow eytometry. Results Our data indicate that AST induced growth-inhibition and apoptosis in AGS cells by activating caspase 3 with subsequent poly (ADP-ribose) polymerase (PARP) cleavage. Cell cycle arrest at the G2/M phase had been observed in AST-treated AGS cells. The anti-proliferative effect of AST was associated with modulation of eydin B1 and p21. We then demonstrate that AST could downregulate the expression of VEGF, of which interaction with its receptors is important for angiogenesis during tumor formation. Conclusions Our findings suggest that AST is an effective agent in gastric cancer treatment by inducing cell cycle arrest and apoptosis, of which anti-angiogenesis could be an alternative mode of action.

  10. UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Dando, Ilaria; Fiorini, Claudia; Pozza, Elisa Dalla; Padroni, Chiara; Costanzo, Chiara; Palmieri, Marta; Donadelli, Massimo

    2013-03-01

    Mitochondrial uncoupling protein 2 (UCP2) can moderate oxidative stress by favoring the influx of protons into the mitochondrial matrix, thus reducing electron leakage from respiratory chain and mitochondrial superoxide production. Here, we demonstrate that UCP2 inhibition by genipin or UCP2 siRNA strongly increases reactive oxygen species (ROS) production inhibiting pancreatic adenocarcinoma cell growth. We also show that UCP2 inhibition triggers ROS-dependent nuclear translocation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), formation of autophagosomes, and the expression of the autophagy marker LC3-II. Consistently, UCP2 over-expression significantly reduces basal autophagy confirming the anti-autophagic role of UCP2. Furthermore, we demonstrate that autophagy induced by UCP2 inhibition determines a ROS-dependent cell death, as indicated by the apoptosis decrease in the presence of the autophagy inhibitors chloroquine (CQ) or 3-methyladenine (3-MA), or the radical scavenger NAC. Intriguingly, the autophagy induced by genipin is able to potentiate the autophagic cell death triggered by gemcitabine, the standard chemotherapeutic drug for pancreatic adenocarcinoma, supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to standard chemotherapy. Our results demonstrate for the first time that UCP2 plays a role in autophagy regulation bringing new insights into mitochondrial uncoupling protein field.

  11. Pathomorphological characteristics of the restructuring of pancreatic ductal system in chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    Kovalenko I.S.

    2013-01-01

    Full Text Available Background. Processes that could precede the development of pancreatic ductal adenocarcinoma are not well understood. Objective. Pathomorphological characteristics of the structural remodeling of the ductal apparatus of pancreas in patients with chronic pancreatitis, considering features of the ductal hypertension, proliferative and apoptotic activity of ductal epithelium. Methods. Complex pathomorphological study of pancreatic biopsies of 16 patients with severe pancreatic fibrosis at a chronic pancreatitis was performed. 10 patients had signs of pancreatic duct dilation, confirmed by ultrasound diagnostic, while in other patients ductal hypertension was not accompanied with the duct dilation. Immunohistochemical markers Ki-67 and Caspase-3 were used to detect proliferative and apoptotic activity, respectively. Results. Main morphological changes were manifested as: the concentric periductal fibrosis and local stenosis, the dysplastic changes of ductal epithelium with low level of proliferative activity and caspase -3 expression (in patients with pancreatic duct dilation; the cystic dilation of small and medium-sized intralobular ducts with low levels of Ki-67 and caspase-3 expression (in patients with ductal hypertension, but without pancreatic duct dilation; pancreatic intraepithelial neoplasia (PanIN is accompanied with the excessive nuclear Ki-67 expression and the low cytoplasmic caspase-3 levels. Conclusion. Structural remodeling of the pancreatic ductal system during chronic pancreatitis were not associated with rising of Ki-67 or Caspase-3 expression levels, unless in case of pancreatic intraepithelial neoplasia.

  12. Detection of circulating tumor cells in patients with esophagogastric or pancreatic adenocarcinoma using the CellSearch(®) system: An observational feasibility study.

    Science.gov (United States)

    Piegeler, Tobias; Winder, Thomas; Kern, Sabine; Pestalozzi, Bernhard; Schneider, Paul Magnus; Beck-Schimmer, Beatrice

    2016-08-01

    Circulating tumor cells (CTCs) in the blood of cancer patients have been demonstrated to be of prognostic value regarding metastasis and survival. The CellSearch(®) system has been certified for the detection of CTCs and as a prognostic tool in patients with metastatic breast, colon and prostate cancer. Few studies have evaluated the detection of CTCs originating from esophagogastric or pancreatic cancer with the CellSearch(®) system. In the present small pilot study, a total of 16 patients with either esophagogastric (n=8) or pancreatic (n=8) adenocarcinomas at various disease stages were randomly screened and included. A total of 7.5 ml of blood was drawn from each patient and analyzed for CTCs using the CellSearch(®) device. CTCs could be detected in 1 out of 8 patients (12.5%) with esophagogastric and in 7 out of 8 patients (87.5%) with pancreatic cancer. The preliminary data obtained from this observational feasibility study suggested that the CellSearch(®) system may become a valuable tool for the detection of CTCs in patients with pancreatic adenocarcinoma, whereas the usefulness in patients with early-stage esophagogastric adenocarcinoma may be limited. This study clearly points towards a requirement for larger studies focusing on patients with pancreatic adenocarcinoma at various disease stages and assessing CTCs, whereas patients with esophagogastric adenocarcinomas should be part of further pilot studies.

  13. Detection of circulating tumor cells in patients with esophagogastric or pancreatic adenocarcinoma using the CellSearch® system: An observational feasibility study

    Science.gov (United States)

    Piegeler, Tobias; Winder, Thomas; Kern, Sabine; Pestalozzi, Bernhard; Schneider, Paul Magnus; Beck-Schimmer, Beatrice

    2016-01-01

    Circulating tumor cells (CTCs) in the blood of cancer patients have been demonstrated to be of prognostic value regarding metastasis and survival. The CellSearch® system has been certified for the detection of CTCs and as a prognostic tool in patients with metastatic breast, colon and prostate cancer. Few studies have evaluated the detection of CTCs originating from esophagogastric or pancreatic cancer with the CellSearch® system. In the present small pilot study, a total of 16 patients with either esophagogastric (n=8) or pancreatic (n=8) adenocarcinomas at various disease stages were randomly screened and included. A total of 7.5 ml of blood was drawn from each patient and analyzed for CTCs using the CellSearch® device. CTCs could be detected in 1 out of 8 patients (12.5%) with esophagogastric and in 7 out of 8 patients (87.5%) with pancreatic cancer. The preliminary data obtained from this observational feasibility study suggested that the CellSearch® system may become a valuable tool for the detection of CTCs in patients with pancreatic adenocarcinoma, whereas the usefulness in patients with early-stage esophagogastric adenocarcinoma may be limited. This study clearly points towards a requirement for larger studies focusing on patients with pancreatic adenocarcinoma at various disease stages and assessing CTCs, whereas patients with esophagogastric adenocarcinomas should be part of further pilot studies. PMID:27446462

  14. Metastatic Pulmonary Adenocarcinoma 6 Years After Curative Resection for Ampullary Adenocarcinoma. Metastatic Disease from Initial Primary or Metachronous Tumour?

    Directory of Open Access Journals (Sweden)

    Alexandros Giakoustidis

    2011-01-01

    Full Text Available Context With patients surviving longer after pancreatic resection, the challenges now is the management of the unresolved longerterm issues. Case report A 53-year-old woman with painless obstructive jaundice, underwent a pylorous preserving pancreaticoduodenectomy for a pT3N0M0 ampullary adenocarcinoma in 2001 (patchy chronic pancreatitis with mucinous metaplasia of background pancreatic duct epithelium and acinar atrophy were noted. Despite adjuvant chemotherapy, at month 54 she required a pulmonary wedge resection for metastatic adenocarcinoma, followed by a pulmonary relapse at 76 months when she underwent 6 neoadjuvant cycles of gemcitabine/capecitabine and a left pneumonectomy. Finally 7 years after the initial Whipple’s, a single 18F fluorodeoxyglucose (FDG avid pancreatic tail lesion led to completion pancreatectomy for a well-differentiated ductal adenocarcinoma with clear resection margins albeit peripancreatic adipose tissue infiltration. On review all resected tumour cells had identical immunophenotype (CK7+/CK20-/MUC1+/MUC2- as that of the primary. She is currently asymptomatic on follow-up. Conclusions These findings suggest that in selected cases even in the presence of pulmonary metastasis, repeat resections could result in long-term survival of patients with metachronous ampullary cancer. Second, even ampullary tumours maybe should be regarded as index tumors in the presence of ductal precursor lesions in the resection specimen. Three distant metastases, particularly if long after the initial tumour, should instigate a search for metachronous tumour, especially in the presence of field change in the initial specimen. Risk-adapted follow-up protocols with recognition of such factors could result in cost-effective surveillance and potentially improved outcomes.

  15. SOX10-positive salivary gland tumors: a growing list, including mammary analogue secretory carcinoma of the salivary gland, sialoblastoma, low-grade salivary duct carcinoma, basal cell adenoma/adenocarcinoma, and a subgroup of mucoepidermoid carcinoma.

    Science.gov (United States)

    Hsieh, Min-Shu; Lee, Yi-Hsuan; Chang, Yih-Leong

    2016-10-01

    Transcription factor SRY-related HMG-box 10 (SOX10) is an important marker for melanocytic, schwannian, myoepithelial, and some salivary gland tumors. The aim of this study was to investigate SOX10 expression more thoroughly in the salivary gland neoplasms, including mammary analogue secretory carcinoma and hyalinizing clear cell carcinoma harboring specific genetic rearrangements. A new rabbit monoclonal anti-SOX10 antibody (clone EP268) was used to examine SOX10 expression in 14 different types of salivary gland tumors. We found that acinic cell carcinoma (AciCC), adenoid cystic carcinoma, mammary analogue secretory carcinoma (MASC), epithelial-myoepithelial carcinoma, low-grade salivary duct carcinoma, sialoblastoma, basal cell adenocarcinoma, basal cell adenoma, and pleomorphic adenoma were SOX10 positive. Salivary duct carcinoma, lymphoepithelial carcinoma, hyalinizing clear cell carcinoma, and oncocytoma were SOX10 negative. Earlier, mucoepidermoid carcinoma (MEC) was considered a SOX10-negative tumor. This study identified a subgroup of SOX10-positive MEC cases with characteristic polygonal epithelial cells, pale-to-eosinophilic cytoplasm, and colloid-like dense eosinophilic material. Our data show SOX10 expression can be observed in salivary gland tumors with either one of the 4 cell types: acinic cells, cuboidal ductal cells with low-grade cytologic features, basaloid cells, and myoepithelial cells. In this article we thoroughly evaluated SOX10 expression in salivary gland tumors. SOX10 is useful in the differential diagnosis between myoepithelial carcinoma with clear cell features and hyalinizing clear cell carcinoma. It can also be used to discriminate low-grade salivary duct carcinoma from high-grade ones. Pathologists should be cautious with the interpretation of SOX10 positivity in salivary gland tumors, and correlation with histologic feature is mandatory.

  16. Seminal plasma enhances cervical adenocarcinoma cell proliferation and tumour growth in vivo.

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    Jason R Sutherland

    Full Text Available Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2, cytokines interleukin (IL -6, and -11 and vascular endothelial growth factor-A (VEGF-A. To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.

  17. RESTRICTION ENDONUCLEASE ANALYSIS OF MITOCHONDRIAL DNA FROM HUMAN LUNG ADENOCARCINOMA CELL LINE SPC-A-1

    Institute of Scientific and Technical Information of China (English)

    HU Yide; QIAN Guisheng; CHEN Weizhong; LI Shuping; WANG Guansong; MAO Baoling

    1999-01-01

    Objective: To understand the role of mitochondrial DNA (mtDNA) in carcinogenesis. Methods: single-step method was used to isolate the mtDNA from human lung adenocarcinoma cell line SPC-A-1. The mtDNA was analyzed by restriction fragment length polymorphism (RFLP) with 11 kinds of restriction endonuclease, which were Pvu Ⅱ, Xho Ⅰ, Pst Ⅰ, EcoR Ⅰ,BstE Ⅱ, Hind Ⅲ, Hpa Ⅰ, Bcl Ⅰ, EcoR Ⅴ, Sca Ⅰ and Xba Ⅰ.Restriction map of mtDNA from SPC-A-1 cell was obtained by the single and double-digestion method.Results: It was found that no variation at 32 restrictionsites could be detected in the coding region of mtDNA from SPC-A-1 cell line. But a new site was found at nucleotide 16276 (EcoR Ⅴ) within the noncoding region.Conclusion: These results indicate that the primary structure of gene coding region of mtDNA isolated from SPC-A-1 cell is highly stable. While the major variation of nucleotide is probably located in the noncoding region.

  18. Evaluation of lignan (-)-cubebin extracted from Piper cubeba on human colon adenocarcinoma cells (HT29).

    Science.gov (United States)

    Niwa, Andressa Megumi; de Paula, Natalia Aparecida; Vesenick, Diogo Campos; Sartori, Daniele; Maistro, Edson Luis; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

    2016-01-01

    The dibenzylbutyrolactone lignan (-)-cubebin, which is extracted from the seeds of the pepper Piper cubeba, has shown promise as an anti-inflammatory, analgesic, leishmanicidal, antiproliferative, and trypanocidal compound. Given the therapeutic potential of (-)-cubebin, this study aimed to investigate its safety profile by analyzing cytotoxicity, mutagenicity, cell proliferation kinetics, induction of apoptosis, and expression of pro-apoptotic genes in human colon adenocarcinoma cells (HT29) exposed to (-)-cubebin. MTT cytotoxicity assays demonstrated that (-)-cubebin was cytotoxic only at 280 µM, whereas it was not cytotoxic at 2.8, 14, or 28 µM. Data demonstrated that (-)-cubebin was not mutagenic as evidenced by a micronucleus (MN) assay, did not alter cell-growth kinetics over 4 d, and showed absence of induced apoptosis after 24 h. Further, CASP8 and CASP9 gene expression was not markedly changed in HT29 cells exposed to 28 µM or 70 µM (-)-cubebin for 12 h. Based on our observations, (-)-cubebin was cytotoxic at a concentration of 280 µM, suggesting that the use of this concentration should be avoided. However, lower concentrations exerted no apparent damaging effects, indicating that this lignan is safe to use for pharmacological purposes at certain concentrations.

  19. Real-time growth kinetics measuring hormone mimicry for ToxCast chemicals in T-47D human ductal carcinoma cells.

    Science.gov (United States)

    Rotroff, Daniel M; Dix, David J; Houck, Keith A; Kavlock, Robert J; Knudsen, Thomas B; Martin, Matthew T; Reif, David M; Richard, Ann M; Sipes, Nisha S; Abassi, Yama A; Jin, Can; Stampfl, Melinda; Judson, Richard S

    2013-07-15

    High-throughput screening (HTS) assays capable of profiling thousands of environmentally relevant chemicals for in vitro biological activity provide useful information on the potential for disrupting endocrine pathways. Disruption of the estrogen signaling pathway has been implicated in a variety of adverse health effects including impaired development, reproduction, and carcinogenesis. The estrogen-responsive human mammary ductal carcinoma cell line T-47D was exposed to 1815 ToxCast chemicals comprising pesticides, industrial chemicals, pharmaceuticals, personal care products, cosmetics, food ingredients, and other chemicals with known or suspected human exposure potential. Cell growth kinetics were evaluated using real-time cell electronic sensing. T-47D cells were exposed to eight concentrations (0.006-100 μM), and measurements of cellular impedance were repeatedly recorded for 105 h. Chemical effects were evaluated based on potency (concentration at which response occurs) and efficacy (extent of response). A linear growth response was observed in response to prototypical estrogen receptor agonists (17β-estradiol, genistein, bisphenol A, nonylphenol, and 4-tert-octylphenol). Several compounds, including bisphenol A and genistein, induced cell growth comparable in efficacy to that of 17β-estradiol, but with decreased potency. Progestins, androgens, and corticosteroids invoked a biphasic growth response indicative of changes in cell number or cell morphology. Results from this cell growth assay were compared with results from additional estrogen receptor (ER) binding and transactivation assays. Chemicals detected as active in both the cell growth and ER receptor binding assays demonstrated potencies highly correlated with two ER transactivation assays (r = 0.72; r = 0.70). While ER binding assays detected chemicals that were highly potent or efficacious in the T-47D cell growth and transactivation assays, the binding assays lacked sensitivity in detecting

  20. Selected flavonoids potentiate the toxicity of cisplatin in human lung adenocarcinoma cells: A role for glutathione depletion

    OpenAIRE

    Kachadourian, Remy; LEITNER, VHEATHER M.; Day, Brian J.

    2007-01-01

    Adjuvant therapies that enhance the anti-tumor effects of cisplatin are actively being pursued. Growing evidence supports the involvement of mitochondrial dysfunction in the anti-cancer effect of cis-diammineplatinum(II) dichloride (cisplatin, CDDP). We examined the potential of using selective flavonoids that are effective in depleting tumor cells of glu-tathione (GSH) to potentiate cisplatin-mediated cytotoxicity in human lung adenocarcinoma (A549) cells. We found that cisplatin (40 μM, 48-...

  1. Qualidade de vida de doentes esofagectomizados: adenocarcinoma versus carcinoma epidermoide Quality of life of esophagectomized patients: adenocarcinoma versus squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Maricilda Regina Pereira

    2013-02-01

    Full Text Available OBJETIVO: Avaliar e comparar a qualidade de vida de pacientes esofagectomizados para tratamento de adenocarcinoma da junção esofagogástrica e de carcinoma epidermoide. MÉTODOS: estudo transversal no pós-operatório de doentes esofagectomizados por adenocarcinoma da junção esofagogástrica (Adenoca e carcinoma epidermóide (CEC, empregando o questionário SF-36 aplicado em 24 pacientes (10 por Adenoca e 14 por CEC, a partir do 5º mês de pós-operatório, incluindo os sintomas clínicos e a variação de peso. RESULTADOS: A avaliação da QV mostrou melhor resultado de capacidade funcional (p=0,018 para o grupo Adenoca. Houve correlação entre os domínios "saúde mental" e "limitação por aspectos emocionais" (p=0,003 e entre "dor" e "limitação por aspectos físicos" (p=0,003 nos dois tipos histológicos. A perda de peso foi maior nos esofagectomizados por Adenoca (45,9Kg, sem diferença significativa entre o IMC atual (p>0,66. A disfagia foi relatada por 83,3% dos pacientes, a anorexia por 58,3%, a dificuldade de mastigação por 42%, a náuseas e os vômitos por 41,7% e a diarréia por 29,2%, sem correlação com a QV relatada (p>0,05. CONCLUSÃO: O escore mais alto para capacidade funcional indica que o paciente com Adenoca foi capaz de realizar todo tipo de atividade física, incluindo as mais vigorosas em um nível maior que o paciente com CEC. Alguns sintomas persistiram no pós-operatório, porém não interferiram na qualidade de vida dos pacientes.OBJECTIVE: To evaluate and compare the quality of life (QOL of patients undergoing esophagectomy for treatment of adenocarcinoma of the esophagogastric junction and squamous cell carcinoma. METHODS: We conducted a cross-sectional study in postoperative patients submitted to esophagectomy for adenocarcinoma of the esophagogastric junction (ACA and squamous cell carcinoma (SCC, using the SF-36 questionnaire applied in 24 patients (10 ACAs and 14 SCCs, from the 5th months

  2. Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549

    Institute of Scientific and Technical Information of China (English)

    Bin YE; Yan XIE; Zheng-hong QIN; Jun-chao WU; Rong HAN; Jing-kang HE

    2011-01-01

    Aim:To assess the cytotoxic effect of crotoxin (CrTX),a potent neurotoxin extracted from the venom of the pit viper Crotalus durissus terrificus,in human lung adenocarcinoma A549 cells and investigated the underlying mechanisms.Methods:A549 cells were treated with gradient concentrations of CrTX,and the cell cycle and apoptosis were analyzed using a flow cytometric assay.The changes of cellular effectors p53,caspase-3 and cleaved caspase-3,total P38MAPK and pP38MAPK were investigated using Western blot assays.A549 xenograft model was used to examine the inhibition of CrTX on tumor growth in vivo.Results:Treatment of A549 cells with CrTX (25-200 μg/mL) for 48 h significantly inhibited the cell growth in a dose-dependent manner (IC50=78 μg/mL).Treatment with CrTX (25 iJg/mL) for 24 h caused G1 arrest and induced cell apoptosis.CrTX (25 μg/mL) significantly increased the expression of wt p53,cleaved caspase-3 and phospho-P38MAPK.Pretreatment with the specific P38MAPK inhibitor SB203580 (5 μmol/L) significantly reduced CrTX-induced apoptosis and cleaved caspase-3 level,but G1 arrest remained unchanged and highly expressed p53 sustained.Intraperitoneal injection of CrTX (10 μg/kg,twice a week for 4 weeks) significantly inhibited A549 tumor xenograft growth,and decreased MVD and VEGF levels.Conclusion:CrTX produced significant anti-tumor effects by inducing cell apoptosis probably due to activation of P38MAPK and caspase-3,and by cell cycle arrest mediated by increased wt p53 expression.In addition,CrTX displayed anti-angiogenic effects in vivo.

  3. Fisetin, a dietary phytochemical, overcomes Erlotinib-resistance of lung adenocarcinoma cells through inhibition of MAPK and AKT pathways.

    Science.gov (United States)

    Zhang, Liang; Huang, Yi; Zhuo, Wenlei; Zhu, Yi; Zhu, Bo; Chen, Zhengtang

    2016-01-01

    Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor for treatment of non-small cell lung cancer (NSCLC). However, its efficacy is usually reduced by the occurrence of drug resistance. Our recent study showed that a flavonoid found in many plants, Fisetin, might have a potential to reverse the acquired Cisplatin-resistance of lung adenocarcinoma. In the present study, we aimed to test whether Fisetin could have the ability to reverse Erlotinib-resistance of lung cancer cells. Erlotinib-resistant lung adenocarcinoma cells, HCC827-ER, were cultured from the cell line HCC827, and the effects of Fisetin and Erlotinib on the cell viability and apoptosis were evaluated. The possible signaling pathways in this process were also detected. As expected, the results showed that Fisetin effectively increased sensitivity of Erlotinib-resistant lung cancer cells to Erlotinib, possibly by inhibiting aberrant activation of MAPK and AKT signaling pathways resulted from AXL suppression. In conclusion, Fisetin was a potential agent for reversing acquired Erlotinib-resistance of lung adenocarcinoma. Inactivation of AXL, MAPK and AKT pathways might play a partial role in this process.

  4. Identification of crucial microRNAs and genes in hypoxia-induced human lung adenocarcinoma cells

    Directory of Open Access Journals (Sweden)

    Geng Y

    2016-07-01

    Full Text Available Ying Geng,1,* Lili Deng,2,* Dongju Su,1 Jinling Xiao,1 Dongjie Ge,3 Yongxia Bao,1 Hui Jing4 1Department of Respiratory, 2Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 3Department of Respiratory, The First Hospital of Harbin, 4Department of Emergency, The Second Affiliated Hospital of Harbin Medical University Harbin, Heilongjiang, People’s Republic of China *These authors contributed equally to this work Background: Variations of microRNA (miRNA expression profile in hypoxic lung cancer cells have not been studied so far. Therefore, using miRNA microarray technology, this study aimed to study the miRNA expression profile and investigate the potential crucial miRNAs and their target genes in hypoxia-induced human lung adenocarcinoma cells.Materials and methods: Based on miRNA microarray, miRNA expression profiling of hypoxia-induced lung adenocarcinoma A549 cells was obtained. After identification of differentially expressed miRNAs (DE-miRNAs in hypoxic cells, target genes of DE-miRNAs were predicted, and functional enrichment analysis of targets was conducted. Furthermore, the expression levels of DE-miRNAs and their target genes were validated by real-time quantitative polymerase chain reaction. In addition, using miRNA mimics, the effect of overexpressed DE-miRNAs on A549 cell behaviors (cell proliferation, cell cycle, and apoptosis was evaluated.Results: In total, 14 DE-miRNAs (nine upregulated miRNAs and five downregulated miRNAs were identified in hypoxic cells, compared with normoxic cells. Target genes of both upregulated and downregulated miRNAs were enriched in the functions such as chromatin modification, and pathways such as Wnt signaling pathway and transforming growth factor (TGF-β signaling pathway. The expression levels of several miRNAs and their target genes were confirmed, including hsa-miR-301b/FOXF2, hsa-miR-148b-3p/WNT10B, hsa-miR-769-5p/(SMAD2, ARID1A, and hsa-miR-622. Among them

  5. Authentication and characterisation of a new oesophageal adenocarcinoma cell line: MFD-1

    Science.gov (United States)

    Garcia, Edwin; Hayden, Annette; Birts, Charles; Britton, Edward; Cowie, Andrew; Pickard, Karen; Mellone, Massimiliano; Choh, Clarisa; Derouet, Mathieu; Duriez, Patrick; Noble, Fergus; White, Michael J.; Primrose, John N.; Strefford, Jonathan C.; Rose-Zerilli, Matthew; Thomas, Gareth J.; Ang, Yeng; Sharrocks, Andrew D.; Fitzgerald, Rebecca C.; Underwood, Timothy J.; MacRae, Shona; Grehan, Nicola; Abdullahi, Zarah; de la Rue, Rachel; Noorani, Ayesha; Elliott, Rachael Fels; de Silva, Nadeera; Bornschein, Jan; O’Donovan, Maria; Contino, Gianmarco; Yang, Tsun-Po; Chettouh, Hamza; Crawte, Jason; Nutzinger, Barbara; Edwards, Paul A. W.; Smith, Laura; Miremadi, Ahmad; Malhotra, Shalini; Cluroe, Alison; Hardwick, Richard; Davies, Jim; Ford, Hugo; Gilligan, David; Safranek, Peter; Hindmarsh, Andy; Sujendran, Vijayendran; Carroll, Nick; Turkington, Richard; Hayes, Stephen J.; Ang, Yeng; Preston, Shaun R.; Oakes, Sarah; Bagwan, Izhar; Save, Vicki; Skipworth, Richard J. E.; Hupp, Ted R.; O’Neill, J. Robert; Tucker, Olga; Taniere, Philippe; Owsley, Jack; Crichton, Charles; Schusterreiter, Christian; Barr, Hugh; Shepherd, Neil; Old, Oliver; Lagergren, Jesper; Gossage, James; Davies, Andrew; Chang, Fuju; Zylstra, Janine; Sanders, Grant; Berrisford, Richard; Harden, Catherine; Bunting, David; Lewis, Mike; Cheong, Ed; Kumar, Bhaskar; Parsons, Simon L.; Soomro, Irshad; Kaye, Philip; Saunders, John; Lovat, Laurence; Haidry, Rehan; Eneh, Victor; Igali, Laszlo; Welch, Ian; Scott, Michael; Sothi, Shamila; Suortamo, Sari; Lishman, Suzy; Beardsmore, Duncan; Anderson, Charlotte; Smith, Mike L.; Secrier, Maria; Eldridge, Matthew D.; Bower, Lawrence; Achilleos, Achilleas; Lynch, Andy G.; Tavare, Simon

    2016-01-01

    New biological tools are required to understand the functional significance of genetic events revealed by whole genome sequencing (WGS) studies in oesophageal adenocarcinoma (OAC). The MFD-1 cell line was isolated from a 55-year-old male with OAC without recombinant-DNA transformation. Somatic genetic variations from MFD-1, tumour, normal oesophagus, and leucocytes were analysed with SNP6. WGS was performed in tumour and leucocytes. RNAseq was performed in MFD-1, and two classic OAC cell lines FLO1 and OE33. Transposase-accessible chromatin sequencing (ATAC-seq) was performed in MFD-1, OE33, and non-neoplastic HET1A cells. Functional studies were performed. MFD-1 had a high SNP genotype concordance with matched germline/tumour. Parental tumour and MFD-1 carried four somatically acquired mutations in three recurrent mutated genes in OAC: TP53, ABCB1 and SEMA5A, not present in FLO-1 or OE33. MFD-1 displayed high expression of epithelial and glandular markers and a unique fingerprint of open chromatin. MFD-1 was tumorigenic in SCID mouse and proliferative and invasive in 3D cultures. The clinical utility of whole genome sequencing projects will be delivered using accurate model systems to develop molecular-phenotype therapeutics. We have described the first such system to arise from the oesophageal International Cancer Genome Consortium project. PMID:27600491

  6. Expression of squamous cell carcinoma markers and adenocarcinoma markers in primary pulmonary neuroendocrine carcinomas.

    Science.gov (United States)

    Masai, Kyohei; Tsuta, Koji; Kawago, Mitsumasa; Tatsumori, Takahiro; Kinno, Tomoaki; Taniyama, Tomoko; Yoshida, Akihiko; Asamura, Hisao; Tsuda, Hitoshi

    2013-07-01

    Recent clinical trials have revealed that accurate histologic typing of non-small cell lung cancer is essential. Until now, squamous cell carcinoma (SQC) and adenocarcinoma (ADC) markers have not been thoroughly analyzed for pulmonary neuroendocrine carcinomas (NECs). We analyzed the expression of 8 markers [p63, cytokeratin (CK) 5/6, SOX2, CK7, desmocollin 3, thyroid transcription factor-1 (8G7G3/1 and SPT24), and napsin A] in 224 NECs. SOX2 (76.2%) had the greatest expression for NECs. CK5/6 (1.4%), desmocollin 3 (0.5%), and napsin A (0%) were expressed less or not at all in NECs. Although our investigated markers have been reported useful for differentiating between SQC and ADC, some of them were also present in a portion of pulmonary NECs. In our study, CK5/6 and desmocollin 3 were highly specific markers for SQC, and napsin A was highly specific for ADC. These markers are recommended for diagnosis of poorly differentiated non-small cell lung cancer.

  7. Mastic Oil Inhibits the Metastatic Phenotype of Mouse Lung Adenocarcinoma Cells

    Energy Technology Data Exchange (ETDEWEB)

    Loutrari, Heleni, E-mail: elloutrar@med.uoa.gr; Magkouta, Sophia [“G.P. Livanos and M. Simou Laboratories”, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, School of Medicine, University of Athens, 3 Ploutarchou Street, 10675 Athens (Greece); Papapetropoulos, Andreas [Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504 Patras (Greece); Roussos, Charis [“G.P. Livanos and M. Simou Laboratories”, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, School of Medicine, University of Athens, 3 Ploutarchou Street, 10675 Athens (Greece)

    2011-02-23

    Mastic oil from Pistacia lentiscus variation chia, a natural combination of bioactive terpenes, has been shown to exert anti-tumor growth effects against a broad spectrum of cancers including mouse Lewis lung adenocarcinomas (LLC). However, no studies have addressed its anti-metastatic actions. In this study, we showed that treatment of LLC cells with mastic oil within a range of non-toxic concentrations (0.01–0.04% v/v): (a) abrogated their Matrigel invasion and migration capabilities in transwell assays; (b) reduced the levels of secreted MMP-2; (c) restricted phorbol ester-induced actin remodeling and (d) limited the length of neo-vessel networks in tumor microenvironment in the model of chick embryo chorioallantoic membrane. Moreover, exposure of LLC and endothelial cells to mastic oil impaired their adhesive interactions in a co-culture assay and reduced the expression of key adhesion molecules by endothelial cells upon their stimulation with tumor necrosis factor-alpha. Overall, this study provides novel evidence supporting a multipotent role for mastic oil in prevention of crucial processes related to cancer metastasis.

  8. Mastic Oil Inhibits the Metastatic Phenotype of Mouse Lung Adenocarcinoma Cells

    Directory of Open Access Journals (Sweden)

    Heleni Loutrari

    2011-02-01

    Full Text Available Mastic oil from Pistacia lentiscus variation chia, a natural combination of bioactive terpenes, has been shown to exert anti-tumor growth effects against a broad spectrum of cancers including mouse Lewis lung adenocarcinomas (LLC. However, no studies have addressed its anti-metastatic actions. In this study, we showed that treatment of LLC cells with mastic oil within a range of non-toxic concentrations (0.01–0.04% v/v: (a abrogated their Matrigel invasion and migration capabilities in transwell assays; (b reduced the levels of secreted MMP-2; (c restricted phorbol ester-induced actin remodeling and (d limited the length of neo-vessel networks in tumor microenvironment in the model of chick embryo chorioallantoic membrane. Moreover, exposure of LLC and endothelial cells to mastic oil impaired their adhesive interactions in a co-culture assay and reduced the expression of key adhesion molecules by endothelial cells upon their stimulation with tumor necrosis factor-alpha. Overall, this study provides novel evidence supporting a multipotent role for mastic oil in prevention of crucial processes related to cancer metastasis.

  9. Carbon metabolism of enterobacterial human pathogens growing in epithelial colorectal adenocarcinoma (Caco-2 cells.

    Directory of Open Access Journals (Sweden)

    Andreas Götz

    Full Text Available Analysis of the genome sequences of the major human bacterial pathogens has provided a large amount of information concerning their metabolic potential. However, our knowledge of the actual metabolic pathways and metabolite fluxes occurring in these pathogens under infection conditions is still limited. In this study, we analysed the intracellular carbon metabolism of enteroinvasive Escherichia coli (EIEC HN280 and EIEC 4608-58 and Salmonella enterica Serovar Typhimurium (Stm 14028 replicating in epithelial colorectal adenocarcinoma cells (Caco-2. To this aim, we supplied [U-(13C(6]glucose to Caco-2 cells infected with the bacterial strains or mutants thereof impaired in the uptake of glucose, mannose and/or glucose 6-phosphate. The (13C-isotopologue patterns of protein-derived amino acids from the bacteria and the host cells were then determined by mass spectrometry. The data showed that EIEC HN280 growing in the cytosol of the host cells, as well as Stm 14028 replicating in the Salmonella-containing vacuole (SCV utilised glucose, but not glucose 6-phosphate, other phosphorylated carbohydrates, gluconate or fatty acids as major carbon substrates. EIEC 4608-58 used C(3-compound(s in addition to glucose as carbon source. The labelling patterns reflected strain-dependent carbon flux via glycolysis and/or the Entner-Doudoroff pathway, the pentose phosphate pathway, the TCA cycle and anapleurotic reactions between PEP and oxaloacetate. Mutants of all three strains impaired in the uptake of glucose switched to C(3-substrate(s accompanied by an increased uptake of amino acids (and possibly also other anabolic monomers from the host cell. Surprisingly, the metabolism of the host cells, as judged by the efficiency of (13C-incorporation into host cell amino acids, was not significantly affected by the infection with either of these intracellular pathogens.

  10. Mapping of homozygous deletions in verified esophageal adenocarcinoma cell lines and xenografts.

    Science.gov (United States)

    Boonstra, Jurjen J; van Marion, Ronald; Douben, Hannie J C W; Lanchbury, Jerry S; Timms, Kirsten M; Abkevich, Victor; Tilanus, Hugo W; de Klein, Annelies; Dinjens, Winand N M

    2012-03-01

    Human esophageal adenocarcinoma (EAC) cell lines and xenografts are powerful tools in the search for genetic alterations because these models are composed of pure human cancer cell populations without admixture of normal human cells. In particular detection of homozygous deletions (HDs) is easier using these pure populations of cancer cells. Identification of HDs could potentially lead to the subsequent identification of new tumor suppressor genes (TSGs) involved in esophageal