Latest Pancreatic Cancer Genomics Papers

Here are the latest additions to the Pancreatic Cancer Genomics group in Mendeley. Some of the highlights include the results of an promising vaccine trial for PANVAC.  The vaccine has an antigen for MUC1, which as you may recall from previous posts, plays a role in pancreatic cancer.  

There’s also a paper on the use of Dasatinib to inhibit pancreatic cancer metastases, and a paper on the development of  a new diagnostic that holds some promise for the early detection of pancreatic cancer.

  • High Glucose Promotes Pancreatic Cancer Cell Proliferation via the Induction of EGF Expression and Transactivation of EGFR
    PLoS ONE (2011). Volume: 6, Issue: 11. Pages: e27074.

    Multiple lines of evidence suggest that a large portion of pancreatic cancer patients suffer from either hyperglycemia or diabetes, both of which are characterized by high blood glucose level. However, the underlying biological mechanism of this phenomenon is largely unknown. In the present study, we demonstrated that the proliferative ability of two human pancreatic cancer cell lines, BxPC-3 and Panc-1, was upregulated by high glucose in a concentration-dependent manner. Furthermore, the promoting effect of high glucose levels on EGF transcription and secretion but not its receptors in these PC cell lines was detected by using an EGF-neutralizing antibody and RT-PCR. In addition, the EGFR transactivation is induced by high glucose levels in concentration- and time-dependent manners in PC cells in the presence of the EGF-neutralizing antibody. These results suggest that high glucose promotes pancreatic cancer cell proliferation via the induction of EGF expression and transactivation of EGFR. Our findings may provide new insight on the links between high glucose level and PC in terms of the molecular mechanism and reveal a novel therapeutic strategy for PC patients who simultaneously suffer from either diabetes or hyperglycemia.
  • Tyrosine isomers mediate the classical phenomenon of concomitant tumor resistance.

    Cancer research (2011). Volume: 71, Issue: 22. Pages: 7113-24.Raul A Ruggiero, Juan Bruzzo, Paula Chiarella, Pedro di Gianni, Martin A Isturiz, Susana Linskens, Norma Speziale, Roberto P Meiss, Oscar D Bustuoabad, Christiane D Pasqualini et al.Concomitant tumor resistance (CR) is a phenomenon originally described in 1906 in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. Although recent studies have indicated that T-cell-dependent processes mediate CR in hosts bearing immunogenic small tumors, manifestations of CR induced by immunogenic and nonimmunogenic large tumors have been associated with an elusive serum factor. In this study, we identify this serum factor as tyrosine in its meta and ortho isoforms. In three different murine models of cancer that generate CR, both meta-tyrosine and ortho-tyrosine inhibited tumor growth. In addition, we showed that both isoforms of tyrosine blocked metastasis in a fourth model that does not generate CR but is sensitive to CR induced by other tumors. Mechanistic studies showed that the antitumor effects of the tyrosine isoforms were mediated, in part, by early inhibition of mitogen-activated protein/extracellular signal-regulated kinase pathway and inactivation of STAT3, potentially driving tumor cells into a state of dormancy. By revealing a molecular basis for the classical phenomenon of CR, our findings may stimulate new generalized approaches to limit the development of metastases that arise after resection of primary tumors, an issue of pivotal importance to oncologists and their patients. Cancer Res; 71(22); 7113-24. ?2011 AACR.

  • AGR2 is a Novel Surface Antigen that Promotes the Dissemination of Pancreatic Cancer Cells through Regulation of Cathepsins B and D.

    Cancer research (2011). Volume: 71, Issue: 22. Pages: 7091-7102.Laurent Dumartin, Hannah J Whiteman, Mark E Weeks, Deepak Hariharan, Branko Dmitrovic, Christine A Iacobuzio-Donahue, Teresa A Brentnall, Mary P Bronner, Roger M Feakins, John F Timms, Caroline Brennan, Nicholas R Lemoine, Tatjana Crnogorac-Jurcevic et al.Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers largely due to disseminated disease at the time of presentation. Here, we investigated the role and mechanism of action of the metastasis-associated protein anterior gradient 2 (AGR2) in the pathogenesis of pancreatic cancer. AGR2 was induced in all sporadic and familial pancreatic intraepithelial precursor lesions (PanINs), PDACs, circulating tumour cells and metastases studied. Confocal microscopy and flow cytometry analyses indicated that AGR2 localized to the endoplasmic reticulum (ER) and the external surface of tumour cells. Furthermore, induction of AGR2 in tumour cells regulated the expression of several ER chaperones (PDI, CALU, RCN1), proteins of the ubiquitin-proteasome degradation pathway (HIP2, PSMB2, PSMA3, PSMC3, PSMB4) and lysosomal proteases (cathepsins B and D), in addition to promoting the secretion of the precursor form pro CTSD. Importantly, the invasiveness ofpancreatic cancer cells was proportional to the level of AGR2 expression. Functional downstream targets of the pro-invasive activity of AGR2 included CTSB and D in vitro, and AGR2, CTSB and CTSD were essential for the dissemination of pancreatic cancer cells in vivo. Taken together, the results suggest that AGR2 promotes dissemination of pancreatic cancer and that its cell surface targeting may permit new strategies for early detection as well as therapeutic management. In conclusion, this work highlights the major role of AGR2 in the dissemination of pancreatic cancer and reveals previously unknown mechanisms of its action. Targeting AGR2 at the cell surface may provide new avenues for both early detection and therapeutic strategies in pancreatic cancer.

  • Combined blockade of integrin {alpha}4{beta}1 plus cytokines SDF-1{alpha} or IL-1{beta} potently inhibits tumor inflammation and growth.

    Cancer research (2011). Volume: 71, Issue: 22. Pages: 6965-6975.Michael C Schmid, Christie J Avraamides, Philippe Foubert, Yuval Shaked, Sang-Won Kang, Robert S Kerbel, Judith A Varner et al.Tumor-associated macrophages promote tumor growth by stimulating angiogenesis and suppressing anti-tumor immunity. Thus, therapeutics that inhibit macrophage recruitment to tumors may provide new avenues for cancer therapy. Here we show how the chemoattractants SDF-1? and IL-1? collaborate with myeloid cell integrin ?4?1 to promote tumor inflammation and growth. We found that SDF-1? and IL-1? are highly expressed in the microenvironments of murine lung, pancreatic and breast tumors; surprisingly, SDF-1? was expressed only by tumor cells, while IL-1? was produced only by tumor-derived granulocytes and macrophages. In vivo, both factors directly recruited pro-angiogenic macrophages to tissues, while antagonists of both factors suppressed tumor inflammation, angiogenesis and growth. Signals induced by IL-1? and SDF-1? promoted the interaction of talin and paxillin with the cytoplasmic tails of integrin ?4?1, thereby stimulating myeloid cell adhesion to endothelium in vitro and in vivo. While inhibiting integrin ?4?1, SDF-1? or IL-1? was sufficient to block tumor inflammation and growth, the combined blockade of these molecules greatly accentuated these effects. Furthermore, antagonists of integrin ?4?1 inhibited chemotherapy-induced tumor inflammation and synergized with chemotherapeutic agents to suppress tumor inflammation and growth. These results demonstrate that targeting myeloid cell recruitment mechanisms can be an effective approach to suppress tumor progression.

  • Expression of DNMT1 and DNMT3a Are Regulated by GLI1 in Human Pancreatic Cancer
    PLoS ONE (2011). Volume: 6, Issue: 11. Pages: e27684.

    Background and Aims

    GLI1, as an indispensable transcriptional factor of Hedgehog signaling pathway, plays an important role in the development of pancreatic cancer (PC). DNA methyltransferases (DNMTs) mediate the methylation of quantity of tumor-related genes. Our study aimed to explore the relationship between GLI1 and DNMTs.

    Methods

    Expressions of GLI1 and DNMTs were detected in tumor and adjacent normal tissues of PC patients by immunohistochemistry (IHC). PANC-1 cells were treated by cyclopamine and GLI1-siRNA, while BxPC-3 cells were transfected with overexpression-GLI1 lentiviral vector. Then GLI1 and DNMTs expression were analyzed by qRT-PCR and western blot (WB). Then we took chromatin immunoprecipitation (ChIP) to demonstrate GLI1 bind to DNMT1. Finally, nested MSP was taken to valuate the methylation levels of APC and hMLH1, when GLI1 expression altered.

    Results

    IHC result suggested the expressions of GLI1, DNMT1 and DNMT3a in PC tissues were all higher than those in adjacent normal tissues (p<0.05). After GLI1 expression repressed by cyclopamine in mRNA and protein level (down-regulation 88.1±2.2%, 86.4±2.2%, respectively), DNMT1 and DNMT3a mRNA and protein level decreased by 91.6%±2.2% and 83.8±4.8%, 87.4±2.7% and 84.4±1.3%, respectively. When further knocked down the expression of GLI1 by siRNA (mRNA decreased by 88.6±2.1%, protein decreased by 63.5±4.5%), DNMT1 and DNMT3a mRNA decreased by 80.9±2.3% and 78.6±3.8% and protein decreased by 64.8±2.8% and 67.5±5.6%, respectively. Over-expression of GLI1 by GLI1 gene transfection (mRNA increased by 655.5±85.9%, and protein increased by 272.3±14.4%.), DNMT1 and DNMT3a mRNA and protein increased by 293.0±14.8% and 578.3±58.5%, 143.5±17.4% and 214.0±18.9%, respectively. ChIP assays showed GLI1 protein bound to DNMT1 but not to DNMT3a. Results of nested MSP demonstrated GLI1 expression affected the DNA methylation level of APC but not hMLH1 in PC.

    Conclusion

    DNMT1 and DNMT3a are regulated by GLI1 in PC, and DNMT1 is its direct target gene.

  • Direct Signaling between Platelets and Cancer Cells Induces an Epithelial-Mesenchymal-Like Transition and Promotes Metastasis
    Cancer Cell (2011). Volume: 20, Issue: 5. Pages: 576-590.Myriam Labelle, Shahinoor Begum, Richard O. Hynes et al.

    Interactions of cancer cells with the primary tumor microenvironment are important determinants of cancer progression toward metastasis but it is unknown whether additional prometastatic signals are provided during the intravascular transit to the site of metastasis. Here, we show that platelet-tumor cell interactions are sufficient to prime tumor cells for subsequent metastasis. Platelet-derived TGFβ and direct platelet-tumor cell contacts synergistically activate the TGFβ/Smad and NF-κB pathways in cancer cells, resulting in their transition to an invasive mesenchymal-like phenotype and enhanced metastasis in vivo. Inhibition of NF-κB signaling in cancer cells or ablation of TGFβ1 expression solely in platelets protects against lung metastasis in vivo. Thus, cancer cells rely on platelet-derived signals outside of the primary tumor for efficient metastasis.

  • A Pilot Study of MUC-1/CEA/TRICOM Poxviral-Based Vaccine in Patients with Metastatic Breast and Ovarian Cancer

    Clinical Cancer Research (2011). Volume: 17, Issue: 22. Pages: 7164-7173.M. Mohebtash, K.-Y. Tsang, R. A. Madan, N.-Y. Huen, D. J. Poole, C. Jochems, J. Jones, T. Ferrara, C. R. Heery, P. M. Arlen, S. M. Steinberg, M. Pazdur, M. Rauckhorst, E. C. Jones, W. L. Dahut, J. Schlom, J. L. Gulley et al.Purpose: PANVAC is a recombinant poxviral vaccine that contains transgenes for MUC-1, CEA, and 3 T-cell costimulatory molecules. This study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients. Experimental design: Twenty-six patients were enrolled and given monthly vaccinations. Clinical and immune outcomes were evaluated. Results: These patients were heavily pretreated, with 21 of 26 patients having 3 or more prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. For the 12 breast cancer patients enrolled, median time to progression was 2.5 months (1-37+) and median overall survival was 13.7 months. Four patients had stable disease. One patient had a complete response by RECIST and remained on study for 37 months or more, with a significant drop in serum interleukin (IL)-6 and IL-8 by day 71. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. For the ovarian cancer patients (n = 14), the median time to progression was 2 months (1-6) and median overall survival was 15.0 months. Updated data are presented here for one patient treated with this vaccine in a previous trial, with a time to progression of 38 months. Conclusions: Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted. Clin Cancer Res; 17(22); 7164-73. (C)2011 AACR.

  • Mast Cells in Tumor Microenvironment Promotes the in vivo Growth of Pancreatic Ductal Adenocarcinoma.

    Clinical cancer research : an official journal of the American Association for Cancer Research (2011). Volume: 17, Issue: 22. Pages: 7015-7023.David Z Chang, Ying Ma, Baoan Ji, Huamin Wang, Defeng Deng, Yan Liu, James L Abbruzzese, Yongjun Liu, Craig D Logsdon, Patrick Hwu et al.PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. No effective therapy is currently available for PDAC because of the lack of understanding of the mechanisms leading to its growth and development. Inflammatory cells, particularly mast cells have been shown to play key roles in some cancers. We carried out this study to test the hypothesis that mast cells in the tumor microenvironment are essential for PDAC tumorigenesis.EXPERIMENTAL DESIGN: The presence of inflammatory cells at various stages of PDAC development was determined in a spontaneous mouse model of PDAC (K-rasG12V). The importance of mast cells was determined using orthotopically implanted PDAC cells in mast cell-deficient Kitw-sh/w-sh mice and further confirmed by reconstitution of wild-type bone marrow-derived mast cells. Clinical relevance was assessed by correlating the presence of mast cells with clinical outcome in patients with PDAC. RESULTS: In the spontaneous mouse model of PDAC (K-rasG12V), there was an early influx of mast cells to the tumor microenvironment. PDAC tumor growth was in mast cell-deficient Kitw-sh/w-sh mice, but aggressive PDAC growth was restored when PDAC cells were injected into mast cell-deficient mice reconstituted with wild-type bone marrow-derived mast cells. Mast cell infiltration into the tumor microenvironment was predictive of poor prognosis in patients with PDAC. CONCLUSIONS: Mast cells play an important role in PDAC growth and development in mouse models and are indicative of poor prognosis in humans, which makes them a potential novel therapeutic target.

  • Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma.

    Gastroenterology (2010). Volume: 139, Issue: 1. Pages: 292-303.Jennifer P Morton, Saadia A Karim, Kathryn Graham, Paul Timpson, Nigel Jamieson, Dimitris Athineos, Brendan Doyle, Colin McKay, Man-Yeung Heung, Karin A Oien, Margaret C Frame, T R Jeffry Evans, Owen J Sansom, Valerie G Brunton et al.Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive and metastatic disease for which conventional treatments are of limited efficacy. A number of agents in development are potential anti-invasive and antimetastatic agents, including the Src kinase inhibitor dasatinib. The aim of this study was to assess the importance of Src in human PDAC and to use a genetically engineered mouse model of PDAC to determine the effects of dasatinib on PDAC progression.

  • Stool DNA testing for the detection of pancreatic cancer: Assessment of methylation marker candidates.

    Cancer (2011).John B Kisiel, Tracy C Yab, William R Taylor, Suresh T Chari, Gloria M Petersen, Douglas W Mahoney, David A Ahlquist et al.BACKGROUND: Pancreatic cancer (PanC) presents at late stage with high mortality. Effective early detection methods are needed. Aberrantly methylated genes are unexplored as markers for noninvasive detection by stool testing. The authors aimed to select discriminant methylated genes and to assess accuracy of these and mutant KRAS in stool to detect PanC. METHODS: Nine target genes were assayed by real-time methylation-specific polymerase chain reaction (MSP) in bisulfite-treated DNA from microdissected frozen specimens of 24 PanC cases and 30 normal colon controls. Archived stools from 58 PanC cases and 65 controls matched on sex, age, and smoking were analyzed. Target genes from fecal supernatants were enriched by hybrid capture, bisulfite-treated, and assayed by MSP. KRAS mutations were assayed using the QuARTS technique. RESULTS: Areas under the receiver operating characteristics curves (AUCs) for tissue BMP3, NDRG4, EYA4, UCHL1, MDFI, Vimentin, CNTNAP2, SFRP2, and TFPI2 were 0.90, 0.79, 0.78, 0.78, 0.77, 0.77, 0.69, 0.67, and 0.66, respectively. The top 4 markers and mutant KRAS were evaluated in stool. BMP3 was the most discriminant methylation marker in stool. At 90% specificity, methylated BMP3 alone detected 51% of PanCs, mutant KRAS detected 50%, and combination detected 67%. AUCs for methylated BMP3, mutant KRAS, and combination in stool were 0.73, 0.75, and 0.85, respectively. CONCLUSIONS: This study demonstrates that stool assay of a methylated gene marker can detect PanC. Among candidate methylated markers discriminant in tissue, BMP3 alone performed well in stool. Combining methylated BMP3 and mutant KRAS increased stool detection over either marker alone. Cancer 2011;. ? 2011 American Cancer Society.

  • Wogonin and related natural flavones overcome TRAIL-resistance of tumors by down-regulation of c-FLIP and Up-regulation of TRAIL-R2 expression.

    The Journal of biological chemistry (2011).Jie Ding, Gernot Polier, Rebecca Koehler, Marco Giaisi, Peter H Krammer, Min Li-Weber et al.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent that kills various tumor cells without damaging normal tissues. However, many cancers remain resistant to TRAIL. To overcome TRAIL-resistance, combination therapies using sensitizers of the TRAIL pathway would be an efficacious approach. To investigate potential sensitizers of TRAIL-induced apoptosis, we used TRAIL-resistant human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL) cells as a model system. So far, HTLV-1-associated ATL is incurable by presently known therapies. Here, we show that Wogonin and the structurally related natural flavones Apigenin and Chrysin break TRAIL-resistance in HTLV-1-associated ATL by transcriptional down-regulation of c FLIP, a key inhibitor of death-receptor signaling, and by up-regulation of TRAIL receptor 2 (TRAIL-R2). This effect is mediated through transcriptional inhibition of the p53 antagonist Mdm2, leading to an increase in p53 levels and, consequently, to up-regulation of the p53 target gene TRAIL-R2. We also show that these flavones can sensitize to TNFalpha and CD95-mediated cell death. Furthermore, we show that Wogonin, Apigenin and Chrysin also enhance TRAIL-mediated apoptosis in other human cancer cell lines including breast cancer cell line MDA-MB-231, colon cancer cell line HT-29, hepatocellular carcinoma cell line HepG2, melanoma cell line SK-MEL-37 and pancreatic carcinoma cell line Capan-1 by the same mechanism. Thus, our study suggests the potential use of these flavones as an adjuvant for TRAIL-mediated anti-cancer therapy.

  • GLI1 inhibition promotes epithelial-to-mesenchymal transition in pancreatic cancer cells.

    Cancer research (2011).Simon Joost, Luciana L Almada, Verena Rohnalter, Philipp S Holz, Anne M Vrabel, Maite G Fernandez-Barrena, Robert R McWilliams, Michael Krause, Martin E Fernandez-Zapico, Matthias Lauth et al.The Hedgehog (HH) pathway has been identified as an important deregulated signal transduction pathway in pancreatic ductal adenocarcinoma (PDAC), a cancer type characterized by a highly metastatic phenotype. In PDAC, the canonical HH pathway activity is restricted to the stromal compartment while HH signaling in the tumor cells is reduced as a consequence of constitutive KRAS activation. Here we report that in the tumor compartment of PDAC the HH pathway effector transcription factor GLI1 regulates epithelial differentiation. RNAi-mediated knockdown of GLI1 abolished characteristics of epithelial differentiation, increased cell motility and synergized with TGF? to induce an epithelial-to-mesenchymal transition (EMT). Notably, EMT conversion in PDAC cells occurred in the absence of induction of SNAIL or SLUG, two canonical inducers of EMT in many other settings. Further mechanistic analysis revealed that GLI1 directly regulated the transcription of E-cadherin, a key determinant of epithelial tissue organization. Collectively, our findings identify GLI1 as an important positive regulator of epithelial differentiation, and they offer an explanation for how decreased levels of GLI1 are likely to contribute to the highly metastatic phenotype of PDAC.

  • Plasma 25-Hydroxyvitamin D and Risk of Pancreatic Cancer.

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (2011).Brian M Wolpin, Kimmie Ng, Ying Bao, Peter Kraft, Meir J Stampfer, Dominique S Michaud, Jing Ma, Julie E Buring, Howard Sesso, I-Min Lee, Nader Rifai, Barbara B Cochrane, Jean Wactawaski-Wende, Rowan T Chlebowski, Walter C Willett, Joann E Manson, Edward L Giovannucci, Charles S Fuchs et al.BACKGROUND: Laboratory studies suggest vitamin D may inhibit pancreatic cancer cell growth. However, epidemiologic studies of vitamin D and pancreatic cancer risk have been conflicting.METHODS: To determine whether prediagnostic levels of plasma 25-hydroxyvitamin D (25[OH]D) were associated with risk of pancreatic cancer, we performed a nested case-control study of 451 cases and 1167 controls from five cohorts through 2008. Logistic regression was used to compare the odds of pancreatic cancer by plasma level of 25(OH)D.RESULTS: Mean plasma 25(OH)D was lower in cases versus controls (61.3 vs. 64.5 nmol/L, P=0.005). In logistic regression models, plasma 25(OH)D was inversely associated with odds of pancreatic cancer. Participants in quintiles two through five had multivariable-adjusted odds ratios (OR [95% confidence intervals]) of 0.79 (0.56-1.10), 0.75 (0.53-1.06), 0.68 (0.48-0.97), and 0.67 (0.46-0.97); P-trend=0.03), respectively, compared to the bottom quintile. Compared to those with insufficient levels (25[OH]D<50 nmol/L), ORs were 0.75 (0.58-0.98) for subjects with relative insufficiency (25[OH]D 50-<75 nmol/L) and 0.71 (0.52-0.97) for those with sufficient levels (25[OH]D?75 nmol/L). No increased risk was noted in subjects with 25(OH)D ?100 nmol/L, as suggested in a prior study. In subgroup analyses, ORs for the top versus bottom quartile of 25(OH)D were 0.72 (0.48-1.08) for women, 0.73 (0.40-1.31) for men, and 0.73 (0.51-1.03) for Whites. CONCLUSIONS: Among participants in five large prospective cohorts, higher plasma levels of 25(OH)D were associated with a lower risk for pancreatic cancer.Impact: Low circulating 25(OH)D may predispose individuals to the development of pancreatic cancer.

  • An analog of withaferin a activates the MAPK and glutathione ?stress? Pathways and inhibits pancreatic cancer cell proliferation.

    Cancer investigation (2011). Volume: 29, Issue: 10. Pages: 668-75.Xiaobing Liu, Wenqing Qi, Laurence S Cooke, E M Kithsiri Wijeratne, Ya-Ming Xu, Marilyn T Marron, A A Leslie Gunatilaka, Daruka Mahadevan et al.Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin A (3)] were evaluated for antitumor activity in pancreatic cancer cells. IC(50) for 1, 2, and 3 were 0.87, 0.45, and 0.29 ?M (BxPC-3); 1.28, 1.53, and 0.52 ?M (MIAPaCa-2); and 0.59, 2.25, and 0.56 ?M (PANC-1), respectively. We chose WA analog 3 for functional studies with confirmatory RT-PCR and Western blotting. ANOVA identified 33 (MIAPaCa-2), 54 (PANC-1), and 48 (BxPC-3) gene expression changes. Fisher exact test demonstrated MAPK and glutathione pathways to be overexpressed with WA analog 3. WA analog 3 elicits a dose- and time-dependent apoptosis, activates MAPK and glutathione ?stress? pathways, and inhibits proliferation.

  • Proteome of formalin-fixed paraffin-embedded pancreatic ductal adenocarcinoma and lymph node metastases.

    The Journal of pathology (2011).Kalnisha Naidoo, Richard Jones, Branko Dmitrovic, Nilukshi Wijesuriya, Hemant Kocher, Ian R Hart, Tatjana Crnogorac-Jurcevic et al.Pancreatic Ductal Adenocarcinoma (PDAC) is a major cause of cancer-related death, largely due to metastatic disease. To better understand PDAC metastatic spread and identify novel therapeutic targets, we analysed the proteome of primary tumours and matched lymph node (LN) metastases. As frozen specimens of metastatic lesions are scarce, we examined formalin-fixed paraffin-embedded (FFPE) tissues. This poses technical challenges because of the cross-linkages induced by fixation. Using laser capture microdissection (P.A.L.M system), we isolated malignant epithelia from seven FFPE primary PDAC tumours and matched LN metastases. Following dissection, samples were analysed in duplicate using Multidimensional Protein Identification Technology (MudPIT); this resulted in the identification of 1504 proteins, 854 of which were common to all samples analysed. Comparison of the obtained proteins with data from previous proteomics studies on pancreatic tissue, pancreatic juice, serum and urine resulted in a less than 30% overlap, indicating that our study has substantially expanded the current database of proteins expressed in this malignancy. Statistical analysis further showed that 115/854 proteins (13.5%) were significantly differentially expressed (g-value ? 3.8). Two proteins, S100P and 14-3-3 sigma, with highly significant g-values were confirmed to be significantly differentially expressed (S100P: p = 0.05 and 14-3-3 sigma: p < 0.001) in a larger series of 55 cases of matched primary PDAC and LN metastases using immunohistochemistry. Thus, laser capture microdissection of FFPE tissue coupled with downstream proteomic analysis is a valid approach for the investigation of metastatic PDAC. This is the first study to establish and compare the protein composition of primary PDAC and matched LN metastases, and has resulted in the identification of several potential epithelial-specific therapeutic targets, including 14-3-3 sigma and S100P. Copyright ? 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • The Expression and Clinical Significance of pSTAT3, VEGF and VEGF-C in Pancreatic Adenocarcinoma.

    Neoplasma (2011).C Huang, R Huang, W Chang, T Jiang, K Huang, J Cao, X Sun, Z Qiu et al.Signal transducers and activators of transcription 3 (STAT3) is a?central cytoplasmic transcription factor and regulates a?number of pathways important in tumorigenesis including cell cycle progression, apoptosis, tumor angiogenesis, invasion and metastasis.This study aims to investigate the expression of pSTAT3, VEGF and VEGF-C in pancreatic adenocarcinoma and their relations to the clinicopathological features, tumor angiogenesis and prognosis. In the present study, the expression of pSTAT3, VEGF and VEGF-C and microvascular density (MVD) were examined via immunohistochemistry. The clinicopathological information was collected and patients were regularly followed up. The relationship between the parameters and the clinicopathological features were analyzed, and the univariate and multivariate prognostic factors were also analyzed. The expression of pSTAT3 in tumor tissues was significantly higher in contrast to that in normal tissues, and pSTAT3 was related to VEGF and VEGF-C expression, MVD, tumor size, lymphogenous status and TNM staging (P<0.05). </p><p>Survival analysis suggested that tumor size, TNM staging, pSTAT3 and VEGF expression were risk factors of prognosis, but no independent factors were found. We concluded that pSTAT3, which was a?risk factor of prognosis, was abnormally expressed in pancreatic adenocarcinoma and related to tumor size, TNM staging and lymphatic metastasis. pSTAT3 may promote tumor angiogenesis via up-regulating VEGF on protein and even gene levels, and enhance the early lymphatic metastasis through VEGF-C. Better understanding of STAT3 signaling pathways in angiogenesis may contribute to the development of novel therapeutic strategies in angiogenesis and metastasis of pancreatic cancer.

  • Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells.

    Cancer prevention research (Philadelphia, Pa.) (2011).Bin Bao, Zhiwei Wang, Shadan Ali, Aamir Ahmad, Asfar S Azmi, Sanila Sarkar, Sanjeev Banerjee, Dejuan Kong, Yiwei Li, Shivam Thakur, Fazlul H Sarkar et al.Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the United States, which is in part due to intrinsic (de novo) and extrinsic (acquired) resistance to conventional therapeutics, suggesting that innovative treatment strategies are required for overcoming therapeutic resistance in order to improve overall survival of patients. Oral administration of metformin in diabetes mellitus (DM) patients has been reported to be associated with reduced risk of PC and that metformin has been reported to kill cancer stem cells (CSCs); however, the exact molecular mechanism(s) has not been fully elucidated. In the current study, we examined the effect of metformin on cell proliferation, cell migration and invasion, self-renewal capacity of cancer stem-like cells (CSC), and further assessed the expression of CSC marker genes and microRNAs (miRNAs) in human PC cells. We found that metformin significantly decreased cell survival, clonogenicity, wound healing capacity, sphere-forming capacity (pancreatospheres), and increased disintegration of pancreatospheres in both gemcitabine-sensitive and gemcitabine-resistant PC cells. Metformin also decreased the expression of CSC markers, CD44, EpCAM, EZH2, Notch-1, Nanog and Oct4, and caused re-expression of miRNAs (let-7a, b, miR-26a, miR-101, and miR-200b, c) that are typically lost in PC and especially in pancreatospheres. We also found that re-expression of miR-26a by transfection led to decreased expression of EZH2 and EpCAM in PC cells. These results clearly suggest that the biological effects of metformin are mediated through re-expression of miRNAs and decreased expression of CSC-specific genes, suggesting.

  • Molecular Profile of Apomucin and p53 Protein as Predictors of Malignancy in Intraductal Papillary Mucinous Neoplasms of the Pancreas.

    Hepato-gastroenterology. Volume: 58, Issue: 110-111. Pages: 1791-5.Masaki Mizumoto, Gen Honjo, Yoichiro Kobashi, Masaaki Awane, Satoru Matsusue et al.Background/Aims: Invasive intraductal papillary mucinous neoplasms (IPMNs) of the pancreas show poor prognosis similar to ductal adenocarcinomas. The aim of this study was to evaluate the molecular indicators of invasion and risk factors of recurrence of IPMNs. Methodology: For 46 curative resections of IPMNs, we analyzed the expression of apomucin antigens (MUC1, MUC2 and MUC5AC), p53 and Ki67 using resected specimens. Results: All 46 IPMNs were classified into 4 groups; MUC1+/p53+, MUC1+/p53-, MUC2+ and MUC1-/MUC2-. The incidence of MUC1 expression increased according to the grade of dysplasia and all of 5 invasive carcinomas expressed MUC1. None of the invasive carcinoma, but almost half of IPMNs of non-invasive carcinoma and sever dysplasia expressed MUC2. Additionally, p53 expression was limited to invasive IPMNs and a non-invasive IPMN which recurred after the operation. The Ki67 labeling index was increased according to the grade of dysplasia and was highest in the MUC1+/p53+ group. In the MUC2+ cases, Ki67 labeling index was significantly higher than that in the MUC1-/MUC2- cases. MUC5AC was expressed in all IPMNs. Conclusions: The expression of MUC1, MUC2 and p53 might be indicators of malignancy and the expressions of MUC1 and p53 were the predictors of tumor invasion and recurrence.

  • Hedgehog Signaling Antagonist GDC-0449 (Vismodegib) Inhibits Pancreatic Cancer Stem Cell Characteristics: Molecular Mechanisms.

    PloS one (2011). Volume: 6, Issue: 11. Pages: e27306.Brahma N Singh, Junsheng Fu, Rakesh K Srivastava, Sharmila Shankar et al.Recent evidence from in vitro and in vivo studies has demonstrated that aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway regulates genes that promote cellular proliferation in various human cancer stem cells (CSCs). Therefore, the chemotherapeutic agents that inhibit activation of Gli transcription factors have emerged as promising novel therapeutic drugs for pancreatic cancer. GDC-0449 (Vismodegib), orally administrable molecule belonging to the 2-arylpyridine class, inhibits SHH signaling pathway by blocking the activities of Smoothened. The objectives of this study were to examine the molecular mechanisms by which GDC-0449 regulates human pancreatic CSC characteristics in vitro.

  • Novel mutations of PRSS1 gene in patients with pancreatic cancer among Han population.

    Chinese medical journal (2011). Volume: 124, Issue: 13. Pages: 2065-7.Kai Zeng, Qi-Cai Liu, Jian-Hua Lin, Xin-Hua Lin, Ze-Hao Zhuang, Feng Gao, Qi-Shui Ou et al.A high mortality rate of pancreatic cancer becomes a bottleneck for further treatment with long-term efficacy. It is urgent to find a new mean to predict the early onset of pancreatic cancer accurately. The authors hypothesized that genetic variants of cationic trypsinogen (PRSS1) gene could affect trypsin expression/function and result in abnormal activation of protease activated receptor-2 (PAR-2), then lead to pancreatic cancer. The aim of this study was to elaborate some novel mutations of PRSS1 gene in the patients with pancreatic cancer.

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About aspenbio

I write software for scientists. I'm interested in Java/Groovy/Grails, the Semantic Web and Cancer Biology.
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