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Sample records for targeting pancreatic cancer

  1. Biomarkers and Targeted Therapy in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Fataneh Karandish

    2016-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%–3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

  2. Targeted radionuclide therapies for pancreatic cancer.

    Science.gov (United States)

    Shah, M; Da Silva, R; Gravekamp, C; Libutti, S K; Abraham, T; Dadachova, E

    2015-08-01

    Pancreatic malignancies, the fourth leading cause of cancer deaths, have an aggressive behavior with poor prognosis, resulting in a 5-year survival rate of only 4%. It is typically a silent malignancy until patients develop metastatic disease. Targeted radionuclide therapies of cancer such as radiolabeled peptides, which bind to the receptors overexpressed by cancer cells and radiolabeled antibodies to tumor-specific antigens provide a viable alternative to chemotherapy and external beam radiation of metastatic cancers. Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer have been performed in the last decade and demonstrated safety and potential efficacy of radionuclide therapy for treatment of this formidable disease. Although a lot of progress has been made in treatment of pancreatic neuroendocrine tumors with radiolabeled (90)Y and (177)Lu somatostatin peptide analogs, pancreatic adenocarcinomas remain a major challenge. Novel approaches such as peptides and antibodies radiolabeled with alpha emitters, pre-targeting, bispecific antibodies and biological therapy based on the radioactive tumorlytic bacteria might offer a potential breakthrough in treatment of pancreatic adenocarcinomas.

  3. Reactive Oxygen Species and Targeted Therapy for Pancreatic Cancer

    Science.gov (United States)

    2016-01-01

    Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. Reactive oxygen species (ROS) are generally increased in pancreatic cancer cells compared with normal cells. ROS plays a vital role in various cellular biological activities including proliferation, growth, apoptosis, and invasion. Besides, ROS participates in tumor microenvironment orchestration. The role of ROS is a doubled-edged sword in pancreatic cancer. The dual roles of ROS depend on the concentration. ROS facilitates carcinogenesis and cancer progression with mild-to-moderate elevated levels, while excessive ROS damages cancer cells dramatically and leads to cell death. Based on the recent knowledge, either promoting ROS generation to increase the concentration of ROS with extremely high levels or enhancing ROS scavenging ability to decrease ROS levels may benefit the treatment of pancreatic cancer. However, when faced with oxidative stress, the antioxidant programs of cancer cells have been activated to help cancer cells to survive in the adverse condition. Furthermore, ROS signaling and antioxidant programs play the vital roles in the progression of pancreatic cancer and in the response to cancer treatment. Eventually, it may be the novel target for various strategies and drugs to modulate ROS levels in pancreatic cancer therapy. PMID:26881012

  4. Screening Technologies for Target Identification in Pancreatic Cancer

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    Michl, Patrick, E-mail: michlp@med.uni-marburg.de; Ripka, Stefanie; Gress, Thomas; Buchholz, Malte [Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University Marburg, Baldinger Strasse, D-35043 Marburg (Germany)

    2010-12-29

    Pancreatic cancer exhibits an extraordinarily high level of resistance to almost any kind of systemic therapy evaluated in clinical trials so far. Therefore, the identification of novel therapeutic targets is urgently required. High-throughput screens have emerged as an important tool to identify putative targets for diagnosis and therapy in an unbiased manner. More than a decade ago, microarray technology was introduced to identify differentially expressed genes in pancreatic cancer as compared to normal pancreas, chronic pancreatitis and other cancer types located in close proximity to the pancreas. In addition, proteomic screens have facilitated the identification of differentially secreted proteins in body fluids of pancreatic cancer patients, serving as possible biomarkers. Recently, RNA interference-based loss-of-function screens have been used to identify functionally relevant genes, whose knock-down has impact on pancreatic cancer cell viability, thereby representing potential new targets for therapeutic intervention. This review summarizes recent results of transcriptional, proteomic and functional screens in pancreatic cancer and discusses potentials and limitations of the respective technologies as well as their impact on future therapeutic developments.

  5. Screening Technologies for Target Identification in Pancreatic Cancer

    International Nuclear Information System (INIS)

    Michl, Patrick; Ripka, Stefanie; Gress, Thomas; Buchholz, Malte

    2010-01-01

    Pancreatic cancer exhibits an extraordinarily high level of resistance to almost any kind of systemic therapy evaluated in clinical trials so far. Therefore, the identification of novel therapeutic targets is urgently required. High-throughput screens have emerged as an important tool to identify putative targets for diagnosis and therapy in an unbiased manner. More than a decade ago, microarray technology was introduced to identify differentially expressed genes in pancreatic cancer as compared to normal pancreas, chronic pancreatitis and other cancer types located in close proximity to the pancreas. In addition, proteomic screens have facilitated the identification of differentially secreted proteins in body fluids of pancreatic cancer patients, serving as possible biomarkers. Recently, RNA interference-based loss-of-function screens have been used to identify functionally relevant genes, whose knock-down has impact on pancreatic cancer cell viability, thereby representing potential new targets for therapeutic intervention. This review summarizes recent results of transcriptional, proteomic and functional screens in pancreatic cancer and discusses potentials and limitations of the respective technologies as well as their impact on future therapeutic developments

  6. Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers

    Directory of Open Access Journals (Sweden)

    Dongping Wei

    2015-02-01

    Full Text Available In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1, an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells.

  7. The Key Genes of Chronic Pancreatitis which Bridge Chronic Pancreatitis and Pancreatic Cancer Can be Therapeutic Targets.

    Science.gov (United States)

    Li, Shuang; Li, Rui; Wang, Heping; Li, Lisha; Li, Huiyu; Li, Yulin

    2018-04-01

    An important question in systems biology is what role the underlying molecular mechanisms play in disease progression. The relationship between chronic pancreatitis and pancreatic cancer needs further exploration in a system view. We constructed the disease network based on gene expression data and protein-protein interaction. We proposed an approach to discover the underlying core network and molecular factors in the progression of pancreatic diseases, which contain stages of chronic pancreatitis and pancreatic cancer. The chronic pancreatitis and pancreatic cancer core network and key factors were revealed and then verified by gene set enrichment analysis of pathways and diseases. The key factors provide the microenvironment for tumor initiation and the change of gene expression level of key factors bridge chronic pancreatitis and pancreatic cancer. Some new candidate genes need further verification by experiments. Transcriptome profiling-based network analysis reveals the importance of chronic pancreatitis genes and pathways in pancreatic cancer development on a system level by computational method and they can be therapeutic targets.

  8. Neural Regulation of Pancreatic Cancer: A Novel Target for Intervention

    International Nuclear Information System (INIS)

    Chang, Aeson; Kim-Fuchs, Corina; Le, Caroline P.; Hollande, Frédéric; Sloan, Erica K.

    2015-01-01

    The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer

  9. Neural Regulation of Pancreatic Cancer: A Novel Target for Intervention

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Aeson [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Kim-Fuchs, Corina [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Department of Visceral Surgery and Medicine, University Hospital Bern, Bern 3010 (Switzerland); Le, Caroline P. [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Hollande, Frédéric [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Department of Pathology, University of Melbourne, Parkville 3010 (Australia); Sloan, Erica K., E-mail: erica.sloan@monash.edu [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Cousins Center for PNI, UCLA Semel Institute, Jonsson Comprehensive Cancer Center, and UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095 (United States); Peter MacCallum Cancer Centre, Division of Cancer Surgery, East Melbourne, Victoria 3002 (Australia)

    2015-07-17

    The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer.

  10. Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

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    Fillat, Cristina, E-mail: cristina.fillat@crg.es; Jose, Anabel; Ros, Xavier Bofill-De; Mato-Berciano, Ana; Maliandi, Maria Victoria; Sobrevals, Luciano [Programa Gens i Malaltia, Centre de Regulació Genòmica-CRG, UPF, Parc de Recerca Biomedica de Barcelona-PRBB and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona (Spain)

    2011-01-18

    The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed.

  11. Targeted Alpha Therapy Approach to the Management of Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Ross C. Smith

    2011-04-01

    Full Text Available Evidence for the efficacy of targeted alpha therapy for the control of pancreatic cancer in preclinical models is reviewed. Results are given for in vitro pancreatic cancer cells and clusters and micro-metastatic cancer lesions in vivo. Two complementary targeting vectors are examined. These are the C595 monoclonal antibody that targets the MUC1 antigen and the PAI2 ligand that targets the uPA receptor. The expression of the tumor-associated antigen MUC-1 and the uPA receptor on three pancreatic cancer cell lines is reported for cell clusters, human mouse xenografts and lymph node metastases, as well as for human pancreatic cancer tissues, using immuno-histochemistry, confocal microscopy and flow cytometry. The targeting vectors C595 and PAI2 were labeled with the alpha emitting radioisotope 213Bi using the chelators cDTPA and CHX-A″ to form the alpha-conjugates (AC. Cell clusters were incubated with the AC and examined at 48 hours. Apoptosis was documented using the TUNEL assay. In vivo, the anti-proliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AC by local or systemic administration. Changes in tumor progression were assessed by tumor size. MUC-1 and uPA are strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The ACs can target pancreatic cells and regress cell clusters (~100 µm diameter, causing apoptosis in some 70–90 % of cells. At two days post-cell inoculation in mice, a single local injection of 74 MBq/kg of AC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of alpha-conjugate caused significant tumor growth delay in a dose dependent manner after 16 weeks, compared with the non-specific control at 333 MBq/kg. Cytotoxicity was assessed by the MTS and TUNEL assays. The C595 and PAI2-alpha conjugates are indicated for the treatment of

  12. Targeted Alpha Therapy Approach to the Management of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Allen, Barry J., E-mail: barry.allen@sesiahs.health.nsw.gov.au; Abbas Rizvi, Syed M.; Qu, Chang F. [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah, 2217 (Australia); Smith, Ross C. [Cancer Surgery Laboratory, Northern Clinical School, University of Sydney, Kolling Institute, Royal North Shore Hospital, St. Leonards, NSW 2065 (Australia)

    2011-04-01

    Evidence for the efficacy of targeted alpha therapy for the control of pancreatic cancer in preclinical models is reviewed. Results are given for in vitro pancreatic cancer cells and clusters and micro-metastatic cancer lesions in vivo. Two complementary targeting vectors are examined. These are the C595 monoclonal antibody that targets the MUC1 antigen and the PAI2 ligand that targets the uPA receptor. The expression of the tumor-associated antigen MUC-1 and the uPA receptor on three pancreatic cancer cell lines is reported for cell clusters, human mouse xenografts and lymph node metastases, as well as for human pancreatic cancer tissues, using immuno-histochemistry, confocal microscopy and flow cytometry. The targeting vectors C595 and PAI2 were labeled with the alpha emitting radioisotope {sup 213}Bi using the chelators cDTPA and CHX-A″ to form the alpha-conjugates (AC). Cell clusters were incubated with the AC and examined at 48 hours. Apoptosis was documented using the TUNEL assay. In vivo, the anti-proliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AC by local or systemic administration. Changes in tumor progression were assessed by tumor size. MUC-1 and uPA are strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The ACs can target pancreatic cells and regress cell clusters (∼100 μm diameter), causing apoptosis in some 70–90 % of cells. At two days post-cell inoculation in mice, a single local injection of 74 MBq/kg of AC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of alpha-conjugate caused significant tumor growth delay in a dose dependent manner after 16 weeks, compared with the non-specific control at 333 MBq/kg. Cytotoxicity was assessed by the MTS and TUNEL assays. The C595 and PAI2-alpha conjugates are indicated for the treatment of micro

  13. Targeting Cancer Stem Cells and Their Niche: Current Therapeutic Implications and Challenges in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Jiangang Zhao

    2017-01-01

    Full Text Available Cancer stem cells (CSCs have been identified as a subpopulation of stem-like cancer cells with the ability of self-renewal and differentiation in hematological malignancies and solid tumors. Pancreatic cancer is one of the most lethal cancers worldwide. CSCs are thought to be responsible for cancer initiation, progression, metastasis, chemoresistance, and recurrence in pancreatic cancer. In this review, we summarize the characteristics of pancreatic CSCs and discuss the mechanisms involved in resistance to chemotherapy, the interactions with the niche, and the potential role in cancer immunoediting. We propose that immunotherapy targeting pancreatic CSCs, in combination with targeting the niche components, may provide a novel treatment strategy to eradicate pancreatic CSCs and hence improve outcomes in pancreatic cancer.

  14. IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer.

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M; Wang, Liya; Wang, Y Andrew; Chen, Hongyu; Kooby, David; Yu, Qian; Lipowska, Malgorzata; Staley, Charles A; Mao, Hui; Yang, Lily

    2015-08-25

    Overcoming resistance to chemotherapy is a major and unmet medical challenge in the treatment of pancreatic cancer. Poor drug delivery due to stromal barriers in the tumor microenvironment and aggressive tumor biology are additional impediments toward a more successful treatment of pancreatic cancer. In attempts to address these challenges, we developed IGF1 receptor (IGF1R)-directed, multifunctional theranostic nanoparticles for targeted delivery of therapeutic agents into IGF1R-expressing drug-resistant tumor cells and tumor-associated stromal cells. These nanoparticles were prepared by conjugating recombinant human IGF1 to magnetic iron oxide nanoparticles (IONPs) carrying the anthracycline doxorubicin (Dox) as the chemotherapeutic payload. Intravenously administered IGF1-IONPs exhibited excellent tumor targeting and penetration in an orthotopic patient-derived xenograft (PDX) model of pancreatic cancer featuring enriched tumor stroma and heterogeneous cancer cells. IGF1R-targeted therapy using the theranostic IGF1-IONP-Dox significantly inhibited the growth of pancreatic PDX tumors. The effects of the intratumoral nanoparticle delivery and therapeutic responses in the orthotopic pancreatic PDX tumors could be detected by magnetic resonance imaging (MRI) with IONP-induced contrasts. Histological analysis showed that IGF1R-targeted delivery of Dox significantly inhibited cell proliferation and induced apoptotic cell death of pancreatic cancer cells. Therefore, further development of IGF1R-targeted theranostic IONPs and MRI-guided cancer therapy as a precision nanomedicine may provide the basis for more effective treatment of pancreatic cancer.

  15. Pancreatic Cancer

    Science.gov (United States)

    ... hormones that help control blood sugar levels. Pancreatic cancer usually begins in the cells that produce the juices. Some risk factors for developing pancreatic cancer include Smoking Long-term diabetes Chronic pancreatitis Certain ...

  16. Targeting senescence cells in pancreatic cancer | IDRC ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Cellular senescence is a programmed response to oncogenic (tumour-causing) stress that aims to halt the expansion of cells with malignant potential. It does this by stopping the proliferation of pre-cancerous lesions and recruitment of the immune system for their elimination. If these processes fail, senescent cells create ...

  17. Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

    Directory of Open Access Journals (Sweden)

    Maria Victoria Maliandi

    2011-01-01

    Full Text Available The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed.

  18. Imaging and Therapy of Pancreatic Cancer with Phosphatidylserine-Targeted Nanovesicles

    Directory of Open Access Journals (Sweden)

    Victor M. Blanco

    2015-06-01

    Full Text Available Pancreatic cancer remains one of the most intractable cancers, with a dismal prognosis reflected by a 5-year survival of ~6%. Since early disease symptoms are undefined and specific biomarkers are lacking, about 80% of patients present with advanced, inoperable tumors that represent a daunting challenge. Despite many clinical trials, no single chemotherapy agent has been reliably associated with objective response rates above 10% or median survival longer than 5 to 7 months. Although combination chemotherapy regimens have in recent years provided some improvement, overall survival (8-11 months remains very poor. There is therefore a critical need for novel therapies that can improve outcomes for pancreatic cancer patients. Here, we present a summary of the current therapies used in the management of advanced pancreatic cancer and review novel therapeutic strategies that target tumor biomarkers. We also describe our recent research using phosphatidylserine-targeted saposin C–coupled dioleoylphosphatidylserine nanovesicles for imaging and therapy of pancreatic cancer.

  19. A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer

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    Deng L

    2012-09-01

    Full Text Available Li Deng,1,# Xingfa Ke,4,# Zhiying He,3,# Daoqiu Yang,5 Hai Gong,6 Yingying Zhang,1 Xiaolong Jing,4 Jianzhong Yao,2 Jianming Chen11Department of Pharmaceutics, 2Department of Medicinal Chemistry, School of Pharmacy, 3Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China; 4Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian, People's Republic of China; 5Department of Dermatology, 107th Hospital of PLA, Yantai, People's Republic of China; 6Department of Radiation Oncology, General Hospital of Jinan Military Region, Jinan, People’s Republic of China#These authors contributed equally to this workAbstract: Pancreatic cancer is a highly lethal disease with a 5-year survival rate less than 5% due to the lack of an early diagnosis method and effective therapy. To provide a novel early diagnostic method and targeted therapy for pancreatic cancer, a multifunctional nanoimmunoliposome with high loading of ultrasmall superparamagnetic iron oxides (USPIOs and doxorubicin (DOX was prepared by transient binding and reverse-phase evaporation method, and was conjugated with anti-mesothelin monoclonal antibody by post-insertion method to target anti-mesothelin-overexpressed pancreatic cancer cells. The in vitro and in vivo properties of this anti-mesothelin antibody-conjugated PEGlyated liposomal DOX and USPIOs (M-PLDU; and PEGlyated nanoimmunoliposome without antibody conjugation [PLDU] were evaluated both in human pancreatic cancer cell line Panc-1 cell and in a pancreatic cancer xenograft animal model. Results showed that M-PLDUs were spherical and uniform with a diameter about ~180 nm, with a zeta potential of about −28~−30 mV, and had good efficacy encapsulating DOX and USPIOs. The in vitro study demonstrated that M-PLDUs possessed good magnetic resonance imaging (MRI capability with a transverse relaxivity (r2 of about 58.5 mM–1 • s–1. Confocal microscopy showed more

  20. Targeting and cytotoxicity of SapC-DOPS nanovesicles in pancreatic cancer.

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    Zhengtao Chu

    Full Text Available Only a small number of promising drugs target pancreatic cancer, which is the fourth leading cause of cancer deaths with a 5-year survival of less than 5%. Our goal is to develop a new biotherapeutic agent in which a lysosomal protein (saposin C, SapC and a phospholipid (dioleoylphosphatidylserine, DOPS are assembled into nanovesicles (SapC-DOPS for treating pancreatic cancer. A distinguishing feature of SapC-DOPS nanovesicles is their high affinity for phosphatidylserine (PS rich microdomains, which are abnormally exposed on the membrane surface of human pancreatic tumor cells. To evaluate the role of external cell PS, in vitro assays were used to correlate PS exposure and the cytotoxic effect of SapC-DOPS in human tumor and nontumorigenic pancreatic cells. Next, pancreatic tumor xenografts (orthotopic and subcutaneous models were used for tumor targeting and therapeutic efficacy studies with systemic SapC-DOPS treatment. We observed that the nanovesicles selectively killed human pancreatic cancer cells in vitro by inducing apoptotic death, whereas untransformed cells remained unaffected. This in vitro cytotoxic effect correlated to the surface exposure level of PS on the tumor cells. Using xenografts, animals treated with SapC-DOPS showed clear survival benefits and their tumors shrank or disappeared. Furthermore, using a double-tracking method in live mice, we showed that the nanovesicles were specifically targeted to orthotopically-implanted, bioluminescent pancreatic tumors. These data suggest that the acidic phospholipid PS is a biomarker for pancreatic cancer that can be effectively targeted for therapy utilizing cancer-selective SapC-DOPS nanovesicles. This study provides convincing evidence in support of developing a new therapeutic approach to pancreatic cancer.

  1. Plectin-1 Targeted Dual-modality Nanoparticles for Pancreatic Cancer Imaging

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    Xiao Chen

    2018-04-01

    Full Text Available Background: Biomarker-targeted molecular imaging holds promise for early detection of pancreatic cancer. The aim of this study was to design and evaluate a plectin-1 targeted multi-functional nanoparticle probe for pancreatic cancer imaging. Methods: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-amino(polyethylene glycol (DSPE-PEG-NH2-modified superparamagnetic iron oxide (Fe3O4 nanoparticles (SPION were conjugated with plectin-1 antibody and/or Cy7 to create the multi-functional targeted nanoparticle targeted probe (Plectin-SPION-Cy7 or non-targeted probe (SPION-Cy7. Pancreatic carcinoma cell lines expressing plectin-1 were cultured with the targeted or control probes and then were imaged using confocal laser scanning microscopy and magnetic resonance imaging (MRI. Accumulations of the nanoparticles in pancreatic tumor xenografted mice were determined by MRI and fluorescence imaging. Results: In vitro optical imaging and MRI showed that the targeted nanoparticles were highly accumulated in MIAPaCa2 and XPA-1 carcinoma cells but not in non-carcinoma MIN6 cells, which was further confirmed by Prussian blue staining. In vivo MRI showed a significant T2 signal reduction. Prussian blue staining further confirmed that the plectin-1 targeted nanoparticles were highly accumulated in the tumor mass but not in normal pancreatic tissues, or in the liver and kidney, and few nanoparticles were observed in the tumors of mice injected with SPION-Cy7. Conclusions: Our data demonstrate that plectin-1 targeted fluorescence and MR dual-functional nanoparticle can visualize pancreatic cancer, and it has great potential to be used with various imaging devices for pancreatic cancer detection. Keywords: Pancreatic cancer, Plectin-1, Magnetic resonance imaging, Optical imaging, Nanoparticle

  2. Emerging targets in pancreatic cancer: epithelial–mesenchymal transition and cancer stem cells

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    Castellanos JA

    2013-09-01

    Full Text Available Jason A Castellanos,1 Nipun B Merchant,1–3 Nagaraj S Nagathihalli1–31Department of Surgery, 2Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; 3Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, TN, USAAbstract: Pancreatic ductal adenocarcinoma is one of the most aggressive solid malignancies and is characterized by poor response to current therapy and a dismal survival rate. Recent insights regarding the role of cancer stem cells (CSCs and epithelial–mesenchymal transition (EMT in tumorigenesis have brought further understanding to the field and have highlighted new therapeutic targets. CSCs are a distinct subset of cancer cells, with the ability to differentiate into other cell types and self-renew in order to fuel the maintenance of tumor amplification. Transition of a cancer cell from an EMT leads to increased migratory and invasive properties, and thus facilitates initiation of metastasis. EMT is regulated by a complex network of factors that includes cytokines, growth factors, aberrant signaling pathways, transcription factors, and the tumor microenvironment. There is emerging evidence that the EMT process may give rise to CSCs, or at least cells with stem cell-like properties. We review the key pathways involved in both of these processes, the biomarkers used to identify CSCs, and new therapeutic approaches targeting CSCs and EMT in pancreatic ductal adenocarcinoma.Keywords: epithelial-mesenchymal transition, cancer stem cells, tumor microenvironment, pancreatic ductal adenocarcinoma

  3. Therapy of pancreatic cancer

    International Nuclear Information System (INIS)

    Takeda, Yutaka; Kitagawa, Toru; Nakamori, Shoji

    2009-01-01

    Pancreatic cancer remains one of the most difficult diseases to cure. Japan pancreas society guidelines for management of pancreatic cancer indicate therapeutic algorithm according to the clinical stage. For locally limited pancreatic cancer (cStage I, II, III in Japanese classification system), surgical resection is recommended, however prognosis is still poor. Major randomized controlled trials of resected pancreatic cancer indicates that adjuvant chemotherapy is superior to observation and gemcitabine is superior to 5-fluorouracil (FU). For locally advanced resectable pancreatic cancer (cStage IVa in Japanese classification system (JCS)), we perform neoadjuvant chemoradiotherapy. Phase I study established a recommended dose of 800 mg gemcitabine and radiation dose of 36 Gy. For locally advanced nonresectable pancreatic cancer (cStage IVa in JCS), chemoradiotherapy followed by chemotherapy is recommended. Although pancreatic cancer is chemotherapy resistant tumor, systemic chemotherapy is recommended for metastatic pancreatic cancer (cStage IVb in JCS). Single-agent gemcitabine is the standard first line agent for the treatment of advanced pancreatic cancer. Meta-analysis of chemotherapy showed possibility of survival benefit of gemcitabine combination chemotherapy over gemcitabine alone. We hope gemcitabine combination chemotherapy or molecular targeted therapy will improve prognosis of pancreatic cancer in the future. (author)

  4. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling

    DEFF Research Database (Denmark)

    Balic, Anamaria; Sørensen, Morten Dræby; Trabulo, Sara Maria

    2014-01-01

    is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer......Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs...... as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts...

  5. Emerging Drug Target In Pancreatic Cancer: Placing Sirtuin 1 on the Canvas.

    Science.gov (United States)

    Giry-Laterriere, Marc; Pinho, Andreia V; Eling, Nils; Chantrill, Lorraine; Rooman, Ilse

    2015-01-01

    Sirtuin 1 is a protein deacetylase that regulates a large number of proteins often functionally implicated in tumor development and progression. Its pleiotropic function has turned SIRT1 into an attractive chemotherapeutic target, underscored by very promising preclinical results with SIRT1 inhibitors in the treatment of chronic myeloid leukemia. Here, we revisit the studies on SIRT1 as an emerging target for therapy in pancreatic cancer, a tumor with dismal outcomes for which currently few therapeutic options are available. We highlight those potential SIRT1 target genes that are commonly affected in pancreatic cancer according to recent genomic analyses.

  6. Repurposing Established Compounds to Target Pancreatic Cancer Stem Cells (CSCs

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    Bernhard W. Renz

    2017-06-01

    Full Text Available The diagnosis of pancreatic ductal adenocarcinoma (PDAC carries a dismal prognosis, in particular, when patients present with unresectable disease. While significant progress has been made in understanding the biology of PDAC, this knowledge has not translated into a clear clinical benefit and current chemotherapeutic strategies only offer a modest improvement in overall survival. Accordingly, novel approaches are desperately needed. One hypothesis that could—at least in part—explain the desolate response of PDAC to chemotherapy is the so-called cancer stem cell (CSC concept, which attributes specific traits, such as chemoresistance, metastatic potential and a distinct metabolism to a small cellular subpopulation of the whole tumor. At the same time, however, some of these attributes could make CSCs more permissive for novel therapeutic strategies with compounds that are already in clinical use. Most recently, several publications have tried to enlighten the field with the idea of repurposing established drugs for antineoplastic use. As such, recycling drugs could present an intriguing and fast-track method with new therapeutic paradigms in anti-cancer and anti-CSC treatments. Here, we aim to summarize important aspects and novel findings of this emerging field.

  7. EGFR-targeted gelatin nanoparticles for systemic administration of gemcitabine in an orthotopic pancreatic cancer model.

    Science.gov (United States)

    Singh, Amit; Xu, Jing; Mattheolabakis, George; Amiji, Mansoor

    2016-04-01

    In this study, we have formulated redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a targeted vector for systemic delivery of gemcitabine therapy in pancreatic cancer. The gelatin nanoparticles were formed by ethanol-induced desolvation process to encapsulate the bound drug. The surface of the nanoparticles was decorated either with poly(ethylene glycol) (PEG) chains to impart enhanced circulation time or with EGFR targeting peptide to confer target specificity. Our in vitro studies in Panc-1 human pancreatic ductal adenocarcinoma cells confirm that gemcitabine encapsulated in EGFR-targeted gelatin nanoparticles, released through disulfide bond cleavage, had a significantly improved cytotoxic profile. Further, the in vivo anticancer activity was evaluated in an orthotopic pancreatic adenocarcinoma tumor bearing SCID beige mice, which confirmed that EGFR-targeted gelatin nanoparticles could efficiently deliver gemcitabine to the tumor leading to higher therapeutic benefit as compared to the drug in solution. The treatment of pancreatic cancer remains unsatisfactory, with an average 5-year survival of less than 5%. New treatment modalities are thus urgently needed. In this study, the authors presented their formulation of redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a carrier for gemcitabine. In-vitro and in-vivo experiments showed encouraging results. It is hoped that the findings would provide a novel and alternative drug delivery platform for the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Pathology, genetic alterations, and targets of differentially expressed microRNAs in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Azevedo-Pouly ACP

    2014-06-01

    Full Text Available Ana Clara P Azevedo-Pouly, Thomas D SchmittgenDivision of Pharmaceutics and Pharmaceutical Chemistry, the Ohio State University College of Pharmacy, Columbus, OH, USAAbstract: Since their discovery in mammals in 2001, the field of microRNA (miRNA research has grown exponentially. miRNAs regulate protein translation following binding to conserved sequences within the 3' untranslated region of messenger RNAs. miRNAs are found to regulate nearly all biological processes, and their expression has been shown to differentially regulate a large number of diseases including cancer. Pancreatic ductal adenocarcinoma (PDAC was one of the initial groups of cancers to demonstrate differential miRNA expression. Since then, there have been numerous studies linking differential miRNA expression to PDAC. Translational extrapolation of these studies has been done linking diagnostic, prognostic, and therapeutic applications, and multiple review articles and book chapters have been written on these subjects. The intent here is to provide an overview of pancreatic cancer and review the current state of the validated and published findings on the messenger RNA targets of differentially expressed miRNAs in PDAC. We then attempt to summarize these findings to extrapolate them in the hopes of better understanding how altered miRNA expression in PDAC may alter the phenotype of this disease.Keywords: microRNA, pancreatic cancer, pancreatic ductal adenocarcinoma, target

  9. Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal.

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    Mariana Rodova

    Full Text Available Dysregulation of the sonic hedgehog (Shh signaling pathway has been associated with cancer stem cells (CSC and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN, an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4 as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway

  10. PANCREATIC CANCER

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    Alojz Pleskovič

    2003-12-01

    Full Text Available Background. The pancreatic cancer is quite common malignant tumor of gastointestinal tract and its incidence is increasing in well developed part of the world. Despite of all advanced diagnostic methods the disease is in most cases recognised too late when the tumor is not resectable.Conclusions. Only in 20–30% of patients with pancreatic cancer surgical resection is possible, and even in this group 5year survival is very low. In the patients where the tumor is not resectable, sometimes only palliative procedures are indicated and sometimes only simptomatic therapy is possible. The average survival period in this group of patients is 12–20 months. Adjuvant chemo and radiotherapy has not shown much of benefit and the prognosis is still very bad.

  11. Identification of RegIV as a novel GLI1 target gene in human pancreatic cancer.

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    Feng Wang

    2011-04-01

    Full Text Available GLI1 is the key transcriptional factor in the Hedgehog signaling pathway in pancreatic cancer. RegIV is associated with regeneration, and cell growth, survival, adhesion and resistance to apoptosis. We aimed to study RegIV expression in pancreatic cancer and its relationship to GLI1.GLI1 and RegIV expression were evaluated in tumor tissue and adjacent normal tissues of pancreatic cancer patients and 5 pancreatic cancer cell lines by qRT-PCR, Western blot, and immunohistochemistry (IHC, and the correlation between them. The GLI1-shRNA lentiviral vector was constructed and transfected into PANC-1, and lentiviral vector containing the GLI1 expression sequence was constructed and transfected into BxPC-3. GLI1 and RegIV expression were evaluated by qRT-PCR and Western blot. Finally we demonstrated RegIV to be the target of GLI1 by chromatin immunoprecipitation (CHIP and electrophoretic mobility shift assays (EMSA.The results of IHC and qRT-PCR showed that RegIV and GLI1 expression was higher in pancreatic cancer tissues versus adjacent normal tissues (p<0.001. RegIV expression correlated with GLI1 expression in these tissues (R = 0.795, p<0.0001. These results were verified for protein (R = 0.939, p = 0.018 and mRNA expression (R = 0.959, p = 0.011 in 5 pancreatic cancer cell lines. RegIV mRNA and protein expression was decreased (94.7±0.3%, 84.1±0.5%; respectively when GLI1 was knocked down (82.1±3.2%, 76.7±2.2%; respectively by the RNAi technique. GLI1 overexpression in mRNA and protein level (924.5±5.3%, 362.1±3.5%; respectively induced RegIV overexpression (729.1±4.3%, 339.0±3.7%; respectively. Moreover, CHIP and EMSA assays showed GLI1 protein bound to RegIV promotor regions (GATCATCCA in pancreatic cancer cells.GLI1 promotes RegIV transcription by binding to the RegIV gene promoter in pancreatic cancer.

  12. Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy.

    Science.gov (United States)

    Vennin, Claire; Rath, Nicola; Pajic, Marina; Olson, Michael F; Timpson, Paul

    2017-10-03

    Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease; the identification of novel targets and development of effective treatment strategies are urgently needed to improve patient outcomes. Remodeling of the pancreatic stroma occurs during PDAC development, which drives disease progression and impairs responses to therapy. The actomyosin regulatory ROCK1 and ROCK2 kinases govern cell motility and contractility, and have been suggested to be potential targets for cancer therapy, particularly to reduce the metastatic spread of tumor cells. However, ROCK inhibitors are not currently used for cancer patient treatment, largely due to the overwhelming challenge faced in the development of anti-metastatic drugs, and a lack of clarity as to the cancer types most likely to benefit from ROCK inhibitor therapy. In 2 recent publications, we discovered that ROCK1 and ROCK2 expression were increased in PDAC, and that increased ROCK activity was associated with reduced survival and PDAC progression by enabling extracellular matrix (ECM) remodeling and invasive growth of pancreatic cancer cells. We also used intravital imaging to optimize ROCK inhibition using the pharmacological ROCK inhibitor fasudil (HA-1077), and demonstrated that short-term ROCK targeting, or 'priming', improved chemotherapy efficacy, disrupted cancer cell collective movement, and impaired metastasis. This body of work strongly indicates that the use of ROCK inhibitors in pancreatic cancer therapy as 'priming' agents warrants further consideration, and provides insights as to how transient mechanical manipulation, or fine-tuning the ECM, rather than chronic stromal ablation might be beneficial for improving chemotherapeutic efficacy in the treatment of this deadly disease.

  13. Reprogramming pancreatic stellate cells via p53 activation: A putative target for pancreatic cancer therapy.

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    Maya Saison-Ridinger

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is characterized by an extremely dense fibrotic stroma, which contributes to tumor growth, metastasis, and drug resistance. During tumorigenesis, quiescent pancreatic stellate cells (PSCs are activated and become major contributors to fibrosis, by increasing growth factor signaling and extracellular matrix deposition. The p53 tumor suppressor is known to restrict tumor initiation and progression through cell autonomous mechanisms including apoptosis, cell cycle arrest, and senescence. There is growing evidence that stromal p53 also exerts anti-tumor activity by paracrine mechanisms, though a role for stromal p53 in PDAC has not yet been described. Here, we demonstrate that activation of stromal p53 exerts anti-tumor effects in PDAC. We show that primary cancer-associated PSCs (caPSCs isolated from human PDAC express wild-type p53, which can be activated by the Mdm2 antagonist Nutlin-3a. Our work reveals that p53 acts as a major regulator of PSC activation and as a modulator of PDAC fibrosis. In vitro, p53 activation by Nutlin-3a induces profound transcriptional changes, which reprogram activated PSCs to quiescence. Using immunofluorescence and lipidomics, we have also found that p53 activation induces lipid droplet accumulation in both normal and tumor-associated fibroblasts, revealing a previously undescribed role for p53 in lipid storage. In vivo, treatment of tumor-bearing mice with the clinical form of Nutlin-3a induces stromal p53 activation, reverses caPSCs activation, and decreases fibrosis. All together our work uncovers new functions for stromal p53 in PDAC.

  14. Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

    DEFF Research Database (Denmark)

    Giannuzzo, Andrea; Saccomano, Mara; Napp, Joanna

    2016-01-01

    The ATP-gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which...... into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120-treated mice showed reduced bioluminescence compared to saline-treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct...

  15. MicroRNA-1291 targets the FOXA2-AGR2 pathway to suppress pancreatic cancer cell proliferation and tumorigenesis.

    Science.gov (United States)

    Tu, Mei-Juan; Pan, Yu-Zhuo; Qiu, Jing-Xin; Kim, Edward J; Yu, Ai-Ming

    2016-07-19

    Pancreatic cancer is the fourth leading cause of cancer death in the United States. Better understanding of pancreatic cancer biology may help identify new oncotargets towards more effective therapies. This study investigated the mechanistic actions of microRNA-1291 (miR-1291) in the suppression of pancreatic tumorigenesis. Our data showed that miR-1291 was downregulated in a set of clinical pancreatic carcinoma specimens and human pancreatic cancer cell lines. Restoration of miR-1291 expression inhibited pancreatic cancer cell proliferation, which was associated with cell cycle arrest and enhanced apoptosis. Furthermore, miR-1291 sharply suppressed the tumorigenicity of PANC-1 cells in mouse models. A proteomic profiling study revealed 32 proteins altered over 2-fold in miR-1291-expressing PANC-1 cells that could be assembled into multiple critical pathways for cancer. Among them anterior gradient 2 (AGR2) was reduced to the greatest degree. Through computational and experimental studies we further identified that forkhead box protein A2 (FOXA2), a transcription factor governing AGR2 expression, was a direct target of miR-1291. These results connect miR-1291 to the FOXA2-AGR2 regulatory pathway in the suppression of pancreatic cancer cell proliferation and tumorigenesis, providing new insight into the development of miRNA-based therapy to combat pancreatic cancer.

  16. A meta analysis of pancreatic microarray datasets yields new targets as cancer genes and biomarkers.

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    Nalin C W Goonesekere

    Full Text Available The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC, which has a five year survival rate of less than 5%. Improved screening for earlier diagnosis, through the detection of diagnostic and prognostic biomarkers provides the best hope of increasing the rate of curatively resectable carcinomas. Though many serum markers have been reported to be elevated in patients with PC, so far, most of these markers have not been implemented into clinical routine due to low sensitivity or specificity. In this study, we have identified genes that are significantly upregulated in PC, through a meta-analysis of large number of microarray datasets. We demonstrate that the biological functions ascribed to these genes are clearly associated with PC and metastasis, and that that these genes exhibit a strong link to pathways involved with inflammation and the immune response. This investigation has yielded new targets for cancer genes, and potential biomarkers for pancreatic cancer. The candidate list of cancer genes includes protein kinase genes, new members of gene families currently associated with PC, as well as genes not previously linked to PC. In this study, we are also able to move towards developing a signature for hypomethylated genes, which could be useful for early detection of PC. We also show that the significantly upregulated 800+ genes in our analysis can serve as an enriched pool for tissue and serum protein biomarkers in pancreatic cancer.

  17. CD47-CAR-T Cells Effectively Kill Target Cancer Cells and Block Pancreatic Tumor Growth.

    Science.gov (United States)

    Golubovskaya, Vita; Berahovich, Robert; Zhou, Hua; Xu, Shirley; Harto, Hizkia; Li, Le; Chao, Cheng-Chi; Mao, Mike Ming; Wu, Lijun

    2017-10-21

    CD47 is a glycoprotein of the immunoglobulin superfamily that is often overexpressed in different types of hematological and solid cancer tumors and plays important role in blocking phagocytosis, increased tumor survival, metastasis and angiogenesis. In the present report, we designed CAR (chimeric antigen receptor)-T cells that bind CD47 antigen. We used ScFv (single chain variable fragment) from mouse CD47 antibody to generate CD47-CAR-T cells for targeting different cancer cell lines. CD47-CAR-T cells effectively killed ovarian, pancreatic and other cancer cells and produced high level of cytokines that correlated with expression of CD47 antigen. In addition, CD47-CAR-T cells significantly blocked BxPC3 pancreatic xenograft tumor growth after intratumoral injection into NSG mice. Moreover, we humanized mouse CD47 ScFv and showed that it effectively bound CD47 antigen. The humanized CD47-CAR-T cells also specifically killed ovarian, pancreatic, and cervical cancer cell lines and produced IL-2 that correlated with expression of CD47. Thus, CD47-CAR-T cells can be used as a novel cellular therapeutic agent for treating different types of cancer.

  18. Rationale for Possible Targeting of Histone Deacetylase Signaling in Cancer Diseases with a Special Reference to Pancreatic Cancer

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    Mehdi Ouaïssi

    2011-01-01

    Full Text Available There is ongoing interest to identify signaling pathways and genes that play a key role in carcinogenesis and the development of resistance to antitumoral drugs. Given that histone deacetylases (HDACs interact with various partners through complex molecular mechanims leading to the control of gene expression, they have captured the attention of a large number of researchers. As a family of transcriptional corepressors, they have emerged as important regulators of cell differentiation, cell cycle progression, and apoptosis. Several HDAC inhibitors (HDACis have been shown to efficiently protect against the growth of tumor cells in vitro as well as in vivo. The pancreatic cancer which represents one of the most aggressive cancer still suffers from inefficient therapy. Recent data, although using in vitro tumor cell cultures and in vivo chimeric mouse model, have shown that some of the HDACi do express antipancreatic tumor activity. This provides hope that some of the HDACi could be potential efficient anti-pancreatic cancer drugs. The purpose of this review is to analyze some of the current data of HDACi as possible targets of drug development and to provide some insight into the current problems with pancreatic cancer and points of interest for further study of HDACi as potential molecules for pancreatic cancer adjuvant therapy.

  19. Targeting Trysin-Inflammation Axis for Pancreatitis Therapy in a Humanized Pancreatitis Model

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0258 TITLE: Targeting trypsin-inflammation axis for pancreatitis therapy in a humanized pancreatitis model PRINCIPAL...From - To) 15 Sep 2016 – 14 Sep 2017 4. TITLE AND SUBTITLE Targeting trypsin-inflammation axis for pancreatitis therapy in a humanized pancreatitis ... pancreatitis especially due to alcohol and smoking goes onto chronic pancreatitis which, in turn, is a risk factor for pancreatic cancer. Because only a

  20. CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR

    Science.gov (United States)

    Wang, Tianxiao; Yang, Jingxuan; Xu, Jianwei; Li, Jian; Cao, Zhe; Zhou, Li; You, Lei; Shu, Hong; Lu, Zhaohui; Li, Huihua; Li, Min; Zhang, Taiping; Zhao, Yupei

    2014-01-01

    Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer. PMID:24722501

  1. Targeting of the P2X7 receptor in pancreatic cancer and stellate cells.

    Science.gov (United States)

    Giannuzzo, Andrea; Saccomano, Mara; Napp, Joanna; Ellegaard, Maria; Alves, Frauke; Novak, Ivana

    2016-12-01

    The ATP-gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu-1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu-1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7(-/-) animals. PancTu-1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120-treated mice showed reduced bioluminescence compared to saline-treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120-treated tumours. © 2016 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

  2. Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Huang J

    2016-07-01

    Full Text Available Jing Huang,1,2 Weiping Qian,3 Liya Wang,1,2 Hui Wu,1 Hongyu Zhou,3 Andrew Yongqiang Wang,4 Hongbo Chen,5 Lily Yang,3 Hui Mao1,2 1Department of Radiology and Imaging Sciences, 2Center for Systems Imaging, 3Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA; 4Ocean Nanotech LLC, Springdale, AR, USA; 5School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, Guangxi, People’s Republic of China Abstract: Engineered nanocarriers have emerged as a promising platform for cancer therapy. However, the therapeutic efficacy is limited by low drug loading efficiency, poor passive targeting to tumors, and severe systemic side effects. Herein, we report a new class of nanoconstructs based on milk protein (casein-coated magnetic iron oxide (CNIO nanoparticles for targeted and image-guided pancreatic cancer treatment. The tumor-targeting amino-terminal fragment (ATF of urokinase plasminogen activator and the antitumor drug cisplatin (CDDP were engineered on this nanoplatform. High drug loading (~25 wt% and sustained release at physiological conditions were achieved through the exchange and encapsulation strategy. These ATF-CNIO-CDDP nanoparticles demonstrated actively targeted delivery of CDDP to orthotopic pancreatic tumors in mice. The effective accumulation and distribution of ATF-CNIO-CDDP was evidenced by magnetic resonance imaging, based on the T2-weighted contrast resulting from the specific accumulation of ATF-CNIO-CDDP in the tumor. Actively targeted delivery of ATF-CNIO-CDDP led to improved therapeutic efficacy in comparison with free CDDP and nontargeted CNIO-CDDP treatment. Meanwhile, less systemic side effects were observed in the nanocarrier-treated groups than that in the group treated with free CDDP. Hematoxylin and Eosin and Sirius Red staining of tumor sections revealed the possible disruption of stroma during the treatment with ATF-CNIO-CDDP. Overall, our results suggest that

  3. Advances in Smoothened-targeting therapies for pancreatic cancer: implication for drug discovery from herbal medicines.

    Science.gov (United States)

    Han, Jin-bin; Hua, Yong-qiang; Chen, Lian-yu; Liu, Lu-ming

    2012-03-01

    Smoothened (SMO) is a member of sonic hedgehog homology (SHH) signaling pathway. It plays a key role as a bridge between patched-1 (PTCH-1) and Gli. Aberrant SHH expression can be detected in various malignant tissues, and the expression in pancreatic cancer stem cells is higher apparently. SHH signals are closely associated with self-duplication of cancer stem cells, formation of tumor vessels as well as matrixes. SMO antagonists such as cyclopamine, GDC-0449 and so on show potential to inhibit activity of SHH signaling, and arrest the growth as well as metastases of tumors. Recently, a few of SMO antagonists have been studied in phase I clinical trials and some are in phase II, meanwhile, phase I or II trials of SMO antagonists to treat pancreatic cancer are performed currently. As the classical SMO antagonist, cyclopamine is extracted from a medicinal plant. Perhaps researchers may be able to determine more effective SMO-targeting drugs from herbal medicines in the future.

  4. DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.

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    Fang Liu

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is a deadly cancer with a poor prognosis that is characterized by excessive mitogenic pathway activation and marked chemoresistance to a broad spectrum of chemotherapeutic drugs. Dual specificity protein phosphatase 1 (DUSP1 is a key negative regulator of mitogen activated protein kinases (MAPKs. Yet, DUSP1 is overexpressed in pancreatic cancer cells (PCCs in PDAC where it paradoxically enhances colony formation in soft agar and promotes in vivo tumorigenicity. However, it is not known whether DUSP1 overexpression contributes to PDAC chemoresistance. Using BxPC3 and COLO-357 human PCCs, we show that gemcitabine activates c-JUN N-terminal kinase (JNK and p38 mitogen activated protein kinase (p38 MAPK, key kinases in two major stress-activated signaling pathways. Gemcitabine-induced JNK and p38 MAPK activation mediates increased apoptosis, but also transcriptionally upregulates DUSP1, as evidenced by increased DUSP1 mRNA levels and RNA polymerase II loading at DUSP1 gene body. Conversely, shRNA-mediated inhibition of DUSP1 enhances JNK and p38 MAPK activation and gemcitabine chemosensitivity. Using doxycycline-inducible knockdown of DUSP1 in established orthotopic pancreatic tumors, we found that combining gemcitabine with DUSP1 inhibition improves animal survival, attenuates angiogenesis, and enhances apoptotic cell death, as compared with gemcitabine alone. Taken together, these results suggest that gemcitabine-mediated upregulation of DUSP1 contributes to a negative feedback loop that attenuates its beneficial actions on stress pathways and apoptosis, raising the possibility that targeting DUSP1 in PDAC may have the advantage of enhancing gemcitabine chemosensitivity while suppressing angiogenesis.

  5. Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma.

    Science.gov (United States)

    Kanteti, Rajani; Mirzapoiazova, Tamara; Riehm, Jacob J; Dhanasingh, Immanuel; Mambetsariev, Bolot; Wang, Jiale; Kulkarni, Prakash; Kaushik, Garima; Seshacharyulu, Parthasarathy; Ponnusamy, Moorthy P; Kindler, Hedy L; Nasser, Mohd W; Batra, Surinder K; Salgia, Ravi

    2018-04-03

    The non-receptor cytoplasmic tyrosine kinase, Focal Adhesion Kinase (FAK) is known to play a key role in a variety of normal and cancer cellular functions such as survival, proliferation, migration and invasion. It is highly active and overexpressed in various cancers including Pancreatic Ductal Adenocarcinoma (PDAC) and Malignant Pleural Mesothelioma (MPM). Here, initially, we demonstrate that FAK is overexpressed in both PDAC and MPM cell lines. Then we analyze effects of two small molecule inhibitors PF-573228, and PF-431396, which are dual specificity inhibitors of FAK and proline rich tyrosine kinase 2 (PYK2), as well as VS-6063, another small molecule inhibitor that specifically inhibits FAK but not PYK2 for cell growth, motility and invasion of PDAC and MPM cell lines. Treatment with PF-573228, PF-431396 and VS-6063 cells resulted in a dose-dependent inhibition of growth and anchorage-independent colony formation in both cancer cell lines. Furthermore, these compounds suppressed the phosphorylation of FAK at its active site, Y397, and functionally induced significant apoptosis and cell cycle arrest in both cell lines. Using the ECIS (Electric cell-substrate impedance sensing) system, we found that treatment of both PF compounds suppressed adherence and migration of PDAC cells on fibronectin. Interestingly, 3D-tumor organoids derived from autochthonous KC (Kras;PdxCre) mice treated with PF-573228 revealed a significant decrease in tumor organoid size and increase in organoid cell death. Taken together, our results show that FAK is an important target for mesothelioma and pancreatic cancer therapy that merit further translational studies.

  6. Quantification of pancreatic cancer proteome and phosphorylome: indicates molecular events likely contributing to cancer and activity of drug targets.

    Directory of Open Access Journals (Sweden)

    David Britton

    Full Text Available LC-MS/MS phospho-proteomics is an essential technology to help unravel the complex molecular events that lead to and propagate cancer. We have developed a global phospho-proteomic workflow to determine activity of signaling pathways and drug targets in pancreatic cancer tissue for clinical application.Peptides resulting from tryptic digestion of proteins extracted from frozen tissue of pancreatic ductal adenocarcinoma and background pancreas (n = 12, were labelled with tandem mass tags (TMT 8-plex, separated by strong cation exchange chromatography, then were analysed by LC-MS/MS directly or first enriched for phosphopeptides using IMAC and TiO2, prior to analysis. In-house, commercial and freeware bioinformatic platforms were used to identify relevant biological events from the complex dataset.Of 2,101 proteins identified, 152 demonstrated significant difference in abundance between tumor and non-tumor tissue. They included proteins that are known to be up-regulated in pancreatic cancer (e.g. Mucin-1, but the majority were new candidate markers such as HIPK1 & MLCK. Of the 6,543 unique phosphopeptides identified (6,284 unique phosphorylation sites, 635 showed significant regulation, particularly those from proteins involved in cell migration (Rho guanine nucleotide exchange factors & MRCKα and formation of focal adhesions. Activator phosphorylation sites on FYN, AKT1, ERK2, HDAC1 and other drug targets were found to be highly modulated (≥2 fold in different cases highlighting their predictive power.Here we provided critical information enabling us to identify the common and unique molecular events likely contributing to cancer in each case. Such information may be used to help predict more bespoke therapy suitable for an individual case.

  7. The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer.

    Science.gov (United States)

    Hashim, Yassar M; Vangveravong, Suwanna; Sankpal, Narendra V; Binder, Pratibha S; Liu, Jingxia; Goedegebuure, S Peter; Mach, Robert H; Spitzer, Dirk; Hawkins, William G

    2017-01-17

    Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine. Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer. The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer. We believe that the strong sensitizing capacity of

  8. Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: A New Therapeutic Approach

    International Nuclear Information System (INIS)

    Muñoz, Miguel; Coveñas, Rafael

    2015-01-01

    Pancreatic cancer (PC) is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can promote PC and increase PC progression. To date, the prevention of PC is crucial because there is no curative treatment. After binding to the neurokinin-1 (NK-1) receptor (a receptor coupled to the stimulatory G-protein Gαs that activates adenylate cyclase), the peptide substance P (SP)—at high concentrations—is involved in many pathophysiological functions, such as depression, smoking, alcoholism, chronic inflammation and cancer. It is known that PC cells and samples express NK-1 receptors; that the NK-1 receptor is overexpressed in PC cells in comparison with non-tumor cells, and that nanomolar concentrations of SP induce PC cell proliferation. By contrast, NK-1 receptor antagonists exert antidepressive, anxiolytic and anti-inflammatory effects and anti-alcohol addiction. These antagonists also exert an antitumor action since in vitro they inhibit PC cell proliferation (PC cells death by apoptosis), and in a xenograft PC mouse model they exert both antitumor and anti-angiogenic actions. NK-1 receptor antagonists could be used for the treatment of PC and hence the NK-1 receptor could be a new promising therapeutic target in PC

  9. Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: A New Therapeutic Approach

    Energy Technology Data Exchange (ETDEWEB)

    Muñoz, Miguel, E-mail: mmunoz@cica.es [Research Laboratory on Neuropeptides (IBIS), Virgen del Rocío University Hospital, 41013 Sevilla (Spain); Coveñas, Rafael [Laboratory of Neuroanatomy of the Peptidergic System (Lab. 14), Institute of Neurosciences of Castilla y León (INCYL), University of Salamanca, 37008 Salamanca (Spain)

    2015-07-06

    Pancreatic cancer (PC) is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can promote PC and increase PC progression. To date, the prevention of PC is crucial because there is no curative treatment. After binding to the neurokinin-1 (NK-1) receptor (a receptor coupled to the stimulatory G-protein Gαs that activates adenylate cyclase), the peptide substance P (SP)—at high concentrations—is involved in many pathophysiological functions, such as depression, smoking, alcoholism, chronic inflammation and cancer. It is known that PC cells and samples express NK-1 receptors; that the NK-1 receptor is overexpressed in PC cells in comparison with non-tumor cells, and that nanomolar concentrations of SP induce PC cell proliferation. By contrast, NK-1 receptor antagonists exert antidepressive, anxiolytic and anti-inflammatory effects and anti-alcohol addiction. These antagonists also exert an antitumor action since in vitro they inhibit PC cell proliferation (PC cells death by apoptosis), and in a xenograft PC mouse model they exert both antitumor and anti-angiogenic actions. NK-1 receptor antagonists could be used for the treatment of PC and hence the NK-1 receptor could be a new promising therapeutic target in PC.

  10. Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: a New Therapeutic Approach

    Directory of Open Access Journals (Sweden)

    Miguel Muñoz

    2015-07-01

    Full Text Available Pancreatic cancer (PC is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can promote PC and increase PC progression. To date, the prevention of PC is crucial because there is no curative treatment. After binding to the neurokinin-1 (NK-1 receptor (a receptor coupled to the stimulatory G-protein Gαs that activates adenylate cyclase, the peptide substance P (SP—at high concentrations—is involved in many pathophysiological functions, such as depression, smoking, alcoholism, chronic inflammation and cancer. It is known that PC cells and samples express NK-1 receptors; that the NK-1 receptor is overexpressed in PC cells in comparison with non-tumor cells, and that nanomolar concentrations of SP induce PC cell proliferation. By contrast, NK-1 receptor antagonists exert antidepressive, anxiolytic and anti-inflammatory effects and anti-alcohol addiction. These antagonists also exert An antitumor action since in vitro they inhibit PC cell proliferation (PC cells death by apoptosis, and in a xenograft PC mouse model they exert both antitumor and anti-angiogenic actions. NK-1 receptor antagonists could be used for the treatment of PC and hence the NK-1 receptor could be a new promising therapeutic target in PC.

  11. Critical analysis of the potential for the therapeutic targeting of the Sp1 transcription factor in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Jutooru I

    2014-06-01

    Full Text Available Indira Jutooru,1 Gayathri Chadalapaka,1 Stephen Safe1,21Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA; 2Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USAAbstract: Pancreatic ductal adenocarcinoma (PDAC is a major cause of cancer-related deaths in developed countries and, in 2013, it is estimated that in excess of 45,220 new cases were diagnosed in the United States. PDAC is a highly aggressive disease that invariably evades early diagnosis. The mean survival time for patients with metastatic disease is only 3–6 months, and only 20%–30% of pancreatic cancer patients are alive after 12 months. Because pancreatic cancers are frequently detected at an advanced stage, treatments have provided very limited improvements in tumor regression and overall survival times after diagnosis. 5-Fluorouracil alone or in combination with other drugs has been extensively used for treatment of advanced pancreatic cancer, and gemcitabine has partially replaced 5-fluorouracil as a treatment for pancreatic cancer. Gemcitabine provides increased clinical benefits in terms of response rate; however, future studies need to focus on developing treatment modalities that will improve the survival rate for pancreatic cancer patients. Specificity protein 1 (Sp1 is overexpressed in PDAC patients, and high expression is associated with poor prognosis, lymph node metastasis, and low survival. Knockdown studies have shown that Sp1 plays an important role in cell growth, angiogenesis, inflammation, survival, and metastasis. Sp1 expression is low in normal tissue when compared to tumor tissue, which makes Sp1 a potential target for development of new mechanism-based drugs for treatment of pancreatic cancer. Several drugs such as tolfenamic acid, betulinic acid, and methyl-2-cyano3,12-dioxooleana-1,9(11-dien-28-oate are shown to downregulate Sp1 expression through various pathways

  12. Dosimetric Evaluation of VMAT, IMRT, and Proton Treatment Techniques Targeting Borderline Resectable Pancreatic Cancer Lesions

    Science.gov (United States)

    Harpool, Kristyn Brenna

    Purpose: With the advent of Volumetric Modulated Arc Therapy (VMAT), clinicians opted to favor this technology assuming it a better form of treatment. It was of interest to investigate its benefits compared to Intensity Modulated Radiation Therapy (IMRT) when creating treatment plans for pancreatic cancer for which challenges are considered: target location, avoiding excess dose to surrounding organs, and keeping highest dose within the planned target volume. This study aimed to determine which technique offered the best dose conformity and healthy organ sparing based on dosimetry and radiobiology models to help the clinic distribute fairly the patient load to the most adequate treatment delivery machine. Materials and Methods: Twenty pancreatic cancer treatment plans were analyzed. Original plans were re-planned and calculated with Varian Eclipse treatment planning system using VMAT or IMRT to create paired data sets. IMRT plans utilized 6-9 fields and VMAT plans used two arc fields. Both techniques used 6 MV beams and prescription dose of 4950 cGy in 18 fractions. Plan evaluations were based on Conformity Index (CI) and normal tissue (kidneys, liver, spinal cord, and bowel) doses analyzed using QUANTEC; and radiobiology analysis using the Uncomplicated Tumor Control Probability (UTCP). Results: On average, VMAT resulted in 10.56% (p = 0.19) and 17.46% (p = 0.16) higher mean doses to the total kidneys and liver and 7.48% (p = 0.10) and 0.44% (p = 0.93) lower mean doses to the bowel and maximum spinal cord dose, respectively. Conclusions: VMAT has not shown to be a significantly superior technique at providing target coverage and sparing normal structures, thus determination of the treatment technique should be based on individual cases. Purpose: To examine dosimetric differences between AAA and Acuros XB mathematical treatment planning software in the treatment of pancreatic cancer. Materials and Methods: CT images from twelve pancreatic cancer patients were used

  13. Variability of Target and Normal Structure Delineation Using Multimodality Imaging for Radiation Therapy of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Dalah, Entesar; Moraru, Ion [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Paulson, Eric [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Erickson, Beth [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Li, X. Allen, E-mail: ali@mcw.edu [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States)

    2014-07-01

    compared with those from CT, except for the kidneys. Conclusions: Differences exists between DCE-, ADC-, and FDG-PET–defined target volumes for RT of pancreatic cancer. Organ at risk volumes based on MRI are generally smaller than those based on CT. Further studies combined with pathologic specimens are required to identify the optimal imaging modality or sequence to define GTV.

  14. Neural plasticity in pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Demir, Ihsan Ekin; Friess, Helmut; Ceyhan, Güralp O

    2015-11-01

    Pancreatic nerves undergo prominent alterations during the evolution and progression of human chronic pancreatitis and pancreatic cancer. Intrapancreatic nerves increase in size (neural hypertrophy) and number (increased neural density). The proportion of autonomic and sensory fibres (neural remodelling) is switched, and are infiltrated by perineural inflammatory cells (pancreatic neuritis) or invaded by pancreatic cancer cells (neural invasion). These neuropathic alterations also correlate with neuropathic pain. Instead of being mere histopathological manifestations of disease progression, pancreatic neural plasticity synergizes with the enhanced excitability of sensory neurons, with Schwann cell recruitment toward cancer and with central nervous system alterations. These alterations maintain a bidirectional interaction between nerves and non-neural pancreatic cells, as demonstrated by tissue and neural damage inducing neuropathic pain, and activated neurons releasing mediators that modulate inflammation and cancer growth. Owing to the prognostic effects of pain and neural invasion in pancreatic cancer, dissecting the mechanism of pancreatic neuroplasticity holds major translational relevance. However, current in vivo models of pancreatic cancer and chronic pancreatitis contain many discrepancies from human disease that overshadow their translational value. The present Review discusses novel possibilities for mechanistically uncovering the role of the nervous system in pancreatic disease progression.

  15. Pancreatic Exocrine Insufficiency in Pancreatic Cancer.

    Science.gov (United States)

    Vujasinovic, Miroslav; Valente, Roberto; Del Chiaro, Marco; Permert, Johan; Löhr, J-Matthias

    2017-02-23

    Abstract : Cancer patients experience weight loss for a variety of reasons, commencing with the tumor's metabolism (Warburg effect) and proceeding via cachexia to loss of appetite. In pancreatic cancer, several other factors are involved, including a loss of appetite with a particular aversion to meat and the incapacity of the pancreatic gland to function normally when a tumor is present in the pancreatic head. Pancreatic exocrine insufficiency is characterized by a deficiency of the enzymes secreted from the pancreas due to the obstructive tumor, resulting in maldigestion. This, in turn, contributes to malnutrition, specifically a lack of fat-soluble vitamins, antioxidants, and other micronutrients. Patients with pancreatic cancer and pancreatic exocrine insufficiency have, overall, an extremely poor prognosis with regard to surgical outcome and overall survival. Therefore, it is crucial to be aware of the mechanisms involved in the disease, to be able to diagnose pancreatic exocrine insufficiency early on, and to treat malnutrition appropriately, for example, with pancreatic enzymes.

  16. The Marine Natural Product Manzamine A Targets Vacuolar ATPases and Inhibits Autophagy in Pancreatic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Amy E. Wright

    2013-09-01

    Full Text Available Manzamine A, a member of the manzamine alkaloids, was originally isolated from marine sponges of the genus Haliclona. It was recently shown to have activity against pancreatic cancer cells, but the precise mechanism of action remained unclear. To further our understanding of the mechanism of action of manzamine A, chemogenomic profiling in the yeast S. cerevisiae was performed, suggesting that manzamine A is an uncoupler of vacuolar ATPases. Fluorescence microscopy confirmed this effect on yeast vacuoles, where manzamine A produced a phenotype very similar to that of the established v-ATPase inhibitor bafilomycin A1. In pancreatic cancer cells, 10 µM manzamine A affected vacuolar ATPase activity and significantly increased the level of autophagosome marker LC3-II and p62/SQSTM1 as observed by western blot analysis. Treatment with manzamine A in combination with bafilomycin A1 (inhibitor of autophagosome-lysosome fusion did not change the levels of LC3-II when compared to cells treated with bafilomycin A1 alone, suggesting that manzamine A is a potential inhibitor of autophagy by preventing autophagosome turnover. As autophagy is essential for pancreatic tumor growth, blocking this pathway with manzamine A suggests a promising strategy for the treatment of pancreatic cancer.

  17. Dosimetric Advantages of Midventilation Compared With Internal Target Volume for Radiation Therapy of Pancreatic Cancer

    NARCIS (Netherlands)

    Lens, Eelco; van der Horst, Astrid; Versteijne, Eva; van Tienhoven, Geertjan; Bel, Arjan

    2015-01-01

    The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were

  18. A novel monoclonal antibody targeting carboxymethyllysine, an advanced glycation end product in atherosclerosis and pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Ulrika Wendel

    Full Text Available Advanced glycation end products are formed by non-enzymatic reactions between proteins and carbohydrates, causing irreversible lysine and arginine alterations that severely affect protein structure and function. The resulting modifications induce inflammation by binding to scavenger receptors. An increase in advanced glycation end products is observed in a number of diseases e.g. atherosclerosis and cancer. Since advanced glycation end products also are present in healthy individuals, their detection and quantification are of great importance for usage as potential biomarkers. Current methods for advanced glycation end product detection are though limited and solely measure total glycation. This study describes a new epitope-mapped single chain variable fragment, D1-B2, against carboxymethyllysine, produced from a phage library that was constructed from mouse immunizations. The phage library was selected against advanced glycation end product targets using a phage display platform. Characterization of its binding pattern was performed using large synthetic glycated peptide and protein libraries displayed on microarray slides. D1-B2 showed a preference for an aspartic acid, three positions N-terminally from a carboxymethyllysine residue and also bound to a broad collection of glycated proteins. Positive immunohistochemical staining of mouse atherosclerotic plaques and of a tissue microarray of human pancreatic tumors confirmed the usability of the new scFv for advanced glycation end product detection in tissues. This study demonstrates a promising methodology for high-throughput generation of epitope-mapped monoclonal antibodies against AGE.

  19. Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy

    Science.gov (United States)

    Tamburrino, Anna; Piro, Geny; Carbone, Carmine; Tortora, Giampaolo; Melisi, Davide

    2013-01-01

    Pancreatic cancer remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21st century. Despite efforts over the past three decades to improve diagnosis and treatment, the prognosis for patients with pancreatic cancer is extremely poor with or without treatment, and incidence rates are virtually identical to mortality rates. Although advances have been made through the identification of relevant molecular pathways in pancreatic cancer, there is still a critical, unmet need for the translation of these findings into effective therapeutic strategies that could reduce the intrinsic drug resistance of this disease and for the integration of these molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve patients’ survival. Tumors are heterogeneous cellular entities whose growth and progression depend on reciprocal interactions between genetically altered neoplastic cells and a non-neoplastic microenvironment. To date, most of the mechanisms of resistance studied have been related to tumor cell-autonomous signaling pathways. However, recent data suggest a putative important role of tumor microenvironment in the development and maintenance of resistance to classic chemotherapeutic and targeted therapies. This present review is meant to describe and discuss some of the most important advances in the comprehension of the tumor cell-autonomous and tumor microenvironment-related molecular mechanisms responsible for the resistance of pancreatic cancer to the proapoptotic activity of the classic chemotherapeutic agents and to the most novel anti-angiogenic drugs. We present some of the emerging therapeutic targets for the modulation of this resistant phenotype. PMID:23641216

  20. Pancreatic cancer stem cells.

    Science.gov (United States)

    Lee, Cheong J; Dosch, Joseph; Simeone, Diane M

    2008-06-10

    Cellular heterogeneity in cancer was observed decades ago by studies in mice which showed that distinct subpopulations of cells within a tumor mass are capable of driving tumorigenesis. Conceptualized from this finding was the stem-cell hypothesis for cancer, which suggests that only a specific subset of cancer cells within each tumor is responsible for tumor initiation and propagation, termed tumor initiating cells or cancer stem cells (CSCs). Recent data has been provided to support the existence of CSCs in human blood cell-derived cancers and solid organ tumors of the breast, brain, prostate, colon, and skin. Study of human pancreatic cancers has also revealed a specific subpopulation of cancer cells that possess the characteristics of CSCs. These pancreatic cancer stem cells express the cell surface markers CD44, CD24, and epithelial-specific antigen, and represent 0.5% to 1.0% of all pancreatic cancer cells. Along with the properties of self-renewal and multilineage differentiation, pancreatic CSCs display upregulation of important developmental genes that maintain self-renewal in normal stem cells, including Sonic hedgehog (SHH) and BMI-1. Signaling cascades that are integral in tumor metastasis are also upregulated in the pancreatic CSC. Understanding the biologic behavior and the molecular pathways that regulate growth, survival, and metastasis of pancreatic CSCs will help to identify novel therapeutic approaches to treat this dismal disease.

  1. Radiotherapy of pancreatic cancers

    International Nuclear Information System (INIS)

    Pobijakova, M.; Scepanovic, D.

    2012-01-01

    Pancreatic cancer is the tenth most common cancer in the western world and has become the fourth leading cause of cancer-related death. Surgery remains the only potentially curative treatment modality for pancreatic cancer. However, only a minority of patients are candidates for surgery at diagnosis, and only a minority of patients who undergo surgery are cured. The role of radiation therapy in pancreatic cancer continues to be investigated. Its use in the adjuvant setting remains controversial. Indication of radiotherapy is more generally accepted in borderline resectable disease, but prospective data are sparse. Randomized trials have yielded conflicting data in locally advanced disease. Radiation techniques have improved over time. This article aims to give an overview of the current knowledge regarding the role of radiotherapy in the treatment of pancreatic ductal adenocarcinoma. (author)

  2. miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jong-Kook [College of Pharmacy, Ohio State University, Columbus, OH 43210 (United States); Henry, Jon C. [Department of Surgery, Ohio State University, Columbus, OH 43210 (United States); Jiang, Jinmai [College of Pharmacy, Ohio State University, Columbus, OH 43210 (United States); Esau, Christine [Regulus Therapeutics, Carlsbad, CA (United States); Gusev, Yuriy [Lombardi Cancer Center, Georgetown University, Washington, DC (United States); Lerner, Megan R. [Veterans Affairs Medical Center, Oklahoma City, OK (United States); Postier, Russell G. [Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Brackett, Daniel J. [Veterans Affairs Medical Center, Oklahoma City, OK (United States); Schmittgen, Thomas D., E-mail: Schmittgen.2@osu.edu [College of Pharmacy, Ohio State University, Columbus, OH 43210 (United States)

    2011-03-25

    Research highlights: {yields} The expression of miR-132 and miR-212 are significantly increased in pancreatic cancer. {yields} miR-132 and miR-212 target the tumor suppressor pRb, resulting in enhanced proliferation. {yields} miR-132 and miR-212 expression is increased by a {beta}2 adrenergic receptor agonist, suggesting a novel mechanism for pancreatic cancer progression. -- Abstract: Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR-212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target the retinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR-132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G{sub 2}/M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the {beta}2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over-expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The {beta}2 adrenergic pathway may play an important role in this novel mechanism.

  3. Activator protein 1 promotes gemcitabine-induced apoptosis in pancreatic cancer by upregulating its downstream target Bim.

    Science.gov (United States)

    Ren, Xiaoxia; Zhao, Wenjing; Du, Yongxing; Zhang, Taiping; You, Lei; Zhao, Yupei

    2016-12-01

    Gemcitabine is a commonly used chemotherapy drug in pancreatic cancer. The function of activator protein 1 (AP-1) is cell-specific, and its function depends on the expression of other complex members. In the present study, we added gemcitabine to the media of Panc-1 and SW1990 cells at clinically achieved concentrations (10 µM). Compared with constitutive c-Fos expression, c-Jun expression increased in a dose-dependent manner upon gemcitabine treatment. c-Jun overexpression increased gemcitabine-induced apoptosis through Bim activation, while cell apoptosis and Bim expression decreased following c-Jun knockdown. Furthermore, gemcitabine-induced apoptosis and Bim levels decreased when c-Jun phosphorylation was blocked by SP600125. Our findings suggest that c-Jun, which is a member of the AP-1 complex, functions in gemcitabine-induced apoptosis by regulating its downstream target Bim in pancreatic cancer cells.

  4. Hedgehog signaling and therapeutics in pancreatic cancer.

    LENUS (Irish Health Repository)

    Kelleher, Fergal C

    2012-02-01

    OBJECTIVE: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. METHOD: PubMed search (2000-2010) and literature based references. RESULTS: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. CONCLUSIONS: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer.

  5. Inhibition of the mammalian target of rapamycin (mTOR in advanced pancreatic cancer: results of two phase II studies

    Directory of Open Access Journals (Sweden)

    Zhang Yujian

    2010-07-01

    Full Text Available Abstract Background The phosphoinositide 3-kinase (PI3K/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin (mTOR kinase is an important mediator for its signaling. Our recent in vitro studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop. The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in preclinical tumor models. Methods Two studies prospectively enrolled adult patients with advanced pancreatic cancer, Eastern Cooperative Oncology Group performance status 0-1, adequate hematologic, hepatic and renal parameters and measurable disease. In Study A, temsirolimus was administered intravenously at 25 mg weekly. In Study B, everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily. The primary endpoint in both studies was overall survival at 6 months. Secondary endpoints included time to progression, progression-free survival, overall survival, response rate, safety and toxicity. Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1 and PTEN. Results Five patients enrolled in Study A; Two patients died within a month (rapid disease progression and hemorrhagic stroke, respectively. One patient developed dehydration and another developed asthenia. Sixteen patients enrolled in Study B.: 12 males, all ECOG PS = 1. Median cycles = 1 (range 1-2. Grade 4 toxicity: hyponatremia (n = 1, Grade 3: diarrhea (n = 1, cholangitis (n = 3, hyperglycemia (n = 1, fatigue (n = 1. Grade 2: pneumonia (n = 2, dehydration (n = 2, nausea (n = 2, neutropenia (n = 1, mucositis (n = 2

  6. Targeted agents for patients with advanced/metastatic pancreatic cancer: A protocol for systematic review and network meta-analysis.

    Science.gov (United States)

    Di, Baoshan; Pan, Bei; Ge, Long; Ma, Jichun; Wu, Yiting; Guo, Tiankang

    2018-03-01

    Pancreatic cancer (PC) is a devastating malignant tumor. Although surgical resection may offer a good prognosis and prolong survival, approximately 80% patients with PC are always diagnosed as unresectable tumor. National Comprehensive Cancer Network's (NCCN) recommended gemcitabine-based chemotherapy as efficient treatment. While, according to recent studies, targeted agents might be a better available option for advanced or metastatic pancreatic cancer patients. The aim of this systematic review and network meta-analysis will be to examine the differences of different targeted interventions for advanced/metastatic PC patients. We will conduct this systematic review and network meta-analysis using Bayesian method and according to Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. To identify relevant studies, 6 electronic databases including PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of science, CNKI (Chinese National Knowledge Infrastructure), and CBM (Chinese Biological Medical Database) will be searched. The risk of bias in included randomized controlled trials (RCTs) will be assessed using the Cochrane Handbook version 5.1.0. And we will use GRADE approach to assess the quality of evidence from network meta-analysis. Data will be analyzed using R 3.4.1 software. To the best of our knowledge, this systematic review and network meta-analysis will firstly use both direct and indirect evidence to compare the differences of different targeted agents and targeted agents plus chemotherapy for advanced/metastatic pancreatic cancer patients. This is a protocol of systematic review and meta-analysis, so the ethical approval and patient consent are not required. We will disseminate the results of this review by submitting to a peer-reviewed journal.

  7. Targeted screening of individuals at high risk for pancreatic cancer: results of a simulation model.

    Science.gov (United States)

    Pandharipande, Pari V; Heberle, Curtis; Dowling, Emily C; Kong, Chung Yin; Tramontano, Angela; Perzan, Katherine E; Brugge, William; Hur, Chin

    2015-04-01

    To identify when, from the standpoint of relative risk, magnetic resonance (MR) imaging-based screening may be effective in patients with a known or suspected genetic predisposition to pancreatic cancer. The authors developed a Markov model of pancreatic ductal adenocarcinoma (PDAC). The model was calibrated to National Cancer Institute Surveillance, Epidemiology, and End Results registry data and informed by the literature. A hypothetical screening strategy was evaluated in which all population individuals underwent one-time MR imaging screening at age 50 years. Screening outcomes for individuals with an average risk for PDAC ("base case") were compared with those for individuals at an increased risk to assess for differential benefits in populations with a known or suspected genetic predisposition. Effects of varying key inputs, including MR imaging performance, surgical mortality, and screening age, were evaluated with a sensitivity analysis. RESULTS In the base case, screening resulted in a small number of cancer deaths averted (39 of 100 000 men, 38 of 100 000 women) and a net decrease in life expectancy (-3 days for men, -4 days for women), which was driven by unnecessary pancreatic surgeries associated with false-positive results. Life expectancy gains were achieved if an individual's risk for PDAC exceeded 2.4 (men) or 2.7 (women) times that of the general population. When relative risk increased further, for example to 30 times that of the general population, averted cancer deaths and life expectancy gains increased substantially (1219 of 100 000 men, life expectancy gain: 65 days; 1204 of 100 000 women, life expectancy gain: 71 days). In addition, results were sensitive to MR imaging specificity and the surgical mortality rate. Although PDAC screening with MR imaging for the entire population is not effective, individuals with even modestly increased risk may benefit. © RSNA, 2014 Online supplemental material is available for this article.

  8. Cancer Stem Cells in Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bao, Qi; Zhao, Yue; Renner, Andrea; Niess, Hanno; Seeliger, Hendrik; Jauch, Karl-Walter; Bruns, Christiane J., E-mail: christiane.bruns@med.uni-muenchen.de [Department of Surgery, Ludwig Maximilian University of Munich, Klinikum Grosshadern, Marchioninistr. 15, D-81377, Munich (Germany)

    2010-08-19

    Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer.

  9. Cancer Stem Cells in Pancreatic Cancer

    Science.gov (United States)

    Bao, Qi; Zhao, Yue; Renner, Andrea; Niess, Hanno; Seeliger, Hendrik; Jauch, Karl-Walter; Bruns, Christiane J.

    2010-01-01

    Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs). Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer. PMID:24281178

  10. Cancer Stem Cells in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Karl-Walter Jauch

    2010-08-01

    Full Text Available Pancreatic cancer is an aggressive malignant solid tumor well-known by early metastasis, local invasion, resistance to standard chemo- and radiotherapy and poor prognosis. Increasing evidence indicates that pancreatic cancer is initiated and propagated by cancer stem cells (CSCs. Here we review the current research results regarding CSCs in pancreatic cancer and discuss the different markers identifying pancreatic CSCs. This review will focus on metastasis, microRNA regulation and anti-CSC therapy in pancreatic cancer.

  11. A nuclear-directed human pancreatic ribonuclease (PE5) targets the metabolic phenotype of cancer cells.

    Science.gov (United States)

    Vert, Anna; Castro, Jessica; Ribó, Marc; Benito, Antoni; Vilanova, Maria

    2016-04-05

    Ribonucleases represent a new class of antitumor RNA-damaging drugs. However, many wild-type members of the vertebrate secreted ribonuclease family are not cytotoxic because they are not able to evade the cytosolic ribonuclease inhibitor. We previously engineered the human pancreatic ribonuclease to direct it to the cell nucleus where the inhibitor is not present. The best characterized variant is PE5 that kills cancer cells through apoptosis mediated by the p21(WAF1/CIP1) induction and the inactivation of JNK. Here, we have used microarray-derived transcriptional profiling to identify PE5 regulated genes on the NCI/ADR-RES ovarian cancer cell line. RT-qPCR analyses have confirmed the expression microarray findings. The results show that PE5 cause pleiotropic effects. Among them, it is remarkable the down-regulation of multiple genes that code for enzymes involved in deregulated metabolic pathways in cancer cells.

  12. Adenovirus-Mediated Delivery of Decoy Hyper Binding Sites Targeting Oncogenic HMGA1 Reduces Pancreatic and Liver Cancer Cell Viability

    Directory of Open Access Journals (Sweden)

    Faizule Hassan

    2018-03-01

    Full Text Available High mobility group AT-hook 1 (HMGA1 protein is an oncogenic architectural transcription factor that plays an essential role in early development, but it is also implicated in many human cancers. Elevated levels of HMGA1 in cancer cells cause misregulation of gene expression and are associated with increased cancer cell proliferation and increased chemotherapy resistance. We have devised a strategy of using engineered viruses to deliver decoy hyper binding sites for HMGA1 to the nucleus of cancer cells with the goal of sequestering excess HMGA1 at the decoy hyper binding sites due to binding competition. Sequestration of excess HMGA1 at the decoy binding sites is intended to reduce HMGA1 binding at the naturally occurring genomic HMGA1 binding sites, which should result in normalized gene expression and restored sensitivity to chemotherapy. As proof of principle, we engineered the replication defective adenovirus serotype 5 genome to contain hyper binding sites for HMGA1 composed of six copies of an individual HMGA1 binding site, referred to as HMGA-6. A 70%–80% reduction in cell viability and increased sensitivity to gemcitabine was observed in five different pancreatic and liver cancer cell lines 72 hr after infection with replication defective engineered adenovirus serotype 5 virus containing the HMGA-6 decoy hyper binding sites. The decoy hyper binding site strategy should be general for targeting overexpression of any double-stranded DNA-binding oncogenic transcription factor responsible for cancer cell proliferation. Keywords: adenovirus, cancer therapy, oncogenic transcription factor, chemotherapy resistance, high mobility group A protein, decoy binding site, pancreatic cancer, liver cancer, HMGA1, neoadjuvant therapy

  13. Pancreatic Exocrine Insufficiency in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Miroslav Vujasinovic

    2017-02-01

    Full Text Available Abstract: Cancer patients experience weight loss for a variety of reasons, commencing with the tumor’s metabolism (Warburg effect and proceeding via cachexia to loss of appetite. In pancreatic cancer, several other factors are involved, including a loss of appetite with a particular aversion to meat and the incapacity of the pancreatic gland to function normally when a tumor is present in the pancreatic head. Pancreatic exocrine insufficiency is characterized by a deficiency of the enzymes secreted from the pancreas due to the obstructive tumor, resulting in maldigestion. This, in turn, contributes to malnutrition, specifically a lack of fat-soluble vitamins, antioxidants, and other micronutrients. Patients with pancreatic cancer and pancreatic exocrine insufficiency have, overall, an extremely poor prognosis with regard to surgical outcome and overall survival. Therefore, it is crucial to be aware of the mechanisms involved in the disease, to be able to diagnose pancreatic exocrine insufficiency early on, and to treat malnutrition appropriately, for example, with pancreatic enzymes.

  14. Safety and efficacy of enzyme targeting intraoperative radiosensitization therapy (KORTUC-IORT) for advanced pancreatic cancer

    International Nuclear Information System (INIS)

    Nishioka, Akihito; Hamada, Norihiko; Kariya, Shinji; Ogawa, Yasuhiro

    2012-01-01

    We developed a new radiosensitizer injection containing hydrogen peroxide and sodium hyaluronate just followed by intraoperative radiotherapy (IORT) for locally advanced pancreatic cancer, named KORTUC-IORT (Kochi Oxydol-Radiation Therapy for Unresectable Carcinoma + IORT). Fourteen patients were treated with KORTUC-IORT, external beam radiotherapy (EBRT), and systemic chemotherapy. With KORTUC-IORT, the agent containing hydrogen peroxide and sodium hyaluronate, was injected into tumor tissue just prior to administration of IORT under ultrasonic guidance. All treatments related with KORTUC-IORT were well tolerated, with few adverse effects. One year survival rate is 67% and median survival period is 15 months. The present formulation can be delivered safely and effectively under the conditions used. (author)

  15. Dosimetric Advantages of Midventilation Compared With Internal Target Volume for Radiation Therapy of Pancreatic Cancer.

    Science.gov (United States)

    Lens, Eelco; van der Horst, Astrid; Versteijne, Eva; van Tienhoven, Geertjan; Bel, Arjan

    2015-07-01

    The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were investigated. For each of the 18 patients, 2 treatment plans (25 × 2.0 Gy) were created, 1 using an ITV and 1 using a midV approach. The midV dose distribution was blurred using the respiratory-induced motion from 4-dimensional computed tomography. The resulting planning target volume (PTV) coverage for this blurred dose distribution was analyzed; PTV coverage was required to be at least V95% >98%. In addition, the change in PTV size and the changes in V10Gy, V20Gy, V30Gy, V40Gy, Dmean and D2cc for the stomach and for the duodenum were analyzed; differences were tested for significance using the Wilcoxon signed-rank test. Using a midV approach resulted in sufficient target coverage. A highly significant PTV size reduction of 13.9% (P<.001) was observed. Also, all dose parameters for the stomach and duodenum, except the D2cc of the duodenum, improved significantly (P≤.002). By using the midV approach to account for respiratory-induced tumor motion, a significant PTV reduction and significant dose reductions to the stomach and to the duodenum can be achieved when irradiating pancreatic tumors. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Dosimetric Advantages of Midventilation Compared With Internal Target Volume for Radiation Therapy of Pancreatic Cancer

    International Nuclear Information System (INIS)

    Lens, Eelco; Horst, Astrid van der; Versteijne, Eva; Tienhoven, Geertjan van; Bel, Arjan

    2015-01-01

    Purpose: The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were investigated. Methods and Materials: For each of the 18 patients, 2 treatment plans (25 × 2.0 Gy) were created, 1 using an ITV and 1 using a midV approach. The midV dose distribution was blurred using the respiratory-induced motion from 4-dimensional computed tomography. The resulting planning target volume (PTV) coverage for this blurred dose distribution was analyzed; PTV coverage was required to be at least V 95% >98%. In addition, the change in PTV size and the changes in V 10Gy , V 20Gy , V 30Gy , V 40Gy , D mean and D 2cc for the stomach and for the duodenum were analyzed; differences were tested for significance using the Wilcoxon signed-rank test. Results: Using a midV approach resulted in sufficient target coverage. A highly significant PTV size reduction of 13.9% (P<.001) was observed. Also, all dose parameters for the stomach and duodenum, except the D 2cc of the duodenum, improved significantly (P≤.002). Conclusions: By using the midV approach to account for respiratory-induced tumor motion, a significant PTV reduction and significant dose reductions to the stomach and to the duodenum can be achieved when irradiating pancreatic tumors

  17. Dosimetric Advantages of Midventilation Compared With Internal Target Volume for Radiation Therapy of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lens, Eelco, E-mail: e.lens@amc.uva.nl; Horst, Astrid van der; Versteijne, Eva; Tienhoven, Geertjan van; Bel, Arjan

    2015-07-01

    Purpose: The midventilation (midV) approach can be used to take respiratory-induced pancreatic tumor motion into account during radiation therapy. In this study, the dosimetric consequences for organs at risk and tumor coverage of using a midV approach compared with using an internal target volume (ITV) were investigated. Methods and Materials: For each of the 18 patients, 2 treatment plans (25 × 2.0 Gy) were created, 1 using an ITV and 1 using a midV approach. The midV dose distribution was blurred using the respiratory-induced motion from 4-dimensional computed tomography. The resulting planning target volume (PTV) coverage for this blurred dose distribution was analyzed; PTV coverage was required to be at least V{sub 95%} >98%. In addition, the change in PTV size and the changes in V{sub 10Gy}, V{sub 20Gy}, V{sub 30Gy}, V{sub 40Gy}, D{sub mean} and D{sub 2cc} for the stomach and for the duodenum were analyzed; differences were tested for significance using the Wilcoxon signed-rank test. Results: Using a midV approach resulted in sufficient target coverage. A highly significant PTV size reduction of 13.9% (P<.001) was observed. Also, all dose parameters for the stomach and duodenum, except the D{sub 2cc} of the duodenum, improved significantly (P≤.002). Conclusions: By using the midV approach to account for respiratory-induced tumor motion, a significant PTV reduction and significant dose reductions to the stomach and to the duodenum can be achieved when irradiating pancreatic tumors.

  18. Adenovirus-Mediated Delivery of Decoy Hyper Binding Sites Targeting Oncogenic HMGA1 Reduces Pancreatic and Liver Cancer Cell Viability.

    Science.gov (United States)

    Hassan, Faizule; Ni, Shuisong; Arnett, Tyler C; McKell, Melanie C; Kennedy, Michael A

    2018-03-30

    High mobility group AT-hook 1 (HMGA1) protein is an oncogenic architectural transcription factor that plays an essential role in early development, but it is also implicated in many human cancers. Elevated levels of HMGA1 in cancer cells cause misregulation of gene expression and are associated with increased cancer cell proliferation and increased chemotherapy resistance. We have devised a strategy of using engineered viruses to deliver decoy hyper binding sites for HMGA1 to the nucleus of cancer cells with the goal of sequestering excess HMGA1 at the decoy hyper binding sites due to binding competition. Sequestration of excess HMGA1 at the decoy binding sites is intended to reduce HMGA1 binding at the naturally occurring genomic HMGA1 binding sites, which should result in normalized gene expression and restored sensitivity to chemotherapy. As proof of principle, we engineered the replication defective adenovirus serotype 5 genome to contain hyper binding sites for HMGA1 composed of six copies of an individual HMGA1 binding site, referred to as HMGA-6. A 70%-80% reduction in cell viability and increased sensitivity to gemcitabine was observed in five different pancreatic and liver cancer cell lines 72 hr after infection with replication defective engineered adenovirus serotype 5 virus containing the HMGA-6 decoy hyper binding sites. The decoy hyper binding site strategy should be general for targeting overexpression of any double-stranded DNA-binding oncogenic transcription factor responsible for cancer cell proliferation.

  19. miR-197 induces epithelial-mesenchymal transition in pancreatic cancer cells by targeting p120 catenin.

    Science.gov (United States)

    Hamada, Shin; Satoh, Kennichi; Miura, Shin; Hirota, Morihisa; Kanno, Atsushi; Masamune, Atsushi; Kikuta, Kazuhiro; Kume, Kiyoshi; Unno, Jun; Egawa, Shinichi; Motoi, Fuyuhiko; Unno, Michiaki; Shimosegawa, Tooru

    2013-06-01

    Invasive ductal adenocarcinoma (IDA) of the pancreas manifests poor prognosis due to the early invasion and distant metastasis. In contrast, intraductal papillary mucinous adenoma or carcinoma (IPMA or IPMC) reveals better clinical outcomes. Various molecular mechanisms contribute to these differences but entire picture is still unclear. Recent researches emphasized the important role of miRNA in biological processes including cancer invasion and metastasis. We previously described that miR-126 is down-regulated in IDA compared with IPMA or IPMC, and miR-126 regulates the expression of invasion related molecule disintegrin and metalloproteinase domain-containing protein 9 (ADAM9). Assessing the difference of miRNA expression profiles of IDA, IPMA, and IPMC, we newly identified miR-197 as an up-regulated miRNA specifically in IDA. Expression of miR-197 in pancreatic cancer cells resulted in the induction of epithelial-mesenchymal transition (EMT) along with the down-regulation of p120 catenin which is a putative target of miR-197. Direct interaction between miR-197 and p120 catenin mRNA sequence was confirmed by 3'UTR assay, and knockdown of p120 catenin recapitulated EMT induction in pancreatic cancer cells. In situ hybridization of miR-197 and immunohistochemistry of p120 catenin showed mutually exclusive patterns suggesting pivotal role of miR-197 in the regulation of p120 catenin. This miR-197/p120 catenin axis could be a novel therapeutic target. Copyright © 2012 Wiley Periodicals, Inc.

  20. Vaginal metastasis of pancreatic cancer.

    Science.gov (United States)

    Benhayoune, Khadija; El Fatemi, Hinde; El Ghaouti, Meryem; Bannani, Abdelaziz; Melhouf, Abdelilah; Harmouch, Taoufik

    2015-01-01

    Vaginal metastasis from pancreatic cancer is an extreme case and often indicates a poor prognosis. We present a case of pancreatic carcinoma with metastasis to the vagina that was discovered by vaginal bleeding. To our knowledge, this is the third case in the world of a primary pancreatic adenocarcinoma discovered of symptoms from a vaginal metastasis.

  1. The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1α targeted gene expression.

    Science.gov (United States)

    Miyake, Kotaro; Nishioka, Masanori; Imura, Satoru; Batmunkh, Erdenebulgan; Uto, Yoshihiro; Nagasawa, Hideko; Hori, Hitoshi; Shimada, Mitsuo

    2012-08-01

    Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1α (HIF-1α), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P<0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P<0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Danish Pancreatic Cancer Database

    DEFF Research Database (Denmark)

    Fristrup, Claus; Detlefsen, Sönke; Palnæs Hansen, Carsten

    2016-01-01

    AIM OF DATABASE: The Danish Pancreatic Cancer Database aims to prospectively register the epidemiology, diagnostic workup, diagnosis, treatment, and outcome of patients with pancreatic cancer in Denmark at an institutional and national level. STUDY POPULATION: Since May 1, 2011, all patients...... with microscopically verified ductal adenocarcinoma of the pancreas have been registered in the database. As of June 30, 2014, the total number of patients registered was 2,217. All data are cross-referenced with the Danish Pathology Registry and the Danish Patient Registry to ensure the completeness of registrations....... MAIN VARIABLES: The main registered variables are patient demographics, performance status, diagnostic workup, histological and/or cytological diagnosis, and clinical tumor stage. The following data on treatment are registered: type of operation, date of first adjuvant, neoadjuvant, and first...

  3. ETS-1: A potential target of glycolysis for metabolic therapy by regulating glucose metabolism in pancreatic cancer.

    Science.gov (United States)

    Zhang, Xiu; Wu, Dan; Aldarouish, Mohanad; Yin, Xiaodong; Li, Chunyan; Wang, Cailian

    2017-01-01

    Pancreatic cancer is one of the most lethal malignancies of all types of cancer due to lack of early symptoms and its resistance to conventional therapy. In our previous study, we have shown that v‑ets erythroblastosis virus E26 oncogene homolog‑1 (ETS‑1) promote cell migration and invasion in pancreatic cancer cells. However, the function of ETS‑1 in regulation of glycolysis and autophagy during progression of pancreatic cancer has not been defined yet. In this study, we sought to identify the potential role for silencing ETS‑1 in reducing the expression of glucose transporter‑1 (GLUT‑1) to disturb glycolysis through alteration of 'Warburg effect', by which could result in AMP‑activated protein kinase (AMPK) activation, autophagy induction and reduction of cell viability. MTT assay was applied to assess the cell viability in ETS‑1 silencing cells and control groups. Glucose absorption rate, lactate production rate and cellular ATP level were measured by standard colorimetric assay kits. The levels of mRNAs of ETS‑1, GLUT‑1, autophagy‑related gene 5 (ATG5) and ATG7 were analyzed by qRT‑PCR. The expression of ETS‑1, GLUT‑1, ATG5, ATG7, p‑AMPK, and LC3II proteins were evaluated by western blot analysis. GraphPad Prism 5.0 was used for all statistical analysis. We found that cell viability was obviously attenuated after silencing ETS‑1. Besides, our results also showed that the expression of GLUT‑1 significantly declined in ETS‑1 silencing cell lines which resulted in a lower glucose utilization and lactate production. Furthermore, the inhibition of glycolysis, which depends on glucose utilization and lactate production, reduced the generation of energy in the form of ATP. Moreover, the reduction of cellular ATP was associated with stimulation of AMP‑activated protein kinase (AMPK) and induction of autophagy. Our results indicated that ETS‑1 induced autophagy after inhibition of glycolysis, and thus led to comparative

  4. Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models

    Energy Technology Data Exchange (ETDEWEB)

    Thorek, Daniel L.J., E-mail: dthorek1@jhmi.edu [Division of Nuclear Medicine, The Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins School of Medicine, Baltimore, MD (United States); Kramer, Robin M. [Tri-Institutional Training Program in Laboratory Animal Medicine and Science, Memorial Sloan-Kettering Cancer Center (MSKCC), Weill Cornell Medical College, The Rockefeller University, New York, NY (United States); Chen, Qing; Jeong, Jeho; Lupu, Mihaela E. [Department of Medical Physics, MSKCC, New York, NY (United States); Lee, Alycia M.; Moynahan, Mary E.; Lowery, Maeve [Department of Medicine, MSKCC, New York, NY (United States); Ulmert, David [Molecular Pharmacology and Chemistry Program, MSKCC, New York, NY (United States); Department of Surgery (Urology), Skåne University Hospital, Malmö (Sweden); Zanzonico, Pat; Deasy, Joseph O.; Humm, John L. [Department of Medical Physics, MSKCC, New York, NY (United States); Russell, James, E-mail: russellj@mskcc.org [Department of Medical Physics, MSKCC, New York, NY (United States)

    2015-10-01

    Purpose: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360° arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. Results: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response.

  5. Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models

    International Nuclear Information System (INIS)

    Thorek, Daniel L.J.; Kramer, Robin M.; Chen, Qing; Jeong, Jeho; Lupu, Mihaela E.; Lee, Alycia M.; Moynahan, Mary E.; Lowery, Maeve; Ulmert, David; Zanzonico, Pat; Deasy, Joseph O.; Humm, John L.; Russell, James

    2015-01-01

    Purpose: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360° arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. Results: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response

  6. miR-1271 inhibits migration, invasion and epithelial-mesenchymal transition by targeting ZEB1 and TWIST1 in pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Huaize [Department of Developmental Genetics, Nanjing Medical University, Nanjing 210029 (China); Wang, Han [The First Clinical Medical College of Nanjing Medical University, Nanjing 210029 (China); Liu, Xiaoxiao [Department of Biotechnology, Nanjing Medical University, Nanjing 210029 (China); Yu, Tingting, E-mail: tingting@njmu.edu.cn [Department of Developmental Genetics, Nanjing Medical University, Nanjing 210029 (China)

    2016-04-01

    Pancreatic cancer (PC) remains one of the most lethal types of cancer in adults. The purpose of this study was to determine the role of miR-1271 in regulation of epithelial mesenchymal transition (EMT) and metastasis of pancreatic cancer cells. miR-1271 was identified to be significantly down-regulated in PC tissues by miRNA array. Also, an increase of EMT-regulators ZEB1 and TWIST1 expression level is accompanied by a decrease of miR-1271. We showed that expression of miR-1271 was significantly down-regulated in PC tissues as compared with that in normal tissues. In addition, our results showed that miR-1271 expression levels were decreased while ZEB1 and TWIST1 expression levels were increased in detected PC cell lines. Moreover, ectopic expression of miR-1271 suppressed and antagomiR-1271 promoted proliferation, migration, and invasion in SW1990 and PANC-1 cells. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-1271 inhibited expression of ZEB1 and TWIST1, which are master regulators of tumor metastasis. Our study first indicates that miR-1271 functions as a suppressor in regulating of pancreatic cancer EMT by targeting ZEB1 and TWIST1, and it promise as a therapeutic target and prognostic marker for metastatic pancreatic cancer. - Highlights: • miR-1271 is downregulated in pancreatic cancer tissues and cell lines. • miR-1271 regulates cell metastasis ability and EMT marker expression. . • miR-1271 directly targets ZEB1 and TWIST1. • ZEB1 and TWIST1 are functionally related to the effects of miR-1271.

  7. Drugs Approved for Pancreatic Cancer

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for pancreatic cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  8. The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1{alpha} targeted gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Miyake, Kotaro, E-mail: hif.panc@gmail.com [Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Nishioka, Masanori; Imura, Satoru; Batmunkh, Erdenebulgan [Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Uto, Yoshihiro [Department of Biological Science and Technology, Institute of Socio Technosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Nagasawa, Hideko [Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu 501-1196 (Japan); Hori, Hitoshi [Department of Biological Science and Technology, Institute of Socio Technosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan); Shimada, Mitsuo [Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503 (Japan)

    2012-08-01

    Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1{alpha} (HIF-1{alpha}), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P < 0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P < 0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules. -- Highlights: Black-Right-Pointing-Pointer We designed and synthesized novel hypoxic cytoxin, TX-2098. Black-Right-Pointing-Pointer TX-2098 inhibited the proliferation of human pancreatic cancer cells than TPZ. Black-Right-Pointing-Pointer TX-2098 reduced VEGF protein level than TPZ. Black-Right-Pointing-Pointer TX-2098

  9. Pancreatic Metastasis from Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Julian Jacob

    2010-01-01

    Full Text Available The pancreas is an unusual location for metastases from other primary cancers. Rarely, pancreatic metastases from kidney or colorectal cancers have been reported. However, a variety of other cancers may also spread to the pancreas. We report an exceptional case of pancreatic metastasis from prostate cancer. Differences in management between primary and secondary pancreatic tumors make recognition of metastases to the pancreas an objective of first importance. Knowledge of unusual locations for metastatic spread will reduce diagnostic delay and lead to a timely delivery of an appropriate treatment.

  10. Proposing the lymphatic target volume for elective radiation therapy for pancreatic cancer: a pooled analysis of clinical evidence

    Directory of Open Access Journals (Sweden)

    Lu Jiade J

    2010-04-01

    Full Text Available Abstract Background Radiation therapy is an important cancer treatment modality in both adjuvant and definitive setting, however, the use of radiation therapy for elective treatment of regional lymph nodes is controversial for pancreatic cancer. No consensus on proper selection and delineation of subclinical lymph nodal areas in adjuvant or definitive radiation therapy has been suggested either conclusively or proposed for further investigation. This analysis aims to study the pattern of lymph node metastasis through a pooled analysis of published results after radical tumor and lymph nodal resection with histological study in pancreatic cancer. Methods Literature search using electronic databases including MEDLINE, EMBASE, and CANCERLIT from January 1970 to June 2009 was performed, supplemented by review of references. Eighteen original researches and a total of 5954 pancreatic cancer patients underwent radical surgical resection were included in this analysis. The probability of metastasis in regional lymph nodal stations (using Japan Pancreas Society [JPS] Classification was calculated and analyzed based on the location and other characteristics of the primary disease. Results Commonly involved nodal regions in patients with pancreatic head tumor include lymph nodes around the common hepatic artery (Group 8, 9.79%, posterior pancreaticoduodenal lymph nodes (Group 13, 32.31%, lymph nodes around the superior mesenteric artery (Group 14, 15.85%, paraaortic lymph nodes (Group 16, 10.92%, and anterior pancreaticoduodenal lymph nodes (Group 17, 19.78%; The probability of metastasis in other lymph nodal regions were Commonly involved nodal regions in patients with pancreatic body/tail tumor include lymph nodes around the common hepatic artery (Group 8, 15.07%, lymph nodes around the celiac trunk (Group 9, 9.59%, lymph nodes along the splenic artery (Group 11, 35.62%, lymph nodes around the superior mesenteric artery (Group 14, 9.59%, paraaortic

  11. Nanotechnologies in Pancreatic Cancer Therapy.

    Science.gov (United States)

    Manzur, Ayesha; Oluwasanmi, Adeolu; Moss, Darren; Curtis, Anthony; Hoskins, Clare

    2017-09-25

    Pancreatic cancer has been classified as a cancer of unmet need. After diagnosis the patient prognosis is dismal with few surviving over 5 years. Treatment regimes are highly patient variable and often the patients are too sick to undergo surgical resection or chemotherapy. These chemotherapies are not effective often because patients are diagnosed at late stages and tumour metastasis has occurred. Nanotechnology can be used in order to formulate potent anticancer agents to improve their physicochemical properties such as poor aqueous solubility or prolong circulation times after administration resulting in improved efficacy. Studies have reported the use of nanotechnologies to improve the efficacy of gemcitabine (the current first line treatment) as well as investigating the potential of using other drug molecules which have previously shown promise but were unable to be utilised due to the inability to administer through appropriate routes-often related to solubility. Of the nanotechnologies reported, many can offer site specific targeting to the site of action as well as a plethora of other multifunctional properties such as image guidance and controlled release. This review focuses on the use of the major nanotechnologies both under pre-clinical development and those which have recently been approved for use in pancreatic cancer therapy.

  12. Recent Progress in Pancreatic Cancer

    Science.gov (United States)

    Wolfgang, Christopher L.; Herman, Joseph M.; Laheru, Daniel A.; Klein, Alison P.; Erdek, Michael A.; Fishman, Elliot K.; Hruban, Ralph H.

    2013-01-01

    Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in our understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer. PMID:23856911

  13. Immunological and Functional Characterization of RhoGDI3 and Its Molecular Targets RhoG and RhoB in Human Pancreatic Cancerous and Normal Cells.

    Directory of Open Access Journals (Sweden)

    Mercedes Piedad de León-Bautista

    Full Text Available RhoGDI proteins have been implicated in several human cancers; changes in their expression levels have shown pro- or anti-tumorigenic effects. Pancreatic Ductal Adenocarcinoma (PDAC is a complex pathology, with poor prognosis, and most patients die shortly after diagnosis. Efforts have been focused on understanding the role of RhoGDI's in PDAC, specially, RhoGDI1 and RhoGDI2. However, the role of RhoGDI3 has not been studied in relation to cancer or to PDAC. Here, we characterized the expression and functionality of RhoGDI3 and its target GTPases, RhoG and RhoB in pancreatic cell lines from both normal pancreatic tissue and tissue in late stages of PDAC, and compared them to human biopsies. Through immunofluorescences, pulldown assays and subcellular fractionation, we found a reduction in RhoGDI3 expression in the late stages of PDAC, and this reduction correlates with tumor progression and aggressiveness. Despite the reduction in the expression of RhoGDI3 in PDAC, we found that RhoB was underexpressed while RhoG was overexpressed, suggesting that cancerous cells preserve their capacity to activate this pathway, thus these cells may be more eager to response to the stimuli needed to proliferate and become invasive unlike normal cells. Surprisingly, we found nuclear localization of RhoGDI3 in non-cancerous pancreatic cell line and normal pancreatic tissue biopsies, which could open the possibility of novel nuclear functions for this protein, impacting gene expression regulation and cellular homeostasis.

  14. Surgery for pancreatic cancer -- discharge

    Science.gov (United States)

    ... in the bathroom and prevent falls at home. Wound care Your health care provider will explain how ... Kennedy EP, Yeo CJ. Pancreatic cancer: Clinical aspects, assessment, and management. In: Jarnagin WR, ed. Blumgart's Surgery ...

  15. Radiotherapy in pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Klautke, G. [Dept. of Radiation Therapy, Univ. of Rostock (Germany); Brunner, T.B. [Dept. of Radiation Oncology and Biology, Univ. of Oxford (United Kingdom)

    2008-11-15

    Purpose and approach: to summarize the current knowledge on the role of radiotherapy in the treatment of pancreatic ductal adenocarcinoma (PDAC). The results of meta-analyses, phase III-studies, and phase II-studies using chemoradiation (CRT) and chemotherapy for resectable and non-resectable PDAC are reviewed. Results and conclusion: the role of CRT is undefined in the adjuvant setting but there may be a role as additive treatment after R1 resection. Locally advanced borderline resectable tumors may shrink down and be subject to potentially curative resections. In locally advanced clearly unresectable cancers the effect of CRT as well as chemotherapy is poorly defined and the sequence of chemotherapy and CRT should be re-evaluated. Patients with PDAC should always be treated within studies to identify optimal treatment results. (orig.)

  16. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis

    Science.gov (United States)

    Sanford, Dominic E.; Belt, Brian A.; Panni, Roheena Z.; Mayer, Allese; Deshpande, Anjali D.; Carpenter, Danielle; Mitchem, Jonathan B.; Plambeck-Suess, Stacey M.; Worley, Lori A.; Goetz, Brian D.; Wang-Gillam, Andrea; Eberlein, Timothy J.; Denardo, David G.; Goedegebuure, S. Peter; Linehan, David C.

    2013-01-01

    Purpose To determine the role of the CCL2/CCR2 axis and inflammatory monocytes (IM; CCR2+/CD14+) as immunotherapeutic targets in the treatment of pancreatic cancer (PC). Experimental Design Survival analysis was performed to determine if the prevalence of pre-operative blood monocytes correlates with survival in PC patients following tumor resection. IM prevalence in the blood and bone marrow of PC patients and controls was compared. The immunosuppressive properties of IM and macrophages in the blood and tumors, respectively, of PC patients were assessed. CCL2 expression by human PC tumors was compared to normal pancreas. A novel CCR2 inhibitor (PF-04136309) was tested in an orthotopic model of murine PC. Results Monocyte prevalence in the peripheral blood correlates inversely with survival, and low monocyte prevalence is an independent predictor of increased survival in PC patients with resected tumors. IM are increased in the blood and decreased in the bone marrow of PC patients compared to controls. An increased ratio of IM in the blood versus the bone marrow is a novel predictor of decreased patient survival following tumor resection. Human PC produces CCL2, and immunosuppressive CCR2+ macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T cell infiltrate have significantly decreased survival. In mice, CCR2 blockade depletes IM and macrophages from the primary tumor and premetastatic liver resulting in enhanced anti-tumor immunity, decreased tumor growth, and reduced metastasis. Conclusions IM recruitment is critical to PC progression, and targeting CCR2 may be an effective immunotherapeutic strategy in this disease. PMID:23653148

  17. MiR-142 modulates human pancreatic cancer proliferation and invasion by targeting hypoxia-inducible factor 1 (HIF-1α in the tumor microenvironments

    Directory of Open Access Journals (Sweden)

    Yebin Lu

    2017-02-01

    Full Text Available MicroRNAs regulate most protein-coding genes, including genes important in cancer and other diseases. In this study, we demonstrated that the expression of miR-142 could be significantly suppressed in pancreatic cancer specimens and cell lines compared to their adjacent tissues and normal pancreatic cells. Growth and invasion of PANC-1 and SW1990 cells were attenuated by overexpression of miR-142 in vitro. With the help of bioinformatics analysis, hypoxia-inducible factor 1 (HIF-1α was identified to be a direct target of miR-142, and a luciferase reporter experiment confirmed this discovery. Overexpression of miR-142 decreases protein expression of HIF-1α. In the hypoxic microenvironment, HIF-1α was up-regulated while miR-142 was down-regulated. The invaded cells significantly increased in the hypoxic microenvironment compared to the normoxic microenvironment. The hypoxia treatment induced cells’ proliferation, and invasion could be inhibited by miR-142 overexpression or HIF-1α inhibition. Moreover, expression of epithelial-mesenchymal transition (EMT markers, Vimentin, VEGF-C and E-cad, was altered under hypoxia conditions and regulated by miR-142/HIF-1α. Above all, these findings provided insights on the functional mechanism of miR-142, suggesting that the miR-142/HIF-1α axis may interfere with the proliferative and invasive properties of pancreatic cancer cells, and indicated that miR-142 could be a potential therapeutic target for pancreatic cancer.

  18. Potential dosimetric benefits of adaptive tumor tracking over the internal target volume concept for stereotactic body radiation therapy of pancreatic cancer.

    Science.gov (United States)

    Karava, Konstantina; Ehrbar, Stefanie; Riesterer, Oliver; Roesch, Johannes; Glatz, Stefan; Klöck, Stephan; Guckenberger, Matthias; Tanadini-Lang, Stephanie

    2017-11-09

    Radiotherapy for pancreatic cancer has two major challenges: (I) the tumor is adjacent to several critical organs and, (II) the mobility of both, the tumor and its surrounding organs at risk (OARs). A treatment planning study simulating stereotactic body radiation therapy (SBRT) for pancreatic tumors with both the internal target volume (ITV) concept and the tumor tracking approach was performed. The two respiratory motion-management techniques were compared in terms of doses to the target volume and organs at risk. Two volumetric-modulated arc therapy (VMAT) treatment plans (5 × 5 Gy) were created for each of the 12 previously treated pancreatic cancer patients, one using the ITV concept and one the tumor tracking approach. To better evaluate the overall dose delivered to the moving tumor volume, 4D dose calculations were performed on four-dimensional computed tomography (4DCT) scans. The resulting planning target volume (PTV) size for each technique was analyzed. Target and OAR dose parameters were reported and analyzed for both 3D and 4D dose calculation. Tumor motion ranged from 1.3 to 11.2 mm. Tracking led to a reduction of PTV size (max. 39.2%) accompanied with significant better tumor coverage (p<0.05, paired Wilcoxon signed rank test) both in 3D and 4D dose calculations and improved organ at risk sparing. Especially for duodenum, stomach and liver, the mean dose was significantly reduced (p<0.05) with tracking for 3D and 4D dose calculations. By using an adaptive tumor tracking approach for respiratory-induced pancreatic motion management, a significant reduction in PTV size can be achieved, which subsequently facilitates treatment planning, and improves organ dose sparing. The dosimetric benefit of tumor tracking is organ and patient-specific.

  19. PCMdb: Pancreatic Cancer Methylation Database

    Science.gov (United States)

    Nagpal, Gandharva; Sharma, Minakshi; Kumar, Shailesh; Chaudhary, Kumardeep; Gupta, Sudheer; Gautam, Ankur; Raghava, Gajendra P. S.

    2014-02-01

    Pancreatic cancer is the fifth most aggressive malignancy and urgently requires new biomarkers to facilitate early detection. For providing impetus to the biomarker discovery, we have developed Pancreatic Cancer Methylation Database (PCMDB, http://crdd.osdd.net/raghava/pcmdb/), a comprehensive resource dedicated to methylation of genes in pancreatic cancer. Data was collected and compiled manually from published literature. PCMdb has 65907 entries for methylation status of 4342 unique genes. In PCMdb, data was compiled for both cancer cell lines (53565 entries for 88 cell lines) and cancer tissues (12342 entries for 3078 tissue samples). Among these entries, 47.22% entries reported a high level of methylation for the corresponding genes while 10.87% entries reported low level of methylation. PCMdb covers five major subtypes of pancreatic cancer; however, most of the entries were compiled for adenocarcinomas (88.38%) and mucinous neoplasms (5.76%). A user-friendly interface has been developed for data browsing, searching and analysis. We anticipate that PCMdb will be helpful for pancreatic cancer biomarker discovery.

  20. Vascular Targeting in Pancreatic Cancer: The Novel Tubulin-Binding Agent ZD6126 Reveals Antitumor Activity in Primary and Metastatic Tumor Models

    Directory of Open Access Journals (Sweden)

    Axel Kleespies

    2005-10-01

    Full Text Available ZD6126 is a novel vascular-targeting agent that acts by disrupting the tubulin cytoskeleton of an immature tumor endothelium, leading to an occlusion of tumor blood vessels and a subsequent tumor necrosis. We wanted to evaluate ZD6126 in primary and metastatic tumor models of human pancreatic cancer. Nude mice were injected orthotopically with L3.6pl pancreatic cancer cells. In single and multiple dosing experiments, mice received ZD6126, gemcitabine, a combination of both agents, or no treatment. For the induction of metastatic disease, additional groups of mice were injected with L3.6pl cells into the spleen. Twenty-four hours after a single-dose treatment, ZD6126 therapy led to an extensive central tumor necrosis, which was not seen after gemcitabine treatment. Multiple dosing of ZD6126 resulted in a significant growth inhibition of primary tumors and a marked reduction of spontaneous liver and lymph node metastases. Experimental metastatic disease could be significantly controlled by a combination of ZD6126 and gemcitabine, as shown by a reduction of the number and size of established liver metastases. As shown by additional in vitro and in vivo experiments, possible mechanisms involve antivascular activities and subsequent antiproliferative and proapoptotic effects of ZD6126 on tumor cells, whereas direct activities against tumor cells seem unlikely. These data highlight the antitumor and antimetastatic effects of ZD6126 in human pancreatic cancer and reveal benefits of adding ZD6126 to standard gemcitabine therapy.

  1. Pancreatic Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing pancreatic cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  2. Radionuclide therapy with tissue factor targeting Lu-177-FVIIai inhibits growth in an experimental mouse model of human pancreatic cancer

    DEFF Research Database (Denmark)

    Nielsen, Carsten; Jensen, Mette; Fonslet, Jesper

    2017-01-01

    Objectives: Tissue factor (TF) is related to aggressiveness and invasiveness of cancer and there is a correlation between tumor TF expression, metastatic potential, and patient outcome. The aim of the study was to test the therapeutic potential and toxicity of a novel compound for localized TF...... of pancreatic cancer. Methods: p-SCN-Bn-CHX-A’’-DTPA was conjugated to FVIIai followed by radiolabeling with 177Lu (177Lu-CHX-A’’-DTPA-FVIIai). A pancreas xenograft mouse model (BxPC3) was used to assess the therapeutic potential of 177Lu-FVIIai. NMRI nude mice with subcutaneous BxPC3 tumors were used. The mice...... of 177Lu-FVIIai (from 2.5±0.16 %ID/g to 1.7±0.05 %ID/g; pkidney...

  3. Incidence of pancreatic cancer in Denmark

    DEFF Research Database (Denmark)

    Weble, Tanja Cruusberg; Bjerregaard, Jon Kroll; Kissmeyer, Peter

    2017-01-01

    standardization. We used absolute numbers from the Cancer Registry and the Pancreatic Cancer Database, including distribution of topography of cancers registered in 2012-2013, to compare registration in the two data sources. RESULTS: The incidence rates of pancreatic cancer among Danish men increased until 1968......BACKGROUND: The aim of this study was to monitor the evolution of the incidence of pancreatic cancer in Denmark over 70 years. We also compared registrations of pancreatic cancer in a nationwide population-based database, the Danish Cancer Registry, and a clinical database, the Danish Pancreatic...... Cancer Database, in 2012-2013. MATERIAL AND METHODS: Registrations of pancreatic cancer from the Danish Cancer Registry over 1943-2012 were used to calculate age-specific incidence rates per 100 000 person years by sex and age in 5-year period, weighted by the Segi World Standard Population for age...

  4. [Treatments for Pancreatic Cancer with Oligometastasis].

    Science.gov (United States)

    Furuse, Junji

    2017-10-01

    Pancreatic cancer, adenocarcinoma, generally rapidly progresses, and if a metastatic lesion is detected, chemotherapy is applied even in solitary metastasis. However, surgical resection for solitary metastasis have been reported to achieve long survival in some pancreatic cancer patients. In a prospective study of surgery for hepatic and lymph node oligometastasis of pancreatic cancer, long survival of 5 years or more was reported around 10%. Furthermore, longer survival and fewer rerecurrence were achieved with surgery in lung metastasis than in liver metastasis and loco-regional recurrence. Although there has been no establishment of concept or no consensus of treatment strategy for oligometastasis in pancreatic cancer, some patients with pancreatic cancer have long disease-free survival by surgery for oligometastasis. A population of pancreatic cancer patients who have benefits of surgery for oligometastasis should be identified, and it is necessary to establish treatments for oligometastasis as standard treatments in pancreatic cancer.

  5. Polyphenols from marine brown algae target radiotherapy-coordinated EMT and stemness-maintenance in residual pancreatic cancer.

    Science.gov (United States)

    Aravindan, Sheeja; Ramraj, Satish Kumar; Somasundaram, Somasundaram T; Herman, Terence S; Aravindan, Natarajan

    2015-09-22

    Therapy-associated onset of stemness-maintenance in surviving tumor-cells dictates tumor relapse/recurrence. Recently, we recognized the anti-pancreatic cancer (PC) potential of seaweed polyphenol manifolds and narrowed down three superior drug-deliverables that could serve as adjuvants and benefit PC cure. Utilizing the PC- cancer stem cells (PC-CSCs) grown ex vivo and mouse model of residual-PC, we investigated the benefits of seaweed polyphenols in regulating stemness-maintenance. ALDH(+)CD44(+)CD24(+) PC-CSCs from Panc-1, Panc-3.27, MiaPaCa-2, or BxPC-3 cells-derived xenografts grown ex vivo were either mock-irradiated, exposed to fractionated irradiation (FIR, 2Gy/D for 5 days), treated with polyphenols (100 μg/ml) of Hormophysa triquerta (HT-EA), Spatoglossum asperum (SA-EA) or Padina tetrastromatica (PT-EA) with/without FIR were examined for cell viability, transcription of 93 stem-cell-related molecules (QPCR profiling). Polyphenol-dependent regulation of FIR-transactivated Oct4, Zic3, EIF4C, Nanog, and LIF (QPCR) and functional translation of Nanog, SOX2, and OCT3/4 (immunoblotting) were examined in Panc-1/Panc-3.27/MiaPaCa-2/BxPC-3-xenografts derived PC-CSCs. Effect of seaweed-polyphenols in the regulation of EMT (N-Cadherin), pluripotency- (SOX2, OCT3/4, Nanog) and stemness-maintenance (PI3KR1, LIF, CD44) in therapy (FIR, 2Gy/D for 5D/wk for 3-weeks) resistant residual tumors were examined by tissue microarray construction and automated immunohistochemistry. Ex vivo exposure of PC-CSCs to SA-EA, PT-EA and HT-EA exhibit dose-dependent inhibition of cell viability. FIR amplified the transcription of 69, 80, 74 and 77 stem-cell related genes in MiaPaCa-2-, Panc-1-, Panc-3.27- and BXPC3-established xenograft-derived ALDH(+)CD44(+)CD24(+)PC-CSCs. Treatment with SA-EA, PT-EA, or HT-EA completely suppressed FIR-activated stem-cell transcriptional machinery in ALDH(+)CD44(+)CD24(+)PC-CSCs established from MiaPaCa-2, Panc-1, Panc-3.27 and BXPC3 xenografts. QPCR

  6. Endoscopic Palliation for Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Mihir Bakhru

    2011-04-01

    Full Text Available Pancreatic cancer is devastating due to its poor prognosis. Patients require a multidisciplinary approach to guide available options, mostly palliative because of advanced disease at presentation. Palliation including relief of biliary obstruction, gastric outlet obstruction, and cancer-related pain has become the focus in patients whose cancer is determined to be unresectable. Endoscopic stenting for biliary obstruction is an option for drainage to avoid the complications including jaundice, pruritus, infection, liver dysfunction and eventually failure. Enteral stents can relieve gastric obstruction and allow patients to resume oral intake. Pain is difficult to treat in cancer patients and endoscopic procedures such as pancreatic stenting and celiac plexus neurolysis can provide relief. The objective of endoscopic palliation is to primarily address symptoms as well improve quality of life.

  7. Percutaneous ablation of pancreatic cancer

    Science.gov (United States)

    D’Onofrio, Mirko; Ciaravino, Valentina; De Robertis, Riccardo; Barbi, Emilio; Salvia, Roberto; Girelli, Roberto; Paiella, Salvatore; Gasparini, Camilla; Cardobi, Nicolò; Bassi, Claudio

    2016-01-01

    Pancreatic ductal adenocarcinoma is a highly aggressive tumor with an overall 5-year survival rate of less than 5%. Prognosis and treatment depend on whether the tumor is resectable or not, which mostly depends on how quickly the diagnosis is made. Chemotherapy and radiotherapy can be both used in cases of non-resectable pancreatic cancer. In cases of pancreatic neoplasm that is locally advanced, non-resectable, but non-metastatic, it is possible to apply percutaneous treatments that are able to induce tumor cytoreduction. The aim of this article will be to describe the multiple currently available treatment techniques (radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation), their results, and their possible complications, with the aid of a literature review. PMID:27956791

  8. Pain Management in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Michael Erdek

    2010-12-01

    Full Text Available A majority of pancreatic cancer patients present with pain at the time of diagnosis. Pain management can be challenging in light of the aggressive nature of this cancer. Apart from conventional pharmacotherapy, timely treatment with neurolytic celiac plexus block (NCPB has been shown to be of benefit. NCPB has demonstrated efficacious pain control in high quality studies with analgesic effects lasting one to two months. NCPB has also shown to decrease the requirements of narcotics, and thus decrease opioid related side effects. Another option for the control of moderate to severe pain is intrathecal therapy (IT. Delivery of analgesic medications intrathecally allows for lower dosages of medications and thus reduced toxicity. Both of the above mentioned interventional procedures have been shown to have low complication rates, and be safe and effective. Ultimately, comprehensive pancreatic cancer pain management necessitates understanding of pain mechanisms and delivery of sequential validated therapeutic interventions within a multidisciplinary patient care model.

  9. 5-FU resistant EMT-like pancreatic cancer cells are hypersensitive to photochemical internalization of the novel endoglin-targeting immunotoxin CD105-saporin.

    Science.gov (United States)

    Lund, Kaja; Olsen, Cathrine Elisabeth; Wong, Judith Jing Wen; Olsen, Petter Angell; Solberg, Nina Therese; Høgset, Anders; Krauss, Stefan; Selbo, Pål Kristian

    2017-12-19

    -expressing 5-FUR cells, whereas little effect was seen in the CD105-negative non-resistant parental cancer cell lines. Strikingly, using the intracellular drug delivery method photochemical internalization (PCI) by combining light-controlled activation of the TPCS 2a with nanomolar levels of CD105-saporin resulted in strong cytotoxic effects in the 5-FUR cell population. Our findings suggested that autophagy is an important resistance mechanism against the chemotherapeutic drug 5-FU in pancreatic cancer cells, and that inhibition of the autophagy process, either by CQ or lysosomal photodamage, can contribute to increased sensitivity to 5-FU. For the first time, we demonstrate the promise of PCI-based targeting of CD105 in site-specific elimination of 5-FU resistant pancreatic cancer cells in vitro. In conclusion, PCI-based targeting of CD105 may represent a potent anticancer strategy and should be further evaluated in pre-clinical models.

  10. Contemporary Management of Localized Resectable Pancreatic Cancer.

    Science.gov (United States)

    Kommalapati, Anuhya; Tella, Sri Harsha; Goyal, Gaurav; Ma, Wen Wee; Mahipal, Amit

    2018-01-20

    Pancreatic cancer is the third most common cause of cancer deaths in the United States. Surgical resection with negative margins still constitutes the cornerstone of potentially curative therapy, but is possible only in 15-20% of patients at the time of initial diagnosis. Accumulating evidence suggests that the neoadjuvant approach may improve R0 resection rate in localized resectable and borderline resectable diseases, and potentially downstage locally advanced disease to achieve surgical resection, though the impact on survival is to be determined. Despite advancements in the last decade in developing effective combinational chemo-radio therapeutic options, preoperative treatment strategies, and better peri-operative care, pancreatic cancer continues to carry a dismal prognosis in the majority. Prodigious efforts are currently being made in optimizing the neoadjuvant therapy with a better toxicity profile, developing novel agents, imaging techniques, and identification of biomarkers for the disease. Advancement in our understanding of the tumor microenvironment and molecular pathology is urgently needed to facilitate the development of novel targeted and immunotherapies for this setting. In this review, we detail the current literature on contemporary management of resectable, borderline resectable and locally advanced pancreatic cancer with a focus on future directions in the field.

  11. MicroRNA-gene signaling pathways in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Alexandra Drakaki

    2013-10-01

    Full Text Available Pancreatic cancer is the fourth most frequent cause of cancer-related deaths and is characterized by early metastasis and pronounced resistance to chemotherapy and radiation therapy. Despite extensive esearch efforts, there is not any substantial progress regarding the identification of novel drugs against pancreatic cancer. Although the introduction of the chemotherapeutic agent gemcitabine improved clinical response, the prognosis of these patients remained extremely poor with a 5-year survival rate of 3-5%. Thus, the identification of the novel molecular pathways involved in pancreatic oncogenesis and the development of new and potent therapeutic options are highly desirable. Here, we describe how microRNAs control signaling pathways that are frequently deregulated during pancreatic oncogenesis. In addition, we provide evidence that microRNAs could be potentially used as novel pancreatic cancer therapeutics through reversal of chemotherapy and radiotherapy resistance or regulation of essential molecular pathways. Further studies should integrate the deregulated genes and microRNAs into molecular networks in order to identify the central regulators of pancreatic oncogenesis. Targeting these central regulators could lead to the development of novel targeted therapeutic approaches for pancreatic cancer patients.

  12. Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

    Directory of Open Access Journals (Sweden)

    Spadavecchia J

    2016-02-01

    Full Text Available Jolanda Spadavecchia,1,2,* Dania Movia,3,* Caroline Moore,3,4 Ciaran Manus Maguire,3,4 Hanane Moustaoui,2 Sandra Casale,1 Yuri Volkov,3,4 Adriele Prina-Mello3,4 1Laboratoire de Réactivité de Surface, Sorbonne Universités, UPMC Univ Paris VI, Paris, 2Centre National de la recherche française, UMR 7244, CSPBAT, Laboratory of Chemistry, Structures, and Properties of Biomaterials and Therapeutic Agents, Université Paris 13, Sorbonne Paris Cité, Bobigny, France; 3AMBER Centre, CRANN Institute, 4Department of Clinical Medicine, School of Medicine, Trinity College, Dublin, Ireland *These authors contributed equally to this work Abstract: The main objective of this study was to optimize and characterize a drug delivery carrier for doxorubicin, intended to be intravenously administered, capable of improving the therapeutic index of the chemotherapeutic agent itself, and aimed at the treatment of pancreatic cancer. In light of this goal, we report a robust one-step method for the synthesis of dicarboxylic acid-terminated polyethylene glycol (PEG-gold nanoparticles (AuNPs and doxorubicin-loaded PEG-AuNPs, and their further antibody targeting (anti-Kv11.1 polyclonal antibody [pAb]. In in vitro proof-of-concept studies, we evaluated the influence of the nanocarrier and of the active targeting functionality on the anti-tumor efficacy of doxorubicin, with respect to its half-maximal effective concentration (EC50 and drug-triggered changes in the cell cycle. Our results demonstrated that the therapeutic efficacy of doxorubicin was positively influenced not only by the active targeting exploited through anti-Kv11.1-pAb but also by the drug coupling with a nanometer-sized delivery system, which indeed resulted in a 30-fold decrease of doxorubicin EC50, cell cycle blockage, and drug localization in the cell nuclei. The cell internalization pathway was strongly influenced by the active targeting of the Kv11.1 subunit of the human Ether-à-go-go related gene

  13. PCCR: Pancreatic Cancer Collaborative Registry

    Science.gov (United States)

    Sherman, Simon; Shats, Oleg; Ketcham, Marsha A.; Anderson, Michelle A.; Whitcomb, David C.; Lynch, Henry T.; Ghiorzo, Paola; Rubinstein, Wendy S.; Sasson, Aaron R.; Grizzle, William E.; Haynatzki, Gleb; Feng, Jianmin; Sherman, Alexander; Kinarsky, Leo; Brand, Randall E.

    2011-01-01

    The Pancreatic Cancer Collaborative Registry (PCCR) is a multi-institutional web-based system aimed to collect a variety of data on pancreatic cancer patients and high-risk subjects in a standard and efficient way. The PCCR was initiated by a group of experts in medical oncology, gastroenterology, genetics, pathology, epidemiology, nutrition, and computer science with the goal of facilitating rapid and uniform collection of critical information and biological samples to be used in developing diagnostic, prevention and treatment strategies against pancreatic cancer. The PCCR is a multi-tier web application that utilizes Java/JSP technology and has Oracle 10 g database as a back-end. The PCCR uses a “confederation model” that encourages participation of any interested center, irrespective of its size or location. The PCCR utilizes a standardized approach to data collection and reporting, and uses extensive validation procedures to prevent entering erroneous data. The PCCR controlled vocabulary is harmonized with the NCI Thesaurus (NCIt) or Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT). The PCCR questionnaire has accommodated standards accepted in cancer research and healthcare. Currently, seven cancer centers in the USA, as well as one center in Italy are participating in the PCCR. At present, the PCCR database contains data on more than 2,700 subjects (PC patients and individuals at high risk of getting this disease). The PCCR has been certified by the NCI Center for Biomedical Informatics and Information Technology as a cancer Biomedical Informatics Grid (caBIG®) Bronze Compatible product. The PCCR provides a foundation for collaborative PC research. It has all the necessary prerequisites for subsequent evolution of the developed infrastructure from simply gathering PC-related data into a biomedical computing platform vital for successful PC studies, care and treatment. Studies utilizing data collected in the PCCR may engender new approaches

  14. Radiotherapy of pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Tadayoshi; Sugiyama, Akira; Nakata, Yoshinori (Tokyo Metropolitan Hospital of Komagome (Japan))

    1983-07-01

    Sixteen inoperable patients with progressive pancreatic carcinoma were treated by external irradiation. In Stage II and III of the carcinoma, irradiation with 6,000 to 7,000 rad prolonged the survival. Conformation radiotherapy combined with chemotherapy was most effective. Intraoperative irradiation was done in 38 patients, and was followed by postoperative irradiation in 15 of these patients. Study of complications and autopsy findings showed that intraoperative irradiation with 2,000 to 3,000 rad followed by conformation radiotherapy of 4,000 rad was adequate. This combined therapy was done in 12 Stage I - III patients. Their survival period was certainly prolonged by the combined intraoperative and postoperative irradiation, and the effect was equivalent to that of interstitial irradiation of /sup 125/I combined with external beam irradiation, and was better than that of pancreatico-duodenalectomy.

  15. Radiotherapy of pancreatic cancer

    International Nuclear Information System (INIS)

    Matsuda, Tadayoshi; Sugiyama, Akira; Nakata, Yoshinori

    1983-01-01

    Sixteen inoperable patients with porgressive pancreatic carcinoma were treated by external irradiation. In Stage II and III of the carcinoma, irradiation with 6,000 to 7,000 rad prolonged the survival. Conformation radiotherapy combined with chemotherapy was most effective. Intraoperative irradiation was done in 38 patients, and was followed by postoperative irradiation in 15 of these patients. Study of complications and autopsy findings showed that intraoperative irradiation with 2,000 to 3,000 rad followed by conformation radiotherapy of 4,000 rad was adequate. This combined therapy was done in 12 Stage I - III patients. Their survival period was certainly prolonged by the combined intraoperative and postoperative irradiation, and the effect was equivalent to that of interstitial irradiation of 125 I combined with external beam irradiation, and was better than that of pancreatico-duodenalectomy. (Ueda, J.)

  16. Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection

    Directory of Open Access Journals (Sweden)

    Taylor M. Gilliland

    2017-03-01

    Full Text Available Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL. The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995–2016 addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC. We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1 patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2 patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3 enteral nutrition (EN should be preferred as a nutritional intervention over total parenteral nutrition (TPN postoperatively; and, (4 a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of

  17. Ultrasonographic diagnosis of pancreatic and peripancreatic cancer

    International Nuclear Information System (INIS)

    Park, Churl Min; Kim, Ho Kyun; Yoon, Yup; Lee, Sun Wha; Kim, Soon Yong; Ahn, Chi Yul

    1982-01-01

    Seventeen cases of cancers in and adjacent to the pancreas were studied by high resolution and wide field real time ultrasonographic scanner with 3.5 MHz linear array electronically focusing transducer. The result were as follows: 1. In a total of 17 cases, 7 cases were pancreatic cancers and the rests were 3 cases of ampulla of Vaster cancer, 3 cases of distal CBD cancers, and 4 cases of metastatic cancers, respectively. 2. Pancreatic cancers were located mainly in head portion, and metastatic cancers were noted in head, tail, and retropancreatic areas. 3. The sizes of all distal CBD cancer were less than 1.8 cm, usually smaller than other tumors, and the size of metastatic cancers were variable (1-6 cm). 4. The shape, margin, contour and echogenicity of the tumors were variable. 5. Pancreatic duct showed marked dilatation in one of pancreatic cancer, and mild dilatation in one of ampulla of Vater cancer. 6. The caliber of extrahepatic duct were moderately or markedly dilated in nearly all cases except 2 cases of pancreatic body cancer. 7. The pancreatic margin is partially obliterated in pancreatic and ampulla of Vater cancers but not in distal CBD cancer. 8. Gallbladder enlargement is secondary change due to the obstruction of extrahepatic bile duct. 9. Effects on the vessels are due to not only direct mass effect but direct invasion resulting in obliteration. The most commonly involved vessels are spleno-portal junction, splenic vein and portal vein. In case of pancreatic cancer in uncinate process, the superior mesenteric vessels are displaced anteriorly. 10. Surrounding metastatic lesions were suspected in pancreatic and ampulla of Vater cancer, but not seen in distal CBD cancer. 11. Ascites were seen in only two cases of metastasis

  18. Pancreatic cancer vaccine: a unique potential therapy

    Directory of Open Access Journals (Sweden)

    Cappello P

    2015-12-01

    Full Text Available Paola Cappello, Moitza Principe, Francesco Novelli Department of Molecular Biotechnologies and Health Sciences, Center for Experimental Research and Medical Studies, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy Abstract: Pancreatic ductal adenocarcinoma (PDA is a lethal disease and is one of the cancers that is most resistant to traditional therapies. Historically, neither chemotherapy nor radiotherapy has provided any significant increase in the survival of patients with PDA. Despite intensive efforts, any attempts to improve the survival in the past 15 years have failed. This holds true even after the introduction of molecularly targeted agents, chosen on the basis of their involvement in pathways that are considered to be important in PDA development and progression. Recently, however, FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin treatment has provided a limited survival advantage in patients with advanced PDA. Therefore, effective therapeutic strategies are urgently needed to improve the survival rate of patients with PDA. Results from the last 10 years of research in the field of PDA have helped to identify new immunological targets and develop new vaccines that are capable of stimulating an immune response. In addition, the information obtained about the role of the tumor microenvironment in suppressing the immune response and the possibility of targeting PDA microenvironment to limit immune suppression and enhance the response of effector T-cells has opened new avenues for treating this incurable disease. The time is ripe for developing new therapeutic approaches that are able to effectively counteract the progression and spreading of PDA. This review discusses the potential prospects in the care of patients with pancreatic cancer through vaccination and its combination therapy with surgery, chemotherapy, targeting of the tumor microenvironment, and inhibition of immunological

  19. Challenges of drug resistance in the management of pancreatic cancer.

    LENUS (Irish Health Repository)

    Sheikh, Rizwan

    2012-02-01

    The current treatment of choice for metastatic pancreatic cancer involves single-agent gemcitabine or a combination of gemcitabine with capecitabine or erlotinib (a tyrosine kinase inhibitor). Only 25–30% of patients respond to this treatment and patients who do respond initially ultimately exhibit disease progression. Median survival for pancreatic cancer patients has reached a plateau due to inherent and acquired resistance to these agents. Key molecular factors implicated in this resistance include: deficiencies in drug uptake, alteration of drug targets, activation of DNA repair pathways, resistance to apoptosis and the contribution of the tumor microenvironment. Moreover, for newer agents including tyrosine kinase inhibitors, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target and\\/or amplification of the target represent key challenges for treatment efficacy. Here we will review the contribution of known mechanisms and markers of resistance to key pancreatic cancer drug treatments.

  20. Targeting hyaluronan for the treatment of pancreatic ductal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Norihiro Sato

    2016-03-01

    Full Text Available Progression of cancer is often associated with interactions between cancer cells and extracellular matrix (ECM surrounding them. Increasing evidence has suggested that accumulation of hyaluronan (HA, a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma (PDAC is characterized typically by a dense desmoplastic stroma with a large amount of HA, making this molecule as an attractive target for therapy. Several studies have shown efficacy of inhibitors of HA synthesis or signaling for the treatment of PDAC. Recent studies have also demonstrated substantial improvements in the effects of chemotherapy by a targeted depletion of stromal HA in PDAC using an enzymatic agent. Thus, targeting HA has been recognized as a promising therapeutic strategy to treat this highly aggressive neoplasm. In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA.

  1. Pancreatic cancer: systemic combination therapies for a heterogeneous disease.

    Science.gov (United States)

    Melisi, Davide; Calvetti, Lorenzo; Frizziero, Melissa; Tortora, Giampaolo

    2014-01-01

    Pancreatic cancer is the only human malignancy for which patients' survival has not improved substantially during the past 30 years. Despite advances in the comprehension of the molecular mechanisms underlying pancreatic carcinogenesis, current systemic treatments offer only a modest benefit in tumor-related symptoms and survival. Over the past decades, gemcitabine and its combination with other standard cytotoxic agents have been the reference treatments for advanced pancreatic cancer patients. The recent introduction of the three-drug combination regimen FOLFIRINOX or the new taxane nab-paclitaxel represent key advances for a better control of the disease. Novel agents targeting molecular mechanisms involved in cancer development and maintenance are currently under clinical investigation. This review describes the most important findings in the field of systemic combination therapies for the treatment of pancreatic cancer. We discuss the emerging evidences for the clinical activity of combination treatments with standard chemotherapy plus novel agents targeting tumor cell-autonomous and tumor microenvironment signaling pathways. We present some of the most important advances in the comprehension of the molecular mechanisms responsible for the chemoresistance of pancreatic cancer and the emerging therapeutic targets to overcome this resistance.

  2. Identification of genes highly downregulated in pancreatic cancer through a meta-analysis of microarray datasets: implications for discovery of novel tumor-suppressor genes and therapeutic targets.

    Science.gov (United States)

    Goonesekere, Nalin C W; Andersen, Wyatt; Smith, Alex; Wang, Xiaosheng

    2018-02-01

    The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a 5-year survival rate of about 7%. Recent failures of targeted therapies inhibiting kinase activity in clinical trials have highlighted the need for new approaches towards combating this deadly disease. In this study, we have identified genes that are significantly downregulated in PC, through a meta-analysis of large number of microarray datasets. We have used qRT-PCR to confirm the downregulation of selected genes in a panel of PC cell lines. This study has yielded several novel candidate tumor-suppressor genes (TSGs) including GNMT, CEL, PLA2G1B and SERPINI2. We highlight the role of GNMT, a methyl transferase associated with the methylation potential of the cell, and CEL, a lipase, as potential therapeutic targets. We have uncovered genetic links to risk factors associated with PC such as smoking and obesity. Genes important for patient survival and prognosis are also discussed, and we confirm the dysregulation of metabolic pathways previously observed in PC. While many of the genes downregulated in our dataset are associated with protein products normally produced by the pancreas for excretion, we have uncovered some genes whose downregulation appear to play a more causal role in PC. These genes will assist in providing a better understanding of the disease etiology of PC, and in the search for new therapeutic targets and biomarkers.

  3. Immunotherapy for pancreatic cancer: present and future.

    Science.gov (United States)

    Aroldi, Francesca; Zaniboni, Alberto

    2017-06-01

    Despite the identification of some efficient drugs for the treatment of metastatic pancreatic cancer, this tumor remains one of the most lethal cancers and is characterized by a strong resistance to therapies. Pancreatic cancer has some unique features including the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma, which is both a physical barrier to drug penetration and a dynamic entity involved in immune system control. Therefore, the immune system has been hypothesized to play an important role in pancreatic cancer. Thus, therapies acting on innate or adaptive immunity are being investigated. Here, we review the literature, report the most interesting results and hypothesize future treatment directions.

  4. Human pancreatic cancer progression: an anarchy among CCN-siblings.

    Science.gov (United States)

    Banerjee, Sushanta K; Maity, Gargi; Haque, Inamul; Ghosh, Arnab; Sarkar, Sandipto; Gupta, Vijayalaxmi; Campbell, Donald R; Von Hoff, Daniel; Banerjee, Snigdha

    2016-09-01

    Decades of basic and translational studies have identified the mechanisms by which pancreatic cancer cells use molecular pathways to hijack the normal homeostasis of the pancreas, promoting pancreatic cancer initiation, progression, and metastasis, as well as drug resistance. These molecular pathways were explored to develop targeted therapies to prevent or cure this fatal disease. Regrettably, the studies found that majority of the molecular events that dictate carcinogenic growth in the pancreas are non-actionable (potential non-responder groups of targeted therapy). In this review we discuss exciting discoveries on CCN-siblings that reveal how CCN-family members contribute to the different aspects of the development of pancreatic cancer with special emphasis on therapy.

  5. Risk of Pancreatic Cancer After a Primary Episode of Acute Pancreatitis

    NARCIS (Netherlands)

    Rijkers, Anton P.; Bakker, Olaf J.; Ahmed Ali, Usama; Hagenaars, Julia C. J. P.; van Santvoort, Hjalmar C.; Besselink, Marc G.; Bollen, Thomas L.; van Eijck, Casper H.

    2017-01-01

    Objective Acute pancreatitis may be the first manifestation of pancreatic cancer. The aim of this study was to assess the risk of pancreatic cancer after a first episode of acute pancreatitis. Methods Between March 2004 and March 2007, all consecutive patients with a first episode of acute

  6. Preoperative biliary drainage for pancreatic cancer

    NARCIS (Netherlands)

    van Heek, N. T.; Busch, O. R.; van Gulik, T. M.; Gouma, D. J.

    2014-01-01

    This review is to summarize the current knowledge about preoperative biliary drainage (PBD) in patients with biliary obstruction caused by pancreatic cancer. Most patients with pancreatic carcinoma (85%) will present with obstructive jaundice. The presence of toxic substances as bilirubin and bile

  7. Peripancreatic fat necrosis mimicking pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Thurnher, M.M.; Schima, W.; Turetschek, K.; Thurnher, S.A. [Vienna Univ. (Austria). Inst. fuer Radiologie; Fuegger, R. [Dept. of Surgery, University of Vienna (Austria); Oberhuber, G. [Dept. of Pathology, University of Vienna (Austria)

    2001-06-01

    A case of peripancreatic fat necrosis, after an episode of acute pancreatitis, which mimicked pancreatic cancer with lymph node metastases, is presented. We describe the imaging findings with helical CT scanning and with unenhanced and mangafodipir-enhanced MR imaging, with special emphasis on the differential diagnoses. (orig.)

  8. Complex role for the immune system in initiation and progression of pancreatic cancer.

    Science.gov (United States)

    Inman, Kristin S; Francis, Amanda A; Murray, Nicole R

    2014-08-28

    The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.

  9. Optimizing Adjuvant Therapy for Resected Pancreatic Cancer

    Science.gov (United States)

    In this clinical trial, patients with resected pancreatic head cancer will be randomly assigned to receive either gemcitabine with or without erlotinib for 5 treatment cycles. Patients who do not experience disease progression or recurrence will then be r

  10. Color-coded intravital imaging demonstrates a transforming growth factor-β (TGF-β) antagonist selectively targets stromal cells in a human pancreatic-cancer orthotopic mouse model.

    Science.gov (United States)

    Murakami, Takashi; Hiroshima, Yukihiko; Miyake, Kentaro; Hwang, Ho Kyoung; Kiyuna, Tasuku; DeLong, Jonathan C; Lwin, Thinzar M; Matsuyama, Ryusei; Mori, Ryutaro; Kumamoto, Takafumi; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2017-05-19

    Pancreatic cancer is a recalcitrant malignancy, partly due to desmoplastic stroma which stimulates tumor growth, invasion, and metastasis, and inhibits chemotherapeutic drug delivery. Transforming growth factor-β (TGF-β) has an important role in the formation of stromal desmoplasia. The present study describes the ability of color-coded intravital imaging to demonstrate the efficacy of a TGF-β inhibitor to target stroma in an orthotopic mouse model of pancreatic cancer. The BxPC-3 human pancreatic adenocarcinoma cell line expressing green fluorescent protein (GFP), which also has a high TGF-β expression level, was used in an orthotopic model in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). Fourteen mice were randomized into a control group (n = 7, vehicle, i.p., weekly, for 3 weeks) and a treated group (n = 7, SB431542 [TGF-β receptor type I inhibitor] 0.3 mg, i.p., weekly, for 3 weeks). Stromal cells expressing RFP and cancer cells expressing GFP were observed weekly for 3 weeks by real-time color-coded intravital imaging. The RFP fluorescence area from the stromal cells, relative to the GFP fluorescence area of the cancer cells, was significantly decreased in the TGF-β-inhibitor-treatment group compared to the control group. The present study demonstrated color-coded imaging in an orthotopic pancreatic-cancer cell-line mouse model can readily detect the selective anti-stromal-cell targeting of a TGF-β inhibitor.

  11. SU-E-T-170: Characterization of the Location, Extent, and Proximity to Critical Structures of Target Volumes Provides Detail for Improved Outcome Predictions Among Pancreatic Cancer Patients

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Z; Moore, J; Rosati, L; Mian, O; Narang, A; Herman, J; McNutt, T [Johns Hopkins University, Baltimore, MD (United States)

    2015-06-15

    Purpose: In radiotherapy, size, location and proximity of the target to critical structures influence treatment decisions. It has been shown that proximity of the target predicts dosimetric sparing of critical structures. In addition to dosimetry, precise location of disease has further implications such as tumor invasion, or proximity to major arteries that inhibit surgery. Knowledge of which patients can be converted to surgical candidates by radiation may have high impact on future treat/no-treat decisions. We propose a method to improve our characterization of the location of pancreatic cancer and treatment volume extent with respect to nearby arteries with the goal of developing features to improve clinical predictions and decisions. Methods: Oncospace is a local learning health system that systematically captures clinical outcomes and all aspects of radiotherapy treatment plans, including overlap volume histograms (OVH) – a measure of spatial relationships between two structures. Minimum and maximum distances of PTV and OARs based on OVH, PTV volume, anatomic location by ICD-9 code, and surgical outcome were queried. Normalized distance to center from the left and right kidney was calculated to indicate tumor location and laterality. Distance to critical arteries (celiac, superior mesenteric, common hepatic) is validated by surgical status (borderline resectable, locally advanced converted to resectable). Results: There were 205 pancreas stereotactic body radiotherapy patients treated from 2009–2015 queried. Location/laterality of tumor based on kidney OVH show strong trends between location by OVH and by ICD-9. Compared to the locally advanced group, the borderline resectable group showed larger geometrical distance from critical arteries (p=0.03). Conclusion: Our platform enabled analysis of shape/size-location relationships. These data suggest that PTV volume and attention to distance between PTVs and surrounding OARs and major arteries may be

  12. SU-E-T-170: Characterization of the Location, Extent, and Proximity to Critical Structures of Target Volumes Provides Detail for Improved Outcome Predictions Among Pancreatic Cancer Patients

    International Nuclear Information System (INIS)

    Cheng, Z; Moore, J; Rosati, L; Mian, O; Narang, A; Herman, J; McNutt, T

    2015-01-01

    Purpose: In radiotherapy, size, location and proximity of the target to critical structures influence treatment decisions. It has been shown that proximity of the target predicts dosimetric sparing of critical structures. In addition to dosimetry, precise location of disease has further implications such as tumor invasion, or proximity to major arteries that inhibit surgery. Knowledge of which patients can be converted to surgical candidates by radiation may have high impact on future treat/no-treat decisions. We propose a method to improve our characterization of the location of pancreatic cancer and treatment volume extent with respect to nearby arteries with the goal of developing features to improve clinical predictions and decisions. Methods: Oncospace is a local learning health system that systematically captures clinical outcomes and all aspects of radiotherapy treatment plans, including overlap volume histograms (OVH) – a measure of spatial relationships between two structures. Minimum and maximum distances of PTV and OARs based on OVH, PTV volume, anatomic location by ICD-9 code, and surgical outcome were queried. Normalized distance to center from the left and right kidney was calculated to indicate tumor location and laterality. Distance to critical arteries (celiac, superior mesenteric, common hepatic) is validated by surgical status (borderline resectable, locally advanced converted to resectable). Results: There were 205 pancreas stereotactic body radiotherapy patients treated from 2009–2015 queried. Location/laterality of tumor based on kidney OVH show strong trends between location by OVH and by ICD-9. Compared to the locally advanced group, the borderline resectable group showed larger geometrical distance from critical arteries (p=0.03). Conclusion: Our platform enabled analysis of shape/size-location relationships. These data suggest that PTV volume and attention to distance between PTVs and surrounding OARs and major arteries may be

  13. Treatment of Pancreatic Cancer by Aptamer Conjugated C/EBPα-saRNA.

    Science.gov (United States)

    Yoon, Sorah; Rossi, John J

    2017-01-01

    Pancreatic cancer is estimated to become the second-leading cause of cancer-related mortality by 2020. While the death rates of most other cancers continue to decline recently, the death rates of pancreatic cancer are still increasing, with less than 5% of patients achieving 5-year survival. Despite great efforts to improve treatment with combinational therapies in pancreatic cancer patients, limited progress has been made. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) has been depicted as a therapeutic target in pancreatic cancer for many years. However, the clinical outcome of KRAS-directed therapies has not been successful, suggesting that KRAS is an undruggable target. For the new druggable target, epigenetically silenced transcriptional factor C/EBPα (CCAAT/enhancer-binding protein α), upregulator of a strong inhibitor of cell proliferation (p21), is upregulated by small activating RNA (saRNA) in pancreatic cancer. For the cell type-specific delivery, pancreatic cancer-specific 2'-Fluoropyrimidine RNA-aptamers (2'F-RNAs) are conjugated with C/EBPα-saRNA via sticky bridge sequences. The conjugates of aptamer-C/EBPα-saRNA upregulate the expression of C/EBPα in vitro and inhibit the tumor growth in vivo. It suggests that aptamer-mediated targeted delivery of therapeutic C/EBPα-saRNA might be the effective therapeutics under the current therapeutic modality failure in pancreatic cancer.

  14. Common variables in European pancreatic cancer registries

    DEFF Research Database (Denmark)

    De Leede, E. M.; Sibinga Mulder, B. G.; Bastiaannet, E.

    2016-01-01

    Care, is a platform aiming to harmonize cancer data collection and improve cancer care by feedback. After the prior launch of the projects on colorectal, breast and upper GI cancer, EURECCA's newest project is collecting data on pancreatic cancer in several European countries. Methods National cancer......Background Quality assurance of cancer care is of utmost importance to detect and avoid under and over treatment. Most cancer data are collected by different procedures in different countries, and are poorly comparable at an international level. EURECCA, acronym for European Registration of Cancer...... registries, as well as specific pancreatic cancer audits/registries, were invited to participate in EURECCA Pancreas. Participating countries were requested to share an overview of their collected data items. Of the received datasets, a shared items list was made which creates insight in similarities between...

  15. Acute Pancreatitis and Pancreatic Cancer Risk: A Nationwide Matched-cohort Study in Denmark

    DEFF Research Database (Denmark)

    Kirkegård, Jakob; Cronin Fenton, Deirdre; Heide-Jørgensen, Uffe

    2018-01-01

    . Pancreatic cancer risk was expressed as hazard ratios (HRs) with 95% CIs, calculated using the Cox proportional hazards model. Cox models were stratified by age, sex, and year of pancreatitis diagnosis and adjusted for alcohol- and smoking-related conditions, and Charlson Comorbidity Index score. Results We...... included 41,669 patients diagnosed with incident acute pancreatitis and 208,340 comparison individuals. Patients with acute pancreatitis had an increased risk of pancreatic cancer compared with the age- and sex-matched general population throughout the follow-up period. The risk decreased over time......Background & Aims Acute pancreatitis may be a risk factor for pancreatic cancer. However, findings from studies on this association are conflicting. We investigated the association between acute pancreatitis and increased risk of pancreatic cancer. Methods We conducted a nationwide, population...

  16. Adipocytes and Neutrophils Give a Helping Hand to Pancreatic Cancers.

    Science.gov (United States)

    Bronte, Vincenzo; Tortora, Giampaolo

    2016-08-01

    Obesity-induced inflammation can build up a confined microenvironment in pancreatic adenocarcinoma that is associated with increased desmoplasia, neutrophil recruitment, reduced delivery of chemotherapeutic drugs, and immune evasion. Targeting molecular pathways empowering this circuit might represent a necessary measure to reach clinical efficacy for combination therapies in patients with excess body weight. Cancer Discov; 6(8); 821-3. ©2016 AACR.See related article by Incio et al., p. 852. ©2016 American Association for Cancer Research.

  17. Advancements in the management of pancreatic cancer.

    Science.gov (United States)

    Li, Jia; Saif, Muhammad Wasif

    2009-03-09

    Management of pancreatic cancer remains the most challenging work in oncology. Though pancreatic cancer represents only 2-3% of all cancers, it is the most fatal one accounting for the 6% of all cancer death. It remains the 4th cause of death by cancer since 1970s in the U.S.. Gemcitabine remains the only standard of care for this disease. More and more combination therapies containing gemcitabine have been tested or undergoing investigation. The interest in treating pancreatic cancer is apparently global. Over 75 abstracts were presented in the 2009 ASCO Gastrointestinal Cancers Symposium at San Francisco in the field of pancreatic cancer. In this highlights article, authors summarize the critical studies in the management of pancreatic cancer. A large retrospective study evaluated the role of post-operative adjuvant radiation (Abstract #181) and correlated the receipt of radiation with survival benefit. Borderline resectable pancreatic cancer remains an area that requires multi-disciplinary approach. Neo-adjuvant therapy very likely plays a role to downstage to a resectable state in these subgroup patients (Abstracts #197 and #248). In advanced or metastatic setting, studies aiming at the gemcitabine-based triplet or doublet combinations are still the mainstream. FFCD 0301 trial (Abstract #180), the only large phase III trial presented in the first-line setting, failed to demonstrate any survival advantage of either 5-FU and leucovorin plus cisplatin followed by gemcitabine or vice versa. Biologic agents containing regimens were also presented. Of note, gemcitabine and oxaliplatin plus bevacizumab achieved a high response rate of 39% (Abstract #182) while gemcitabine with dual monoclonal antibody regimen was disappointing (Abstract #183). The clear benefit of all other combinations over gemcitabine alone remains questionable given most studies are small. Newer agents, especially S-1 (Abstracts #213 and #251), are very promising, and further studies are warranted

  18. Assessment value of quantitative indexes of pancreatic CT perfusion scanning for malignant degree of pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Jiang-Xia Lei

    2016-10-01

    Full Text Available Objective: To analyze the assessment value of the quantitative indexes of pancreatic CT perfusion scanning for malignant degree of pancreatic cancer. Methods: A total of 58 patients with space-occupying pancreatic lesions were divided into 20 patients with pancreatic cancer and 38 patients with benign pancreatic lesions after pancreatic CT perfusion. Patients with pancreatic cancer received palliative surgery, and the cancer tissue and para-carcinoma tissue specimens were collected during operation. The differences in pancreatic CT perfusion scanning parameter values and serum tumor marker levels were compared between patients with pancreatic cancer and patients with benign pancreatic lesions, mRNA expression levels of malignant molecules in pancreatic cancer tissue and para-carcinoma tissue were further determined, and the correlation between pancreatic CT perfusion scanning parameter values and malignant degree of pancreatic cancer was analyzed. Results: CT perfusion scanning BF, BV and Per values of patients with pancreatic cancer were lower than those of patients with benign pancreatic lesions; serum CA19-9, CEA, CA125 and CA242 levels were higher than those of patients with benign pancreatic lesions (P<0.05; mRNA expression levels of Bcl-2, Bcl-xL and survivin in pancreatic cancer tissue samples were higher than those in paracarcinoma tissue samples, and mRNA expression levels of P53 and Bax were lower than those in para-carcinoma tissue samples (P<0.05; CT perfusion scanning parameters BF, BV and Per values of patients with pancreatic cancer were negatively correlated with CA19-9, CEA, CA125 and CA242 levels in serum as well as mRNA expression levels of Bcl-2, Bcl-xL and survivin in pancreatic cancer tissue, and positively correlated with mRNA expression levels of P53 and Bax in pancreatic cancer tissue (P<0.05. Conclusions: Pancreatic CT perfusion scanning is a reliable way to judge the malignant degree of pancreatic cancer and plays a

  19. Hypoxia Induced Tumor Metabolic Switch Contributes to Pancreatic Cancer Aggressiveness

    Energy Technology Data Exchange (ETDEWEB)

    Vasseur, Sophie, E-mail: sophie.vasseur@inserm.fr; Tomasini, Richard; Tournaire, Roselyne; Iovanna, Juan L. [INSERM U624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, BP 915,13288 Marseille cedex 9 (France)

    2010-12-16

    Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumors with an overall five-year survival rate of only 3–5%. Its aggressive biology and resistance to conventional and targeted therapeutic agents lead to a typical clinical presentation of incurable disease once diagnosed. The disease is characterized by the presence of a dense stroma of fibroblasts and inflammatory cells, termed desmoplasia, which limits the oxygen diffusion in the organ, creating a strong hypoxic environment within the tumor. In this review, we argue that hypoxia is responsible for the highly aggressive and metastatic characteristics of this tumor and drives pancreatic cancer cells to oncogenic and metabolic changes facilitating their proliferation. However, the molecular changes leading to metabolic adaptations of pancreatic cancer cells remain unclear. Cachexia is a hallmark of this disease and illustrates that this cancer is a real metabolic disease. Hence, this tumor must harbor metabolic pathways which are probably tied in a complex inter-organ dialog during the development of this cancer. Such a hypothesis would better explain how under fuel source limitation, pancreatic cancer cells are maintained, show a growth advantage, and develop metastasis.

  20. Hypoxia Induced Tumor Metabolic Switch Contributes to Pancreatic Cancer Aggressiveness

    Directory of Open Access Journals (Sweden)

    Juan L. Iovanna

    2010-12-01

    Full Text Available Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumors with an overall five-year survival rate of only 3–5%. Its aggressive biology and resistance to conventional and targeted therapeutic agents lead to a typical clinical presentation of incurable disease once diagnosed. The disease is characterized by the presence of a dense stroma of fibroblasts and inflammatory cells, termed desmoplasia, which limits the oxygen diffusion in the organ, creating a strong hypoxic environment within the tumor. In this review, we argue that hypoxia is responsible for the highly aggressive and metastatic characteristics of this tumor and drives pancreatic cancer cells to oncogenic and metabolic changes facilitating their proliferation. However, the molecular changes leading to metabolic adaptations of pancreatic cancer cells remain unclear. Cachexia is a hallmark of this disease and illustrates that this cancer is a real metabolic disease. Hence, this tumor must harbor metabolic pathways which are probably tied in a complex inter-organ dialog during the development of this cancer. Such a hypothesis would better explain how under fuel source limitation, pancreatic cancer cells are maintained, show a growth advantage, and develop metastasis.

  1. PBI-05204, a supercritical CO₂ extract of Nerium oleander, inhibits growth of human pancreatic cancer via targeting the PI3K/mTOR pathway.

    Science.gov (United States)

    Pan, Yong; Rhea, Patrea; Tan, Lin; Cartwright, Carrie; Lee, Ho-Jeong; Ravoori, Murali K; Addington, Crandell; Gagea, Mihai; Kundra, Vikas; Kim, Sun-Jin; Newman, Robert A; Yang, Peiying

    2015-04-01

    Introduction Oleandrin, a cardiac glycoside, exerts strong anti-proliferative activity against various human malignancies in in vitro cells. Here, we report the antitumor efficacy of PBI-05204, a supercritical C0₂ extract of Nerium oleander containing oleandrin, in a human pancreatic cancer Panc-1 orthotopic model. Results While all the control mice exhibited tumors by the end of treatment, only 2 of 8 mice (25%) treated for 6 weeks with PBI-05204 (40 mg/kg) showed dissectible tumor at the end of the treatment period. The average tumor weight (222.9 ± 116.9 mg) in mice treated with PBI-05204 (20 mg/kg) was significantly reduced from that in controls (920.0 ± 430.0 mg) (p PBI-05204 (40 mg/kg) treated group showed that the pancreatic tissues of 5/6 mice were normal while the remaining mouse had a tumor the largest diameter of which was less than 2.3 mm. In contrast, while gemcitabine alone did not significantly reduce tumor growth, PBI-05204 markedly enhanced the antitumor efficacy of gemcitabine in this particular model. Ki-67 staining was reduced in pancreatic tumors from mice treated with PBI-05204 (20 mg/kg) compared to that of control, suggesting that PBI-05204 inhibited the proliferation of the Panc-1 tumor cells. PBI-05204 suppressed expression of pAkt, pS6, and p4EPB1 in a concentration-dependent manner in both Panc-1 tumor tissues and human pancreatic cancer cell lines, implying that this novel botanical drug exerts its potent antitumor activity, at least in part, through down-regulation of PI3k/Akt and mTOR pathways.

  2. Immunotherapy in pancreatic cancer: Unleash its potential through novel combinations.

    Science.gov (United States)

    Guo, Songchuan; Contratto, Merly; Miller, George; Leichman, Lawrence; Wu, Jennifer

    2017-06-10

    Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States, with poor response to current standard of care, short progression-free and overall survival. Immunotherapies that target cytotoxic T lymphocyte antigen-4, programmed cell death protein-1, and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma, renal cell carcinoma, and non-small cell lung cancer due to high numbers of somatic mutations, combined with cytotoxic T-cell responses. However, single checkpoint blockade was ineffective in pancreatic cancer, highlighting the challenges including the poor antigenicity, a dense desmoplastic stroma, and a largely immunosuppressive microenvironment. In this review, we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy, radiotherapy, and targeted therapy. These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.

  3. Current status and progress of pancreatic cancer in China.

    Science.gov (United States)

    Lin, Quan-Jun; Yang, Feng; Jin, Chen; Fu, De-Liang

    2015-07-14

    Cancer is currently one of the most important public health problems in the world. Pancreatic cancer is a fatal disease with poor prognosis. As in most other countries, the health burden of pancreatic cancer in China is increasing, with annual mortality rates almost equal to incidence rates. The increasing trend of pancreatic cancer incidence is more significant in the rural areas than in the urban areas. Annual diagnoses and deaths of pancreatic cancer in China are now beyond the number of cases in the United States. GLOBOCAN 2012 estimates that cases in China account for 19.45% (65727/337872) of all newly diagnosed pancreatic cancer and 19.27% (63662/330391) of all deaths from pancreatic cancer worldwide. The population's growing socioeconomic status contributes to the rapid increase of China's proportional contribution to global rates. Here, we present an overview of control programs for pancreatic cancer in China focusing on prevention, early diagnosis and treatment. In addition, we describe key epidemiological, demographic, and socioeconomic differences between China and developed countries. Facts including no nationwide screening program for pancreatic cancer, delay in early detection resulting in a late stage at presentation, lack of awareness of pancreatic cancer in the Chinese population, and low investment compared with other cancer types by government have led to backwardness in China's pancreatic cancer diagnosis and treatment. Finally, we suggest measures to improve health outcomes of pancreatic cancer patients in China.

  4. The Burden of Systemic Adiposity on Pancreatic Disease: Acute Pancreatitis, Non-Alcoholic Fatty Pancreas Disease, and Pancreatic Cancer.

    Science.gov (United States)

    Malli, Ahmad; Li, Feng; Conwell, Darwin L; Cruz-Monserrate, Zobeida; Hussan, Hisham; Krishna, Somashekar G

    2017-01-01

    Obesity is a global epidemic as recognized by the World Health Organization. Obesity and its related comorbid conditions were recognized to have an important role in a multitude of acute, chronic, and critical illnesses including acute pancreatitis, nonalcoholic fatty pancreas disease, and pancreatic cancer. This review summarizes the impact of adiposity on a spectrum of pancreatic diseases.

  5. Pancreatic cancer and depression: myth and truth

    Directory of Open Access Journals (Sweden)

    Schmid Roland M

    2010-10-01

    Full Text Available Abstract Background Various studies reported remarkable high incidence rates of depression in cancer patients compared with the general population. Pancreatic cancer is still one of the malignancies with the worst prognosis and therefore it seems quite logical that it is one of the malignancies with the highest incidence rates of major depression. However, what about the scientific background of this relationship? Is depression in patients suffering from pancreatic cancer just due to the confrontation with a life threatening disease and its somatic symptoms or is depression in this particular group of patients a feature of pancreatic cancer per se? Discussion Several studies provide evidence of depression to precede the diagnosis of pancreatic cancer and some studies even blame it for its detrimental influence on survival. The immense impact of emotional distress on quality of life of cancer patients enhances the need for its early diagnosis and adequate treatment. Knowledge about underlying pathophysiological mechanisms is required to provide the optimal therapy. Summary A review of the literature on this issue should reveal which are the facts and what is myth.

  6. SU-F-T-395: Evaluation of Best Dosimetry Achievable with VMAT and IMRT Treatment Techniques Targeting Borderline Resectable Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Harpool, K; Schnell, E; Herman, T; Ahmad, S; De La Fuente Herman, T [University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States)

    2016-06-15

    Purpose: To determine from retrospective study the most appropriate technique for targeting small borderline operable pancreatic cancer surrounding blood vessels by evaluating the dosimetry and normal tissue sparing achievable using Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT). Methods: Treatment plans from ten patients who have undergone treatment with a prescribed dose of 4950 cGy, at 275 cGy per fraction, were analyzed. All plans were replanned using Eclipse TPS (Varian Medical Systems, Palo Alto, CA) with complementary VMAT or IMRT techniques to obtain paired data sets for comparison. The coverage to at least 95% of the planned target volume (PTV) was normalized to receive 100% of the prescription dose. The normal tissue constraints followed the quantitative analysis of normal tissue effects in the clinic (QUANTEC) guidelines and the organs at risks (OARs) were liver, kidneys, spinal cord and bowel. The plan evaluation was based on conformity index (CI), homogeneity index (HI), uniformity index (UI), DVH parameters, and student’s-t statistics (2 tails). Results: The VMAT technique delivered less maximum dose to the right kidney, left kidney, total kidney, liver, spinal cord, and bowel by 9.3%, 5.9%, 6.7%, 3.9%, 15.1%, 3.9%, and 4.3%, respectively. The averaged V15 for the total kidney was 10.21% for IMRT and 7.29% for VMAT. The averaged V20 for the bowel was 19.89% for IMRT and 14.06% for VMAT. On average, the CI for IMRT was 1.20 and 1.16 for VMAT (p = 0.20). The HI was 0.08 for both techniques (p = 0.91) and UI was 1.05 and 1.06 for IMRT and VMAT respectively (p = 0.59). Conclusion: Both techniques achieve adequate PTV coverage. Although VMAT techniques show better normal tissue sparing from excessive dose, no significant differences were observed. Slight discrepancies may rise from different versions of calculation algorithms.

  7. Interleukin-9 Promotes Pancreatic Cancer Cells Proliferation and Migration via the miR-200a/Beta-Catenin Axis.

    Science.gov (United States)

    Hu, Bangli; Qiu-Lan, Huang; Lei, Rong-E; Shi, Cheng; Jiang, Hai-Xing; Qin, Shan-Yu

    2017-01-01

    Background . Both IL-9 and miR-200a are involved in the pathogenesis of cancers; however, the role of IL-9 in pancreatic cancer and the possible underlying mechanisms remain unknown. The aim of this study was to investigate the effect of IL-9 on pancreatic cancer cells and its interaction with miR-200a. Methods . Pancreatic cancer cells (PANC-1 and AsPC-1) were treated with IL-9 and the expression of miR-200a and β -catenin in pancreatic cancer cells was measured. β -Catenin was examined as a target gene of miR-200a in pancreatic cancer cells. The interaction between IL-9 and miR-200a in pancreatic cancer cells was determined by infecting miR-200a mimics prior to IL-9 treatment and then measuring miR-200a and β -catenin expression. Results . IL-9 significantly promoted the proliferation, invasion, and migration of pancreatic cancer cells; however, the effect on pancreatic cancer cell apoptosis was insignificant. β -Catenin was verified as a target gene of miR-200a in pancreatic cancer cells. Overexpression of miR-200a in pancreatic cancer cells significantly attenuated proliferation and metastasis and reduced β -catenin expression. IL-9 treatment of pancreatic cancer cells decreased miR-200a expression and increased β -catenin expression. The effect of miR-200a on pancreatic cancer cells decreased following IL-9 treatment. Conclusions . IL-9 promotes proliferation and metastasis in pancreatic cancer cells; this effect may partly involve regulation of the miR-200a/ β -catenin axis.

  8. Hepatocyte Growth Factor from a Clinical Perspective: A Pancreatic Cancer Challenge

    International Nuclear Information System (INIS)

    Rizwani, Wasia; Allen, Amanda E.; Trevino, Jose G.

    2015-01-01

    Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and incidence rates are rising. Both detection and treatment options for pancreatic cancer are limited, providing a less than 5% five-year survival advantage. The need for new biomarkers for early detection and treatment of pancreatic cancer demands the efficient translation of bench knowledge to provide clinical benefit. One source of therapeutic resistance is the pancreatic tumor microenvironment, which is characterized by desmoplasia and hypoxia making it less conducive to current therapies. A major factor regulating desmoplasia and subsequently promoting chemoresistance in pancreatic cancer is hepatocyte growth factor (HGF), the sole ligand for c-MET (mesenchymal-epithelial transition), an epithelial tyrosine kinase receptor. Binding of HGF to c-MET leads to receptor dimerization and autophosphorylation resulting in the activation of multiple cellular processes that support cancer progression. Inhibiting activation of c-MET in cancer cells, in combination with other approaches for reducing desmoplasia in the tumor microenvironment, might significantly improve the success of chemotherapy. Therefore, HGF makes a potent novel target for developing therapeutic strategies in combination with existing drugs for treating pancreatic adenocarcinoma. This review provides a comprehensive analysis of HGF and its promising potential as a chemotherapeutic target for pancreatic cancer

  9. New therapeutic directions for advanced pancreatic cancer: cell cycle inhibitors, stromal modifiers and conjugated therapies.

    Science.gov (United States)

    Matera, Robert; Saif, Muhammad Wasif

    2017-09-01

    Pancreatic adenocarcinoma is a devastating malignancy with an extremely poor prognosis. These tumors progress rapidly and somewhat silently with few specific symptoms and are relatively resistant to chemotherapeutic agents. Many agents, including cell cycle inhibitors, are under development for the treatment of this cancer for which there are disappointingly few treatment options. Areas covered: Here we outline the existing approved treatments for advanced pancreatic disease and discuss a range of novel therapies currently under development including cell cycle inhibitors, stromal modifiers and conjugated therapies. We also describe the current state of the pancreatic cancer therapeutics market both past and future. Expert opinion: Despite the recent explosion of novel therapies with an array of unique targets, the core treatment of pancreatic cancer still with traditional cytotoxic agents with a few exceptions. However, as these novel treatments move through the pipeline, we are hopeful that there will soon be a number of effective options for patients with advanced pancreatic cancer.

  10. Approach to patients with pancreatic cancer without detectable metastases.

    Science.gov (United States)

    Heestand, Gregory M; Murphy, James D; Lowy, Andrew M

    2015-06-01

    The poors outcomes associated with pancreatic cancer clearly reflect the advanced stage of disease at diagnosis for most patients. Through this lens, it is easy to lose sight of the fact that roughly 50% of patients with pancreatic cancer have no clinically detectable metastases at presentation. Herein, we discuss how patients with localized pancreatic cancer are currently managed. The primary goal of care for patients with resectable and borderline-resectable tumors is cure, facilitated by achieving margin-negative resection of the primary disease and delivering effective adjuvant and/or neoadjuvant therapy. For patients with locally advanced disease, the focus is on limiting local progression and outgrowth of metastatic disease and maintaining quality of life. Although it was once a centerpiece of therapy for localized pancreatic cancer, the value and place of radiation therapy in the treatment algorithm is now under increased scrutiny. In contrast, given its value as demonstrated in multiple prospective trials, chemotherapy is an established part of the treatment paradigm for all patients. With the demonstration that cytotoxic combinations such as fluorouracil, leucovorin, irinotecan, and oxaliplatin as well as gemcitabine/nab-paclitaxel are active in the metastatic setting, these agents are now being studied in patients with localized disease. The neoadjuvant setting provides a particularly favorable setting for evaluating new systemic strategies. Given the array of new targets, including immunomodulatory approaches, there is reason for optimism that we can markedly improve survival for all patients with pancreatic cancer and enter an era in which surgery with curative intent actually fulfills this goal on a much more regular basis. © 2015 by American Society of Clinical Oncology.

  11. Prognosis Relevance of Serum Cytokines in Pancreatic Cancer

    Science.gov (United States)

    Alejandre, Maria José; Palomino-Morales, Rogelio J.; Prados, Jose; Aránega, Antonia; Delgado, Juan R.; Irigoyen, Antonio; Martínez-Galán, Joaquina; Ortuño, Francisco M.

    2015-01-01

    The overall survival of patients with pancreatic ductal adenocarcinoma is extremely low. Although gemcitabine is the standard used chemotherapy for this disease, clinical outcomes do not reflect significant improvements, not even when combined with adjuvant treatments. There is an urgent need for prognosis markers to be found. The aim of this study was to analyze the potential value of serum cytokines to find a profile that can predict the clinical outcome in patients with pancreatic cancer and to establish a practical prognosis index that significantly predicts patients' outcomes. We have conducted an extensive analysis of serum prognosis biomarkers using an antibody array comprising 507 human cytokines. Overall survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox's proportional hazard models were used to analyze prognosis factors. To determine the extent that survival could be predicted based on this index, we used the leave-one-out cross-validation model. The multivariate model showed a better performance and it could represent a novel panel of serum cytokines that correlates to poor prognosis in pancreatic cancer. B7-1/CD80, EG-VEGF/PK1, IL-29, NRG1-beta1/HRG1-beta1, and PD-ECGF expressions portend a poor prognosis for patients with pancreatic cancer and these cytokines could represent novel therapeutic targets for this disease. PMID:26346854

  12. Prognosis Relevance of Serum Cytokines in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Carolina Torres

    2015-01-01

    Full Text Available The overall survival of patients with pancreatic ductal adenocarcinoma is extremely low. Although gemcitabine is the standard used chemotherapy for this disease, clinical outcomes do not reflect significant improvements, not even when combined with adjuvant treatments. There is an urgent need for prognosis markers to be found. The aim of this study was to analyze the potential value of serum cytokines to find a profile that can predict the clinical outcome in patients with pancreatic cancer and to establish a practical prognosis index that significantly predicts patients’ outcomes. We have conducted an extensive analysis of serum prognosis biomarkers using an antibody array comprising 507 human cytokines. Overall survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox’s proportional hazard models were used to analyze prognosis factors. To determine the extent that survival could be predicted based on this index, we used the leave-one-out cross-validation model. The multivariate model showed a better performance and it could represent a novel panel of serum cytokines that correlates to poor prognosis in pancreatic cancer. B7-1/CD80, EG-VEGF/PK1, IL-29, NRG1-beta1/HRG1-beta1, and PD-ECGF expressions portend a poor prognosis for patients with pancreatic cancer and these cytokines could represent novel therapeutic targets for this disease.

  13. PHGDH is an independent prognosis marker and contributes cell proliferation, migration and invasion in human pancreatic cancer.

    Science.gov (United States)

    Song, Zhiwang; Feng, Chan; Lu, Yonglin; Lin, Yun; Dong, Chunyan

    2018-02-05

    To investigate the expression, clinical significance, biological function, and the potential mechanism of PHGDH in pancreatic cancer. The expression of PHGDH in human pancreatic cancer tissues and corresponding adjacent normal tissues were analyzed through immunohistochemistry staining. Simultaneously, the association between the PHGDH expression and the clinicopathological parameters and OS and DFS was evaluated. Human pancreatic cancer cell line BxPC-3 and SW1990 were selected to investigate the effect of PHGDH knockdown on cell proliferation, migration, and invasion. In addition, we performed western blot to assess the expression of cyclin B1, and cyclin D1, MMP-2, and MMP-9 protein. Our results suggested that the expression of PHGDH is increased in pancreatic cancer compared with adjacent normal tissues and the increased expression of PHGDH is associated with tumor size, lymph node metastasis, and TNM state of pancreatic cancer patients. Moreover, the expression of PHGDH is an independent prognostic indicator for pancreatic cancer patients. In addition, we found that knockdown of PHGDH in pancreatic cancer cells inhibits the cell proliferation, migration, and invasion abilities by down-regulating the expression of cyclin B1, and cyclin D1, MMP-2, and MMP-9. Our data indicated that the expression of PHGDH is increased in pancreatic cancer and is an independent molecular prognostic factor for pancreatic cancer patients. In addition, PHGDH controls cell proliferation, migration and invasion abilities. Therefore, PHGDH could serve as an important prognostic indicator and therapeutic target for pancreatic cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells

    International Nuclear Information System (INIS)

    Hamada, Shin; Masamune, Atsushi; Takikawa, Tetsuya; Suzuki, Noriaki; Kikuta, Kazuhiro; Hirota, Morihisa; Hamada, Hirofumi; Kobune, Masayoshi; Satoh, Kennichi; Shimosegawa, Tooru

    2012-01-01

    Highlights: ► Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. ► Pancreatic cancer cells co-cultured with PSCs showed enhanced spheroid formation. ► Expression of stem cell-related genes ABCG2, Nestin and LIN28 was increased. ► Co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. ► This study suggested a novel role of PSCs as a part of the cancer stem cell niche. -- Abstract: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called “cancer stem cells”, within the entire cancer tissue harbor highly tumorigenic and chemo-resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the “stemness” of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell-like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche.

  15. Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells

    International Nuclear Information System (INIS)

    Kikuta, Kazuhiro; Masamune, Atsushi; Watanabe, Takashi; Ariga, Hiroyuki; Itoh, Hiromichi; Hamada, Shin; Satoh, Kennichi; Egawa, Shinichi; Unno, Michiaki; Shimosegawa, Tooru

    2010-01-01

    Research highlights: → Recent studies have shown that pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. → Pancreatic cancer cells co-cultured with PSCs showed loose cell contacts and scattered, fibroblast-like appearance. → PSCs decreased the expression of epithelial markers but increased that of mesenchymal markers, along with increased migration. → This study suggests epithelial-mesenchymal transition as a novel mechanism by which PSCs contribute to the aggressive behavior of pancreatic cancer cells. -- Abstract: The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Because epithelial-mesenchymal transition (EMT) plays a critical role in the progression of pancreatic cancer, we hypothesized that PSCs promote EMT in pancreatic cancer cells. Panc-1 and SUIT-2 pancreatic cancer cells were indirectly co-cultured with human PSCs isolated from patients undergoing operation for pancreatic cancer. The expression of epithelial and mesenchymal markers was examined by real-time PCR and immunofluorescent staining. The migration of pancreatic cancer cells was examined by scratch and two-chamber assays. Pancreatic cancer cells co-cultured with PSCs showed loose cell contacts and a scattered, fibroblast-like appearance. The expression of E-cadherin, cytokeratin 19, and membrane-associated β-catenin was decreased, whereas vimentin and Snail (Snai-1) expression was increased more in cancer cells co-cultured with PSCs than in mono-cultured cells. The migration of pancreatic cancer cells was increased by co-culture with PSCs. The PSC-induced decrease of E-cadherin expression was not altered by treatment with anti

  16. Early Detection of Sporadic Pancreatic Cancer

    Science.gov (United States)

    Kenner, Barbara J.; Chari, Suresh T.; Cleeter, Deborah F.; Go, Vay Liang W.

    2015-01-01

    Abstract Innovation leading to significant advances in research and subsequent translation to clinical practice is urgently necessary in early detection of sporadic pancreatic cancer. Addressing this need, the Early Detection of Sporadic Pancreatic Cancer Summit Conference was conducted by Kenner Family Research Fund in conjunction with the 2014 American Pancreatic Association and Japan Pancreas Society Meeting. International interdisciplinary scientific representatives engaged in strategic facilitated conversations based on distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. Ideas generated from the summit have led to the development of a Strategic Map for Innovation built upon 3 components: formation of an international collaborative effort, design of an actionable strategic plan, and implementation of operational standards, research priorities, and first-phase initiatives. Through invested and committed efforts of leading researchers and institutions, philanthropic partners, government agencies, and supportive business entities, this endeavor will change the future of the field and consequently the survival rate of those diagnosed with pancreatic cancer. PMID:25938853

  17. Indications for staging laparoscopy in pancreatic cancer

    Science.gov (United States)

    De Rosa, Antonella; Cameron, Iain C.; Gomez, Dhanwant

    2015-01-01

    Background To identify indications for staging laparoscopy (SL) in patients with resectable pancreatic cancer, and suggest a pre-operative algorithm for staging these patients. Methods Relevant articles were reviewed from the published literature using the Medline database. The search was performed using the keywords ‘pancreatic cancer’, ‘resectability’, ‘staging’, ‘laparoscopy’, and ‘Whipple's procedure’. Results Twenty four studies were identified which fulfilled the inclusion criteria. Of the published data, the most reliable surrogate markers for selecting patients for SL to predict unresectability in patients with CT defined resectable pancreatic cancer were CA 19.9 and tumour size. Although there are studies suggesting a role for tumour location, CEA levels, and clinical findings such as weight loss and jaundice, there is currently not enough evidence for these variables to predict resectability. Based on the current data, patients with a CT suggestive of resectable disease and (1) CA 19.9 ≥150 U/mL; or (2) tumour size >3 cm should be considered for SL. Conclusion The role of laparoscopy in the staging of pancreatic cancer patients remains controversial. Potential predictors of unresectability to select patients for SL include CA 19.9 levels and tumour size. PMID:26776846

  18. Pancreatic cancer: Incidence, clinical profile, and frequency of ...

    African Journals Online (AJOL)

    Hana T. Al-Majed

    2012-08-09

    Aug 9, 2012 ... Abstract Background: Pancreatic cancer is an uncommon tumor, but because the mortality rate approaches 100%, this form of cancer has now become a common cause of cancer mortality. Diabetes has been postulated to be both a risk factor and a consequence of pancreatic cancer, but the degree of risk ...

  19. Impact of Diabetes Mellitus on the Outcome of Pancreatic Cancer

    OpenAIRE

    Beg, Muhammad Shaalan; Dwivedi, Alok Kumar; Ahmad, Syed Arif; Ali, Sadia; Olowokure, Olugbenga

    2014-01-01

    Introduction Diabetes mellitus (DM) has the potential to impact the pathogenesis, treatment, and outcome of pancreatic cancer. This study evaluates the impact of DM on pancreatic cancer survival. Methods We conducted a retrospective cohort study from the Veterans Affairs (VA) Central Cancer Registry (VACCR) for pancreatic cancer cases between 1995 and 2008. DM and no-DM cases were identified from comorbidity data. Univariate and multivariable analysis was performed. Multiple imputation method...

  20. Biomarkers for pancreatic cancer: promising new markers and options beyond CA 19-9.

    Science.gov (United States)

    Ballehaninna, Umashankar K; Chamberlain, Ronald S

    2013-12-01

    Pancreatic adenocarcinoma accounts for nearly 90-95% of exocrine malignant tumors of the pancreas. Traditionally, overexpressed proteins/epitopes such as CA 19-9, CA-50, CEA, and many others were being used as pancreatic cancer tumor markers. The main utility of these biomarkers was in the diagnosis of pancreatic cancer as well as to assess response to chemotherapy and to determine prognosis and to predict tumor recurrence. However, these markers had significant limitations such as lack of sensitivity, false-negative results in certain blood groups, as well as false-positive elevation in the presence of obstructive jaundice. To circumvent these limitations, an extraordinary amount of research is being performed to identify an accurate tumor marker or a panel of markers that could aid in the management of the pancreatic cancer. Although this research has identified a large number and different variety of biomarkers, few hold future promise as a preferred marker for pancreatic cancer. This review provides an insight into exciting new areas of pancreatic biomarker research such as salivary, pancreatic juice, and stool markers that can be used as a noninvasive test to identify pancreatic cancer. This manuscript also provides a discussion on newer biomarkers, the role of microRNAs, and pancreatic cancer proteomics, which have the potential to identify a preferred tumor marker for pancreatic adenocarcinoma. This review further elaborates on important genetic changes associated with the development and progression of pancreatic cancer that holds the key for the identification of a sensitive biomarker and which could also serve as a therapeutic target.

  1. Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiang-Yuan; Wang, Zhen [Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Li, Bei [Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Zhang, Ying-Jian, E-mail: yjzhang111@aliyun.com [Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Li, Ying-Yi, E-mail: liyingyi@fudan.edu.cn [Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China)

    2016-04-22

    Resistance of cancer cells to chemoradiotherapy is a major clinical problem in pancreatic cancer treatment. Therefore, understanding the molecular basis of cellular resistance and identifying novel targets are essential for improving treatment efficacy for pancreatic cancer patients. Previous studies have demonstrated a significant role for Pim-3 in pancreatic cancer survival against gemcitabine-induced genotoxic stress. Here, we observed that radiation treatment enhanced Pim-3 expression in human pancreatic cancer cells in vitro. Stable overexpression of Pim-3 in pancreatic cancer cells significantly protected cells against radiation treatment by attenuating G2/M phase cell cycle arrest and DNA damage response. Silencing of Pim-3 expression significantly elevated the phosphorylation of histone variant H2AX, a marker of DNA double strand breaks, and decreased the activation of ataxia-telangiectasia-mutated (ATM) kinase, along with its downstream targets, eventually enhancing the radiosensitivity of human pancreatic cancer cells in vitro and in vivo. Hence, we demonstrated a novel function for Pim-3 in human pancreatic cancer cell survival against radiation. Targeting Pim-3 may be a promising way to improve treatment efficacy in combination with radiotherapy in human pancreatic cancer. - Highlights: • This is first study to demonstrate that Pim-3 is endogenously induced by ionizing radiation in pancreatic cancer cells, and Pim-3 overexpression enhanced radioresistance of pancreatic cancer cells both in vitro and in vivo. • This is first study to provide evidence that radioresistance induced by Pim-3 is mainly attributed to Pim-3 induces activation of ATM, which subsequently activates checkpoint 1, leading to amplification of DNA repair through cell cycle arrest and DNA repair pathways. • This is first study to indicate that targeting Pim-3 may be a promising strategy to provide better treatment efficacy in combination with radiotherapy in human pancreatic

  2. Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells

    International Nuclear Information System (INIS)

    Chen, Xiang-Yuan; Wang, Zhen; Li, Bei; Zhang, Ying-Jian; Li, Ying-Yi

    2016-01-01

    Resistance of cancer cells to chemoradiotherapy is a major clinical problem in pancreatic cancer treatment. Therefore, understanding the molecular basis of cellular resistance and identifying novel targets are essential for improving treatment efficacy for pancreatic cancer patients. Previous studies have demonstrated a significant role for Pim-3 in pancreatic cancer survival against gemcitabine-induced genotoxic stress. Here, we observed that radiation treatment enhanced Pim-3 expression in human pancreatic cancer cells in vitro. Stable overexpression of Pim-3 in pancreatic cancer cells significantly protected cells against radiation treatment by attenuating G2/M phase cell cycle arrest and DNA damage response. Silencing of Pim-3 expression significantly elevated the phosphorylation of histone variant H2AX, a marker of DNA double strand breaks, and decreased the activation of ataxia-telangiectasia-mutated (ATM) kinase, along with its downstream targets, eventually enhancing the radiosensitivity of human pancreatic cancer cells in vitro and in vivo. Hence, we demonstrated a novel function for Pim-3 in human pancreatic cancer cell survival against radiation. Targeting Pim-3 may be a promising way to improve treatment efficacy in combination with radiotherapy in human pancreatic cancer. - Highlights: • This is first study to demonstrate that Pim-3 is endogenously induced by ionizing radiation in pancreatic cancer cells, and Pim-3 overexpression enhanced radioresistance of pancreatic cancer cells both in vitro and in vivo. • This is first study to provide evidence that radioresistance induced by Pim-3 is mainly attributed to Pim-3 induces activation of ATM, which subsequently activates checkpoint 1, leading to amplification of DNA repair through cell cycle arrest and DNA repair pathways. • This is first study to indicate that targeting Pim-3 may be a promising strategy to provide better treatment efficacy in combination with radiotherapy in human pancreatic

  3. Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia

    OpenAIRE

    Delitto, Daniel; Judge, Sarah M.; Delitto, Andrea E.; Nosacka, Rachel L.; Rocha, Fernanda G.; DiVita, Bayli B.; Gerber, Michael H.; George, Thomas J.; Behrns, Kevin E.; Hughes, Steven J.; Wallet, Shannon M.; Judge, Andrew R.; Trevino, Jose G.

    2016-01-01

    Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu ...

  4. Indicative findings of pancreatic cancer in prediagnostic CT

    International Nuclear Information System (INIS)

    Ahn, Sung Soo; Choi, Jin-Young; Hong, Hye-Suk; Chung, Yong Eun; Lim, Joon Seok; Kim, Myeong-Jin

    2009-01-01

    We examined 20 prediagnostic CTs from 16 patients for whom the diagnosis of pancreatic cancer was delayed until full diagnostic CT was performed. Three radiologists independently reviewed the prediagnostic CTs along with 50 CTs of control subjects, including patients without pancreatic disease (n = 38) or with chronic pancreatitis without calcification visible on CT (n=12). The reviewers recorded the presence of biliary or pancreatic ductal dilation, interruption of the pancreatic duct, distal parenchymal atrophy, contour abnormality and focal hypoattenuation. Frequency, sensitivity and specificity of the significant findings were calculated. Logistic regression analysis was performed. Findings indicative of pancreatic cancer were seen on 85% (17/20) of the prediagnostic CTs. Patients with pancreatic cancer were significantly (p<0.05) more likely to show focal hypoattenuation, pancreatic duct dilation, interruption of the pancreatic duct, and distal parenchymal atrophy, with sensitivities and specificities of 75%/84%, 50%/78%, 45%/82% and 45%/96%, respectively. Focal hypoattenuation and distal parenchymal atrophy were the independent predictors of pancreatic cancer with odds ratios of 20.92 and 11.22, respectively. In conclusion, focal hypoattenuation and pancreatic duct dilation with or without interruption, especially when accompanied by distal parenchymal atrophy, were the most useful findings for avoiding delayed diagnosis of pancreatic cancer. (orig.)

  5. Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Elvira Pelosi

    2017-11-01

    Full Text Available Pancreatic Ductal Adenocarcinoma (PDAC is the fourth most common cause of cancer-related death and is the most lethal of common malignancies with a five-year survival rate of <10%. PDAC arises from different types of non-invasive precursor lesions: intraductal papillary mucinous neoplasms, mucinous cystic neoplasms and pancreatic intraepithelial neoplasia. The genetic landscape of PDAC is characterized by the presence of four frequently-mutated genes: KRAS, CDKN2A, TP53 and SMAD4. The development of mouse models of PDAC has greatly contributed to the understanding of the molecular and cellular mechanisms through which driver genes contribute to pancreatic cancer development. Particularly, oncogenic KRAS-driven genetically-engineered mouse models that phenotypically and genetically recapitulate human pancreatic cancer have clarified the mechanisms through which various mutated genes act in neoplasia induction and progression and have led to identifying the possible cellular origin of these neoplasias. Patient-derived xenografts are increasingly used for preclinical studies and for the development of personalized medicine strategies. The studies of the purification and characterization of pancreatic cancer stem cells have suggested that a minority cell population is responsible for initiation and maintenance of pancreatic adenocarcinomas. The study of these cells could contribute to the identification and clinical development of more efficacious drug treatments.

  6. Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Kristen S Hill

    Full Text Available At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.

  7. Chronic alcohol drinking: Liver and pancreatic cancer?

    Science.gov (United States)

    Zakhari, Samir

    2015-09-01

    Cancer is a multifactorial disease that results from complex interactions of numerous risk factors - genetic and environmental - over time, eventually leading to the diseased phenotypes. Thus, while epidemiological studies can point to risk factors, they cannot determine cause and effect relationships, and are unable to give biological and clinical insights into carcinogenesis. The link between any risk factor and carcinogenesis needs to be validated in experimental models. This is particularly true in epidemiological studies on alcohol consumption and its consequences. While there is no doubt that heavy alcohol consumption has devastating health effects, the inconsistencies in alcohol-related epidemiological studies and cancer suffer from possible sources of the variability in outcomes, ranging from inaccuracy of self-report of consumption to the problem of correlating cancer that started decades earlier to current or recent alcohol consumption. To further study the interactions between alcohol and cancer, the use of "Molecular Pathological Epidemiology" (MPE) advocated by Ogino et al. for dissecting the interplay between etiological factors, cellular and molecular characteristics, and disease progression in cancer is appropriate. MPE does not consider cancer as a single entity, rather it integrates analyses of epidemiological studies with the macroenvironment and molecular and microenvironment. This approach allows investigating the relationships between potential etiological agents and cancer based on molecular signatures. More research is needed to fully elucidate the link between heavy alcohol consumption and pancreatic cancer, and to further investigate the roles of acetaldehyde and FAEEs in pancreatic carcinogenesis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  8. Borderline resectable pancreatic cancer: Definitions and management

    Science.gov (United States)

    Lopez, Nicole E; Prendergast, Cristina; Lowy, Andrew M

    2014-01-01

    Pancreatic cancer is the fourth leading cause of cancer death in the United States. While surgical resection remains the only curative option, more than 80% of patients present with unresectable disease. Unfortunately, even among those who undergo resection, the reported median survival is 15-23 mo, with a 5-year survival of approximately 20%. Disappointingly, over the past several decades, despite improvements in diagnostic imaging, surgical technique and chemotherapeutic options, only modest improvements in survival have been realized. Nevertheless, it remains clear that surgical resection is a prerequisite for achieving long-term survival and cure. There is now emerging consensus that a subgroup of patients, previously considered poor candidates for resection because of the relationship of their primary tumor to surrounding vasculature, may benefit from resection, particularly when preceded by neoadjuvant therapy. This stage of disease, termed borderline resectable pancreatic cancer, has become of increasing interest and is now the focus of a multi-institutional clinical trial. Here we outline the history, progress, current treatment recommendations, and future directions for research in borderline resectable pancreatic cancer. PMID:25152577

  9. Increased pancreatic cancer risk following radiotherapy for testicular cancer

    DEFF Research Database (Denmark)

    Hauptmann, Michael; Børge Johannesen, Tom; Gilbert, Ethel S

    2016-01-01

    BACKGROUND: Pancreatic cancer risk is elevated among testicular cancer (TC) survivors. However, the roles of specific treatments are unclear. METHODS: Among 23 982 5-year TC survivors diagnosed during 1947-1991, doses from radiotherapy to the pancreas were estimated for 80 pancreatic cancer...... patients and 145 matched controls. Chemotherapy details were recorded. Logistic regression was used to estimate odds ratios (ORs). RESULTS: Cumulative incidence of second primary pancreatic cancer was 1.1% at 30 years after TC diagnosis. Radiotherapy (72 (90%) cases and 115 (80%) controls) was associated...... with a 2.9-fold (95% confidence interval (CI) 1.0-7.8) increased risk. The OR increased linearly by 0.12 per Gy to the pancreas (P-trendrisks remained elevated ⩾20 years after TC diagnosis (P=0.020). The risk increased...

  10. Retinoid signaling in pancreatic cancer, injury and regeneration.

    Directory of Open Access Journals (Sweden)

    Emily K Colvin

    Full Text Available BACKGROUND: Activation of embryonic signaling pathways quiescent in the adult pancreas is a feature of pancreatic cancer (PC. These discoveries have led to the development of novel inhibitors of pathways such as Notch and Hedgehog signaling that are currently in early phase clinical trials in the treatment of several cancer types. Retinoid signaling is also essential for pancreatic development, and retinoid therapy is used successfully in other malignancies such as leukemia, but little is known concerning retinoid signaling in PC. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the role of retinoid signaling in vitro and in vivo in normal pancreas, pancreatic injury, regeneration and cancer. Retinoid signaling is active in occasional cells in the adult pancreas but is markedly augmented throughout the parenchyma during injury and regeneration. Both chemically induced and genetically engineered mouse models of PC exhibit a lack of retinoid signaling activity compared to normal pancreas. As a consequence, we investigated Cellular Retinoid Binding Protein 1 (CRBP1, a key regulator of retinoid signaling known to play a role in breast cancer development, as a potential therapeutic target. Loss, or significant downregulation of CRBP1 was present in 70% of human PC, and was evident in the very earliest precursor lesions (PanIN-1A. However, in vitro gain and loss of function studies and CRBP1 knockout mice suggested that loss of CRBP1 expression alone was not sufficient to induce carcinogenesis or to alter PC sensitivity to retinoid based therapies. CONCLUSIONS/SIGNIFICANCE: In conclusion, retinoid signalling appears to play a role in pancreatic regeneration and carcinogenesis, but unlike breast cancer, it is not mediated directly by CRBP1.

  11. Targeting the Epidermal Growth Factor Receptor in Addition to Chemotherapy in Patients with Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Jaseela Chiramel

    2017-04-01

    Full Text Available Overexpression of epidermal growth factor receptors (EGFR occurs in >90% of pancreatic ductal adenocarcinomas (PDACs and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs. Meta-regression was utilised to explore factors associated with improved prognosis (all studies and benefit from EGFR-targeted therapy (RCTs. Twenty-eight studies (7 RCTs and 21 cohort studies comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR: 0.90, p = 0.15 or overall survival (HR: 0.94, p = 0.18. EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR: 5.18, p = 0.007, and grade (G3/4 rash (OR: 4.82, p = 0.03. There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06, but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25. Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = −0.69, p < 0.001. Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined.

  12. microRNA-7 impairs autophagy-derived pools of glucose to suppress pancreatic cancer progression.

    Science.gov (United States)

    Gu, Dian-Na; Jiang, Ming-Jie; Mei, Zhu; Dai, Juan-Juan; Dai, Chen-Yun; Fang, Chi; Huang, Qian; Tian, Ling

    2017-08-01

    Pancreatic cancer commonly addicts to aerobic glycolysis, and abnormally activates autophagy to adapt the stringent metabolic microenvironment. microRNA-7 (miR-7) was supposed to modulate various gastrointestinal cancer progression. We wonder whether miR-7 could destroy the reprogrammed metabolic homeostasis in pancreatic cancer via modulating the level of autophagy, and further affect tumor proliferation and survival. Herein, we first reported that pancreatic cancer could take advantage of autophagy as a survival strategy to provide essential glucose required for glycolysis metabolism. Of note, under the stressful tumor microenvironment, miR-7 could repress autophagy through up-regulation of LKB1-AMPK-mTOR signaling, and directly targeting the stages of autophagy induction and vesicle elongation to reduce the supply of intracellular glucose to glycolysis metabolism. Furthermore, miR-7 inhibited pancreatic cancer cell proliferation and metastasis in vitro and in vivo. Consistently, lentivirus-mediated miR-7 effectively reduced the growth of patient-derived xenograft by interfering glycolysis via inhibition of autophagy. Together, these data suggested miR-7 might function as an important regulator to impair autophagy-derived pools of glucose to suppress pancreatic cancer progress. Hence, miR-7 might be a potential therapeutic target in pancreatic cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Enteric duplication cyst of the pancreas associated with chronic pancreatitis and pancreatic cancer.

    Science.gov (United States)

    Chiu, Alexander S; Bluhm, David; Xiao, Shu-Yan; Waxman, Irving; Matthews, Jeffrey B

    2014-05-01

    Pancreas-associated enteric duplication cysts are rare developmental anomalies that communicate with the main pancreatic duct and may be associated with recurrent acute and chronic abdominal pain in children. In adults, these lesions may masquerade as pancreatic pseudocysts or pancreatic cystic neoplasms. An adult patient with a pancreas-associated enteric duplication is described which represents the first reported instance of association with both chronic calcific pancreatitis and pancreatic cancer. The clinical spectrum of pancreas-associated enteric duplication cyst, including diagnostic and therapeutic options, is reviewed.

  14. Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery.

    Science.gov (United States)

    de Geus, Susanna W L; Boogerd, Leonora S F; Swijnenburg, Rutger-Jan; Mieog, J Sven D; Tummers, Willemieke S F J; Prevoo, Hendrica A J M; Sier, Cornelis F M; Morreau, Hans; Bonsing, Bert A; van de Velde, Cornelis J H; Vahrmeijer, Alexander L; Kuppen, Peter J K

    2016-12-01

    The purpose of this study was to identify suitable molecular targets for tumor-specific imaging of pancreatic adenocarcinoma. The expression of eight potential imaging targets was assessed by the target selection criteria (TASC)-score and immunohistochemical analysis in normal pancreatic tissue (n = 9), pancreatic (n = 137), and periampullary (n = 28) adenocarcinoma. Integrin α v β 6 , carcinoembryonic antigen (CEA), epithelial growth factor receptor (EGFR), and urokinase plasminogen activator receptor (uPAR) showed a significantly higher (all p < 0.001) expression in pancreatic adenocarcinoma compared to normal pancreatic tissue and were confirmed by the TASC score as promising imaging targets. Furthermore, these biomarkers were expressed in respectively 88 %, 71 %, 69 %, and 67 % of the pancreatic adenocarcinoma patients. The results of this study show that integrin α v β 6 , CEA, EGFR, and uPAR are suitable targets for tumor-specific imaging of pancreatic adenocarcinoma.

  15. Pancreatic cancer: overview of descriptive epidemiology.

    Science.gov (United States)

    Bosetti, Cristina; Bertuccio, Paola; Negri, Eva; La Vecchia, Carlo; Zeegers, Maurice P; Boffetta, Paolo

    2012-01-01

    Pancreatic cancer mortality rates have been increasing in high-income countries between the 1950s and the 1980s, and have leveled off or declined thereafter, particularly in men. To provide a global overview of recent pancreatic cancer mortality, we analyzed official death of the world certification data derived from the World Health Organization for 35 European countries and 19 other countries over the period 1980-2007. In 2007, the highest mortality rates from pancreatic cancer were in the Baltic countries, and some central/eastern and northern European countries (over 9.5/100 000 men and 6/100 000 women), whereas the lowest ones were in Latin America and Hong Kong (below 5/100 000 men and 3/100 000 women). Japan, the USA, Russia and the European Union (EU), as well as the largest countries in the EU, had rates around 7-9/100 000 men and 5-6/100 000 women. In the early 2000s, rates have been approximately stable in many European countries, as in the USA, Japan, and Australia. In Nordic countries and the UK, where declines in rates have been observed between the 1980s and the 1990s, mortality from pancreatic cancer has tended to rise over most recent calendar years. Some persisting rises were still found in men from a few countries of southern and central/eastern Europe (with low rates in the past), as well as in the EU overall, and in women from European and Asian countries. Recent trends were generally more favorable in young adults (30-49 yr), suggesting that overall trends are likely to improve in the near future. Copyright © 2011 Wiley Periodicals, Inc.

  16. Proteomics analysis of bodily fluids in pancreatic cancer.

    Science.gov (United States)

    Pan, Sheng; Brentnall, Teresa A; Chen, Ru

    2015-08-01

    Proteomics study of pancreatic cancer using bodily fluids emphasizes biomarker discovery and clinical application, presenting unique prospect and challenges. Depending on the physiological nature of the bodily fluid and its proximity to pancreatic cancer, the proteomes of bodily fluids, such as pancreatic juice, pancreatic cyst fluid, blood, bile, and urine, can be substantially different in terms of protein constitution and the dynamic range of protein concentration. Thus, a comprehensive discovery and specific detection of cancer-associated proteins within these varied fluids is a complex task, requiring rigorous experiment design and a concerted approach. While major challenges still remain, fluid proteomics studies in pancreatic cancer to date have provided a wealth of information in revealing proteome alterations associated with pancreatic cancer in various bodily fluids. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Hyaluronic acid-coated, prodrug-based nanostructured lipid carriers for enhanced pancreatic cancer therapy.

    Science.gov (United States)

    Lu, Zhihe; Su, Jingrong; Li, Zhengrong; Zhan, Yuzhu; Ye, Decai

    2017-01-01

    Gemcitabine (GEM) and Baicalein (BCL) are reported to have anti-tumor effects including pancreatic cancer. Hyaluronic acid (HA) can bind to over-expressed receptors in various kinds of cancer cells. The aim of this study is to develop prodrugs containing HA, BCL and GEM, and construct nanomedicine incorporate GEM and BCL in the core and HA on the surface. This system could target the cancer cells and co-deliver the drugs. GEM-stearic acid lipid prodrug (GEM-SA) and hyaluronic acid-amino acid-baicalein prodrug (HA-AA-BCL) were synthesized. Then, GEM and BCL prodrug-based targeted nanostructured lipid carriers (HA-GEM-BCL NLCs) were prepared by the nanoprecipitation technique. The in vitro cytotoxicity studies of the NLCs were evaluated on AsPC1 pancreatic cancer cell line. In vivo anti-tumor effects were observed on the murine-bearing pancreatic cancer model. HA-GEM-BCL NLCs were effective in entering pancreatic cancer cells over-expressing HA receptors, and showed cytotoxicity of tumor cells in vitro. In vivo study revealed significant tumor growth inhibition ability of HA-GEM-BCL NLCs in murine pancreatic cancer model. It could be concluded that HA-GEM-BCL NLCs could be featured as promising co-delivery, tumor-targeted nanomedicine for the treatment of cancers.

  18. Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8+ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic-Cancer Orthotopic Mouse Model.

    Science.gov (United States)

    Murakami, Takashi; Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Kiyuna, Tasuku; Hwang, Ho Kyoung; Miyake, Kentaro; Homma, Yuki; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Ichikawa, Yasushi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2018-01-01

    The present study determined the effect of the tumor-targeting strain Salmonella typhimurium A1-R (S. typhimurium A1-R) on CD8 + tumor-infiltrating lymphocytes (TILs) in a syngeneic pancreatic-cancer orthotopic mouse model. The effect of tumor-targeting S. typhimurium A1-R on CD8 + TILs was determined on the Pan02 murine pancreatic-adenocarcinoma implanted orthotopically in the pancreatic tail of C57BL/6 immunocompromised mice. Three weeks after orthotopic implantation, mice were randomized as follows G1: untreated control group (n = 8); and G2: S. typhimurium A1-R-treatment group (n = 8, 1 × 10 7 colony forming units [CFU]/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor-volume ratio was defined as ratio of tumor volume on the 22nd day relative to the 1st day. The tumor volume ratio was significantly lower in the S. typhimurium A1-R-treated group (G2) (3.0 ± 2.8) than the untreated control (G1) (39.9 ± 30.7, P R-treated mice (G2). Six mice in G1 had peritoneal dissemination, whereas no mice showed peritoneal dissemination in G2 (P R promotes CD8 + T cell infiltration and inhibition of tumor growth and metastasis. J. Cell. Biochem. 119: 634-639, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  19. Molecular analysis of precursor lesions in familial pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Tatjana Crnogorac-Jurcevic

    Full Text Available With less than a 5% survival rate pancreatic adenocarcinoma (PDAC is almost uniformly lethal. In order to make a significant impact on survival of patients with this malignancy, it is necessary to diagnose the disease early, when curative surgery is still possible. Detailed knowledge of the natural history of the disease and molecular events leading to its progression is therefore critical.We have analysed the precursor lesions, PanINs, from prophylactic pancreatectomy specimens of patients from four different kindreds with high risk of familial pancreatic cancer who were treated for histologically proven PanIN-2/3. Thus, the material was procured before pancreatic cancer has developed, rather than from PanINs in a tissue field that already contains cancer. Genome-wide transcriptional profiling using such unique specimens was performed. Bulk frozen sections displaying the most extensive but not microdissected PanIN-2/3 lesions were used in order to obtain the holistic view of both the precursor lesions and their microenvironment. A panel of 76 commonly dysregulated genes that underlie neoplastic progression from normal pancreas to PanINs and PDAC were identified. In addition to shared genes some differences between the PanINs of individual families as well as between the PanINs and PDACs were also seen. This was particularly pronounced in the stromal and immune responses.Our comprehensive analysis of precursor lesions without the invasive component provides the definitive molecular proof that PanIN lesions beget cancer from a molecular standpoint. We demonstrate the need for accumulation of transcriptomic changes during the progression of PanIN to PDAC, both in the epithelium and in the surrounding stroma. An identified 76-gene signature of PDAC progression presents a rich candidate pool for the development of early diagnostic and/or surveillance markers as well as potential novel preventive/therapeutic targets for both familial and sporadic

  20. In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Alessandro Carugo

    2016-06-01

    Full Text Available Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4 MLL (1–4 methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease.

  1. Nanotechnology advances in upper gastrointestinal, liver and pancreatic cancer.

    Science.gov (United States)

    Sykes, Paul D; Neoptolemos, John P; Costello, Eithne; Halloran, Christopher M

    2012-06-01

    Cancers of the upper GI tract, liver and pancreas have some of the poorest prognoses of any malignancies. Advances in diagnosis and treatment are sorely needed to improve the outcomes of patients. Nanotechnology offers the potential for constructing tailor-made therapies capable of targeting specific cancers. The particles themselves may be endowed with multifunctional properties that can be exploited for both diagnosis and treatment. Although development of therapies is still in the early stages, the use of nanoparticles (NPs) is widespread in diagnostic applications and will probably involve all areas of medicine in the future. Research into NPs is ongoing for upper gastrointestinal, liver and pancreatic cancers, and their use is becoming increasingly popular as contrast media for radiological investigations. Although more sophisticated technologies capable of active targeting are still in the early stages of assessment for clinical use, a small number of NP-based therapies are in clinical use.

  2. Selection and Outcome of Portal Vein Resection in Pancreatic Cancer

    International Nuclear Information System (INIS)

    Nakao, Akimasa

    2010-01-01

    Pancreatic cancer has the worst prognosis of all gastrointestinal neoplasms. Five-year survival of pancreatic cancer after pancreatectomy is very low, and surgical resection is the only option to cure this dismal disease. The standard surgical procedure is pancreatoduodenectomy (PD) for pancreatic head cancer. The morbidity and especially the mortality of PD have been greatly reduced. Portal vein resection in pancreatic cancer surgery is one attempt to increase resectability and radicality, and the procedure has become safe to perform. Clinicohistopathological studies have shown that the most important indication for portal vein resection in patients with pancreatic cancer is the ability to obtain cancer-free surgical margins. Otherwise, portal vein resection is contraindicated

  3. Selection and Outcome of Portal Vein Resection in Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Nakao, Akimasa [Department of Surgery II, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan)

    2010-11-24

    Pancreatic cancer has the worst prognosis of all gastrointestinal neoplasms. Five-year survival of pancreatic cancer after pancreatectomy is very low, and surgical resection is the only option to cure this dismal disease. The standard surgical procedure is pancreatoduodenectomy (PD) for pancreatic head cancer. The morbidity and especially the mortality of PD have been greatly reduced. Portal vein resection in pancreatic cancer surgery is one attempt to increase resectability and radicality, and the procedure has become safe to perform. Clinicohistopathological studies have shown that the most important indication for portal vein resection in patients with pancreatic cancer is the ability to obtain cancer-free surgical margins. Otherwise, portal vein resection is contraindicated.

  4. Genetics and Genetic Testing in Pancreatic Cancer.

    Science.gov (United States)

    Whitcomb, David C; Shelton, Celeste A; Brand, Randall E

    2015-10-01

    Genetic testing of germline DNA is used in patients suspected of being at risk of pancreatic ductal adenocarcinoma (PDAC) to better define the individual's risk and to determine the mechanism of risk. A high genetic risk increases the pretest probability that a biomarker of early cancer is a true positive and warrants further investigation. The highest PDAC risk is generally associated with a hereditary predisposition. However, the majority of PDAC results from complex, progressive gene-environment interactions that currently fall outside the traditional risk models. Over many years, the combination of inflammation, exposure to DNA-damaging toxins, and failed DNA repair promote the accumulation of somatic mutations in pancreatic cells; PDAC risk is further increased by already present oncogenic germline mutations. Predictive models and new technologies are needed to classify patients into more accurate and mechanistic PDAC risk categories that can be linked to improved surveillance and preventative strategies. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

  5. Childhood body mass index and risk of adult pancreatic cancer

    DEFF Research Database (Denmark)

    Nogueira, Leticia; Stolzenberg-Solomon, Rachael; Gamborg, Michael

    2017-01-01

    Background: Excess weight in adulthood is one of the few modifiable risk factors for pancreatic cancer, and height has associations as well. This leads to question whether body weight and height in childhood are associated with adult pancreatic cancer. Objective: To examine if childhood body mass...

  6. Pancreatic cancer in Nigeria: Past, present and future | Alatise ...

    African Journals Online (AJOL)

    Abstract. Pancreatic cancer remains a lethal disease worldwide despite an improved understanding of the disease. The main risk factors are age, smoking and genetic factors, however, the primary causal factors for pancreatic cancers are poorly understood. Advances in molecular biology have, however, greatly improved ...

  7. Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

    Energy Technology Data Exchange (ETDEWEB)

    Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong; Jun, Seung Won; Kim, Chang Seok [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of); Kang, Ho Young [Department of Microbiology, Pusan National University, Busan 609-736 (Korea, Republic of); Kim, Manbok [Department of Medical Science, Dankook University College of Medicine, Cheonan 330-714 (Korea, Republic of); Koh, Sang Seok [Department of Biological Sciences, Dong-A University, Busan 604-714 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of)

    2015-04-03

    Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells.

  8. A Case of Pancreatic Cancer in the Setting of Autoimmune Pancreatitis with Nondiagnostic Serum Markers

    Directory of Open Access Journals (Sweden)

    Manju D. Chandrasegaram

    2013-01-01

    Full Text Available Background. Autoimmune pancreatitis (AIP often mimics pancreatic cancer. The diagnosis of both conditions is difficult preoperatively let alone when they coexist. Several reports have been published describing pancreatic cancer in the setting of AIP. Case Report. The case of a 53-year-old man who presented with abdominal pain, jaundice, and radiological features of autoimmune pancreatitis, with a “sausage-shaped” pancreas and bulky pancreatic head with portal vein impingement, is presented. He had a normal serum IgG4 and only mildly elevated Ca-19.9. Initial endoscopic ultrasound-(EUS- guided fine-needle aspiration (FNA of the pancreas revealed an inflammatory sclerosing process only. A repeat EUS guided biopsy following biliary decompression demonstrated both malignancy and features of autoimmune pancreatitis. At laparotomy, a uniformly hard, bulky pancreas was found with no sonographically definable mass. A total pancreatectomy with portal vein resection and reconstruction was performed. Histology revealed adenosquamous carcinoma of the pancreatic head and autoimmune pancreatitis and squamous metaplasia in the remaining pancreas. Conclusion. This case highlights the diagnostic and management difficulties in a patient with pancreatic cancer in the setting of serum IgG4-negative, Type 2 AIP.

  9. Peptide-Conjugated Quantum Dots Act as the Target Marker for Human Pancreatic Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Shuang-ling Li

    2016-03-01

    Full Text Available Background/Aims: In the present study, we describe a novel and straightforward approach to produce a cyclic- arginine-glycine-aspartic (RGD-peptide-conjugated quantum dot (QD probe as an ideal target tumor biomarker. Due to its specific structure, the probe can be used for targeted imaging of pancreatic carcinoma cells. Methods: Pancreatic carcinoma cells were routinely cultured and marked with QD-RGD probe. The QD-RGD probe on the fluorescence-labeled cancer cell was observed by fluorescence microscopy and laser confocal microscopy. Cancer cell viability was detected by MTT assay after culturing with QD-RGD probe. Results: Fluorescence microscopy and laser confocal microscopy displayed that 10nmol/L QD-RGD probe was able to effectively mark pancreatic carcinoma cells. In comparison with organic dyes and fluorescent proteins, the quantum dot-RGD probe had unique optical and electronic properties. Conclusion: QD-RGD probe has a low cytotoxicity with an excellent optical property and biocompatibility. These findings support further evaluation of QD-RGD probes for the early detection of pancreatic cancer.

  10. Emphasis on neoadjuvant therapy for “resectable” pancreatic cancer

    Directory of Open Access Journals (Sweden)

    LIU Chang

    2015-05-01

    Full Text Available The treatment concept for pancreatic cancer is being transferred from “surgery first” to MDT model. The postoperative adjuvant treatment of pancreatic cancer can significantly improve the prognosis of patients and has become the standardized diagnostic and treatment practice; the value and significance of neoadjuvant therapy remains unclear. Limited clinical studies of “borderline resectable” pancreatic cancer have shown that neoadjuvant therapy can improve the R0 resection rate and improve the prognosis of patients, and it is recommended for clinical application. But the significance of neoadjuvant therapy in “resectable” pancreatic cancer is still controversial. There is a lack of consensus on indications, cycles, and regimens. It is necessary to carry out a series of prospective control studies to objectively evaluate the value of neoadjuvant therapy in improving the prognosis of “resectable” pancreatic cancer.

  11. Designing of promiscuous inhibitors against pancreatic cancer cell lines

    Science.gov (United States)

    Kumar, Rahul; Chaudhary, Kumardeep; Singla, Deepak; Gautam, Ankur; Raghava, Gajendra P. S.

    2014-04-01

    Pancreatic cancer remains the most devastating disease with worst prognosis. There is a pressing need to accelerate the drug discovery process to identify new effective drug candidates against pancreatic cancer. We have developed QSAR models for predicting promiscuous inhibitors using the pharmacological data. Our models achieved maximum Pearson correlation coefficient of 0.86, when evaluated on 10-fold cross-validation. Our models have also successfully validated the drug-to-oncogene relationship and further we used these models to screen FDA approved drugs and tested them in vitro. We have integrated these models in a webserver named as DiPCell, which will be useful for screening and designing novel promiscuous drug molecules. We have also identified the most and least effective drugs for pancreatic cancer cell lines. On the other side, we have identified resistant pancreatic cancer cell lines, which need investigative scanner on them to put light on resistant mechanism in pancreatic cancer.

  12. Systemic Targeted Alpha Radiotherapy for Cancer

    Directory of Open Access Journals (Sweden)

    Allan B. J.

    2013-09-01

    Full Text Available Background: The fundamental principles of internal targeted alpha therapy for cancer were established many decades ago.The high linear energy transfer (LET of alpha radiation to the targeted cancer cellscauses double strand breaks in DNA. At the same time, the short range radiation spares adjacent normal tissues. This targeted approach complements conventional external beam radiotherapy and chemotherapy. Such therapies fail on several fronts, such as lack of control of some primary cancers (e.g.glioblastoma multiformeand to inhibit the development of lethal metastatic cancer after successful treatment of the primary cancer. Objective: This review charts the developing role of systemic high LET, internal radiation therapy. Method: Targeted alpha therapy is a rapidly advancing experimental therapy that holds promise to deliver high cytotoxicity to targeted cancer cells. Initially thought to be indicated for leukemia and micrometastases, there is now evidence that solid tumors can also be regressed. Results: Alpha therapy may be molecular or physiological in its targeting. Alpha emitting radioisotopes such as Bi-212, Bi-213, At-211 and Ac-225 are used to label monoclonal antibodies or proteins that target specifc cancer cells. Alternatively, Radium-233 is used for palliative therapy of breast and prostate cancers because of its bone seeking properties. Conclusion: Preclinical studies and clinical trials of alpha therapy are discussed for leukemia, lymphoma, melanoma, glioblastoma multiforme, bone metastases, ovarian cancer, pancreatic cancer and other cancers.

  13. HIF1 Contributes to Hypoxia-Induced Pancreatic Cancer Cells Invasion via Promoting QSOX1 Expression

    Directory of Open Access Journals (Sweden)

    Chen-Ye Shi

    2013-08-01

    Full Text Available Background: Quiescin sulfhydryl oxidase 1 (QSOX1, which oxidizes sulfhydryl groups to form disulfide bonds in proteins, is found to be over-expressed in various pancreatic cancer cell lines and patients. QSOX1 promotes invasion of pancreatic cancer cells by activating MMP-2 and MMP-9. However, its regulatory mechanism remains largely undefined. Methods: Real-time PCR and Western blot were employed to detect the expression of QSOX1 in human pancreatic cancer cell lines under hypoxic condition. Luciferase reporter and ChIP assays were used to assess the regulation of QSOX1 by hypoxia-inducible factor 1 (HIF-1. Small interfering RNA (siRNA was applied to knock down endogenous expression of QSOX1. Matrigel-coated invasion chamber essays were conducted to detect the invasion capacity of QSOX1-depleted cells. Results: Both hypoxia and hypoxia mimicking reagent up-regulated the expression of QSOX1 in human pancreatic cancer cell lines. Knockdown of HIF-1α eliminated hypoxia induced QSOX1 expression. HIF-1α was found directly bound to two hypoxia-response elements (HRE of QSOX1 gene, both of which were required for HIF-1 induced QSOX1 expression. Moreover, QSOX1 silencing blocked hypoxia-induced pancreatic cancer cells invasion. Conclusion: QSOX1 is a direct target of HIF-1 and may contribute to hypoxia-induced pancreatic cancer cells invasion.

  14. KIF20A-Mediated RNA Granule Transport System Promotes the Invasiveness of Pancreatic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Keisuke Taniuchi

    2014-12-01

    Full Text Available Pancreatic cancers are aggressive because they are highly invasive and highly metastatic; moreover, effective treatments for aggressive pancreatic cancers are lacking. Here, we report that the motor kinesin protein KIF20A promoted the motility and invasiveness of pancreatic cancer cells through transporting the RNA-binding protein IGF2BP3 and IGF2BP3-bound transcripts toward cell protrusions along microtubules. We previously reported that IGF2BP3 and its target transcripts are assembled into cytoplasmic stress granules of pancreatic cancer cells, and that IGF2BP3 promotes the motility and invasiveness of pancreatic cancer cells through regulation of localized translation of IGF2BP3-bound transcripts in cell protrusions. We show that knockdown of KIF20A inhibited accumulation of IGF2BP3-containing stress granules in cell protrusions and suppressed local protein expression from specific IGF2BP3-bound transcripts, ARF6 and ARHGEF4, in the protrusions. Our results provide insight into the link between regulation of KIF20A-mediated trafficking of IGF2BP3-containing stress granules and modulation of the motility and invasiveness in pancreatic cancers.

  15. Nationwide prospective audit of pancreatic surgery: design, accuracy, and outcomes of the Dutch Pancreatic Cancer Audit

    NARCIS (Netherlands)

    van Rijssen, L. Bengt; Koerkamp, Bas G.; Zwart, Maurice J.; Bonsing, Bert A.; Bosscha, Koop; van Dam, Ronald M.; van Eijck, Casper H.; Gerhards, Michael F.; van der Harst, Erwin; de Hingh, Ignace H.; de Jong, Koert P.; Kazemier, Geert; Klaase, Joost; van Laarhoven, Cornelis J.; Molenaar, I. Quintus; Patijn, Gijs A.; Rupert, Coen G.; van Santvoort, Hjalmar C.; Scheepers, Joris J.; van der Schelling, George P.; Busch, Olivier R.; Besselink, Marc G.; Bollen, Thomas L.; Bruno, Marco J.; van Tienhoven, Geert-Jan; Norduyn, Arnold; Berry, David P.; Tingstedt, Bobby; Tseng, Jennifer F.; Wolfgang, Christopher L.

    2017-01-01

    Background: Auditing is an important tool to identify practice variation and 'best practices'. The Dutch Pancreatic Cancer Audit is mandatory in all 18 Dutch centers for pancreatic surgery. Methods: Performance indicators and case-mix factors were identified by a PubMed search for randomized

  16. Targeted therapies for cancer

    Science.gov (United States)

    ... Kummar S, Murgo AJ, Tomaszewski JE, Doroshow JH. Therapeutic targeting of cancer cells: era of molecularly targeted agents. ... ADAM Health Solutions. About MedlinePlus Site Map FAQs Customer Support Get email updates Subscribe to RSS Follow ...

  17. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia.

    Science.gov (United States)

    Shukla, Surendra K; Gebregiworgis, Teklab; Purohit, Vinee; Chaika, Nina V; Gunda, Venugopal; Radhakrishnan, Prakash; Mehla, Kamiya; Pipinos, Iraklis I; Powers, Robert; Yu, Fang; Singh, Pankaj K

    2014-01-01

    Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in view the significant role of metabolic alterations in cancer, we hypothesized that a ketogenic diet may diminish glycolytic flux in tumor cells to alleviate cachexia syndrome and, hence, may provide an efficient therapeutic strategy. We observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. A decrease in levels of c-Myc, a metabolic master regulator, and its recruitment on glycolytic gene promoters, was in part responsible for the metabolic phenotype in tumor cells. Ketone body-induced intracellular metabolomic reprogramming in pancreatic cancer cells also leads to a significantly diminished cachexia in cell line models. Our mouse orthotopic xenograft models further confirmed the effect of a ketogenic diet in diminishing tumor growth and cachexia. Thus, our studies demonstrate that the cachectic phenotype is in part due to metabolic alterations in tumor cells, which can be reverted by a ketogenic diet, causing reduced tumor growth and inhibition of muscle and body weight loss.

  18. Salivary MicroRNA in Pancreatic Cancer Patients.

    Science.gov (United States)

    Humeau, Marine; Vignolle-Vidoni, Alix; Sicard, Flavie; Martins, Frédéric; Bournet, Barbara; Buscail, Louis; Torrisani, Jérôme; Cordelier, Pierre

    2015-01-01

    Pancreatic cancer is the fourth leading cause of cancer death in Western countries, with the lowest 1-year survival rate among commonly diagnosed cancers. Reliable biomarkers for pancreatic cancer diagnosis are lacking and are urgently needed to allow for curative surgery. As microRNA (miRNA) recently emerged as candidate biomarkers for this disease, we explored in the present pilot study the differences in salivary microRNA profiles between patients with pancreatic tumors that are not eligible for surgery, precancerous lesions, inflammatory disease or cancer-free patients as a potential early diagnostic tool. Whole saliva samples from patients with pancreatic cancer (n = 7), pancreatitis (n = 4), IPMN (n = 2), or healthy controls (n = 4) were obtained during endoscopic examination. After total RNA isolation, expression of 94 candidate miRNAs was screened by q(RT)PCR using Biomark Fluidgm. Human-derived pancreatic cancer cells were xenografted in athymic mice as an experimental model of pancreatic cancer. We identified hsa-miR-21, hsa-miR-23a, hsa-miR-23b and miR-29c as being significantly upregulated in saliva of pancreatic cancer patients compared to control, showing sensitivities of 71.4%, 85.7%, 85,7% and 57%, respectively and excellent specificity (100%). Interestingly, hsa-miR-23a and hsa-miR23b are overexpressed in the saliva of patients with pancreatic cancer precursor lesions. We found that hsa-miR-210 and let-7c are overexpressed in the saliva of patients with pancreatitis as compared to the control group, with sensitivity of 100% and 75%, and specificity of 100% and 80%, respectively. Last hsa-miR-216 was upregulated in cancer patients as compared to patients diagnosed with pancreatitis, with sensitivity of 50% and specificity of 100%. In experimental models of PDAC, salivary microRNA detection precedes systemic detection of cancer cells markers. Our novel findings indicate that salivary miRNA are discriminatory in pancreatic cancer patients that are not

  19. Pancreatic cancer in an 18-year-old boy | Kitara | African Health ...

    African Journals Online (AJOL)

    ... well differentiated adenocarcinona of the body and tail of the pancreas. This highlights the differentiation of pancreatic cancer from autoimmune pancreatitis and, to a lesser extent, other forms of pancreatitis and benign pancreatic lesions. Keywords: Pancreatic cancer, laparotomy, distal pancreatectomy, ultrasonography.

  20. Vitamin D metabolic pathway genes and pancreatic cancer risk.

    Directory of Open Access Journals (Sweden)

    Hannah Arem

    Full Text Available Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN totaling 213 single nucleotide polymorphisms (SNPs, and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L for the most significant SNPs using a subset of cohort cases (n = 713 and controls (n = 878. The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830. Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186, LRP2 (rs4668123, CYP24A1 (rs2762932, GC (rs2282679, and CUBN (rs1810205 genes were the top SNPs associated with pancreatic cancer (p-values 0.008-0.037, but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.

  1. Preliminary study of pancreatic cancer associated with Helicobacter pylori infection.

    Science.gov (United States)

    Ai, Fulu; Hua, Xiangdong; Liu, Yefu; Lin, Jie; Feng, Zhaoqiang

    2015-01-01

    Little is known about the relationship about Helicobacter pylori (H. pylori) infection and pancreatic, and this study was set to investigate how H. pylori infection is correlated with pancreatic cancer and provide references for the clinical prevention and treatment of pancreatic cancer. 56 cases of pancreatic cancer patients admitted to the hospital from August 2012 to August 2013 were collected as the observation group. The anti-Hp IgG (H. pylori-specific antibodies), Hp IgM (H. pylori antibodies), and CagA-Hp-IgG (H. pylori serotoxin-associated protein a antibody) in the serum were measured and compared with the related indicators of control group (60 cases of healthy subjects). The H. pylori infection rate was 64.29% in the observation group, and that in the control group was 46.67%. Our results showed that the H. pylori infection rate in the observation group was significantly higher than that in the control group, which was statistically different (P pylori infection in patients with pancreatic cancer was also positively correlated with the smoking history and the history of chronic pancreatitis (P Helicobacter pylori infection is one of the risk factors for pancreatic cancer, and the patients with positive CagA-Hp have the higher risk, so the prevention and treatment of H. pylori infection would be beneficial for the prevention and treatment of pancreatic cancer.

  2. Key players in pancreatic cancer-stroma interaction

    DEFF Research Database (Denmark)

    Nielsen, Michael Friberg Bruun; Mortensen, Michael Bau; Detlefsen, Sönke

    2016-01-01

    Pancreatic cancer (PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction...... surrounding the cancer cells. Cancer-associated fibroblasts (CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim...

  3. Pentoxifylline Treatment in Acute Pancreatitis (AP)

    Science.gov (United States)

    2018-02-21

    Acute Pancreatitis (AP); Gallstone Pancreatitis; Alcoholic Pancreatitis; Post-ERCP/Post-procedural Pancreatitis; Trauma Acute Pancreatitis; Hypertriglyceridemia Acute Pancreatitis; Idiopathic (Unknown) Acute Pancreatitis; Medication Induced Acute Pancreatitis; Cancer Acute Pancreatitis; Miscellaneous (i.e. Acute on Chronic Pancreatitis)

  4. Ski modulate the characteristics of pancreatic cancer stem cells via regulating sonic hedgehog signaling pathway.

    Science.gov (United States)

    Song, Libin; Chen, Xiangyuan; Gao, Song; Zhang, Chenyue; Qu, Chao; Wang, Peng; Liu, Luming

    2016-10-12

    Evidence from in vitro and in vivo studies shows that Ski may act as both a tumor proliferation-promoting factor and a metastatic suppressor in human pancreatic cancer and also may be a therapeutic target of integrative therapies. At present, pancreatic cancer stem cells (CSCs) are responsible for tumor recurrence accompanied by resistance to conventional therapies. Sonic hedgehog (Shh) signaling pathway is found to be aberrantly activated in CSCs. The objectives of this study were to investigate the role of Ski in modulating pancreatic CSCs and to examine the molecular mechanisms involved in pancreatic cancer treatment both in vivo and in vitro. In in vitro study, the results showed that enhanced Ski expression could increase the expression of pluripotency maintaining markers, such as CD24, CD44, Sox-2, and Oct-4, and also components of Shh signaling pathway, such as Shh, Ptch-1, Smo, Gli-1, and Gli-2, whereas depletion of Ski to the contrary. Then, we investigated the underlying mechanism and found that inhibiting Gli-2 expression by short interfering RNA (siRNA) can decrease the effects of Ski on the maintenance of pancreatic CSCs, indicating that Ski mediates the pluripotency of pancreatic CSCs mainly through Shh pathway. The conclusion is that Ski may be an important factor in maintaining the stemness of pancreatic CSCs through modulating Shh pathway.

  5. Systemic immune dysfunction in pancreatic cancer patients.

    Science.gov (United States)

    Poch, Bertram; Lotspeich, Errki; Ramadani, Marco; Gansauge, Susanne; Beger, Hans G; Gansauge, Frank

    2007-05-01

    We investigated the immune status in 32 pancreatic cancer patients (PC) in comparison with healthy controls (HC). Using flow cytometry, peripheral blood lymphocytes (PBL) were characterized by the expression of surface markers for T helper cells (CD4), T suppressor cells (CD8), B cells (CD19) and NK cells (CD56). The blastogenic response of PBL was analyzed after stimulation with concavalin A (ConA), phytohemagglutinin (PHA), pokeweed mitogen (PWM) and anti-CD3 antibodies. The serum levels of TNF-alpha, IL-1beta, IL-2, IL-10, IL-12, IL-18, IL-1RA, sIL-2R and TGF-beta were determined by ELISA. No differences in the distribution of peripheral immunocytes in PC were found, whereas the blastogenic response of peripheral blood lymphocytes (PBL) after stimulation with PHA or anti-CD3 antibodies was significantly decreased in PC. In PC, we found reduced serum levels of IL-2 and significantly elevated levels of TNF-alpha, TGF-beta1, IL-10, IL-2R, IL-1beta and IL-1RA. These data provide evidence for a systemic immune dysfunction in pancreatic cancer patients characterized by a shift towards a T helper cell type 2 cytokine profile, a significant elevation of substances related to T cell suppression and a reduced blastogenic response to PHA and anti-CD3 antibodies of PBL.

  6. Multimodal treatment for unresectable pancreatic cancer

    International Nuclear Information System (INIS)

    Katayama, Kanji; Iida, Atsushi; Fujita, Takashi; Kobayashi, Taizo; Shinmoto, Syuichi; Hirose, Kazuo; Yamaguchi, Akio; Yoshida, Masanori

    1998-01-01

    In order to improve in prognosis and quality of life (QOL), the multimodal treatment for unresectable pancreatic cancers were performed. Bypass surgery was carried out for unresectable pancreatic cancer with intraoperative irradiation (IOR). After surgery, patients were treated with the combination of CDDP (25 mg) and MMC (4 mg) administration, intravenously continuous injection of 5-FU (250 mg for 24 hours), external radiation by the high voltage X-ray (1.5 Gy per irradiation, 4 times a week, and during hyperthermia 3 Gy per irradiation) and hyperthermia using the Thermotron RF-8 warmer. Six out of 13 patients received hyperthermia at over 40degC, were obtained PR, and their survival periods were 22, 21, 19, 18, 11 and 8 months and they could return to work. For all patients with pain, the symptom was abolished or reduced. The survival periods in cases of the multimodal treatment were longer than those of only bypass-surgery or of the resective cases with the curability C. The multimodal treatment combined with radiation, hyperthermia and surgery is more useful for the removal of pain and the improvement of QOL, and also expected the improvement of the prognosis than pancreatectomy. And hyperthermia has an important role on the effect of this treatment. (K.H.)

  7. Multimodal treatment for unresectable pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Katayama, Kanji; Iida, Atsushi; Fujita, Takashi; Kobayashi, Taizo; Shinmoto, Syuichi; Hirose, Kazuo; Yamaguchi, Akio; Yoshida, Masanori [Fukui Medical School, Matsuoka (Japan)

    1998-07-01

    In order to improve in prognosis and quality of life (QOL), the multimodal treatment for unresectable pancreatic cancers were performed. Bypass surgery was carried out for unresectable pancreatic cancer with intraoperative irradiation (IOR). After surgery, patients were treated with the combination of CDDP (25 mg) and MMC (4 mg) administration, intravenously continuous injection of 5-FU (250 mg for 24 hours), external radiation by the high voltage X-ray (1.5 Gy per irradiation, 4 times a week, and during hyperthermia 3 Gy per irradiation) and hyperthermia using the Thermotron RF-8 warmer. Six out of 13 patients received hyperthermia at over 40degC, were obtained PR, and their survival periods were 22, 21, 19, 18, 11 and 8 months and they could return to work. For all patients with pain, the symptom was abolished or reduced. The survival periods in cases of the multimodal treatment were longer than those of only bypass-surgery or of the resective cases with the curability C. The multimodal treatment combined with radiation, hyperthermia and surgery is more useful for the removal of pain and the improvement of QOL, and also expected the improvement of the prognosis than pancreatectomy. And hyperthermia has an important role on the effect of this treatment. (K.H.)

  8. Occupational exposures and risk of pancreatic cancer

    International Nuclear Information System (INIS)

    Santibanez, Miguel; Vioque, Jesus; Alguacil, Juan; Hera, Manuela Garcia de la; Moreno-Osset, Eduardo; Carrato, Alfredo; Porta, Miquel; Kauppinen, Timo

    2010-01-01

    The objective was to analyze the relationship between occupation (and specific occupational exposures) and risk of exocrine pancreatic cancer (EPC). We conducted a multicenter hospital-based case-control study in Eastern Spain. We included 161 incident cases of EPC (59.6% men, 94 with histological confirmation, of whom 80% had ductal adenocarcinoma). Cases were frequency-matched with 455 controls by sex, age and province of residence. Information was elicited using structured questionnaires. Occupations were coded according to the Spanish version of the International Standard Classification of Occupations 1988. Occupational exposure to a selection of carcinogenic substances was assessed with the Finnish Job-Exposure Matrix (FINJEM). Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multiple logistic regression, adjusting for sex, age, province, education, alcohol and smoking. A higher risk of EPC was associated with having worked as 'Miners, shotfirers, stone cutters and carvers', 'Machinery mechanics and fitters', 'Building trades workers' and 'Motor vehicle drivers' in men, 'Office Clerks' in women, and 'Waiters' in both sexes. Cases with ductal adenocarcinomas were more likely to have been exposed to chlorinated hydrocarbon solvents (OR = 4.1, 95% CI: 1.1-15.2, p-trend = 0.04). We also observed significant associations with exposure to 'synthetic polymer dust exposure' and 'ionizing radiation'. Suggestive increases in risk were observed for 'pesticides', 'diesel and gasoline engine exhaust', and 'hydrocarbon solvents'. Results support the hypothesis that occupational exposure to chlorinated hydrocarbon solvents is associated with exocrine pancreatic cancer.

  9. Recruitment and activation of pancreatic stellate cells from the bone marrow in pancreatic cancer: a model of tumor-host interaction.

    Directory of Open Access Journals (Sweden)

    Christopher J Scarlett

    Full Text Available BACKGROUND AND AIMS: Chronic pancreatitis and pancreatic cancer are characterised by extensive stellate cell mediated fibrosis, and current therapeutic development includes targeting pancreatic cancer stroma and tumor-host interactions. Recent evidence has suggested that circulating bone marrow derived stem cells (BMDC contribute to solid organs. We aimed to define the role of circulating haematopoietic cells in the normal and diseased pancreas. METHODS: Whole bone marrow was harvested from male β-actin-EGFP donor mice and transplanted into irradiated female recipient C57/BL6 mice. Chronic pancreatitis was induced with repeat injections of caerulein, while carcinogenesis was induced with an intrapancreatic injection of dimethylbenzanthracene (DMBA. Phenotype of engrafted donor-derived cells within the pancreas was assessed by immunohistochemistry, immunofluorescence and in situ hybridisation. RESULTS: GFP positive cells were visible in the exocrine pancreatic epithelia from 3 months post transplantation. These exhibited acinar morphology and were positive for amylase and peanut agglutinin. Mice administered caerulein developed chronic pancreatitis while DMBA mice exhibited precursor lesions and pancreatic cancer. No acinar cells were identified to be donor-derived upon cessation of cerulein treatment, however rare occurrences of bone marrow-derived acinar cells were observed during pancreatic regeneration. Increased recruitment of BMDC was observed within the desmoplastic stroma, contributing to the activated pancreatic stellate cell (PaSC population in both diseases. Expression of stellate cell markers CELSR3, PBX1 and GFAP was observed in BMD cancer-associated PaSCs, however cancer-associated, but not pancreatitis-associated BMD PaSCs, expressed the cancer PaSC specific marker CELSR3. CONCLUSIONS: This study demonstrates that BMDC can incorporate into the pancreas and adopt the differentiated state of the exocrine compartment. BMDC that

  10. Molecular Endoscopic Ultrasound for Diagnosis of Pancreatic Cancer

    International Nuclear Information System (INIS)

    Bournet, Barbara; Pointreau, Adeline; Delpu, Yannick; Selves, Janick; Torrisani, Jerome; Buscail, Louis; Cordelier, Pierre

    2011-01-01

    Endoscopic ultrasound-guided fine needle aspiration-biopsy is a safe and effective technique in diagnosing and staging of pancreatic ductal adenocarcinoma. However its predictive negative value does not exceed 50% to 60%. Unfortunately, the majority of pancreatic cancer patients have a metastatic and/or a locally advanced disease (i.e., not eligible for curative resection) which explains the limited access to pancreatic tissue specimens. Endoscopic ultrasound-guided fine needle aspiration-biopsy is the most widely used approach for cytological and histological material sampling in these situations used in up to two thirds of patients with pancreatic cancer. Based on this unique material, we and others developed strategies to improve the differential diagnosis between carcinoma and inflammatory pancreatic lesions by analysis of KRAS oncogene mutation, microRNA expression and methylation, as well as mRNA expression using both qRT-PCR and Low Density Array Taqman analysis. Indeed, differentiating pancreatic cancer from pseudotumoral chronic pancreatitis remains very difficult in current clinical practice, and endoscopic ultrasound-guided fine needle aspiration-biopsy analysis proved to be very helpful. In this review, we will compile the clinical and molecular advantages of using endoscopic ultrasound-guided fine needle aspiration-biopsy in managing pancreatic cancer

  11. Molecular Endoscopic Ultrasound for Diagnosis of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bournet, Barbara [Department of Gastroenterology, University Hospital Center Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9 (France); INSERM U1037, University Hospital Center Rangueil, Toulouse (France); Pointreau, Adeline; Delpu, Yannick; Selves, Janick; Torrisani, Jerome [INSERM U1037, University Hospital Center Rangueil, Toulouse (France); Buscail, Louis, E-mail: buscail.l@chu-toulouse.fr [Department of Gastroenterology, University Hospital Center Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9 (France); INSERM U1037, University Hospital Center Rangueil, Toulouse (France); Cordelier, Pierre [INSERM U1037, University Hospital Center Rangueil, Toulouse (France)

    2011-02-24

    Endoscopic ultrasound-guided fine needle aspiration-biopsy is a safe and effective technique in diagnosing and staging of pancreatic ductal adenocarcinoma. However its predictive negative value does not exceed 50% to 60%. Unfortunately, the majority of pancreatic cancer patients have a metastatic and/or a locally advanced disease (i.e., not eligible for curative resection) which explains the limited access to pancreatic tissue specimens. Endoscopic ultrasound-guided fine needle aspiration-biopsy is the most widely used approach for cytological and histological material sampling in these situations used in up to two thirds of patients with pancreatic cancer. Based on this unique material, we and others developed strategies to improve the differential diagnosis between carcinoma and inflammatory pancreatic lesions by analysis of KRAS oncogene mutation, microRNA expression and methylation, as well as mRNA expression using both qRT-PCR and Low Density Array Taqman analysis. Indeed, differentiating pancreatic cancer from pseudotumoral chronic pancreatitis remains very difficult in current clinical practice, and endoscopic ultrasound-guided fine needle aspiration-biopsy analysis proved to be very helpful. In this review, we will compile the clinical and molecular advantages of using endoscopic ultrasound-guided fine needle aspiration-biopsy in managing pancreatic cancer.

  12. Pancreatic Cancer, A Mis-interpreter of the Epigenetic Language.

    Science.gov (United States)

    Iguchi, Eriko; Safgren, Stephanie L; Marks, David L; Olson, Rachel L; Fernandez-Zapico, Martin E

    2016-12-01

    Pancreatic cancer is the third leading cause of cancer mortality in the U.S. with close to 40,000 deaths per year. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90 percent of all pancreatic cancer cases and is the most lethal form of the disease. Current therapies for PDAC are ineffective and most patients cannot be treated by surgical resection. Most research efforts have primarily focused on how genetic alterations cause, alter progression, contribute to diagnosis, and influence PDAC management. Over the past two decades, a model has been advanced of PDAC initiation and progression as a multi-step process driven by the acquisition of mutations leading to loss of tumor suppressors and activation of oncogenes. The recognition of the essential roles of these genetic alterations in the development of PDAC has revolutionized our knowledge of this disease. However, none of these findings have turned into effective treatment for this dismal malignancy. In recent years, studies in the areas of chromatin modifications, and non-coding RNAs have uncovered mechanisms for regulating gene expression which occur independently of genetic alterations. Chromatin-based mechanisms are interwoven with microRNA-driven regulation of protein translation to create an integrated epigenetic language, which is grossly dysregulated in PDAC. Thus in PDAC, key tumor suppressors that are well established to play a role in PDAC may be repressed, and oncogenes can be upregulated secondary to epigenetic alterations. Unlike mutations, epigenetic changes are potentially reversible. Given this feature of epigenetic mechanisms, it is conceivable that targeting epigenetic-based events promoting and maintaining PDAC could serve as foundation for the development of new therapeutic and diagnostic approaches for this disease.

  13. Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells

    Science.gov (United States)

    Okumura, Takashi; Ohuchida, Kenoki; Sada, Masafumi; Abe, Toshiya; Endo, Sho; Koikawa, Kazuhiro; Iwamoto, Chika; Miura, Daisuke; Mizuuchi, Yusuke; Moriyama, Taiki; Nakata, Kohei; Miyasaka, Yoshihiro; Manabe, Tatsuya; Ohtsuka, Takao; Nagai, Eishi; Mizumoto, Kazuhiro; Oda, Yoshinao; Hashizume, Makoto; Nakamura, Masafumi

    2017-01-01

    Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells. PMID:28407685

  14. mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions

    OpenAIRE

    Matsubara, Shyuichiro; Ding, Qiang; Miyazaki, Yumi; Kuwahata, Taisaku; Tsukasa, Koichiro; Takao, Sonshin

    2013-01-01

    "Pancreatic cancer is characterized by near-universal mutations in KRAS. The mammalian target of rapamycin (mTOR), which functions downstream of RAS, has divergent effects on stem cells. In the present study, we investigated the significance of the mTOR pathway in maintaining the properties of pancreatic cancer stem cells. The mTOR inhibitor, rapamycin, reduced the viability of CD133+ pancreatic cancer cells and sphere formation which is an index of self-renewal of stem-like cells, indicating...

  15. PCA-1/ALKBH3 contributes to pancreatic cancer by supporting apoptotic resistance and angiogenesis.

    Science.gov (United States)

    Yamato, Ichiro; Sho, Masayuki; Shimada, Keiji; Hotta, Kiyohiko; Ueda, Yuko; Yasuda, Satoshi; Shigi, Naoko; Konishi, Noboru; Tsujikawa, Kazutake; Nakajima, Yoshiyuki

    2012-09-15

    The PCA-1/ALKBH3 gene implicated in DNA repair is expressed in several human malignancies but its precise contributions to cancer remain mainly unknown. In this study, we have determined its functions and clinical importance in pancreatic cancer. PCA-1/ALKBH3 functions in proliferation, apoptosis and angiogenesis were evaluated in human pancreatic cancer cells in vitro and in vivo. Further, PCA-1/ALKBH3 expression in 116 patients with pancreatic cancer was evaluated by immunohistochemistry. siRNA-mediated silencing of PCA-1/ALKBH3 expression induced apoptosis and suppressed cell proliferation. Conversely, overexpression of PCA-1/ALKBH3 increased anchorage-independent growth and invasiveness. In addition, PCA-1/ALKBH3 silencing downregulated VEGF expression and inhibited angiogenesis in vivo. Furthermore, immunohistochemical analysis showed that PCA-1/ALKBH3 expression was abundant in pancreatic cancer tissues, where it correlated with advanced tumor status, pathological stage and VEGF intensity. Importantly, patients with low positivity of PCA-1/ALKBH3 expression had improved postoperative prognosis compared with those with high positivity. Our results establish PCA-1/ALKBH3 as important gene in pancreatic cancer with potential utility as a therapeutic target in this fatal disease.

  16. Characterization of the salivary microbiome in patients with pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Pedro J. Torres

    2015-11-01

    Full Text Available Clinical manifestations of pancreatic cancer often do not occur until the cancer has undergone metastasis, resulting in a very low survival rate. In this study, we investigated whether salivary bacterial profiles might provide useful biomarkers for early detection of pancreatic cancer. Using high-throughput sequencing of bacterial small subunit ribosomal RNA (16S rRNA gene, we characterized the salivary microbiota of patients with pancreatic cancer and compared them to healthy patients and patients with other diseases, including pancreatic disease, non-pancreatic digestive disease/cancer and non-digestive disease/cancer. A total of 146 patients were enrolled at the UCSD Moores Cancer Center where saliva and demographic data were collected from each patient. Of these, we analyzed the salivary microbiome of 108 patients: 8 had been diagnosed with pancreatic cancer, 78 with other diseases and 22 were classified as non-diseased (healthy controls. Bacterial 16S rRNA sequences were amplified directly from salivary DNA extractions and subjected to high-throughput sequencing (HTS. Several bacterial genera differed in abundance in patients with pancreatic cancer. We found a significantly higher ratio of Leptotrichia to Porphyromonas in the saliva of patients with pancreatic cancer than in the saliva of healthy patients or those with other disease (Kruskal–Wallis Test; P < 0.001. Leptotrichia abundances were confirmed using real-time qPCR with Leptotrichia specific primers. Similar to previous studies, we found lower relative abundances of Neisseria and Aggregatibacter in the saliva of pancreatic cancer patients, though these results were not significant at the P < 0.05 level (K–W Test; P = 0.07 and P = 0.09 respectively. However, the relative abundances of other previously identified bacterial biomarkers, e.g., Streptococcus mitis and Granulicatella adiacens, were not significantly different in the saliva of pancreatic cancer patients. Overall, this

  17. Preoperative biliary drainage for pancreatic cancer.

    Science.gov (United States)

    Van Heek, N T; Busch, O R; Van Gulik, T M; Gouma, D J

    2014-04-01

    This review is to summarize the current knowledge about preoperative biliary drainage (PBD) in patients with biliary obstruction caused by pancreatic cancer. Most patients with pancreatic carcinoma (85%) will present with obstructive jaundice. The presence of toxic substances as bilirubin and bile salts, impaired liver function and altered nutritional status due to obstructive jaundice have been characterized as factors for development of complications after surgery. Whereas PBD was to yield beneficial effects in the experimental setting, conflicting results have been observed in clinical studies. The meta-analysis from relative older studies as well as more importantly a recent clinical trial showed that PBD should not be performed routinely. PBD for patients with a distal biliary obstruction is leading to more serious complications compared with early surgery. Arguments for PBD have shifted from a potential therapeutic benefit towards a logistic problem such as patients suffering from cholangitis and severe jaundice at admission or patients who need extra diagnostic tests, or delay in surgery due to a referral pattern or waiting list for surgery as well as candidates for neoadjuvant chemo(radio)therapy. If drainage is indicated in these patients it should be performed with a metal stent to reduce complications after the drainage procedure such as stent occlusion and cholangitis. Considering a change towards more neoadjuvant therapy regimes improvement of the quality of the biliary drainage concept is still important.

  18. Dietary patterns and risk of pancreatic cancer: a systematic review.

    Science.gov (United States)

    Zheng, Jiali; Guinter, Mark A; Merchant, Anwar T; Wirth, Michael D; Zhang, Jiajia; Stolzenberg-Solomon, Rachael Z; Steck, Susan E

    2017-11-01

    Pancreatic cancer has the highest case fatality rate of all major cancers. A systematic review using PRISMA guidelines was conducted to summarize the associations between dietary patterns and risk of pancreatic cancer. PubMed and Web of Science databases were searched for case-control and cohort studies published up to June 15, 2016. Eligible studies included a dietary pattern as exposure and pancreatic cancer incidence or mortality as outcome and reported odds ratios, hazard ratios, or relative risks, along with corresponding 95%CIs. Important characteristics of each study, along with the dietary assessment instrument, the component foods or nutrients included in each dietary pattern or the scoring algorithm of a priori dietary patterns, were presented. For each dietary pattern identified, the estimate of association and the 95%CI comparing the highest versus the lowest category from the model with the most covariate adjustment were reported. A total of 16 studies were identified. Among the 8 studies that examined data-driven dietary patterns, significant positive associations were found between pancreatic cancer risk and the Animal Products, Starch Rich, and Western dietary patterns, with effect estimates ranging from 1.69 to 2.40. Significant inverse relationships were found between risk of pancreatic cancer and dietary patterns designated as Fruits and Vegetables, Vitamins and Fiber, and Prudent, with effect estimates ranging from 0.51 to 0.55. Eight studies of a priori dietary patterns consistently suggested that improved dietary quality was associated with reduced risk of pancreatic cancer. Better diet quality is associated with reduced risk of pancreatic cancer. The associations between dietary patterns and pancreatic cancer were stronger in case-control studies than in cohort studies and were stronger among men than among women. © The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights

  19. Cancer Stem Cells, EMT, and Developmental Pathway Activation in Pancreatic Tumors

    International Nuclear Information System (INIS)

    Hindriksen, Sanne; Bijlsma, Maarten F.

    2012-01-01

    Pancreatic cancer is a disease with remarkably poor patient survival rates. The frequent presence of metastases and profound chemoresistance pose a severe problem for the treatment of these tumors. Moreover, cross-talk between the tumor and the local micro-environment contributes to tumorigenicity, metastasis and chemoresistance. Compared to bulk tumor cells, cancer stem cells (CSC) have reduced sensitivity to chemotherapy. CSC are tumor cells with stem-like features that possess the ability to self-renew, but can also give rise to more differentiated progeny. CSC can be identified based on increased in vitro spheroid- or colony formation, enhanced in vivo tumor initiating potential, or expression of cell surface markers. Since CSC are thought to be required for the maintenance of a tumor cell population, these cells could possibly serve as a therapeutic target. There appears to be a causal relationship between CSC and epithelial-to-mesenchymal transition (EMT) in pancreatic tumors. The occurrence of EMT in pancreatic cancer cells is often accompanied by re-activation of developmental pathways, such as the Hedgehog, WNT, NOTCH, and Nodal/Activin pathways. Therapeutics based on CSC markers, EMT, developmental pathways, or tumor micro-environment could potentially be used to target pancreatic CSC. This may lead to a reduction of tumor growth, metastatic events, and chemoresistance in pancreatic cancer

  20. Embelin suppresses growth of human pancreatic cancer xenografts, and pancreatic cancer cells isolated from KrasG12D mice by inhibiting Akt and Sonic hedgehog pathways.

    Directory of Open Access Journals (Sweden)

    Minzhao Huang

    Full Text Available Pancreatic cancer is a deadly disease, and therefore effective treatment and/or prevention strategies are urgently needed. The objectives of this study were to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer cell growth in vitro, and xenografts in Balb C nude mice, and pancreatic cancer cell growth isolated from KrasG12D transgenic mice. XTT assays were performed to measure cell viability. AsPC-1 cells were injected subcutaneously into Balb c nude mice and treated with embelin. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of Akt, and Sonic Hedgehog (Shh and their target gene products were measured by the immunohistochemistry, and Western blot analysis. The effects of embelin on pancreatic cancer cells isolated from 10-months old KrasG12D mice were also examined. Embelin inhibited cell viability in pancreatic cancer AsPC-1, PANC-1, MIA PaCa-2 and Hs 766T cell lines, and these inhibitory effects were blocked either by constitutively active Akt or Shh protein. Embelin-treated mice showed significant inhibition in tumor growth which was associated with reduced expression of markers of cell proliferation (Ki67, PCNA and Bcl-2 and cell cycle (cyclin D1, CDK2, and CDK6, and induction of apoptosis (activation of caspase-3 and cleavage of PARP, and increased expression of Bax. In addition, embelin inhibited the expression of markers of angiogenesis (COX-2, VEGF, VEGFR, and IL-8, and metastasis (MMP-2 and MMP-9 in tumor tissues. Antitumor activity of embelin was associated with inhibition of Akt and Shh pathways in xenografts, and pancreatic cancer cells isolated from KrasG12D mice. Furthermore, embelin also inhibited epithelial-to-mesenchymal transition (EMT by up-regulating E-cadherin and inhibiting the expression of Snail, Slug, and ZEB1. These data suggest that embelin can inhibit pancreatic cancer growth, angiogenesis and metastasis by suppressing Akt and

  1. Surgical management of malignant bowel obstruction in recurrent pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Hyung Sun Kim

    2017-01-01

    Discussion and conclusion: Palliative surgery improves quality of life in recurrent pancreatic cancer patients and can continue patient’s palliative management. In selected patients, palliative surgery may effective management for progress of survival and quality of life.

  2. Malignant Gastric Outlet Obstruction from Pancreatic Cancer.

    Science.gov (United States)

    McGrath, Clare; Tsang, Adrian; Nithianandan, Harrish; Nguyen, Eric; Bauer, Patrick; Dennis, Kristopher

    2017-01-01

    Patients with advanced-stage pancreatic cancer are typically burdened by many symptoms that impair functioning and worsen quality of life. We report an exceptional case of a 73-year-old woman with T4N1M0 adenocarcinoma of the uncinate process of the pancreas who developed significant gastric outlet obstruction - an uncommon yet potentially life-threatening complication of disease progression. She developed progressive abdominal pain and emesis, and profound dilatation of her stomach was detected on a radiation therapy simulation CT scan that required urgent decompression. Malignant gastric outlet obstruction must be included in the differential diagnosis when patients with known advanced disease of the pancreas present with obstructive upper gastrointestinal symptoms.

  3. Surgery for oligometastasis of pancreatic cancer.

    Science.gov (United States)

    Lu, Fengchun; Poruk, Katherine E; Weiss, Matthew J

    2015-08-01

    The incidence of pancreatic adenocarcinoma (PDAC) has steadily increased over the past several decades. The majority of PDAC patients will present with distant metastases, limiting surgical management in this population. Hepatectomy and pulmonary metastasectomy (PM) has been well established for colorectal cancer patients with isolated, resectable hepatic or pulmonary metastatic disease. Recent advancements in effective systemic therapy for PDAC have led to the selection of certain patients where metastectomy may be potentially indicated. However, the indication for resection of oligometastases in PDAC is not well defined. This review will discuss the current literature on the surgical management of metastatic disease for PDAC with a specific focus on surgical resection for isolated hepatic and pulmonary metastases.

  4. Association between pancreatitis and subsequent risk of pancreatic cancer: a systematic review of epidemiological studies.

    Science.gov (United States)

    Tong, Gui-Xian; Geng, Qing-Qing; Chai, Jing; Cheng, Jing; Chen, Peng-Lai; Liang, Han; Shen, Xing-Rong; Wang, De-Bin

    2014-01-01

    This study aimed to summarize published epidemiological evidence for the relationship between pancreatitis and subsequent risk of pancreatic cancer (PC). We searched Medline and Embase for epidemiological studies published by February 5th, 2014 examining the risk of PC in pancreatitis patients using highly inclusive algorithms. Information about first author, year of publication, country of study, recruitment period, type of pancreatitis, study design, sample size, source of controls and attained age of subjects were extracted by two researchers and Stata 11.0 was used to perform the statistical analyses and examine publication bias. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with the random effects model. A total of 17 articles documenting 3 cohort and 14 case-control studies containing 14,667 PC cases and 17,587 pancreatitis cases were included in this study. The pooled OR between pancreatitis and PC risk was 7.05 (95%CI: 6.42-7.75). However, the pooled ORs of case-control and cohort studies were 4.62 (95%CI: 4.08-5.22) and 16.3 (95%CI: 14.3-18.6) respectively. The risk of PC was the highest in patients with chronic pancreatitis (pooled OR=10.35; 95%CI: 9.13-11.75), followed by unspecified type of pancreatitis (pooled OR=6.41; 95%CI: 4.93-8.34), both acute and chronic pancreatitis (pooled OR=6.13; 95%CI: 5.00-7.52), and acute pancreatitis (pooled OR=2.12; 95%CI: 1.59-2.83). The pooled OR of PC in pancreatitis cases diagnosed within 1 year was the highest (pooled OR=23.3; 95%CI: 14.0-38.9); and the risk in subjects diagnosed with pancreatitis for no less than 2, 5 and 10 years were 3.03 (95%CI: 2.41-3.81), 2.82 (95%CI: 2.12-3.76) and 2.25 (95%CI: 1.59-3.19) respectively. Pancreatitis, especially chronic pancreatitis, was associated with a significantly increased risk of PC; and the risk decreased with increasing duration since diagnosis of pancreatitis.

  5. Resveratrol, a Red Wine Polyphenol, Suppresses Pancreatic Cancer by Inhibiting Leukotriene A4 Hydrolase

    Science.gov (United States)

    Oi, Naomi; Jeong, Chul-Ho; Nadas, Janos; Cho, Yong-Yeon; Pugliese, Angelo; Bode, Ann M.; Dong, Zigang

    2016-01-01

    The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied leukotriene A4 hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol. PMID:20952510

  6. The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Lou, Hai-zhou [Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016 (China); Weng, Xiao-chuan [Department of Anesthesiology, Hangzhou Xia-sha Hospital, Hangzhou 310018 (China); Pan, Hong-ming; Pan, Qin [Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016 (China); Sun, Peng [Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060 (China); Liu, Li-li [Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016 (China); Chen, Bin, E-mail: chenbinhangzhou126@126.com [Department of Hepatopancreatobiliary Surgery, First People’s Hospital of Hangzhou, Hangzhou 310006 (China)

    2014-07-25

    Highlights: • INK-128 inhibits the survival and growth of human pancreatic cancer cells. • INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. • INK-128 blocks mTORC1/2 activation simultaneously in pancreatic cancer cells. • INK-128 down-regulates cyclin D1 and causes pancreatic cancer cell cycle arrest. • INK-128 significantly increases sensitivity of pancreatic cancer cells to gemcitabine. - Abstract: Pancreatic cancer has one of worst prognosis among all human malignancies around the world, the development of novel and more efficient anti-cancer agents against this disease is urgent. In the current study, we tested the potential effect of INK-128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells in vitro. Our results demonstrated that INK-128 concentration- and time-dependently inhibited the survival and growth of pancreatic cancer cells (both primary cells and transformed cells). INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. Further, INK-128 dramatically inhibited phosphorylation of 4E-binding protein 1 (4E-BP1), ribosomal S6 kinase 1 (S6K1) and Akt at Ser 473 in pancreatic cancer cells. Meanwhile, it downregulated cyclin D1 expression and caused cell cycle arrest. Finally, we found that a low concentration of INK-128 significantly increased the sensitivity of pancreatic cancer cells to gemcitabine. Together, our in vitro results suggest that INK-128 might be further investigated as a novel anti-cancer agent or chemo-adjuvant for pancreatic cancer treatment.

  7. The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells

    International Nuclear Information System (INIS)

    Lou, Hai-zhou; Weng, Xiao-chuan; Pan, Hong-ming; Pan, Qin; Sun, Peng; Liu, Li-li; Chen, Bin

    2014-01-01

    Highlights: • INK-128 inhibits the survival and growth of human pancreatic cancer cells. • INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. • INK-128 blocks mTORC1/2 activation simultaneously in pancreatic cancer cells. • INK-128 down-regulates cyclin D1 and causes pancreatic cancer cell cycle arrest. • INK-128 significantly increases sensitivity of pancreatic cancer cells to gemcitabine. - Abstract: Pancreatic cancer has one of worst prognosis among all human malignancies around the world, the development of novel and more efficient anti-cancer agents against this disease is urgent. In the current study, we tested the potential effect of INK-128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells in vitro. Our results demonstrated that INK-128 concentration- and time-dependently inhibited the survival and growth of pancreatic cancer cells (both primary cells and transformed cells). INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. Further, INK-128 dramatically inhibited phosphorylation of 4E-binding protein 1 (4E-BP1), ribosomal S6 kinase 1 (S6K1) and Akt at Ser 473 in pancreatic cancer cells. Meanwhile, it downregulated cyclin D1 expression and caused cell cycle arrest. Finally, we found that a low concentration of INK-128 significantly increased the sensitivity of pancreatic cancer cells to gemcitabine. Together, our in vitro results suggest that INK-128 might be further investigated as a novel anti-cancer agent or chemo-adjuvant for pancreatic cancer treatment

  8. Treatment of Locally Advanced Pancreatic Cancer: The Role of Radiation Therapy

    International Nuclear Information System (INIS)

    Johung, Kimberly; Saif, Muhammad Wasif; Chang, Bryan W.

    2012-01-01

    Pancreatic cancer remains associated with an extremely poor prognosis. Surgical resection can be curative, but the majority of patients present with locally advanced or metastatic disease. Treatment for patients with locally advanced disease is controversial. Therapeutic options include systemic therapy alone, concurrent chemoradiation, or induction chemotherapy followed by chemoradiation. We review the evidence to date regarding the treatment of locally advanced pancreatic cancer (LAPC), as well as evolving strategies including the emerging role of targeted therapies. We propose that if radiation is used for patients with LAPC, it should be delivered with concurrent chemotherapy and following a period of induction chemotherapy.

  9. MicroRNA-29a Promotes Pancreatic Cancer Growth by Inhibiting Tristetraprolin

    Directory of Open Access Journals (Sweden)

    Xian-Jun Sun

    2015-09-01

    Full Text Available Background/Aims: The microRNA (miR 29 family has been studied extensively for its involvement in several diseases, and aberrant expression of its members is associated with tumorigenesis and cancer progression. Here, we examined the role of miR-29a in pancreatic cancer and the involvement of tristetraprolin (TTP. Methods: We monitored miR-29a and TTP expression in pancreatic cancer by qRT-PCR and western blotting. The effect of miR-29a on pancreatic cancer was determined through MTT assay and migration assay. The results were validated in the tumorigenesis model. Results: We found that miR-29a was up regulated in pancreatic tumor tissues and cell lines and positively correlated with metastasis. Ectopic expression of miR-29a increased the expression of pro-inflammatory factors and epithelial-mesenchymal transition (EMT markers, through down regulating TTP. TTP was down regulated in tumor tissues, and its ectopic expression decreased cell viability and migration in vitro, inhibited tumor growth and the EMT phenotype in vivo, and reversed the effect of miR-29a on tumor cell proliferation and invasion in vitro and in vivo. Conclusion: Our results suggest that miR-29a acts as an oncogene by down regulating TTP and provide the basis for further studies exploring the potential of miR-29a and TTP as biomarkers and targets for the treatment of pancreatic cancer.

  10. Transferrin receptor regulates pancreatic cancer growth by modulating mitochondrial respiration and ROS generation

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Seung Min, E-mail: smjeong@catholic.ac.kr [Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Hwang, Sunsook; Seong, Rho Hyun [School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742 (Korea, Republic of)

    2016-03-11

    The transferrin receptor (TfR1) is upregulated in malignant cells and its expression is associated with cancer progression. Because of its pre-eminent role in cell proliferation, TfR1 has been an important target for the development of cancer therapy. Although TfR1 is highly expressed in pancreatic cancers, what it carries out in these refractory cancers remains poorly understood. Here we report that TfR1 supports mitochondrial respiration and ROS production in human pancreatic ductal adenocarcinoma (PDAC) cells, which is required for their tumorigenic growth. Elevated TfR1 expression in PDAC cells contributes to oxidative phosphorylation, which allows for the generation of ROS. Importantly, mitochondrial-derived ROS are essential for PDAC growth. However, exogenous iron supplement cannot rescue the defects caused by TfR1 knockdown. Moreover, we found that TfR1 expression determines PDAC cells sensitivity to oxidative stress. Together, our findings reveal that TfR1 can contribute to the mitochondrial respiration and ROS production, which have essential roles in growth and survival of pancreatic cancer. - Highlights: • Pancreatic ductal adenocarcinoma (PDAC) exhibits an elevated transferrin receptor (TfR1) expression in comparison with non-transformed pancreatic cells. • TfR1 is required for PDAC growth by regulating mitochondrial respiration and ROS production. • TfR1 functions as a determinant of cell viability to oxidative stress in PDAC cells.

  11. Molecular network, pathway, and functional analysis of time-dependent gene changes associated with pancreatic cancer susceptibility to oncolytic vaccinia virotherapy

    Directory of Open Access Journals (Sweden)

    Dana Haddad

    2016-01-01

    Conclusions: Our study reveals the ability to assess time-dependent changes in gene expression patterns in pancreatic cancer cells associated with infection and susceptibility to vaccinia viruses. This suggests that molecular assays may be useful to develop safer and more efficacious oncolyticvirotherapies and support the idea that these treatments may target pathways implicated in pancreatic cancer resistance to conventional therapies.

  12. Multislice CT for preoperative diagnosis of pancreatic cancer

    International Nuclear Information System (INIS)

    Horiguchi, Akihiko; Ishihara, Shin; Ito, Masahiro

    2007-01-01

    We investigated the ability of multislice (MS) CT to visualize and diagnose the progression of pancreatic cancer. With regard to local progression, good diagnosis was possible for detecting the invasion of the intrapancreatic bile duct, duodenum, portal vein, arteries and other organs, and liver metastasis. Sensitivity was high but specificity was not good for detecting the invasion of the anterior and posterior pancreatic tissue. This is thought to be because of the positive diagnosis with pancreatitis that accompanies cancer. Pancreatic plexus invasion was also thought to be a cause of the lipid elevation of the nerve plexus and decreased sensitivity accompanying pancreatitis. Identification of cancer invasion and tumor periphery changes based on concomitant pancreatitis also depends on the amount of fibrous stroma, but this will require further investigation. Factors other than the size of lymph node metastases also need to be investigated. MS-CT can provide detailed volume data in a short time and making it an essential test in diagnosing the stage of pancreatic cancer. (author)

  13. Association between allergies and risk of pancreatic cancer.

    Science.gov (United States)

    Cotterchio, Michelle; Lowcock, Elizabeth; Hudson, Thomas J; Greenwood, Celia; Gallinger, Steven

    2014-03-01

    Less than 10% of pancreatic cancer cases survive 5 years, yet its etiology is not well understood. Studies suggest allergies are associated with reduced pancreatic cancer risk. Our study collected additional information on allergies (including skin prick test results and differentiation of allergic/nonallergic asthma), and is the first to assess possible confounding by allergy medications. A population-based case-control study was designed to comprehensively assess the association between allergy and pancreatic cancer risk. Pancreas cancer cases were diagnosed during 2011 to 2012, and identified through the Ontario Cancer Registry (345 cases). Population-based controls were identified using random digit dialing and age/sex frequency matched to cases (1,285 controls). Questionnaires collected lifetime allergy history (type of allergy, age at onset, skin prick testing results), allergy medications, and established pancreas cancer risk factors. Logistic regression was used to estimate odd ratios and test potential confounders, including allergy medications. Hay fever was associated with a significant reduction in pancreatic cancer risk [AOR = 0.68; 95% confidence intervals (CI), 0.52-0.89], and reduction was greatest for those whose skin prick test was positive for hay fever allergens. No particular patterns were observed as regards age at onset and duration of allergy. Positive dust/mold allergy skin prick test and animal allergies were associated with a statistically significant reduced pancreatic cancer risk; AOR = 0.49; 95% CI, 0.31-0.78 and AOR = 0.68; 95% CI, 0.46-0.99, respectively. Asthma was not associated with pancreatic cancer risk. These findings support the growing body of evidence that suggests certain allergies are associated with reduced pancreatic cancer risk. ©2014 AACR.

  14. Targeted alpha therapy for cancer

    Energy Technology Data Exchange (ETDEWEB)

    Allen, Barry J [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Raja, Chand [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Rizvi, Syed [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Li Yong [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Tsui, Wendy [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Zhang, David [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Song, Emma [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Qu, C F [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Kearsley, John [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Graham, Peter [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Thompson, John [Sydney Melanoma Unit, Royal Prince Alfred Hospital, Camperdown 2050 NSW (Australia)

    2004-08-21

    Targeted alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The practicality and efficacy of TAT is tested by in vitro and in vivo studies in melanoma, leukaemia, colorectal, breast and prostate cancers, and by a phase 1 trial of intralesional TAT for melanoma. The alpha-emitting radioisotope used is Bi-213, which is eluted from the Ac-225 generator and chelated to a cancer specific monoclonal antibody (mab) or protein (e.g. plasminogen activator inhibitor-2 PAI2) to form the alpha-conjugate (AC). Stable alpha-ACs have been produced which have been tested for specificity and cytotoxicity in vitro against melanoma (9.2.27 mab), leukaemia (WM60), colorectal (C30.6), breast (PAI2, herceptin), ovarian (PAI2, herceptin, C595), prostate (PAI2, J591) and pancreatic (PAI2, C595) cancers. Subcutaneous inoculation of 1-1.5 million human cancer cells into the flanks of nude mice causes tumours to grow in all mice. Tumour growth is compared for untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. The {sup 213}Bi-9.2.27 AC is injected into secondary skin melanomas in stage 4 patients in a dose escalation study to determine the effective tolerance dose, and to measure kinematics to obtain the equivalent dose to organs. In vitro studies show that TAT is one to two orders of magnitude more cytotoxic to targeted cells than non-specific ACs, specific beta emitting conjugates or free isotopes. In vivo local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can completely regress advanced sc melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts and gives almost complete control of breast and prostate cancer tumour growth. Intralesional doses up to 450 {mu

  15. Mortality, Cancer, and Comorbidities Associated With Chronic Pancreatitis

    DEFF Research Database (Denmark)

    Bang, Ulrich Christian; Benfield, Thomas; Hyldstrup, Lars

    2014-01-01

    BACKGROUND & AIMS: We aimed to assess the risk of death, cancer, and comorbidities among patients with alcoholic and nonalcoholic chronic pancreatitis (CP). METHODS: We performed a nationwide retrospective cohort study, collecting data from Danish registries from 1995 through 2010. We evaluated...... cases (10.2%) and controls (3.3%). Cancer (particularly pancreatic cancer) was a frequent cause of death among cases; the HR was 6.9 (95% CI, 7.5-11.8). Alcoholic CP did not produce a higher risk for cancer or death than nonalcoholic CP. Cerebrovascular disease (HR, 1.3; 95% CI, 1.2-1.4), chronic...... on a Danish nationwide cohort study, individuals with CP are at higher risk for death from cancer (particularly pancreatic cancer) and have a higher incidence of comorbidities than people without CP....

  16. Prognostic Markers in Pancreatic Cancer: the tumor and its environment

    NARCIS (Netherlands)

    J. van der Zee (Jill)

    2012-01-01

    textabstractIncidence Pancreatic cancer is not one of the most common types of cancer; however it is most certainly one of the most devastating types, ranking fourth in the list of cancer related deaths with a 5-year survival of only 6%. In 2010 there were an estimated 43.140 new cases whereas

  17. Molecular Mechanism Underlying Lymphatic Metastasis in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Zhiwen Xiao

    2014-01-01

    Full Text Available As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer.

  18. Comparison of Oct4, Sox2 and Nanog Expression in Pancreatic Cancer Cell Lines and Human Pancreatic Tumor

    Directory of Open Access Journals (Sweden)

    Vahideh Assadollahi

    2015-12-01

    Full Text Available Background: Genes are involved in the control of stem cell self-renewal as a new class of molecular markers of cancer. Objectives: In this study, the expression of Oct4, Nanog and Sox2 in cell lines MIA Paca-2, PA-TU-8902 and AsPC-1 and pancreatic cancer tissue were examined. Materials and Methods: In this experimental study, cell lines, MIA Paca-2, PA-TU-8902 and AsPC-1, were cultured in DMEM (Dulbecco’s Modified Eagles Medium and RPMI-1640 (Roswell Park Memorial Institute containing FBS 10% (fetal bovine serum in a 37°C incubator containing Co2 5% and humidity 90%. Samples of tumor and non-cancer pancreatic tumor were purchased Iran tumor bank. Extraction of RNA and synthesis of cDNA was performed. Expression levels of Oct4, Nanog and Sox2 were determined using Real-time PCR. The protein expression levels of target genes in the cell lines were studied by flow cytometry and immunocytochemistry. Results: The expression rate of Oct4, Nanog and Sox2 is more in the cancer cell lines than those in the control (normal tissue samples. The protein expression levels of target genes in the cell lines were confirmed by flow cytometry and immunocytochemistry. Conclusions: The genes are involved in stem cell self-renewal as a new class of molecular markers of cancer that detected in the pancreatic cell lines. Maybe, these genes play important role in the uncontrolled proliferation of cancer cells.

  19. Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth

    Directory of Open Access Journals (Sweden)

    Anupama Pal

    2018-02-01

    Full Text Available Usp9x has emerged as a potential therapeutic target in some hematologic malignancies and a broad range of solid tumors including brain, breast, and prostate. To examine Usp9x tumorigenicity and consequence of Usp9x inhibition in human pancreatic tumor models, we carried out gain- and loss-of-function studies using established human pancreatic tumor cell lines (PANC1 and MIAPACA2 and four spontaneously immortalized human pancreatic patient-derived tumor (PDX cell lines. The effect of Usp9x activity inhibition by small molecule deubiquitinase inhibitor G9 was assessed in 2D and 3D culture, and its efficacy was tested in human tumor xenografts. Overexpression of Usp9x increased 3D growth and invasion in PANC1 cells and up-regulated the expression of known Usp9x substrates Mcl-1 and ITCH. Usp9x inhibition by shRNA-knockdown or by G9 treatment reduced 3D colony formation in PANC1 and PDX cell lines, induced rapid apoptosis in MIAPACA2 cells, and associated with reduced Mcl-1 and ITCH protein levels. Although G9 treatment reduced human MIAPACA2 tumor burden in vivo, in mouse pancreatic cancer cell lines established from constitutive (8041 and doxycycline-inducible (4668 KrasG12D/Tp53R172H mouse pancreatic tumors, Usp9x inhibition increased and sustained the 3D colony growth and showed no significant effect on tumor growth in 8041-xenografts. Thus, Usp9x inhibition may be therapeutically active in human PDAC, but this activity was not predicted from studies of genetically engineered mouse pancreatic tumor models.

  20. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

    Science.gov (United States)

    Vennin, Claire; Chin, Venessa T.; Warren, Sean C.; Lucas, Morghan C.; Herrmann, David; Magenau, Astrid; Melenec, Pauline; Walters, Stacey N.; del Monte-Nieto, Gonzalo; Conway, James R. W.; Nobis, Max; Allam, Amr H.; McCloy, Rachael A.; Currey, Nicola; Pinese, Mark; Boulghourjian, Alice; Zaratzian, Anaiis; Adam, Arne A. S.; Heu, Celine; Nagrial, Adnan M.; Chou, Angela; Steinmann, Angela; Drury, Alison; Froio, Danielle; Giry-Laterriere, Marc; Harris, Nathanial L. E.; Phan, Tri; Jain, Rohit; Weninger, Wolfgang; McGhee, Ewan J.; Whan, Renee; Johns, Amber L; Samra, Jaswinder S.; Chantrill, Lorraine; Gill, Anthony J.; Kohonen-Corish, Maija; Harvey, Richard P.; Biankin, Andrew V.; Jeffry Evans, T. R.; Anderson, Kurt I.; Grey, Shane T.; Ormandy, Christopher J.; Gallego-Ortega, David; Wang, Yingxiao; Samuel, Michael S.; Sansom, Owen J.; Burgess, Andrew; Cox, Thomas R.; Morton, Jennifer P.; Pajic, Marina; Timpson, Paul

    2018-01-01

    The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or “priming,” using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer. PMID:28381539

  1. Dynamic Contrast-Enhanced CT in Patients with Pancreatic Cancer

    DEFF Research Database (Denmark)

    Eriksen, Rie Ø; Strauch, Louise S; Sandgaard, Michael

    2016-01-01

    tissue, compared with measurements in pancreatic tissue outside of tumor, or normal pancreatic tissue in control groups of healthy volunteers. The studies were heterogeneous in the number of patients enrolled and scan protocols. Perfusion parameters measured and analyzed by DCE-CT might be useful......The aim of this systematic review is to provide an overview of the use of Dynamic Contrast-enhanced Computed Tomography (DCE-CT) in patients with pancreatic cancer. This study was composed according to the PRISMA guidelines 2009. The literature search was conducted in PubMed, Cochrane Library...... in the investigation of characteristic vascular patterns of exocrine pancreatic tumors. Further clinical studies are desired for investigating the potential of DCE-CT in pancreatic tumors....

  2. Tenascin-C induces resistance to apoptosis in pancreatic cancer cell through activation of ERK/NF-κB pathway.

    Science.gov (United States)

    Shi, Meiyan; He, Xiaodan; Wei, Wei; Wang, Juan; Zhang, Ti; Shen, Xiaohong

    2015-06-01

    processes. TNC mediated gemcitabine chemo-resistance via modulating cell apoptosis in pancreatic cancer. TNC resulted in the enrichment of pancreatic cancer cells in S-phase with a concomitant decrease in number of cells in G1 phase. The present study indicated TNC in cellular matrix induces an activation of ERK1/2/NF-κB/p65 signaling cascade and thereby mediates resistance to apoptosis in pancreatic cancer. TNC could serve as a diagnostic marker and predictor of gemcitabine response and potentially as a target for chemotherapy of pancreatic cancer.

  3. The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Sandra Valle

    2018-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC, the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs, which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (<7 months as they do not affect the pancreatic CSC (PaCSC population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.

  4. Cadmium Exposure and Pancreatic Cancer in South Louisiana

    Science.gov (United States)

    Luckett, Brian G.; Su, L. Joseph; Rood, Jennifer C.; Fontham, Elizabeth T. H.

    2012-01-01

    Cadmium has been hypothesized to be a pancreatic carcinogen. We test the hypothesis that cadmium exposure is a risk factor for pancreatic cancer with a population-based case-control study sampled from a population with persistently high rates of pancreatic cancer (south Louisiana). We tested potential dietary and nondietary sources of cadmium for their association with urinary cadmium concentrations which reflect long-term exposure to cadmium due to the accumulation of cadmium in the kidney cortex. Increasing urinary cadmium concentrations were significantly associated with an increasing risk of pancreatic cancer (2nd quartile OR = 3.34, 3rd = 5.58, 4th = 7.70; test for trend P ≤ 0.0001). Potential sources of cadmium exposure, as documented in the scientific literature, found to be statistically significantly associated with increased risk of pancreatic cancer included working as a plumber, pipefitter or welder (OR = 5.88) and high consumption levels of red meat (4th quartile OR = 6.18) and grains (4th quartile OR = 3.38). Current cigarette smoking, at least 80 pack years of smoking, occupational exposure to cadmium and paints, working in a shipyard, and high consumption of grains were found to be statistically significantly associated with increased concentrations of urinary cadmium. This study provides epidemiologic evidence that cadmium is a potential human pancreatic carcinogen. PMID:23319964

  5. L61H46 shows potent efficacy against human pancreatic cancer through inhibiting STAT3 pathway

    Directory of Open Access Journals (Sweden)

    Bai E

    2018-03-01

    Full Text Available Encheng Bai,1,2,* Lehe Yang,1,* Youqun Xiang,2,* Wanle Hu,3 Caleb Li,4 Jiayuh Lin,5 Xuanxuan Dai,2 Guang Liang,1 Rong Jin,2 Chengguang Zhao1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, 2Department of Epidemiology, First Affiliated Hospital, 3Department of Coloproctology, The Second Affiliated Hospital and Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Dublin Coffman High School, Dublin, OH, 5Department of Biochemistry and Molecular Biology, University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA *These authors contributed equally to this work Background: Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The poor prognosis of this disease highlights the urgent need to develop more effective therapies. Activation of the STAT3 represents a potential drug target for pancreatic cancer therapy. Currently, clinically available small-molecule inhibitors targeting STAT3 are lacking. Methods: Through bioassay screening and molecular docking, we identified a small molecule L61H46 that can potently target constitutive STAT3 signaling and kill human pancreatic cancer cells in vitro and in vivo. Results: L61H46 effectively reduced colony formation and the viability of pancreatic cancer cells in a dose-dependent manner with half-maximal inhibitory concentration (IC50 values in the range between 0.86 and 2.83 µM. L61H46 significantly inhibited STAT3 phosphorylation (Tyr705 and the subsequent nucleus translocation but did not downregulate STAT1 phosphorylation. Moreover, L61H46 demonstrated a potent activity in suppressing pancreatic tumor growth in BXPC-3 xenograft model in vivo. Furthermore, L61H46 showed no signs of adverse effects on liver, heart, and kidney cells in vivo. Conclusion: Collectively, our results suggest that L61H46 could be further optimized into a highly

  6. Cardiorespiratory fitness and muscle strength in pancreatic cancer patients.

    Science.gov (United States)

    Clauss, Dorothea; Tjaden, Christine; Hackert, Thilo; Schneider, Lutz; Ulrich, Cornelia M; Wiskemann, Joachim; Steindorf, Karen

    2017-09-01

    Cancer patients frequently experience reduced physical fitness due to the disease itself as well as treatment-related side effects. However, studies on physical fitness in pancreatic cancer patients are missing. Therefore, we assessed cardiorespiratory fitness and muscle strength of pancreatic cancer patients. We included 65 pancreatic cancer patients, mostly after surgical resection. Cardiorespiratory fitness was assessed using cardiopulmonary exercise testing (CPET) and 6-min walk test (6MWT). Hand-held dynamometry was used to evaluate isometric muscle strength. Physical fitness values were compared to reference values of a healthy population. Associations between sociodemographic and clinical variables with patients' physical fitness were analyzed using multiple regression models. Cardiorespiratory fitness (VO 2 peak, 20.5 ± 6.9 ml/min/kg) was significantly lower (-24%) compared to healthy reference values. In the 6MWT pancreatic cancer patients nearly reached predicted values (555 vs. 562 m). Maximal voluntary isometric contraction (MVIC) of the upper (-4.3%) and lower extremities (-13.8%) were significantly lower compared to reference values. Overall differences were larger in men than those in women. Participating in regular exercise in the year before diagnosis was associated with greater VO 2 peak (p fitness with regard to both cardiorespiratory function and isometric muscle strength, already in the early treatment phase (median 95 days after surgical resection). Our findings underline the need to investigate exercise training in pancreatic cancer patients to counteract the loss of physical fitness.

  7. Characterization of human mesothelin transcripts in ovarian and pancreatic cancer

    International Nuclear Information System (INIS)

    Muminova, Zhanat E; Strong, Theresa V; Shaw, Denise R

    2004-01-01

    Mesothelin is an attractive target for cancer immunotherapy due to its restricted expression in normal tissues and high level expression in several tumor types including ovarian and pancreatic adenocarcinomas. Three mesothelin transcript variants have been reported, but their relative expression in normal tissues and tumors has been poorly characterized. The goal of the present study was to clarify which mesothelin transcript variants are commonly expressed in human tumors. Human genomic and EST nucleotide sequences in the public databases were used to evaluate sequences reported for the three mesothelin transcript variants in silico. Subsequently, RNA samples from normal ovary, ovarian and pancreatic carcinoma cell lines, and primary ovarian tumors were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and nucleotide sequencing to directly identify expressed transcripts. In silico comparisons of genomic DNA sequences with available EST sequences supported expression of mesothelin transcript variants 1 and 3, but there were no sequence matches for transcript variant 2. Newly-derived nucleotide sequences of RT-PCR products from tissues and cell lines corresponded to mesothelin transcript variant 1. Mesothelin transcript variant 2 was not detected. Transcript variant 3 was observed as a small percentage of total mesothelin amplification products from all studied cell lines and tissues. Fractionation of nuclear and cytoplasmic RNA indicated that variant 3 was present primarily in the nuclear fraction. Thus, mesothelin transcript variant 3 may represent incompletely processed hnRNA. Mesothelin transcript variant 1 represents the predominant mature mRNA species expressed by both normal and tumor cells. This conclusion should be important for future development of cancer immunotherapies, diagnostic tests, and gene microarray studies targeting mesothelin

  8. Potential usefulness of apolipoprotein A2 isoforms for screening and risk stratification of pancreatic cancer.

    Science.gov (United States)

    Honda, Kazufumi; Srivastava, Sudhir

    2016-11-01

    Given the low incidence of pancreatic cancer in the general population, screening of pancreatic cancer in the general population using invasive modalities is not feasible. Combination of invasive screening with noninvasive biomarkers for pancreatic cancer and its precancerous lesions has the potential to reduce mortality due to pancreatic cancer. In this review, we focus on biomarkers found in the blood that can indicate early-stage pancreatic cancer, and we discuss current strategies for screening for pancreatic cancer. We recently identified a unique alteration in apolipoprotein A2 isoforms in pancreatic cancer and its precancerous lesions, and we describe its clinical usefulness as a potential biomarker for the early detection and risk stratification of pancreatic cancer.

  9. [Surgery for pancreatic cancer: Evidence-based surgical strategies].

    Science.gov (United States)

    Sánchez Cabús, Santiago; Fernández-Cruz, Laureano

    2015-01-01

    Pancreatic cancer surgery represents a challenge for surgeons due to its technical complexity, the potential complications that may appear, and ultimately because of its poor survival. The aim of this article is to summarize the scientific evidence regarding the surgical treatment of pancreatic cancer in order to help surgeons in the decision making process in the management of these patients .Here we will review such fundamental issues as the need for a biopsy before surgery, the type of pancreatic anastomosis leading to better results, and the need for placement of drains after pancreatic surgery will be discussed. Copyright © 2014 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

  10. Anti-pancreatic cancer deliverables from sea: first-hand evidence on the efficacy, molecular targets and mode of action for multifarious polyphenols from five different brown-algae.

    Directory of Open Access Journals (Sweden)

    Sheeja Aravindan

    Full Text Available Pancreatic cancer (PC remains the fourth leading cause of cancer death with an unacceptable survival that has remained relatively unchanged over the past 25 years. The presence of occult or clinical metastases at the time of diagnosis together with the lack of effective chemotherapies pose a dire need for designing new and targeted therapeutic deliverables that favors the clinical outcome. Herein, we investigated the anti-tumorigenic potential of polyphenols from five different brown-algae in human PC cells (MiaPaCa-2, Panc-1, BXPC-3 and Panc-3.27. Total anti-oxidant capacity (TAC analysis on stepwise polyphenol separations with increasing polarity (Hexane-DCM-EA-methanol identified high levels of TAC in DCM and EA extractions across all seaweeds assessed. All DCM and EA separated polyphenols induced a dose-dependent and sustained (time-independent inhibition of cell proliferation and viability. Further, these polyphenols profoundly enhanced DNA damage (acridine orange/Ethidium bromide staining and DNA fragmentation in all the cell lines investigated. More importantly, luciferase reporter assay revealed a significant inhibition of NFκB transcription in cells treated with polyphenols. Interestingly, QPCR analysis identified a differential yet definite regulation of pro-tumorigenic EGFR, VEGFA, AKT, hTERT, kRas, Bcl2, FGFα and PDGFα transcription in cells treated with DCM and EA polyphenols. Immunoblotting validates the inhibitory potential of seaweed polyphenols in EGFR phosphorylation, kRas, AurKβ and Stat3. Together, these data suggest that intermediate polarity based fractions of seaweed polyphenols may significantly potentiate tumor cell killing and may serve as potential drug deliverable for PC cure. More Studies dissecting out the active constituents in potent fractions, mechanisms of action and synergism, if any, are warranted and are currently in process.

  11. Using Experience-Based Design to Improve the Care Experience for Patients With Pancreatic Cancer.

    Science.gov (United States)

    Hagensen, Ann; London, Amy E; Phillips, Jennifer J; Helton, W Scott; Picozzi, Vincent J; Blackmore, C Craig

    2016-12-01

    Despite the importance of the patient care experience to quality and outcome, the literature detailing the care experience in patients with pancreatic cancer is limited. To elicit the experience of patients with pancreatic cancer for care redesign, we deployed experience-based design, an emerging methodology based on identification of events of high emotional content, known as touch points, to delineate qualitatively what matters most to patients and families. We defined touch points through direct observations, interviews, and a focus group. We then used experience questionnaires to measure emotional content and develop an experience map to graphically display the fluctuating emotional journey through the care processes. Study subjects were patients with pancreatic cancer who were cared for at Virginia Mason Medical Center, family caregivers, and staff. Redesign was initiated through an all-day improvement event in September 2013. During 2013 and 2014, we cared for 485 new patients with pancreatic cancer, the majority of whom had local disease at diagnosis. The response rate for the experience questionnaire was 23% (117 of 500 questionnaires distributed). The experience-based design results were often contrary to staff preconceptions of the care experience for patients with pancreatic cancer, and contributed to redesign in three key areas: understanding and documenting patient goals and values, providing better resources for caregivers/families, and improving care coordination and support services. Experience-based design enabled us to understand the care experience and associated emotional content for patients with pancreatic cancer and their caregivers. This knowledge then supported care redesign targeted at areas of high negative emotional content.

  12. Multifunctional inulin tethered silver-graphene quantum dots nanotheranostic module for pancreatic cancer therapy.

    Science.gov (United States)

    Nigam Joshi, Preeti; Agawane, Sachin; Athalye, Meghana C; Jadhav, Vrushali; Sarkar, Dhiman; Prakash, Rajiv

    2017-09-01

    Cancer nanotechnology is an emerging area of cancer diagnosis and therapy. Although considerable progress has been made for targeted drug delivery systems to deliver anticancer agents to particular site of interest, new nanomaterials are frequently being developed and explored for better drug delivery efficiency. In the present work, we have explored a novel nanoformulation based on silver-graphene quantum dots (Ag-GQDs) nanocomposite for its successful implementation for pancreatic cancer specific drug delivery in wistar rats. Carboxymethyl inulin (CMI); a modified variant of natural polysaccharide inulin is tethered with the nanocomposite via carbodiimide coupling to enhance the biocompatibility of nanoformulation. Experiments are performed to investigate the cytotoxicity reduction of silver nanoparticles after inulin tethering as well as anticancer efficacy of the system using 5-Fluorouracil (5-FU) as model drug. SEM, TEM, FT-IR, UV-vis, photoluminescence and anti proliferative assays (MTT) are performed for characterisation of the nanocomposite. Hyaluronic acid (HA) is conjugated as targeting moiety for CD-44 (cancer stem cell marker) to fabricate a complete targeted drug delivery vehicle specific for pancreatic cancer. In the present work two prime objectives were achieved; mitigation the toxicity of silver nanoparticles by inulin coating and it's in vivo application for pancreatic cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Waging war against pancreatic cancer: an interview with David Tuveson

    Directory of Open Access Journals (Sweden)

    David Tuveson

    2017-04-01

    Full Text Available David Tuveson, Director of the Cancer Center at Cold Spring Harbor Laboratory, is a clinician-scientist with a longstanding interest in understanding and treating pancreatic cancer. Since developing the first mouse model of pancreatic cancer in 2002, the Tuveson lab has made a series of discoveries that shed light on the molecular drivers of this disease and provide promising therapeutic avenues for a malignancy that is notoriously challenging to treat. In collaboration with Hans Clevers, David developed the first pancreatic cancer organoids, which revolutionized the field by providing a powerful model system for basic discoveries and advancement of personalized medicine. Here, David talks to Ross Cagan about his path from chemistry student to world-renowned oncologist, highlighting how his colleagues, mentors and patient interactions shaped his research interests and unique approach to scientific discovery. As well as discussing the story behind some of his breakthroughs, he provides tips on running a lab and succeeding in or outside academia.

  14. Targeting mTOR in Pancreatic Ductal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Sentia eIriana

    2016-04-01

    Full Text Available Treatment options for advanced pancreatic ductal adenocarcinoma (PDAC are limited, however, new therapies targeting specific tumor-related molecular characteristics may help certain patient cohorts. Emerging preclinical data has shown that inhibition of mechanistic target of rapamycin (mTOR in specific KRAS-dependent PDAC subtypes leads to inhibition of tumorigenesis in vitro as well as in vivo. Early phase II studies of mono-mTOR inhibition have not shown promise. However, studies have shown that combined inhibition of multiple steps along the mTOR signaling pathway may lead to sustained responses by targeting mechanisms of tumor resistance. Coordinated inhibition of mTOR along with specific KRAS-dependent mutations in molecularly defined PDAC subpopulations may offer a viable alternative for treatment in the future.

  15. Eukaryotic Translation Initiation Factor 3a (eIF3a) Promotes Cell Proliferation and Motility in Pancreatic Cancer.

    Science.gov (United States)

    Wang, Shu Qian; Liu, Yu; Yao, Min Ya; Jin, Jing

    2016-10-01

    Identifying a target molecule that is crucially involved in pancreatic tumor growth and metastasis is necessary in developing an effective treatment. The study aimed to investigate the role of the eukaryotic translation initiation factor 3a (eIF3a) in the cell proliferation and motility in pancreatic cancer. Our data showed that the expression of eIF3a was upregulated in pancreatic ductal adenocarcinoma as compared with its expression in normal pancreatic tissues. Knockdown of eIF3a by a specific shRNA caused significant decreases in cell proliferation and clonogenic abilities in pancreatic cancer SW1990 and Capan-1 cells. Consistently, the pancreatic cancer cell growth rates were also impaired in xenotransplanted mice. Moreover, wound-healing assay showed that depletion of eIF3a significantly slowed down the wound recovery processes in SW1990 and Capan-1 cells. Transwell migration and invasion assays further showed that cell migration and invasion abilities were significantly inhibited by knockdown of eIF3a in SW1990 and Capan-1 cells. Statistical analysis of eIF3a expression in 140 cases of pancreatic ductal adenocarcinoma samples revealed that eIF3a expression was significantly associated with tumor metastasis and TNM staging. These analyses suggest that eIF3a contributes to cell proliferation and motility in pancreatic ductal adenocarcinoma.

  16. Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

    Energy Technology Data Exchange (ETDEWEB)

    Motoo, Yoshiharu, E-mail: motoo@kanazawa-med.ac.jp [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Shimasaki, Takeo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan); Ishigaki, Yasuhito [Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Nakajima, Hideo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Kawakami, Kazuyuki; Minamoto, Toshinari [Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan)

    2011-01-24

    Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β) is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer). We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation.

  17. Laparoscopic versus open distal pancreatectomy for pancreatic cancer

    NARCIS (Netherlands)

    Riviere, D.M.; Gurusamy, K.S.; Kooby, D.A.; Vollmer, C.M.; Besselink, M.G.; Davidson, B.R.; Laarhoven, C.J.H.M. van

    2016-01-01

    BACKGROUND: Surgical resection is currently the only treatment with the potential for long-term survival and cure of pancreatic cancer. Surgical resection is provided as distal pancreatectomy for cancers of the body and tail of the pancreas. It can be performed by laparoscopic or open surgery. In

  18. Laparoscopic versus open distal pancreatectomy for pancreatic cancer

    NARCIS (Netherlands)

    Riviere, Deniece; Gurusamy, Kurinchi Selvan; Kooby, David A.; Vollmer, Charles M.; Besselink, Marc G. H.; Davidson, Brian R.; van Laarhoven, Cornelis J. H. M.

    2016-01-01

    Surgical resection is currently the only treatment with the potential for long-term survival and cure of pancreatic cancer. Surgical resection is provided as distal pancreatectomy for cancers of the body and tail of the pancreas. It can be performed by laparoscopic or open surgery. In operations on

  19. Survivin as a radioresistance factor in pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Asanuma, Koichi; Moriai, Ryosuke; Yajima, Tomomi; Yagihashi, Atsuhito; Yamada, Mikako; Kobayashi, Daisuke; Watanabe, Naoki [Sapporo Medical Univ., Hokkaido (Japan). School of Medicine

    2000-11-01

    We examined whether survivin acts as a constitutive and inducible radioresistance factor in pancreatic cancer cells. Using a quantitative TaqMan reverse transcription-polymerase chain reaction for survivin mRNA in five pancreatic cancer cell lines, we found an inverse relationship between survivin mRNA expression and radiosensitivity. PANC-1 cells, which had the highest survivin mRNA levels, were most resistant to X-irradiation; MIAPaCa-2 cells, which showed the least survivin mRNA expression, were the most sensitive to X-irradiation. Our results suggested that survivin could act as a constitutive radioresistance factor in pancreatic cancer cells. To determine whether radioresistance is enhanced by induction of survivin expression by irradiation, PANC-1 and MIAPaCa-2 cells were subjected to sublethal doses of X-irradiation followed by a lethal dose. Survivin mRNA expression was increased significantly in both PANC-1 and MIAPaCa-2 cell lines by pretreatment with a sublethal dose of X-irradiation, as was cell survival after exposure to the lethal dose. In this system, enzymatic caspase-3 activity was significantly suppressed in cells with acquired resistance. These results suggest that survivin also acts as an inducible radioresistance factor in pancreatic cancer cells. Survivin, then, appears to enhance radioresistance in pancreatic cancer cells; inhibition of survivin mRNA expression may improve the effectiveness of radiotherapy. (author)

  20. Survivin as a radioresistance factor in pancreatic cancer

    International Nuclear Information System (INIS)

    Asanuma, Koichi; Moriai, Ryosuke; Yajima, Tomomi; Yagihashi, Atsuhito; Yamada, Mikako; Kobayashi, Daisuke; Watanabe, Naoki

    2000-01-01

    We examined whether survivin acts as a constitutive and inducible radioresistance factor in pancreatic cancer cells. Using a quantitative TaqMan reverse transcription-polymerase chain reaction for survivin mRNA in five pancreatic cancer cell lines, we found an inverse relationship between survivin mRNA expression and radiosensitivity. PANC-1 cells, which had the highest survivin mRNA levels, were most resistant to X-irradiation; MIAPaCa-2 cells, which showed the least survivin mRNA expression, were the most sensitive to X-irradiation. Our results suggested that survivin could act as a constitutive radioresistance factor in pancreatic cancer cells. To determine whether radioresistance is enhanced by induction of survivin expression by irradiation, PANC-1 and MIAPaCa-2 cells were subjected to sublethal doses of X-irradiation followed by a lethal dose. Survivin mRNA expression was increased significantly in both PANC-1 and MIAPaCa-2 cell lines by pretreatment with a sublethal dose of X-irradiation, as was cell survival after exposure to the lethal dose. In this system, enzymatic caspase-3 activity was significantly suppressed in cells with acquired resistance. These results suggest that survivin also acts as an inducible radioresistance factor in pancreatic cancer cells. Survivin, then, appears to enhance radioresistance in pancreatic cancer cells; inhibition of survivin mRNA expression may improve the effectiveness of radiotherapy. (author)

  1. Population attributable risk for pancreatic cancer in Northern Italy.

    Science.gov (United States)

    Rosato, Valentina; Polesel, Jerry; Bosetti, Cristina; Serraino, Diego; Negri, Eva; La Vecchia, Carlo

    2015-03-01

    To provide data on the impact of known risk factors on pancreatic cancer burden, we estimated the population attributable risks (PARs) in the Italian population. Data were derived from a case-control study conducted in Northern Italy between 1991 and 2008, including 326 case patients with incident pancreatic cancer and 652 hospital control subjects. We found that 13.6% (95% confidence interval [CI], 6.3-20.8) of pancreatic cancers were attributable to tobacco smoking, 13.0% (95% CI, 2.7-23.2) were attributable to heavy alcohol drinking, 9.7% (95% CI, 5.3-14.1) were attributable to diabetes, 11.9% (95% CI, -8.0 to 31.8) were attributable to a low adherence to Mediterranean diet, and 0.6% (95% CI, -1.8 to 2.9) were attributable to a family history of pancreatic cancer. The PARs for tobacco smoking increased up to 25.7% when we considered it jointly with alcohol, up to 21.7% with diabetes, and up to 24.8% with low Mediterranean diet adherence. For all the risk factors considered, the PARs were higher in men than in women, the differences being particularly evident for heavy alcohol consumption and for a low Mediterranean diet adherence. These results suggest that an appreciable proportion of pancreatic cancers could be avoided in this Italian population by intervention on a few selected modifiable lifestyle factors.

  2. Palliative Care in Improving Quality of Life and Symptoms in Patients With Stage III-IV Pancreatic or Ovarian Cancer

    Science.gov (United States)

    2014-12-18

    Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIA Ovarian Germ Cell Tumor; Stage IIIB Ovarian Epithelial Cancer; Stage IIIB Ovarian Germ Cell Tumor; Stage IIIC Ovarian Epithelial Cancer; Stage IIIC Ovarian Germ Cell Tumor; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Pancreatic Cancer

  3. MicroRNA Biomarkers in Whole Blood for Detection of Pancreatic Cancer

    DEFF Research Database (Denmark)

    Schultz, Nicolai A; Dehlendorff, Christian; Jensen, Benny V

    2014-01-01

    IMPORTANCE: Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis. OBJECTIVES: To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels...... (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer...... of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9). DESIGN, SETTING, AND PARTICIPANTS: A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC...

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  11. File list: Oth.Pan.10.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  13. File list: ALL.Pan.10.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  17. File list: Unc.Pan.50.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

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  18. File list: Pol.Pan.05.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  19. File list: His.Pan.10.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  20. File list: His.Pan.50.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  1. File list: His.Pan.20.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Pan.20.AllAg.Pancreatic_cancer_cells mm9 Histone Pancreas Pancreatic cancer cel...ls http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.Pan.20.AllAg.Pancreatic_cancer_cells.bed ...

  2. File list: DNS.Pan.20.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  3. File list: Oth.Pan.05.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Pan.05.AllAg.Pancreatic_cancer_cells mm9 TFs and others Pancreas Pancreatic cancer... cells SRX174586,SRX174585 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Pan.05.AllAg.Pancreatic_cancer_cells.bed ...

  4. Decision making in the treatment of pancreatic cancer : a retrospective analysis

    NARCIS (Netherlands)

    J.H.G. Klinkenbijl (Jean)

    1994-01-01

    textabstractPancreatic cancer is a major and often frustrating disease in clinical gastroenterology. Diagnosis and treatment are very difficult; 90% of all patients diagnosed with pancreatic cancer die within one year after diagnosis has been made. The incidence of pancreatic cancer has increased

  5. Correlation Between Preoperative Serum Carcinoembryonic Antigen Levels and Expression on Pancreatic and Rectal Cancer Tissue

    Directory of Open Access Journals (Sweden)

    LSF Boogerd

    2017-05-01

    Full Text Available Carcinoembryonic antigen (CEA–targeted imaging and therapeutic agents are being tested in clinical trials. If CEA overexpression in malignant tissue corresponds with elevated serum CEA, serum CEA could assist in selecting patients who may benefit from CEA-targeted agents. This study aims to assess the relationship between serum CEA and CEA expression in pancreatic (n = 20 and rectal cancer tissues (n = 35 using histopathology. According to local laboratory standards, a serum CEA >3 ng/mL was considered elevated. In pancreatic cancer patients a significant correlation between serum CEA and percentage of CEA-expressing tumor cells was observed ( P  = .04, ρ = .47. All 6 patients with homogeneous CEA expression in the tumor had a serum CEA >3 ng/mL. Most rectal cancer tissues (32/35 showed homogeneous CEA expression, independent of serum CEA levels. This study suggests that selection of pancreatic cancer patients for CEA-targeted agents via serum CEA appears adequate. For selection of rectal cancer patients, serum CEA levels are not informative.

  6. Discussion of difficult problems of early diagnosis of pancreatic cancer

    Directory of Open Access Journals (Sweden)

    GUO Xiaozhong

    2014-08-01

    Full Text Available Pancreatic cancer is a common malignant neoplasm of the pancreas with an extremely high mortality. Currently, the early diagnosis of pancreatic cancer is still not ideal. Attention should be paid to some clinical warning symptoms, such as unexplained abdominal and back pain, jaundice, and unexpected diabetes. Additionally, the combined use of CA19-9, CEA, and other tumor markers, the attention to biochemical indicators, the detection of mutation in KAI1 or p53 gene, and the exploration of the value of miRNA in clinical diagnosis are of great significance. On the other hand, ultrasound, CT, MRCP, ERCP, PET-CT, and other imaging methods, as well as effective collection of cytology specimens, should be performed. Thus, there is hope for the early diagnosis of pancreatic cancer.

  7. The Role of Apoptosis in the Pathology of Pancreatic Cancer

    International Nuclear Information System (INIS)

    Samm, Nicole; Werner, Kristin; Rückert, Felix; Saeger, Hans Detlev; Grützmann, Robert; Pilarsky, Christian

    2010-01-01

    Pancreatic cancer is a disease with high resistance to most common therapies and therefore has a poor prognosis, which is partly due to a lack of reaction to apoptotic stimuli. Signal transduction of such stimuli includes a death receptor-mediated extrinsic pathway as well as an intrinsic pathway linked to the mitochondria. Defects in apoptotic pathways and the deregulation of apoptotic proteins, such as Survivin, Bcl-2, Bcl-x L and Mcl-1, play decisive roles in the development of pancreatic cancer. Investigation of the molecular mechanism allowing tumors to resist apoptotic cell death would lead to an improved understanding of the physiology and the development of new molecular strategies in pancreatic cancer

  8. Glycogene expression alterations associated with pancreatic cancer epithelial-mesenchymal transition in complementary model systems.

    Directory of Open Access Journals (Sweden)

    Kevin A Maupin

    2010-09-01

    Full Text Available The ability to selectively detect and target cancer cells that have undergone an epithelial-mesenchymal transition (EMT may lead to improved methods to treat cancers such as pancreatic cancer. The remodeling of cellular glycosylation previously has been associated with cell differentiation and may represent a valuable class of molecular targets for EMT.As a first step toward investigating the nature of glycosylation alterations in EMT, we characterized the expression of glycan-related genes in three in-vitro model systems that each represented a complementary aspect of pancreatic cancer EMT. These models included: 1 TGFβ-induced EMT, which provided a look at the active transition between states; 2 a panel of 22 pancreatic cancer cell lines, which represented terminal differentiation states of either epithelial-like or mesenchymal-like; and 3 actively-migrating and stationary cells, which provided a look at the mechanism of migration. We analyzed expression data from a list of 587 genes involved in glycosylation (biosynthesis, sugar transport, glycan-binding, etc. or EMT. Glycogenes were altered at a higher prevalence than all other genes in the first two models (p<0.05 and <0.005, respectively but not in the migration model. Several functional themes were shared between the induced-EMT model and the cell line panel, including alterations to matrix components and proteoglycans, the sulfation of glycosaminoglycans; mannose receptor family members; initiation of O-glycosylation; and certain forms of sialylation. Protein-level changes were confirmed by Western blot for the mannose receptor MRC2 and the O-glycosylation enzyme GALNT3, and cell-surface sulfation changes were confirmed using Alcian Blue staining.Alterations to glycogenes are a major component of cancer EMT and are characterized by changes to matrix components, the sulfation of GAGs, mannose receptors, O-glycosylation, and specific sialylated structures. These results provide leads for

  9. Helicobacter pylori infection, atrophic gastritis, and pancreatic cancer risk

    Science.gov (United States)

    Liu, Hong; Chen, Yue-Tong; Wang, Rui; Chen, Xin-Zu

    2017-01-01

    Abstract Background: To investigate the associations of Helicobacter pylori (Hp) infection and atrophic gastritis (AG) with pancreatic cancer risk. Methods: A literature search in PubMed was performed up to July 2017. Only prospective cohort and nested case–control studies enrolling cancer-free participants were eligible. Incident pancreatic cancer cases were ascertained during the follow-up. The risks of pancreatic cancer were compared between persons infected and noninfected with Hp, or between those with and without AG status at baseline. Odds ratios (ORs) or hazard ratios were combined. Subgroup and sensitivity analyses were performed, and publication bias was estimated. Results: Three cohort studies and 6 nested case–control studies, including 65,155 observations, were analyzed. The meta-analyses did not confirm the association between pancreatic cancer risk and Hp infection (OR = 1.09, 95% confidence interval [CI] = 0.81–1.47) or AG status (OR = 1.18, 95% CI = 0.80–1.72). However, particular subpopulations potentially had increased risks of pancreatic cancer. Cytotoxin-associated gene A (CagA)-negative strains of Hp might be a causative factor of pancreatic cancer (OR = 1.30, 95% CI = 1.05–1.62), but a sensitivity analysis by leave-one-out method did not fully warrant it (OR = 1.20, 95% CI = 0.93–1.56). In 1 nested case–control study, AG at stomach corpus in Hp-negative subpopulation might have increased risk of pancreatic cancer, but with a poor test power = 0.56. Publication biases were nonsignificant in the present meta-analysis. Conclusion: Based on current prospective epidemiologic studies, the linkage of pancreatic cancer to Hp infection or AG status was not warranted on the whole. Nevertheless, prospective studies only focusing on those specific subpopulations are further required to obtain better power. PMID:28816977

  10. Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling.

    Science.gov (United States)

    Kallifatidis, G; Rausch, V; Baumann, B; Apel, A; Beckermann, B M; Groth, A; Mattern, J; Li, Z; Kolb, A; Moldenhauer, G; Altevogt, P; Wirth, T; Werner, J; Schemmer, P; Büchler, M W; Salnikov, A V; Herr, I

    2009-07-01

    Emerging evidence suggests that highly treatment-resistant tumour-initiating cells (TICs) play a central role in the pathogenesis of pancreatic cancer. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered to be a novel anticancer agent; however, recent studies have shown that many pancreatic cancer cells are resistant to apoptosis induction by TRAIL due to TRAIL-activated nuclear factor-kappaB (NF-kappaB) signalling. Several chemopreventive agents are able to inhibit NF-kappaB, and favourable results have been obtained--for example, for the broccoli compound sulforaphane-in preventing metastasis in clinical studies. The aim of the study was to identify TICs in pancreatic carcinoma for analysis of resistance mechanisms and for definition of sensitising agents. TICs were defined by expression patterns of a CD44(+)/CD24(-), CD44(+)/CD24(+) or CD44(+)/CD133(+) phenotype and correlation to growth in immunodeficient mice, differentiation grade, clonogenic growth, sphere formation, aldehyde dehydrogenase (ALDH) activity and therapy resistance. Mechanistically, specific binding of transcriptionally active cRel-containing NF-kappaB complexes in TICs was observed. Sulforaphane prevented NF-kappaB binding, downregulated apoptosis inhibitors and induced apoptosis, together with prevention of clonogenicity. Gemcitabine, the chemopreventive agents resveratrol and wogonin, and the death ligand TRAIL were less effective. In a xenograft model, sulforaphane strongly blocked tumour growth and angiogenesis, while combination with TRAIL had an additive effect without obvious cytotoxicity in normal cells. Freshly isolated patient tumour cells expressing markers for TICs could be sensitised by sulforaphane for TRAIL-induced cytotoxicity. The data provide new insights into resistance mechanisms of TICs and suggest the combination of sulforaphane with TRAIL as a promising strategy for targeting of pancreatic TICs.

  11. Crosstalk between stromal cells and cancer cells in pancreatic cancer: New insights into stromal biology.

    Science.gov (United States)

    Zhan, Han-Xiang; Zhou, Bin; Cheng, Yu-Gang; Xu, Jian-Wei; Wang, Lei; Zhang, Guang-Yong; Hu, San-Yuan

    2017-04-28

    Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide. Increasing evidence has confirmed the pivotal role of stromal components in the regulation of carcinogenesis, invasion, metastasis, and therapeutic resistance in PC. Interaction between neoplastic cells and stromal cells builds a specific microenvironment, which further modulates the malignant properties of cancer cells. Instead of being a "passive bystander", stroma may play a role as a "partner in crime" in PC. However, the role of stromal components in PC is complex and requires further investigation. In this article, we review recent advances regarding the regulatory roles and mechanisms of stroma biology, especially the cellular components such as pancreatic stellate cells, macrophages, neutrophils, adipocytes, epithelial cells, pericytes, mast cells, and lymphocytes, in PC. Crosstalk between stromal cells and cancer cells is thoroughly investigated. We also review the prognostic value and molecular therapeutic targets of stroma in PC. This review may help us further understand the molecular mechanisms of stromal biology and its role in PC development and therapeutic resistance. Moreover, targeting stroma components may provide new therapeutic strategies for this stubborn disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Association of diabetes and perineural invasion in pancreatic cancer.

    Science.gov (United States)

    Sahin, Ibrahim Halil; Shama, Mohamed A; Tanaka, Motofumi; Abbruzzese, James L; Curley, Steven A; Hassan, Manal; Li, Donghui

    2012-12-01

    Diabetes and perineural invasion are frequently observed in pancreatic cancer. In this study, we tested possible relations between diabetes and perineural invasion in patients with resected pancreatic cancer. We conducted a retrospective study in 544 cases of resected pancreatic adenocarcinoma seen at the University of Texas MD Anderson Cancer Center during 1996-2011. Information on tumor characteristics, diabetes history, and survival time was collected by personal interview and medical record review. Patients with diabetes before or at the time of the pancreatic cancer diagnosis were considered diabetes only. Pearson χ(2) test was used to compare categorical variables in diabetic and nondiabetic groups. Kaplan-Meier plot, log-rank test, and Cox proportional regression models were applied in survival analysis. The prevalence of diabetes and perineural invasion was 26.5% and 86.9%, respectively, in this study population. Patients with diabetes had a significantly higher prevalence of perineural invasion (92.4%) than those without diabetes (85%) (P = 0.025, χ(2) test). Diabetes was not associated with other pathological characteristics of the tumor, such as tumor size, lymphovascular invasion, tumor grade, lymph node metastasis, and resection margin status. Diabetic patients had a significantly lower frequency of abdominal pain (P = 0.01), but a slightly higher frequency of weight loss (P = 0.078) as early symptoms of their cancer. Both diabetes and perineural invasion were related to worse survival and increased risk of death after adjusting for tumor grade and margin and node status (P = 0.036 and 0.019, respectively). The observed associations of diabetes and perineural invasion as well as reduced frequency of pain as early symptom of pancreatic cancer support the hypothesis that diabetes may contribute to pancreatic progression via the mechanism of nerve damage.

  13. Metastatic pancreatic cancer presenting as linitis plastica of the stomach.

    Science.gov (United States)

    Garg, Shivani; Mulki, Ramzi; Sher, Daniel

    2016-03-08

    Metastatic disease from pancreatic carcinoma involving the stomach is an unusual event, and the pattern of spread in the form of linitis plastica, to our knowledge, has not been reported previously. Local recurrence after curative resection for pancreatic cancer is the most common pattern of disease. We report a case of metastatic pancreatic adenocarcinoma presenting as linitis plastica of the stomach 4 years after curative resection. A 52-year-old man presented with epigastric pain and melaena 4 years after undergoing a Whipple's procedure for a poorly-differentiated pancreatic adenocarcinoma, stage IB; T2N0M0. CT imaging of the abdomen revealed thickening of the gastric wall, and subsequent oesophagogastroduodenoscopy (OGD) revealed diffuse friable erythaematous tissue. The biopsy specimen obtained during the OGD revealed a poorly differentiated adenocarcinoma, with similar appearance to the prior specimen obtained from the pancreas. 2016 BMJ Publishing Group Ltd.

  14. CDDO-Me: A Novel Synthetic Triterpenoid for the Treatment of Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Deeb, Dorrah; Gao, Xiaohua [Department of General Surgery, Henry Ford Health System, Detroit, MI 48202 (United States); Arbab, Ali S. [Department of Diagnostic Radiology, Henry Ford Health System, Detroit, MI 48202 (United States); Barton, Kenneth [Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202 (United States); Dulchavsky, Scott A., E-mail: sgautam1@hfhs.org; Gautam, Subhash C., E-mail: sgautam1@hfhs.org [Department of General Surgery, Henry Ford Health System, Detroit, MI 48202 (United States)

    2010-10-13

    Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancy with dismal prognosis and few effective therapeutic options. Novel agents that are safe and effective are urgently needed. Oleanolic acid-derived synthetic triterpenoids are potent antitumorigenic agents, but their efficacy or the mechanism of action for pancreatic cancer has not been adequately investigated. In this study, we evaluated the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid for human pancreatic cancer cell lines. CDDO-Me inhibited the growth of both K-ras mutated (MiaPaca2, Panc1 and Capan2) and wild-type K-ras (BxPC3) pancreatic cancer cells at very low concentrations. The growth inhibitory activity of CDDO-Me was attributed to the induction of apoptosis characterized by increased annexin-V-FITC binding and cleavage of PARP-1 and procaspases-3, -8 and-9. In addition, CDDO-Me induced the loss of mitochondrial membrane potential and release of cytochrome C. The antitumor activity of CDDO-Me was associated with the inhibition of prosurvival p-Akt, NF-κB and mammalian target of rapamycin (mTOR) signaling proteins and the downstream targets of Akt and mTOR, such as p-Foxo3a (Akt) and p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR). Silencing of Akt or mTOR with gene specific-siRNA sensitized the pancreatic cancer cells to CDDO-Me, demonstrating Akt and mTOR as molecular targets of CDDO-Me for its growth inhibitory and apoptosis-inducing activity.

  15. CDDO-Me: A Novel Synthetic Triterpenoid for the Treatment of Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Dorrah Deeb

    2010-10-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDA is one of the most lethal human malignancy with dismal prognosis and few effective therapeutic options. Novel agents that are safe and effective are urgently needed. Oleanolic acid-derived synthetic triterpenoids are potent antitumorigenic agents, but their efficacy or the mechanism of action for pancreatic cancer has not been adequately investigated. In this study, we evaluated the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11-dien-28-oate (CDDO-Me, a oleanane-derived synthetic triterpenoid for human pancreatic cancer cell lines. CDDO-Me inhibited the growth of both K-ras mutated (MiaPaca2, Panc1 and Capan2 and wild-type K-ras (BxPC3 pancreatic cancer cells at very low concentrations. The growth inhibitory activity of CDDO-Me was attributed to the induction of apoptosis characterized by increased annexin-V-FITC binding and cleavage of PARP-1 and procaspases-3, -8 and-9. In addition, CDDO-Me induced the loss of mitochondrial membrane potential and release of cytochrome C. The antitumor activity of CDDO-Me was associated with the inhibition of prosurvival p-Akt, NF-κB and mammalian target of rapamycin (mTOR signaling proteins and the downstream targets of Akt and mTOR, such as p-Foxo3a (Akt and p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR. Silencing of Akt or mTOR with gene specific-siRNA sensitized the pancreatic cancer cells to CDDO-Me, demonstrating Akt and mTOR as molecular targets of CDDO-Me for its growth inhibitory and apoptosis-inducing activity.

  16. Somatostatin receptor gene transfer inhibits established pancreatic cancer xenografts.

    Science.gov (United States)

    Celinski, Scott A; Fisher, William E; Amaya, Felipe; Wu, Yuan Qing; Yao, Q; Youker, Keith A; Li, Min

    2003-11-01

    Most human pancreatic adenocarcinoma cells do not express somatostatin receptors, and somatostatin does not inhibit the growth of these cancers. We have demonstrated previously that somatostatin inhibits the growth of pancreatic cancers expressing somatostatin receptor subtype-2 (SSTR2), but not receptor-negative cancers. SSTR2 expression may be an important tumor-suppressor pathway that is lost in human pancreatic cancer. We hypothesized that SSTR2 gene transfer would restore the growth-inhibitory response of human pancreatic cancer to somatostatin. Palpable human pancreatic adenocarcinoma tumors were established on the backs of nude mice by subcutaneous injection of cultured cells (Panc-1). The animals were divided into 5 groups (n = 10/group). Group I served as an untreated control. Group II received an intramuscular injection of the long-acting somatostatin analogue Sandostatin LAR. Group III received Lac-Z expressing adenovirus via intraperitoneal injection. Group IV received SSTR2 expressing adenovirus via intraperitoneal injection. Group V received SSTR2 expressing adenovirus via intraperitoneal injection and an intramuscular injection of Sandostatin LAR. The rate of tumor growth was assessed with calipers. After 28 days, the animals were anesthetized and exsanguanated, and the tumors were excised and weighed. Plasma somatostatin and octreotide levels were measured by radioimmunoassay. Expression of cell-surface somatostatin-receptor protein and known tumor-suppressor proteins was determined by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. Systemic delivery of SSTR2-expressing adenovirus by intraperitoneal injection resulted in expression of SSTR2 protein in the subcutaneous human pancreatic cancers. Final tumor weight was significantly decreased in the groups expressing SSTR2 receptors compared to the other 3 groups. Treatment with Sandostatin LAR increased plasma octreotide levels as determined by radioimmunoassay

  17. Comprehensive Evaluation of Altered Systemic Metabolism and Pancreatic Cancer Risk

    Science.gov (United States)

    2016-10-01

    capture . 98% of deaths.18 Diagnoses were confirmed by review of medical records, death certificates , and/or tumor registry data by study physicians...REFERENCES 1. Siegel RL, Miller KD, Jemal A: Cancer statis- tics , 2016. CA Cancer J Clin 66:7-30, 2016 2. Hidalgo M: Pancreatic cancer. N Engl J Med 362:1605...controls (Supplementary Table 1). Of these 470 cases, 465 (99%) were confirmed by review of medical records, tumor registry data, or death certificates

  18. MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition.

    Science.gov (United States)

    Roy, L D; Sahraei, M; Subramani, D B; Besmer, D; Nath, S; Tinder, T L; Bajaj, E; Shanmugam, K; Lee, Y Y; Hwang, S I L; Gendler, S J; Mukherjee, P

    2011-03-24

    Increased motility and invasiveness of pancreatic cancer cells are associated with epithelial to mesenchymal transition (EMT). Snai1 and Slug are zinc-finger transcription factors that trigger this process by repressing E-cadherin and enhancing vimentin and N-cadherin protein expression. However, the mechanisms that regulate this activation in pancreatic tumors remain elusive. MUC1, a transmembrane mucin glycoprotein, is associated with the most invasive forms of pancreatic ductal adenocarcinomas (PDA). In this study, we show that over expression of MUC1 in pancreatic cancer cells triggers the molecular process of EMT, which translates to increased invasiveness and metastasis. EMT was significantly reduced when MUC1 was genetically deleted in a mouse model of PDA or when all seven tyrosines in the cytoplasmic tail of MUC1 were mutated to phenylalanine (mutated MUC1 CT). Using proteomics, RT-PCR and western blotting, we revealed a significant increase in vimentin, Slug and Snail expression with repression of E-Cadherin in MUC1-expressing cells compared with cells expressing the mutated MUC1 CT. In the cells that carried the mutated MUC1 CT, MUC1 failed to co-immunoprecipitate with β-catenin and translocate to the nucleus, thereby blocking transcription of the genes associated with EMT and metastasis. Thus, functional tyrosines are critical in stimulating the interactions between MUC1 and β-catenin and their nuclear translocation to initiate the process of EMT. This study signifies the oncogenic role of MUC1 CT and is the first to identify a direct role of the MUC1 in initiating EMT during pancreatic cancer. The data may have implications in future design of MUC1-targeted therapies for pancreatic cancer.

  19. Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy

    Directory of Open Access Journals (Sweden)

    Neoptolemos John P

    2011-04-01

    Full Text Available Abstract Background Nrf2 is a key transcriptional regulator of a battery of genes that facilitate phase II/III drug metabolism and defence against oxidative stress. Nrf2 is largely regulated by Keap1, which directs Nrf2 for proteasomal degradation. The Nrf2/Keap1 system is dysregulated in lung, head and neck, and breast cancers and this affects cellular proliferation and response to therapy. Here, we have investigated the integrity of the Nrf2/Keap1 system in pancreatic cancer. Results Keap1, Nrf2 and the Nrf2 target genes AKR1c1 and GCLC were detected in a panel of five pancreatic cancer cell lines. Mutation analysis of NRF2 exon 2 and KEAP1 exons 2-6 in these cell lines identified no mutations in NRF2 and only synonomous mutations in KEAP1. RNAi depletion of Nrf2 caused a decrease in the proliferation of Suit-2, MiaPaca-2 and FAMPAC cells and enhanced sensitivity to gemcitabine (Suit-2, 5-flurouracil (FAMPAC, cisplatin (Suit-2 and FAMPAC and gamma radiation (Suit-2. The expression of Nrf2 and Keap1 was also analysed in pancreatic ductal adenocarcinomas (n = 66 and 57, respectively and matching normal benign epithelium (n = 21 cases. Whilst no significant correlation was seen between the expression levels of Keap1 and Nrf2 in the tumors, interestingly, Nrf2 staining was significantly greater in the cytoplasm of tumors compared to benign ducts (P Conclusions Expression of Nrf2 is up-regulated in pancreatic cancer cell lines and ductal adenocarcinomas. This may reflect a greater intrinsic capacity of these cells to respond to stress signals and resist chemotherapeutic interventions. Nrf2 also appears to support proliferation in certain pancreatic adenocarinomas. Therefore, strategies to pharmacologically manipulate the levels and/or activity of Nrf2 may have the potential to reduce pancreatic tumor growth, and increase sensitivity to therapeutics.

  20. Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xu Zhu

    2018-02-01

    Full Text Available Pancreatic cancer is characterized by mutated signaling pathways and a high incidence of drug resistance. Comprehensive, large-scale proteomic analysis can provide a system-wide view of signaling networks, assist in understanding drug mechanisms of action and interactions, and serve as a useful tool for pancreatic cancer research. In this study, liquid chromatography-mass spectrometry-based proteomic analysis was applied to characterize the combination of gemcitabine and birinapant in pancreatic cancer cells, which was shown previously to be synergistic. A total of 4069 drug-responsive proteins were identified and quantified in a time-series proteome analysis. This rich dataset provides broad views and accurate quantification of signaling pathways. Pathways relating to DNA damage response regulations, DNA repair, anti-apoptosis, pro-migration/invasion were implicated as underlying mechanisms for gemcitabine resistance and for the beneficial effects of the drug combination. Promising drug targets were identified for future investigation. This study also provides a database for systems mathematical modeling to relate drug effects and interactions in various signaling pathways in pancreatic cancer cells.

  1. Profile and potential of ixabepilone in the treatment of pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Smaglo BG

    2014-07-01

    Full Text Available Brandon G Smaglo, Michael J PishvaianLombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USAAbstract: The management of metastatic pancreatic adenocarcinoma is a challenge for medical oncologists because of both the aggressive nature of the disease and the relative paucity of effective systemic treatments with activity against this type of tumor. In the effort to discover new agents and combinations that may augment the therapeutic arsenal available for the management of this cancer, early phase clinical trials have been performed using ixabepilone, an epothilone B analog, with promising results. Targeting the microtubule system with certain taxanes in the management of pancreatic adenocarcinoma has been validated; ixabepilone also targets the microtubule system, interfering with it in an alternate manner from the taxane mechanism. Ixabepilone has demonstrated activity in cancers that have become taxane-resistant as well as those that never had any demonstrable taxane susceptibility. The available data for the use of ixabepilone in the management of pancreatic adenocarcinoma are limited but promising. Single-arm studies have demonstrated both clinical efficacy and tolerable toxicity for the use of ixabepilone as monotherapy. The trial data available for ixabepilone used as a part of combination therapy are similar: it has been paired with chemotherapy (carboplatin, irinotecan and biologic therapy (dasatinib, sunitinib at the Phase I level to treat solid tumors in general, again with tolerable side effects and a suggestion of benefit. A single Phase II study has evaluated combination therapy with ixabepilone in the management of patients with pancreatic cancer, pairing it with cetuximab with clinical benefit. Although these trials are promising with regard to addition of ixabepilone to the slim armamentarium for management of pancreatic cancer, further work is still to be done. Importantly, this work bears the burden of

  2. Regular use of aspirin and pancreatic cancer risk

    Directory of Open Access Journals (Sweden)

    Mahoney Martin C

    2002-09-01

    Full Text Available Abstract Background Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs has been consistently associated with reduced risk of colorectal cancer and adenoma, and there is some evidence for a protective effect for other types of cancer. As experimental studies reveal a possible role for NSAIDs is reducing the risk of pancreatic cancer, epidemiological studies examining similar associations in human populations become more important. Methods In this hospital-based case-control study, 194 patients with pancreatic cancer were compared to 582 age and sex-matched patients with non-neoplastic conditions to examine the association between aspirin use and risk of pancreatic cancer. All participants received medical services at the Roswell Park Cancer Institute in Buffalo, NY and completed a comprehensive epidemiologic questionnaire that included information on demographics, lifestyle factors and medical history as well as frequency and duration of aspirin use. Patients using at least one tablet per week for at least six months were classified as regular aspirin users. Unconditional logistic regression was used to compute crude and adjusted odds ratios (ORs with 95% confidence intervals (CIs. Results Pancreatic cancer risk in aspirin users was not changed relative to non-users (adjusted OR = 1.00; 95% CI 0.72–1.39. No significant change in risk was found in relation to greater frequency or prolonged duration of use, in the total sample or in either gender. Conclusions These data suggest that regular aspirin use may not be associated with lower risk of pancreatic cancer.

  3. The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion.

    Science.gov (United States)

    Lu, Chunwan; Paschall, Amy V; Shi, Huidong; Savage, Natasha; Waller, Jennifer L; Sabbatini, Maria E; Oberlies, Nicholas H; Pearce, Cedric; Liu, Kebin

    2017-01-01

    Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided. PD-L1 is expressed in 60% to 90% of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2% to 52.1% of pancreatic tumor-infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P = .03-.001) and when CTLs are neutralized (P = .03-evasion. Targeting the MLL1-H3K4me3 axis is an effective approach to enhance the efficacy of checkpoint immunotherapy against pancreatic cancer. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. The Role of Platelet-Derived ADP and ATP in Promoting Pancreatic Cancer Cell Survival and Gemcitabine Resistance

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    Omar Elaskalani

    2017-10-01

    Full Text Available Platelets have been demonstrated to be vital in cancer epithelial-mesenchymal transition (EMT, an important step in metastasis. Markers of EMT are associated with chemotherapy resistance. However, the association between the development of chemoresistance, EMT, and the contribution of platelets to the process, is still unclear. Here we report that platelets regulate the expression of (1 human equilibrative nucleoside transporter 1 (hENT1 and (2 cytidine deaminase (CDD, markers of gemcitabine resistance in pancreatic cancer. Human ENT1 (hENT1 is known to enable cellular uptake of gemcitabine while CDD deactivates gemcitabine. Knockdown experiments demonstrate that Slug, a mesenchymal transcriptional factor known to be upregulated during EMT, regulates the expression of hENT1 and CDD. Furthermore, we demonstrate that platelet-derived ADP and ATP regulate Slug and CDD expression in pancreatic cancer cells. Finally, we demonstrate that pancreatic cancer cells express the purinergic receptor P2Y12, an ADP receptor found mainly on platelets. Thus ticagrelor, a P2Y12 inhibitor, was used to examine the potential therapeutic effect of an ADP receptor antagonist on cancer cells. Our data indicate that ticagrelor negated the survival signals initiated in cancer cells by platelet-derived ADP and ATP. In conclusion, our results demonstrate a novel role of platelets in modulating chemoresistance in pancreatic cancer. Moreover, we propose ADP/ATP receptors as additional potential drug targets for treatment of pancreatic cancer.

  5. TM4SF1 Promotes Gemcitabine Resistance of Pancreatic Cancer In Vitro and In Vivo.

    Directory of Open Access Journals (Sweden)

    Jia Cao

    Full Text Available TM4SF1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC and affects the development of this cancer. Also, multidrug resistance (MDR is generally associated with tumor chemoresistance in pancreatic cancer. However, the correlation between TM4SF1 and MDR remains unknown. This research aims to investigate the effect of TM4SF1 on gemcitabine resistance in PDAC and explore the possible molecular mechanism between TM4SF1 and MDR.The expression of TM4SF1 was evaluated in pancreatic cancer cell lines and human pancreatic duct epithelial (HPDE cell lines by quantitative RT-PCR. TM4SF1 siRNA transfection was carried out using Hiperfect transfection reagent to knock down TM4SF1. The transcripts were analyzed by quantitative RT-PCR, RT-PCR and western blotting for further study. The cell proliferation and apoptosis were obtained to investigate the sensitivity to gemcitabine of pancreatic cancer cells after silencing TM4SF1 in vitro. We demonstrated that cell signaling of TM4SF1 mediated chemoresistance in cancer cells by assessing the expression of multidrug resistance (MDR genes using quantitative RT-PCR. In vivo, we used orthotopic pancreatic tumor models to investigate the effect of proliferation after silencing TM4SF1 by a lentivirus-mediated shRNA in MIA PaCa-2 cell lines.The mRNA expression of TM4SF1 was higher in seven pancreatic cancer cell lines than in HPDE cell lines. In three gemcitabine-sensitive cell lines (L3.6pl, BxPC-3, SU86.86, the expression of TM4SF1 was lower than that in four gemcitabine-resistant cell lines (MIA PaCa-2, PANC-1, Hs766T, AsPC-1. We evaluated that TM4SF1 was a putative target for gemcitabine resistance in pancreatic cancer cells. Using AsPC-1, MIA PaCa-2 and PANC-1, we investigated that TM4SF1 silencing affected cell proliferation and increased the percentages of cell apoptosis mediated by treatment with gemcitabine compared with cells which were treated with negative control. This resistance was associated

  6. MiR-371-5p facilitates pancreatic cancer cell proliferation and decreases patient survival.

    Directory of Open Access Journals (Sweden)

    De He

    Full Text Available microRNAs (miRNAs play a critical role in tumorigenesis, either as a tumor suppressor or as an oncogenic miRNA, depending on different tumor types. To date, scientists have obtained a substantial amount of knowledge with regard to miRNAs in pancreatic cancer. However, the expression and function of miR-371-5p in pancreatic cancer has not been clearly elucidated. The aim of this study was to investigate the roles of miR-371-5p in pancreatic cancer and its association with the survival of patients with pancreatic cancer.The expression of miR-371-5p was examined in pancreatic duct adenocarcinoma (PDAC and their adjacent normal pancreatic tissues (ANPT or in pancreatic cancer cell lines by qRT-PCR. The association of miR-371-5p expression with overall survival was determined. The proliferation and apoptosis of SW-1990 and Panc-1 cells, transfected with miR-371-5p mimics or inhibitor, were assessed using MTT assay and flow cytometry, respectively. The tumorigenicity was evaluated via mice xenograft experiments. miR-371-5p promoter interactions were analyzed by chromatin immunoprecipitation assays (ChIP. Protein expression was analyzed by Western blot.The expression level of miR-371-5p was dramatically upregulated in clinical PDAC tissues compared with ANPT. Patients with high miR-371-5p expression had a significantly shorter survival than those with low miR-371-5p expression. The in vitro and in vivo assays showed that overexpression of miR-371-5p resulted in cell proliferation and increased tumor growth, which was associated with inhibitor of growth 1 (ING1 downregulation. Interestingly, we also found that ING1, in turn, inhibited expression of miR-371-5p in the promoter region.our study demonstrates a novel ING1-miR-371-5p regulatory feedback loop, which may have a critical role in PDAC. Thus miR-371-5p can prove to be a novel prognostic factor and therapeutic target for pancreatic cancer treatment.

  7. Aberrant over-expression of TRPM7 ion channels in pancreatic cancer: required for cancer cell invasion and implicated in tumor growth and metastasis

    Directory of Open Access Journals (Sweden)

    Nelson S. Yee

    2015-03-01

    Full Text Available Our previous studies in zebrafish development have led to identification of the novel roles of the transient receptor potential melastatin-subfamily member 7 (TRPM7 ion channels in human pancreatic cancer. However, the biological significance of TRPM7 channels in pancreatic neoplasms was mostly unexplored. In this study, we determined the expression levels of TRPM7 in pancreatic tissue microarrays and correlated these measurements in pancreatic adenocarcinoma with the clinicopathological features. We also investigated the role of TRPM7 channels in pancreatic cancer cell invasion using the MatrigelTM-coated transwell assay. In normal pancreas, TRPM7 is expressed at a discernable level in the ductal cells and centroacinar cells and at a relatively high level in the islet endocrine cells. In chronic pancreatitis, pre-malignant tissues, and malignant neoplasms, there is variable expression of TRPM7. In the majority of pancreatic adenocarcinoma specimens examined, TRPM7 is expressed at either moderate-level or high-level. Anti-TRPM7 immunoreactivity in pancreatic adenocarcinoma significantly correlates with the size and stages of tumors. In human pancreatic adenocarcinoma cells in which TRPM7 is highly expressed, short hairpin RNA-mediated suppression of TRPM7 impairs cell invasion. The results demonstrate that TRPM7 channels are over-expressed in a proportion of the pre-malignant lesions and malignant tumors of the pancreas, and they are necessary for invasion by pancreatic cancer cells. We propose that TRPM7 channels play important roles in development and progression of pancreatic neoplasm, and they may be explored as clinical biomarkers and targets for its prevention and treatment.

  8. Host sphingosine kinase 1 worsens pancreatic cancer peritoneal carcinomatosis.

    Science.gov (United States)

    Aoki, Hiroaki; Aoki, Masayo; Katsuta, Eriko; Ramanathan, Rajesh; Idowu, Michael O; Spiegel, Sarah; Takabe, Kazuaki

    2016-10-01

    There are no effective treatments for pancreatic cancer peritoneal carcinomatosis (PC) or cancer dissemination in abdominal cavity. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by sphingosine kinases (SphK1 and SphK2), plays critical roles in cancer progression. We reported that SphK1, but not SphK2, is responsible for S1P export from breast cancer cells and recently discovered that S1P is linked to inflammation and cancer in colitis-associated cancer progression. Given the fact that inflammation is known to be essential for the establishment and progression of PC, we hypothesized that SphK1 in the host animals is involved in progression of pancreatic cancer PC. Murine pancreatic adenocarcinoma panc02-luc cells were intraperitoneally injected into wildtype or SphK1 knockout (KO) mice to generate a syngeneic PC model. Cell proliferation and apoptosis were determined by Ki67 and TUNEL staining, respectively. All the animals developed panc02-luc PC. SphK1 KO mice developed significantly less tumor burden, less total tumor weight, and fewer number of PC nodules at 14 d after implantation. Histologically, less inflammatory cell infiltration and less cancer cell proliferation were observed in the tumors. There was no difference in apoptosis. Our results raise an intriguing possibility that S1P generated by SphK1 in the host promotes pancreatic cancer PC progression by stimulation of proliferation of cancer cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Radiotherapy technical considerations in the management of locally advanced pancreatic cancer: American-French consensus recommendations.

    Science.gov (United States)

    Huguet, Florence; Goodman, Karyn A; Azria, David; Racadot, Severine; Abrams, Ross A

    2012-08-01

    Pancreatic carcinoma is a leading cause of cancer-related mortality. Approximately 30% of pancreatic cancer patients present with locally advanced, unresectable nonmetastatic disease. For these patients, two therapeutic options exist: systemic chemotherapy or chemoradiotherapy. Within this context, the optimal technique for pancreatic irradiation is not clearly defined. A search to identify relevant studies was undertaken using the Medline database. All Phase III randomized trials evaluating the modalities of radiotherapy in locally advanced pancreatic cancer were included, as were some noncontrolled Phase II and retrospective studies. An expert panel convened with members of the Radiation Therapy Oncology Group and GERCOR cooperative groups to review identified studies and prepare the guidelines. Each member of the working group independently evaluated five endpoints: total dose, target volume definition, radiotherapy planning technique, dose constraints to organs at risk, and quality assurance. Based on this analysis of the literature, we recommend either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to a total dose of 50 to 54 Gy at 1.8 to 2 Gy per fraction. We propose gross tumor volume identification to be followed by an expansion of 1.5 to 2 cm anteriorly, posteriorly, and laterally, and 2 to 3 cm craniocaudally to generate the planning target volume. The craniocaudal margins can be reduced with the use of respiratory gating. Organs at risk are liver, kidneys, spinal cord, stomach, and small bowel. Stereotactic body radiation therapy should not be used for pancreatic cancer outside of clinical trials. Radiotherapy quality assurance is mandatory in clinical trials. These consensus recommendations are proposed for use in the development of future trials testing new chemotherapy combinations with radiotherapy. Not all of these recommendations will be appropriate for trials testing radiotherapy dose or dose intensity

  10. Radiotherapy Technical Considerations in the Management of Locally Advanced Pancreatic Cancer: American-French Consensus Recommendations

    International Nuclear Information System (INIS)

    Huguet, Florence; Goodman, Karyn A.; Azria, David; Racadot, Severine; Abrams, Ross A.

    2012-01-01

    Summary: Pancreatic carcinoma is a leading cause of cancer-related mortality. Approximately 30% of pancreatic cancer patients present with locally advanced, unresectable nonmetastatic disease. For these patients, two therapeutic options exist: systemic chemotherapy or chemoradiotherapy. Within this context, the optimal technique for pancreatic irradiation is not clearly defined. A search to identify relevant studies was undertaken using the Medline database. All Phase III randomized trials evaluating the modalities of radiotherapy in locally advanced pancreatic cancer were included, as were some noncontrolled Phase II and retrospective studies. An expert panel convened with members of the Radiation Therapy Oncology Group and GERCOR cooperative groups to review identified studies and prepare the guidelines. Each member of the working group independently evaluated five endpoints: total dose, target volume definition, radiotherapy planning technique, dose constraints to organs at risk, and quality assurance. Based on this analysis of the literature, we recommend either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to a total dose of 50 to 54 Gy at 1.8 to 2 Gy per fraction. We propose gross tumor volume identification to be followed by an expansion of 1.5 to 2 cm anteriorly, posteriorly, and laterally, and 2 to 3 cm craniocaudally to generate the planning target volume. The craniocaudal margins can be reduced with the use of respiratory gating. Organs at risk are liver, kidneys, spinal cord, stomach, and small bowel. Stereotactic body radiation therapy should not be used for pancreatic cancer outside of clinical trials. Radiotherapy quality assurance is mandatory in clinical trials. These consensus recommendations are proposed for use in the development of future trials testing new chemotherapy combinations with radiotherapy. Not all of these recommendations will be appropriate for trials testing radiotherapy dose or dose

  11. Nanotechnology for delivery of gemcitabine to treat pancreatic cancer.

    Science.gov (United States)

    Birhanu, Gebremariam; Javar, Hamid Akbari; Seyedjafari, Ehsan; Zandi-Karimi, Ali

    2017-04-01

    Pancreatic cancer (PC) is one of the most deadly and quickly fatal human cancers with a 5-year mortality rate close to 100%. Its prognosis is very poor, mainly because of its hostile biological behavior and late onset of symptoms for clinical diagnosis; these bring limitations on therapeutic interventions. Factors contributing for the difficulties in treating PC include: high rate of drug resistance, fast metastasis to different organs, poor prognosis and relapse of the tumor after therapy. After being approved by US FDA 1997, Gemcitabine (Gem) is the first line and the gold standard drug for all stages of advanced PC till now. However, its efficacy is unsatisfactory, mainly due to; its chemical instability and poor cellular uptake, resulting in an extremely short half-life and low bioavailability. To solve this drawbacks and increase the therapeutic outcome important progress has been achieved in the field of nanotechnology and offers a promising and effective alternative. This review mainly focus on the most commonly investigated nanoparticle (NP) delivery systems of Gem for PC treatment and the latest progresses achieved. Novel nanocarriers with better tumor targeting efficiencies and maximum treatment outcome to treat this deadly due are given much attention. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

    NARCIS (Netherlands)

    Klein, Alison P; Wolpin, Brian M; Risch, Harvey A; Stolzenberg-Solomon, Rachael Z; Mocci, Evelina; Zhang, Mingfeng; Canzian, Federico; Childs, Erica J; Hoskins, Jason W; Jermusyk, Ashley; Zhong, Jun; Sund, Malin; Talar-Wojnarowska, Renata; Tavano, Francesca; Thornquist, Mark D; Tobias, Geoffrey S; Van Den Eeden, Stephen K; Vashist, Yogesh; Visvanathan, Kala; Vodicka, Pavel; Wactawski-Wende, Jean; Chen, Fei; Wang, Zhaoming; Wentzensen, Nicolas; White, Emily; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Kraft, Peter; Li, Donghui; Chanock, Stephen; Albanes, Demetrius; Obazee, Ofure; Petersen, Gloria M; Amundadottir, Laufey T; Andreotti, Gabriella; Arslan, Alan A; Babic, Ana; Bamlet, William R; Beane-Freeman, Laura; Berndt, Sonja I; Blackford, Amanda; Borges, Michael; Borgida, Ayelet; Bracci, Paige M; Brais, Lauren; Brennan, Paul; Brenner, Hermann; Bueno-de-Mesquita, Bas; Buring, Julie; Campa, Daniele; Capurso, Gabriele; Cavestro, Giulia Martina; Chaffee, Kari G; Chung, Charles C; Cleary, Sean; Cotterchio, Michelle; Dijk, Frederike; Duell, Eric J; Foretova, Lenka; Fuchs, Charles; Funel, Niccola; Gallinger, Steven; M Gaziano, J Michael; Gazouli, Maria; Giles, Graham G; Giovannucci, Edward; Goggins, Michael; Goodman, Gary E; Goodman, Phyllis J; Hackert, Thilo; Haiman, Christopher; Hartge, Patricia; Hasan, Manal; Hegyi, Peter; Helzlsouer, Kathy J; Herman, Joseph; Holcatova, Ivana; Holly, Elizabeth A; Hoover, Robert; Hung, Rayjean J; Jacobs, Eric J; Jamroziak, Krzysztof; Janout, Vladimir; Kaaks, Rudolf; Khaw, Kay-Tee; Klein, Eric A; Kogevinas, Manolis; Kooperberg, Charles; Kulke, Matthew H; Kupcinskas, Juozas; Kurtz, Robert J; Laheru, Daniel; Landi, Stefano; Lawlor, Rita T; Lee, I-Min; LeMarchand, Loic; Lu, Lingeng; Malats, Núria; Mambrini, Andrea; Mannisto, Satu; Milne, Roger L; Mohelníková-Duchoňová, Beatrice; Neale, Rachel E; Neoptolemos, John P; Oberg, Ann L; Olson, Sara H; Orlow, Irene; Pasquali, Claudio; Patel, Alpa V; Peters, Ulrike; Pezzilli, Raffaele; Porta, Miquel; Real, Francisco X; Rothman, Nathaniel; Scelo, Ghislaine; Sesso, Howard D; Severi, Gianluca; Shu, Xiao-Ou; Silverman, Debra; Smith, Jill P; Soucek, Pavel

    2018-01-01

    In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic

  13. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

    NARCIS (Netherlands)

    Klein, Alison P.; Wolpin, Brian M.; Risch, Harvey A.; Stolzenberg-Solomon, Rachael Z.; Mocci, Evelina; Zhang, Mingfeng; Canzian, Federico; Childs, Erica J.; Hoskins, Jason W.; Jermusyk, Ashley; Zhong, Jun; Chen, Fei; Albanes, Demetrius; Andreotti, Gabriella; Arslan, Alan A.; Babic, Ana; Bamlet, William R.; Beane-Freeman, Laura; Berndt, Sonja I.; Blackford, Amanda; Borges, Michael; Borgida, Ayelet; Bracci, Paige M.; Brais, Lauren; Brennan, Paul; Brenner, Hermann; Bueno-de-Mesquita, Bas; Buring, Julie; Campa, Daniele; Capurso, Gabriele; Cavestro, Giulia Martina; Chaffee, Kari G.; Chung, Charles C.; Cleary, Sean; Cotterchio, Michelle; Dijk, Frederike; Duell, Eric J.; Foretova, Lenka; Fuchs, Charles; Funel, Niccola; Gallinger, Steven; M Gaziano, J. Michael; Gazouli, Maria; Giles, Graham G.; Giovannucci, Edward; Goggins, Michael; Goodman, Gary E.; Goodman, Phyllis J.; Hackert, Thilo; Haiman, Christopher; Hartge, Patricia; Hasan, Manal; Hegyi, Peter; Helzlsouer, Kathy J.; Herman, Joseph; Holcatova, Ivana; Holly, Elizabeth A.; Hoover, Robert; Hung, Rayjean J.; Jacobs, Eric J.; Jamroziak, Krzysztof; Janout, Vladimir; Kaaks, Rudolf; Khaw, Kay-Tee; Klein, Eric A.; Kogevinas, Manolis; Kooperberg, Charles; Kulke, Matthew H.; Kupcinskas, Juozas; Kurtz, Robert J.; Laheru, Daniel; Landi, Stefano; Lawlor, Rita T.; Lee, I.-Min; Lemarchand, Loic; Lu, Lingeng; Malats, Núria; Mambrini, Andrea; Mannisto, Satu; Milne, Roger L.; Mohelníková-Duchoňová, Beatrice; Neale, Rachel E.; Neoptolemos, John P.; Oberg, Ann L.; Olson, Sara H.; Orlow, Irene; Pasquali, Claudio; Patel, Alpa V.; Peters, Ulrike; Pezzilli, Raffaele; Porta, Miquel; Real, Francisco X.; Rothman, Nathaniel; Scelo, Ghislaine; Sesso, Howard D.; Severi, Gianluca; Shu, Xiao-Ou; Silverman, Debra; Smith, Jill P.; Soucek, Pavel; Sund, Malin; Talar-Wojnarowska, Renata; Tavano, Francesca; Thornquist, Mark D.; Tobias, Geoffrey S.; van den Eeden, Stephen K.; Vashist, Yogesh; Visvanathan, Kala; Vodicka, Pavel; Wactawski-Wende, Jean; Wang, Zhaoming; Wentzensen, Nicolas; White, Emily; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Kraft, Peter; Li, Donghui; Chanock, Stephen; Obazee, Ofure; Petersen, Gloria M.; Amundadottir, Laufey T.

    2018-01-01

    In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic

  14. The Hemostasis Apparatus in Pancreatic Cancer and Its Importance beyond Thrombosis

    Directory of Open Access Journals (Sweden)

    Hussein Echrish

    2011-01-01

    Full Text Available Laboratory evidence of aberrant coagulation is found in the majority of patients with advanced pancreatic cancer and a clinical consequence of this is the high incidence and prevalence of vascular thromboembolic events. Other sequelae are hypothesized to be the facilitation and acceleration of mechanisms that define the malignant phenotype, such as invasion, trafficking and anchoring, establishing the metastatic niche and inducing angiogenesis. We review the in vitro and preclinical evidence that supports the role of the coagulation apparatus in the metastatic process of pancreatic cancer, with a particular emphasis on interaction of this pathway with clinically-targeted growth factor receptor pathways. Links between hemostasis, angiogenesis and epidermal growth factor pathways and their significance as therapeutic targets are considered.

  15. The Hemostasis Apparatus in Pancreatic Cancer and Its Importance beyond Thrombosis

    Energy Technology Data Exchange (ETDEWEB)

    Echrish, Hussein; Madden, Leigh A.; Greenman, John [Centre for Biomedical Research, PGMI, University of Hull, Hull, HU6 7RX (United Kingdom); Maraveyas, Anthony, E-mail: anthony.maraveyas@hey.nhs.uk [Queen' s Centre for Oncology and Haematology, Castle Hill Hospital, Castle Road, Cottingham, HU16 5JQ (United Kingdom)

    2011-01-11

    Laboratory evidence of aberrant coagulation is found in the majority of patients with advanced pancreatic cancer and a clinical consequence of this is the high incidence and prevalence of vascular thromboembolic events. Other sequelae are hypothesized to be the facilitation and acceleration of mechanisms that define the malignant phenotype, such as invasion, trafficking and anchoring, establishing the metastatic niche and inducing angiogenesis. We review the in vitro and preclinical evidence that supports the role of the coagulation apparatus in the metastatic process of pancreatic cancer, with a particular emphasis on interaction of this pathway with clinically-targeted growth factor receptor pathways. Links between hemostasis, angiogenesis and epidermal growth factor pathways and their significance as therapeutic targets are considered.

  16. Dynamic Contrast-Enhanced CT in Patients with Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Rie Ø. Eriksen

    2016-09-01

    Full Text Available The aim of this systematic review is to provide an overview of the use of Dynamic Contrast-enhanced Computed Tomography (DCE-CT in patients with pancreatic cancer. This study was composed according to the PRISMA guidelines 2009. The literature search was conducted in PubMed, Cochrane Library, EMBASE, and Web of Science databases to identify all relevant publications. The QUADAS-2 tool was implemented to assess the risk of bias and applicability concerns of each included study. The initial literature search yielded 483 publications. Thirteen articles were included. Articles were categorized into three groups: nine articles concerning primary diagnosis or staging, one article about tumor response to treatment, and three articles regarding scan techniques. In exocrine pancreatic tumors, measurements of blood flow in eight studies and blood volume in seven studies were significantly lower in tumor tissue, compared with measurements in pancreatic tissue outside of tumor, or normal pancreatic tissue in control groups of healthy volunteers. The studies were heterogeneous in the number of patients enrolled and scan protocols. Perfusion parameters measured and analyzed by DCE-CT might be useful in the investigation of characteristic vascular patterns of exocrine pancreatic tumors. Further clinical studies are desired for investigating the potential of DCE-CT in pancreatic tumors.

  17. Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer

    International Nuclear Information System (INIS)

    Forero-Torres, Andres; Infante, Jeffrey R; Waterhouse, David; Wong, Lucas; Vickers, Selwyn; Arrowsmith, Edward; He, Aiwu Ruth; Hart, Lowell; Trent, David; Wade, James; Jin, Xiaoping; Wang, Qiang; Austin, TaShara; Rosen, Michael; Beckman, Robert; Roemeling, Reinhard von; Greenberg, Jonathan; Saleh, Mansoor

    2013-01-01

    Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m 2 once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3–64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2–5.4 months). Median OS was 8.2 months (95% CI, 5.1–9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer

  18. Diagnosing pancreatic cancer: the role of percutaneous biopsy and CT

    International Nuclear Information System (INIS)

    Amin, Z.; Theis, B.; Russell, R.C.G.; House, C.; Novelli, M.; Lees, W.R.

    2006-01-01

    Aims: To determine the sensitivity and complications of percutaneous biopsy of pancreatic masses, and whether typical computed tomography (CT) features of adenocarcinoma can reliably predict this diagnosis. Materials and methods: A 5 year retrospective analysis of percutaneous core biopsies of pancreatic masses and their CT features was undertaken. Data were retrieved from surgical/pathology databases; medical records and CT reports and images. Results: Three hundred and three patients underwent 372 biopsies; 56 of 87 patients had repeat biopsies. Malignancy was diagnosed in 276 patients, with ductal adenocarcinoma in 259 (85%). Final sensitivity of percutaneous biopsy for diagnosing pancreatic neoplasms was 90%; for repeat biopsy it was 87%. Complications occurred in 17 (4.6%) patients, in three of whom the complications were major (1%): one abscess, one duodenal perforation, one large retroperitoneal bleed. CT features typical of ductal adenocarcinoma were: hypovascular pancreatic mass with bile and/or pancreatic duct dilatation. Atypical CT features were: isodense or hypervascular mass, calcification, non-dilated ducts, cystic change, and extensive lymphadenopathy. Defining typical CT features of adenocarcinoma as true-positives, CT had a sensitivity of 68%, specificity of 95%, positive predictive value (PPV) of 98%, and negative predictive value of 41% for diagnosing pancreatic adenocarcinoma. Conclusion: Final sensitivity of percutaneous biopsy for establishing the diagnosis was 90%. CT features typical of pancreatic adenocarcinoma had high specificity and PPV. On some occasions, especially in frail patients with co-morbidity, it might be reasonable to assume a diagnosis of pancreatic cancer if CT features are typical, and biopsy only if CT shows atypical features

  19. Diagnosing pancreatic cancer: the role of percutaneous biopsy and CT

    Energy Technology Data Exchange (ETDEWEB)

    Amin, Z.; Theis, B.; Russell, R.C.G.; House, C.; Novelli, M.; Lees, W.R

    2006-12-15

    Aims: To determine the sensitivity and complications of percutaneous biopsy of pancreatic masses, and whether typical computed tomography (CT) features of adenocarcinoma can reliably predict this diagnosis. Materials and methods: A 5 year retrospective analysis of percutaneous core biopsies of pancreatic masses and their CT features was undertaken. Data were retrieved from surgical/pathology databases; medical records and CT reports and images. Results: Three hundred and three patients underwent 372 biopsies; 56 of 87 patients had repeat biopsies. Malignancy was diagnosed in 276 patients, with ductal adenocarcinoma in 259 (85%). Final sensitivity of percutaneous biopsy for diagnosing pancreatic neoplasms was 90%; for repeat biopsy it was 87%. Complications occurred in 17 (4.6%) patients, in three of whom the complications were major (1%): one abscess, one duodenal perforation, one large retroperitoneal bleed. CT features typical of ductal adenocarcinoma were: hypovascular pancreatic mass with bile and/or pancreatic duct dilatation. Atypical CT features were: isodense or hypervascular mass, calcification, non-dilated ducts, cystic change, and extensive lymphadenopathy. Defining typical CT features of adenocarcinoma as true-positives, CT had a sensitivity of 68%, specificity of 95%, positive predictive value (PPV) of 98%, and negative predictive value of 41% for diagnosing pancreatic adenocarcinoma. Conclusion: Final sensitivity of percutaneous biopsy for establishing the diagnosis was 90%. CT features typical of pancreatic adenocarcinoma had high specificity and PPV. On some occasions, especially in frail patients with co-morbidity, it might be reasonable to assume a diagnosis of pancreatic cancer if CT features are typical, and biopsy only if CT shows atypical features.

  20. Transcriptomic and CRISPR/Cas9 technologies reveal FOXA2 as a tumor suppressor gene in pancreatic cancer.

    Science.gov (United States)

    Vorvis, Christina; Hatziapostolou, Maria; Mahurkar-Joshi, Swapna; Koutsioumpa, Marina; Williams, Jennifer; Donahue, Timothy R; Poultsides, George A; Eibl, Guido; Iliopoulos, Dimitrios

    2016-06-01

    Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates and limited therapeutic options. Thus elucidation of signaling pathways involved in PDAC pathogenesis is essential for identifying novel potential therapeutic gene targets. Here, we used a systems approach to elucidate those pathways by integrating gene and microRNA profiling analyses together with CRISPR/Cas9 technology to identify novel transcription factors involved in PDAC pathogenesis. FOXA2 transcription factor was found to be significantly downregulated in PDAC relative to control pancreatic tissues. Functional experiments revealed that FOXA2 has a tumor suppressor function through inhibition of pancreatic cancer cell growth, migration, invasion, and colony formation. In situ hybridization analysis revealed miR-199a to be significantly upregulated in pancreatic cancer. Bioinformatics and luciferase analyses showed that miR-199a negatively but directly regulates FOXA2 expression through binding in its 3'-untranslated region (UTR). Evaluation of the functional importance of miR-199a on pancreatic cancer revealed that miR-199a acts as an inhibitor of FOXA2 expression, inducing an increase in pancreatic cancer cell proliferation, migration, and invasion. Additionally, gene ontology and network analyses in PANC-1 cells treated with a small interfering RNA (siRNA) against FOXA2 revealed an enrichment for cell invasion mechanisms through PLAUR and ERK activation. FOXA2 deletion (FOXA2Δ) by using two CRISPR/Cas9 vectors in PANC-1 cells induced tumor growth in vivo resulting in upregulation of PLAUR and ERK pathways in FOXA2Δ xenograft tumors. We have identified FOXA2 as a novel tumor suppressor in pancreatic cancer and it is regulated directly by miR-199a, thereby enhancing our understanding of how microRNAs interplay with the transcription factors to affect pancreatic oncogenesis. Copyright © 2016 the American Physiological Society.

  1. Volumetric modulated arc therapy for advanced pancreatic cancer.

    Science.gov (United States)

    Eppinga, Wietse; Lagerwaard, Frank; Verbakel, Wilko; Slotman, Ben; Senan, Suresh

    2010-07-01

    Intensity-modulated radiotherapy (IMRT) allows for improved sparing of organs at risk (OARs) in advanced pancreatic cancer. A planning study evaluated if volumetric modulated arc therapy (RapidArc [RA]) could be used as an alternative to IMRT in such cases. In ten patients, five-field IMRT (5f-IMRT) plans with fixed gantry positions were compared to RA plans using similar constraints for planning target volume (PTV) and OARs. PTV coverage, conformity indices (CI), and OAR doses were compared. One patient was treated using RA and calculated dose distributions were measured in coronal planes in a solid-water phantom. RA plans showed superior mean CI of 1.09 +/- 0.02 (+/- 1 SD [standard deviation]) versus 1.20 +/- 0.10 in 5f-IMRT (p = 0.003). Both techniques achieved similar sparing of the right kidney, but RA significantly reduced left kidney doses with V(15) of 7.2% +/- 5.3% and 15.9% +/- 11.1%, respectively; p = 0.02. RA modestly decreased mean doses to liver (13.8 vs. 15.1 Gy; p = 0.003), stomach (16.7 vs. 17.9 Gy; p = 0.017), small bowel (19.8 vs. 22.1 Gy; p < 0.001), and duodenum (38.8 vs. 41.9 Gy; p = 0.004). Film dosimetry revealed excellent agreement between calculated and measured dose distributions. The delivery time for RA was < 3 min. RA planning achieved superior CI for pancreatic tumors compared to 5f-IMRT, and modestly reduced OAR doses. Fast treatment delivery using RA may decrease the risk of intrafractional organ motion.

  2. Dynamic changes during the treatment of pancreatic cancer.

    Science.gov (United States)

    Wolff, Robert A; Wang-Gillam, Andrea; Alvarez, Hector; Tiriac, Hervé; Engle, Dannielle; Hou, Shurong; Groff, Abigail F; San Lucas, Anthony; Bernard, Vincent; Allenson, Kelvin; Castillo, Jonathan; Kim, Dong; Mulu, Feven; Huang, Jonathan; Stephens, Bret; Wistuba, Ignacio I; Katz, Matthew; Varadhachary, Gauri; Park, YoungKyu; Hicks, James; Chinnaiyan, Arul; Scampavia, Louis; Spicer, Timothy; Gerhardinger, Chiara; Maitra, Anirban; Tuveson, David; Rinn, John; Lizee, Gregory; Yee, Cassian; Levine, Arnold J

    2018-03-13

    This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient's T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment.

  3. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

    Czech Academy of Sciences Publication Activity Database

    Campa, D.; Rizzato, C.; Stolzenberg-Solomon, R.; Pacetti, P.; Vodička, Pavel; Cleary, S.P.; Capurso, G.; Bueno-de-Mesquita, H. B.; Werner, J.; Gazouli, M.; Butterbach, K.; Ivanauskas, A.; Giese, N.; Petersen, G. M.; Fogar, P.; Wang, Z.; Bassi, C.; Ryska, M.; Theodoropoulos, G.E.; Kooperberg, Ch.; Li, D.; Greenhalf, W.; Pasquali, C.; Hackert, T.; Fuchs, Ch.S.; Mohelníková-Duchoňová, B.; Sperti, C.; Funel, N.; Dieffenbach, A.K.; Wareham, N.J.; Buring, J.; Holcátová, I.; Costello, E.; Zambon, C.F.; Kupcinskas, J.; Risch, H.A.; Kraft, P.; Bracci, P.M.; Pezzilli, R.; Olson, S.H.; Sesso, H. D.; Hartge, P.; Strobel, O.; Malecka-Panas, E.; Visvanathan, K.; Arslan, A. A.; Pedrazzoli, S.; Souček, P.; Gioffreda, D.; Key, T.J.; Talar-Wojnarowska, R.; Scarpa, A.; Mambrini, A.; Jacobs, E.J.; Jamroziak, K.; Klein, A.; Tavano, F.; Bambi, F.; Landi, S.; Austin, M. A.; Vodičková, Ludmila; Brenner, H.; Chanock, S. J.; Fave, G.D.; Piepoli, A.; Cantore, M.; Zheng, W.; Wolpin, B.M.; Amundadottir, L. T.; Canzian, F.

    2015-01-01

    Roč. 137, č. 9 (2015), s. 2175-2183 ISSN 0020-7136 R&D Projects: GA ČR GAP301/12/1734 Institutional support: RVO:68378041 Keywords : pancreatic cancer * polymorphisms * telomerase * susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.531, year: 2015

  4. Respiratory motion management for radiotherapy of pancreatic cancer patients

    NARCIS (Netherlands)

    Lens, E.

    2017-01-01

    Pancreatic cancer has one of the worst prognosis with an overall mean 5-year survival of 7%. The only curative treatment remains surgery, but this treatment is often hampered by a difficult anatomical tumor location. The addition of adjuvant (chemo)radiation treatment may be beneficial and may

  5. Adenoviral gene therapy for pancreatic cancer: Where do we stand?

    NARCIS (Netherlands)

    Kuhlmann, Koert F. D.; Gouma, Dirk J.; Wesseling, John G.

    2008-01-01

    Background: The prognosis of patients with pancreatic cancer is poor. This is mainly caused by the late diagnosis, the aggressive biology and the lack of effective treatment modalities. Adenoviral gene therapy has the potential to selectively treat both primary tumor and (micro) metastatic tissue.

  6. Management challenges of pancreatic cancer in a resource scarce ...

    African Journals Online (AJOL)

    Background: Of all forms of gastrointestinal malignancy, adenocarcinoma of the pancreas is associated with the worst survival. Management of pancreatic cancer is associated with some challenges. This study is aimed at determining the hospital incidence, sociodemographic characteristics, managements and ...

  7. Bryostatin I inhibits growth and proliferation of pancreatic cancer ...

    African Journals Online (AJOL)

    Purpose: To evaluate the effect of bryostatin I on proliferation of pancreatic cancer cells as well as tumor growth in mice tumor xenograft model. Methods: Activation of NF-κB was evaluated by preparing nuclear material extract using nuclear extract kit (Carlsbad, CA, USA) followed by enzyme-linked immunosorbent assay ...

  8. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

    Science.gov (United States)

    Biankin, Andrew V; Waddell, Nicola; Kassahn, Karin S; Gingras, Marie-Claude; Muthuswamy, Lakshmi B; Johns, Amber L; Miller, David K; Wilson, Peter J; Patch, Ann-Marie; Wu, Jianmin; Chang, David K; Cowley, Mark J; Gardiner, Brooke B; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J; Gill, Anthony J; Pinho, Andreia V; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R Scott; Humphris, Jeremy L; Kaplan, Warren; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chou, Angela; Chin, Venessa T; Chantrill, Lorraine A; Mawson, Amanda; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Daly, Roger J; Merrett, Neil D; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M; Fisher, William E; Brunicardi, F Charles; Hodges, Sally E; Reid, Jeffrey G; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R; Dinh, Huyen; Buhay, Christian J; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E; Yung, Christina K; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A; Petersen, Gloria M; Gallinger, Steven; Hruban, Ralph H; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Schulick, Richard D; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A; Mann, Karen M; Jenkins, Nancy A; Perez-Mancera, Pedro A; Adams, David J; Largaespada, David A; Wessels, Lodewyk F A; Rust, Alistair G; Stein, Lincoln D; Tuveson, David A; Copeland, Neal G; Musgrove, Elizabeth A; Scarpa, Aldo; Eshleman, James R; Hudson, Thomas J; Sutherland, Robert L; Wheeler, David A; Pearson, John V; McPherson, John D; Gibbs, Richard A; Grimmond, Sean M

    2012-11-15

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

  9. GSK3β and β-Catenin Modulate Radiation Cytotoxicity in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Richard L. Watson

    2010-05-01

    Full Text Available BACKGROUND: Knowledge of factors and mechanisms contributing to the inherent radioresistance of pancreatic cancer may improve cancer treatment. Irradiation inhibits glycogen synthase kinase 3β (GSK3β by phosphorylation at serine 9. In turn, release of cytosolic membrane β-catenin with subsequent nuclear translocation promotes survival. Both GSK3β and β-catenin have been implicated in cancer cell proliferation and resistance to death. METHODS: We investigated pancreatic cancer cell survival after radiation in vitro and in vivo, with a particular focus on the role of the function of the GSK3β/β-catenin axis. RESULTS: Lithium chloride, RNAi-medicated silencing of GSK3β, or the expression of a kinase dead mutant GSK3β resulted in radioresistance of Panc1 and BxPC3 pancreatic cancer cells. Conversely, ectopic expression of a constitutively active form of GSK3β resulted in radiosensitization of Panc1 cells. GSK3β silencing increased radiation-induced β-catenin target gene expression asmeasured by studies of AXIN2 and LEF1 transcript levels. Western blot analysis of total and phosphorylated levels of GSK3β and β-catenin showed that GSK3β inhibition resulted in stabilization of β-catenin. Xenografts of both BxPC3 and Panc1 with targeted silencing of GSK3β exhibited radioresistance in vivo. Silencing of β-catenin resulted in radiosensitization, whereas a nondegradable β-catenin construct induced radioresistance. CONCLUSIONS: These data support the hypothesis that GSK3β modulates the cellular response to radiation in a β-catenin-dependent mechanism. Further understanding of this pathway may enhance the development of clinical trials combining drugs inhibiting β-catenin activation with radiation and chemotherapy in locally advanced pancreatic cancer.

  10. A Yin-Yang 1/miR-30a regulatory circuit modulates autophagy in pancreatic cancer cells.

    Science.gov (United States)

    Yang, Chuang; Zhang, Jing-Jing; Peng, Yun-Peng; Zhu, Yi; Yin, Ling-Di; Wei, Ji-Shu; Gao, Wen-Tao; Jiang, Kui-Rong; Miao, Yi

    2017-10-19

    Autophagy is a highly regulated biological process that mediates the degradation of intracellular components. It is required for tumor cell metabolism and homeostasis. Yin-Yang 1 (YY1) has been reported to be involved in autophagy in several carcinomas. However, its role in autophagy in pancreatic cancer, one of the deadliest human malignancies, is unknown. Here, we investigated the function of YY1 in pancreatic cancer cells autophagy and its mechanisms of action. The activity of cells undergoing autophagy was assessed using transmission electron microscopy, immunofluorescence, and Western blotting. A luciferase activity assay, real-time quantitative polymerase chain reaction (RT-qPCR), and chromatin immunoprecipitation (ChIP) were also used to identify putative downstream targets of YY1. YY1 was confirmed to regulate autophagy in pancreatic cancer cells. It was found to directly regulate the expression of miR-30a, a known modulator of autophagy-associated genes. Furthermore, overexpression of miR-30a attenuated the pro-autophagic effects of YY1. Cumulatively, our data suggest that miR-30a acts in a feedback loop to modulate the pro-autophagic activities of YY1. Thus, autophagy in pancreatic cancer cells may be regulated, in part, by a tightly coordinated YY1/miR-30a regulatory circuit. These findings provide a potential druggable target for the development of treatments for pancreatic cancer.

  11. Using digital surveillance to examine the impact of public figure pancreatic cancer announcements on media and search query outcomes.

    Science.gov (United States)

    Noar, Seth M; Ribisl, Kurt M; Althouse, Benjamin M; Willoughby, Jessica Fitts; Ayers, John W

    2013-12-01

    Announcements of cancer diagnoses from public figures may stimulate cancer information seeking and media coverage about cancer. This study used digital surveillance to quantify the effects of pancreatic cancer public figure announcements on online cancer information seeking and cancer media coverage. We compiled a list of public figures (N = 25) who had been diagnosed with or had died from pancreatic cancer between 2006 and 2011. We specified interrupted time series models using data from Google Trends to examine search query shifts for pancreatic cancer and other cancers. Weekly media coverage archived on Google News were also analyzed. Most public figures' pancreatic cancer announcements corresponded with no appreciable change in pancreatic cancer search queries or media coverage. In contrast, Patrick Swayze's diagnosis was associated with a 285% (95% confidence interval [CI]: 212 to 360) increase in pancreatic cancer search queries, though it was only weakly associated with increases in pancreatic cancer media coverage. Steve Jobs's death was associated with a 197% (95% CI: 131 to 266) increase in pancreatic cancer queries and a 3517% (95% CI: 2882 to 4492) increase in pancreatic cancer media coverage. In general, a doubling in pancreatic cancer-specific media coverage corresponded with a 325% increase in pancreatic cancer queries. Digital surveillance is an important tool for future cancer control research and practice. The current application of these methods suggested that pancreatic cancer announcements (diagnosis or death) by particular public figures stimulated media coverage of and online information seeking for pancreatic cancer.

  12. miR-34a inhibits pancreatic cancer progression through Snail1-mediated epithelial-mesenchymal transition and the Notch signaling pathway.

    Science.gov (United States)

    Tang, Yan; Tang, Yong; Cheng, Ying-Sheng

    2017-02-01

    Epithelial-mesenchymal transition (EMT) and Notch signaling are important for the growth and invasion of pancreatic cancer, which is a leading cause of cancer-related deaths worldwide. miR-34a has been shown to play pivotal roles in the progression of several types of cancer. However, little is known about the regulatory mechanisms of miR-34a in pancreatic cancer processes. The aim of this study was to determine whether miR-34a has negative effects on pancreatic cancer and whether these effects are related to EMT and Notch signaling. In vitro, we demonstrated that miR-34a inhibited, while miR-34a inhibitors enhanced, migration and invasion of pancreatic cancer cell lines (PANC-1 and SW-1990).These effects were reversed by Snail1 overexpression or Snail1 shRNA. Furthermore, the anti-apoptotic effects of the miR-34a inhibitors in pancreatic cancer cells were abrogated by Notch1 shRNA. Luciferase reporter assays revealed that the Snail1 and Notch1 genes were direct targets of miR-34a. In vivo, we also demonstrated that miR-34a inhibited pancreatic cancer growth by decreasing Snail1 and Notch1 expression. Therefore, our results indicate that miR-34a inhibits pancreatic cancer progression by post-transcriptionally regulating Snail1 and Notch1 expression.

  13. Role of tumor markers and mutations in cells and pancreatic juice in the diagnosis of pancreatic cancer

    NARCIS (Netherlands)

    Tascilar, M.; Caspers, E.; Sturm, P. D.; Goggins, M.; Hruban, R. H.; Offerhaus, G. J.

    1999-01-01

    Unresectability at the time of presentation is the most important reason for the poor survival rate of pancreatic carcinoma. Molecular-based tests might improve the early detection of pancreatic cancer at a time when surgical resection is still an option for cure. The literature was reviewed

  14. Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia.

    Directory of Open Access Journals (Sweden)

    Toshiki Hirakawa

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs, the expression of insulin-like growth factor-1 (IGF1 and IGF1 receptor (IGF1R was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9 was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2 and hypoxia (1% O2. IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC.

  15. The Replication Stress Response in Pancreatic Cancer

    Science.gov (United States)

    2014-12-01

    hypogonadotropic hypogonadism and anosmia (10). CHD7 is also dysregulated in 13% to 35% of cases of pancreatic adenocarcinoma, with aberrant expression, copy...Meliciani I, Wenzel W, EomSH, et al. Mutations in CHD7, encoding a chromatin remodeling protein, cause idiopathic hypogonadotropic hypogonadism and

  16. Pancreatitis

    Science.gov (United States)

    ... the hormones insulin and glucagon into the bloodstream. Pancreatitis is inflammation of the pancreas. It happens when digestive enzymes start digesting the pancreas itself. Pancreatitis can be acute or chronic. Either form is ...

  17. Pancreatitis

    Science.gov (United States)

    ... causes. Treatment Treatment for pancreatitis may include a hospital stay for intravenous (IV) fluids, pain medicine, and other medicines. Surgery is sometimes needed to treat complications. Eating, Diet, & Nutrition If you have pancreatitis, your health care ...

  18. Network of microRNAs-mRNAs Interactions in Pancreatic Cancer

    Science.gov (United States)

    Naderi, Elnaz; Mostafaei, Mehdi; Pourshams, Akram

    2014-01-01

    Background. MicroRNAs are small RNA molecules that regulate the expression of certain genes through interaction with mRNA targets and are mainly involved in human cancer. This study was conducted to make the network of miRNAs-mRNAs interactions in pancreatic cancer as the fourth leading cause of cancer death. Methods. 56 miRNAs that were exclusively expressed and 1176 genes that were downregulated or silenced in pancreas cancer were extracted from beforehand investigations. MiRNA–mRNA interactions data analysis and related networks were explored using MAGIA tool and Cytoscape 3 software. Functional annotations of candidate genes in pancreatic cancer were identified by DAVID annotation tool. Results. This network is made of 217 nodes for mRNA, 15 nodes for miRNA, and 241 edges that show 241 regulations between 15 miRNAs and 217 target genes. The miR-24 was the most significantly powerful miRNA that regulated series of important genes. ACVR2B, GFRA1, and MTHFR were significant target genes were that downregulated. Conclusion. Although the collected previous data seems to be a treasure trove, there was no study simultaneous to analysis of miRNAs and mRNAs interaction. Network of miRNA-mRNA interactions will help to corroborate experimental remarks and could be used to refine miRNA target predictions for developing new therapeutic approaches. PMID:24895587

  19. Network of microRNAs-mRNAs Interactions in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Elnaz Naderi

    2014-01-01

    Full Text Available Background. MicroRNAs are small RNA molecules that regulate the expression of certain genes through interaction with mRNA targets and are mainly involved in human cancer. This study was conducted to make the network of miRNAs-mRNAs interactions in pancreatic cancer as the fourth leading cause of cancer death. Methods. 56 miRNAs that were exclusively expressed and 1176 genes that were downregulated or silenced in pancreas cancer were extracted from beforehand investigations. MiRNA–mRNA interactions data analysis and related networks were explored using MAGIA tool and Cytoscape 3 software. Functional annotations of candidate genes in pancreatic cancer were identified by DAVID annotation tool. Results. This network is made of 217 nodes for mRNA, 15 nodes for miRNA, and 241 edges that show 241 regulations between 15 miRNAs and 217 target genes. The miR-24 was the most significantly powerful miRNA that regulated series of important genes. ACVR2B, GFRA1, and MTHFR were significant target genes were that downregulated. Conclusion. Although the collected previous data seems to be a treasure trove, there was no study simultaneous to analysis of miRNAs and mRNAs interaction. Network of miRNA-mRNA interactions will help to corroborate experimental remarks and could be used to refine miRNA target predictions for developing new therapeutic approaches.

  20. Sulforaphane Potentiates the Efficacy of 17-Allylamino 17-Demethoxygeldanamycin Against Pancreatic Cancer Through Enhanced Abrogation of Hsp90 Chaperone Function

    Science.gov (United States)

    Li, Yanyan; Zhang, Tao; Schwartz, Steven J.; Sun, Duxin

    2013-01-01

    Heat shock protein 90 (Hsp90), an essential molecular chaperone that regulates the stability of a wide range of oncogenic proteins, is a promising target for cancer therapeutics. We investigated the combination efficacy and potential mechanisms of sulforaphane, a dietary component from broccoli and broccoli sprouts, and 17-allylamino 17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, in pancreatic cancer. MTS assay demonstrated that sulforaphane sensitized pancreatic cancer cells to 17-AAG in vitro. Caspase-3 was activated to 6.4-fold in response to simultaneous treatment with sulforaphane and 17-AAG, whereas 17-AAG alone induced caspase-3 activity to 2-fold compared to control. ATP binding assay and coimmunoprecipitation revealed that sulforaphane disrupted Hsp90-p50Cdc37 interaction, whereas 17-AAG inhibited ATP binding to Hsp90. Concomitant use of sulforaphane and 17-AAG synergistically downregulated Hsp90 client proteins in Mia Paca-2 cells. Co-administration of sulforaphane and 17-AAG in pancreatic cancer xenograft model led to more than 70% inhibition of the tumor growth, whereas 17-AAG alone only suppressed the tumor growth by 50%. Our data suggest that sulforaphane potentiates the efficacy of 17-AAG against pancreatic cancer through enhanced abrogation of Hsp90 function. These findings provide a rationale for further evaluation of broccoli/broccoli sprout preparations combined with 17-AAG for better efficacy and lower dose-limiting toxicity in pancreatic cancer. PMID:21875325

  1. Dosimetric impact of gastrointestinal air column in radiation treatment of pancreatic cancer.

    Science.gov (United States)

    Estabrook, Neil C; Corn, Jonathan B; Ewing, Marvene M; Cardenes, Higinia R; Das, Indra J

    2018-02-01

    Dosimetric evaluation of air column in gastrointestinal (GI) structures in intensity modulated radiation therapy (IMRT) of pancreatic cancer. Nine sequential patients were retrospectively chosen for dosimetric analysis of air column in the GI apparatus in pancreatic cancer using cone beam CT (CBCT). The four-dimensional CT (4DCT) was used for target and organs at risk (OARs) and non-coplanar IMRT was used for treatment. Once a week, these patients underwent CBCT for air filling, isocentre verification and dose calculations retrospectively. Abdominal air column variation was as great as ±80% between weekly CBCT and 4DCT. Even with such a large air column in the treatment path for pancreatic cancer, changes in anteroposterior dimension were minimal (2.8%). Using IMRT, variations in air column did not correlate dosimetrically with large changes in target volume. An average dosimetric deviation of mere -3.3% and a maximum of -5.5% was observed. CBCT revealed large air column in GI structures; however, its impact is minimal for target coverage. Because of the inherent advantage of segmentation in IMRT, where only a small fraction of a given beam passes through the air column, this technique might have an advantage over 3DCRT in treating upper GI malignancies where the daily air column can have significant impact. Advances in knowledge: Radiation treatment of pancreatic cancer has significant challenges due to positioning, imaging of soft tissues and variability of air column in bowels. The dosimetric impact of variable air column is retrospectively studied using CBCT. Even though, the volume of air column changes by ± 80%, its dosimetric impact in IMRT is minimum.

  2. Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells.

    Directory of Open Access Journals (Sweden)

    Andrej Udelnow

    Full Text Available BACKGROUND: Omeprazole has recently been described as a modulator of tumour chemoresistance, although its underlying molecular mechanisms remain controversial. Since pancreatic tumours are highly chemoresistant, a logical step would be to investigate the pharmacodynamic, morphological and biochemical effects of omeprazole on pancreatic cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Dose-effect curves of omeprazole, pantoprazole, gemcitabine, 5-fluorouracil and the combinations of omeprazole and 5-fluorouracil or gemcitabine were generated for the pancreatic cancer cell lines MiaPaCa-2, ASPC-1, Colo357, PancTu-1, Panc1 and Panc89. They revealed that omeprazole inhibited proliferation at probably non-toxic concentrations and reversed the hormesis phenomena of 5-fluorouracil. Electron microscopy showed that omeprazole led to accumulation of phagophores and early autophagosomes in ASPC-1 and MiaPaCa-2 cells. Signal changes indicating inhibited proliferation and programmed cell death were found by proton NMR spectroscopy of both cell lines when treated with omeprazole which was identified intracellularly. Omeprazole modulates the lysosomal transport pathway as shown by Western blot analysis of the expression of LAMP-1, Cathepsin-D and β-COP in lysosome- and Golgi complex containing cell fractions. Acridine orange staining revealed that the pump function of the vATPase was not specifically inhibited by omeprazole. Gene expression of the autophagy-related LC3 gene as well as of Bad, Mdr-1, Atg12 and the vATPase was analysed after treatment of cells with 5-fluorouracil and omeprazole and confirmed the above mentioned results. CONCLUSIONS: We hypothesise that omeprazole interacts with the regulatory functions of the vATPase without inhibiting its pump function. A modulation of the lysosomal transport pathway and autophagy is caused in pancreatic cancer cells leading to programmed cell death. This may circumvent common resistance mechanisms of

  3. Stromal SPOCK1 supports invasive pancreatic cancer growth

    NARCIS (Netherlands)

    Veenstra, Veronique L.; Damhofer, Helene; Waasdorp, Cynthia; Steins, Anne; Kocher, Hemant M.; Medema, Jan P.; van Laarhoven, Hanneke W.; Bijlsma, Maarten F.

    2017-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is marked by an abundant stromal deposition. This stroma is suspected to harbor both tumor-promoting and tumor-suppressing properties. This is underscored by the disappointing results of stroma targeting in clinical studies. Given the complexity of

  4. Immunotherapy Targets Common Cancer Mutation

    Science.gov (United States)

    In a study of an immune therapy for colorectal cancer that involved a single patient, researchers identified a method for targeting the cancer-causing protein produced by a mutant form of the KRAS gene.

  5. Fast neutron irradiation for locally advanced pancreatic cancer

    Energy Technology Data Exchange (ETDEWEB)

    Smith, F.P. (Georgetown Univ. Medical Center, Washington, DC); Schein, P.S.; MacDonald, J.S.; Woolley, P.V.; Ornitz, R.; Rogers, C.

    1981-11-01

    Nineteen patients with locally advanced pancreatic cancer and one patient with islet cell cancer were treated with 1700-1500 neutron rad alone or in combination with 5-fluorouracil to exploit the theoretic advantages of higher linear energy of transfer, and lower oxygen enhancement ratio of neutrons. Only 5 of 14 (36%) obtained partial tumor regression. The median survival for all patients with pancreatic cancer was 6 months, which is less than that reported with 5-fluorouracil and conventional photon irradiation. Gastrointestinal toxicity was considerable; hemorhagic gastritis in five patients, colitis in two and esophagitis in one. One patient developed radiation myelitis. We therefore, caution any enthusiasm for this modality of therapy until clear evidence of a therapeutic advantage over photon therapy is demonstrated in controlled clinical trials.

  6. Fast neutron irradiation for locally advanced pancreatic cancer

    International Nuclear Information System (INIS)

    Smith, F.P.; Schein, P.S.; MacDonald, J.S.; Woolley, P.V.; Ornitz, R.; Rogers, C.

    1981-01-01

    Nineteen patients with locally advanced pancreatic cancer and one patient with islet cell cancer were treated with 1700-1500 neutron rad alone or in combination with 5-fluorouracil to exploit the theoretic advantages of higher linear energy of transfer, and lower oxygen enhancement ratio of neutrons. Only 5 of 14 (36%) obtained partial tumor regression. The median survival for all patients with pancreatic cancer was 6 months, which is less than that reported with 5-fluorouracil and conventional photon irradiation. Gastrointestinal toxicity was considerable; hemorhagic gastritis in five patients, colitis in two and esophagitis in one. One patient developed radiation myelitis. We therefore, caution any enthusiasm for this modality of therapy until clear evidence of a therapeutic advantage over photon therapy is demonstrated in controlled clinical trials

  7. The Potential for Circulating Tumor Cells in Pancreatic Cancer Management

    Directory of Open Access Journals (Sweden)

    Michael Pimienta

    2017-06-01

    Full Text Available Pancreatic cancer is one the most lethal malignancies. Only a small proportion of patients with this disease benefit from surgery. Chemotherapy provides only a transient benefit. Though much effort has gone into finding new ways for early diagnosis and treatment, average patient survival has only been improved in the order of months. Circulating tumor cells (CTCs are shed from primary tumors, including pre-malignant phases. These cells possess information about the genomic characteristics of their tumor source in situ, and their detection and characterization holds potential in early cancer diagnosis, prognosis, and treatment. Liquid Biopsies present an alternative to tumor biopsy that are hard to sample. Below we summarize current methods of CTC detection, the current literature on CTCs in pancreatic cancer, and future perspectives.

  8. Effect of Protein Hydrolysates on Pancreatic Cancer Cells

    DEFF Research Database (Denmark)

    Ossum, Carlo G.; Andersen, Lisa Lystbæk; Nielsen, Henrik Hauch

    hydrolysates obtained by enzymatic hydrolysis on cancer cell proliferation. Skin and belly flap muscle from trout were hydrolysed with the unspecific proteases Alcalase, Neutrase, or UE1 (all from Novozymes, Bagsværd, Denmark) to a hydrolysis degree of 1-15%. The hydrolysates were tested for biological......Effect of Fish Protein Hydrolysates on Pancreatic Cancer Cells Carlo G. Ossum1, Lisa Lystbæk Andersen2, Henrik Hauch Nielsen2, Else K. Hoffmann1, and Flemming Jessen2 1University of Copenhagen, Department of Biology, Denmark, 2Technical University of Denmark (DTU), National Food Institute, Denmark...... activities affecting cell proliferation and ability to modulate caspase activity in pancreatic cancer cells COLO357 and BxPC-3 in vitro. A number of the hydrolysates showed caspase promoting activity; in particular products containing muscle tissue, i.e. belly flap, were able to stimulate caspase activity...

  9. Current options for palliative treatment in patients with pancreatic cancer.

    Science.gov (United States)

    Ridwelski, K; Meyer, F

    2001-01-01

    Palliative treatment is often the only remaining option in the management of pancreatic carcinoma, but its efficacy is poor due to low tumor sensitivity and inadequate treatment protocols. There are several options of palliative treatment with antitumor or supportive intention. Classical end points of palliative treatment are survival, tumor response, and quality of life. A decade ago, palliative chemotherapy consisted mainly of 5-fluorouracil as the standard agent in combination with either other agents and/or radiotherapy. Only the new antineoplastic drug gemcitabine, which was introduced simultaneously with the definition of novel end points of chemotherapy such as clinical benefit, allowed to achieve some progress. However, while gemcitabine monotherapy appeared to be superior to 5-fluorouracil and improved important parameters of quality of life, it could not provide a significant improvement of survival. A novel concept, therefore, is to improve this beneficial cytostatic response in pancreatic carcinoma using a gemcitabine-based protocol by combining it with antineoplastic drugs such as taxanes or platin analogs. This strategy may have the potential to improve the outcome in palliative chemotherapy of pancreatic carcinoma patients with advanced tumor growth or metastases. Best supportive care in pancreatic cancer consists of the treatment of symptoms, such as pain, jaundice, duodenal obstruction, weight loss, exocrine pancreatic insufficiency, and tumor-associated depression. Copyright 2001 S. Karger AG, Basel

  10. Current evidence for histone deacetylase inhibitors in pancreatic cancer.

    Science.gov (United States)

    Koutsounas, Ioannis; Giaginis, Constantinos; Patsouris, Efstratios; Theocharis, Stamatios

    2013-02-14

    Pancreatic cancer is one of the most aggressive human cancers, with more than 200 000 deaths worldwide every year. Despite recent efforts, conventional treatment approaches, such as surgery and classic chemotherapy, have only slightly improved patient outcomes. More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm. Among new agents, histone deacetylase inhibitors (HDACIs) are now being tested. HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression, apoptosis, cell cycle progression and angiogenesis. HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines. In the present review, the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro, as well as their antiproliferative effects in animal models are presented. HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor effects, at well-tolerated doses.

  11. Value of computed tomography as a screening examination of pancreatic cancer

    International Nuclear Information System (INIS)

    Honda, Hiroshi; Watanabe, Katsushi; Nishikawa, Kiyoshi

    1983-01-01

    The abdominal CT films of 50 patients were reviewed by ten radiologists to evaluate the role of CT examination in the screening of pancreatic cancer. The 50 patients consisted of 10 with pancreatic cancer, 8 with other pancreatic abnormalities, and 32 with normal pancreas. Ten radiologists were divided into two groups according to their experience in evaluating CT examinations, an experienced group and an unexperienced group, respectively. In the detectability of pancreatic abnormality, the experienced group showed a sensitivity of 72.2% and a specificity of 86.2%. The unexperienced group showed a sensitivity of 70.9% and a specificity of 72.0%. In the detectability of pancreatic cancer, the experienced group showed a sensitivity of 62.0% and a specificity of 83.4%. The unexperienced group showed a sensitivity of 66.0% and a specificity of 81.8%. In the localization of the pancreatic cancer, there was no difference between the two groups. Pancreatic abnormality can be detected with high accuracy, but diagnosis of the nature of pancreatic cancer is difficult. Experience in evaluating CT examinations elevates the detectability of pancreatic abnormality but does not elevate the detectability of pancreatic cancer. These results suggest the difficulty in diagnosis of pancreatic cancer. (author)

  12. Dynamic MR imaging of pancreatic cancer

    International Nuclear Information System (INIS)

    Akaki, Shiro; Kohno, Yoshihiro; Gohbara, Hideo

    1994-01-01

    Dynamic MRI was performed on 21 patients with pancreatic duct cell carcinoma. Turbo-FLASH or FLASH3D was performed immediately following rapid bolus injection of gadopentetate dimeglumine, and these FLASH images and conventional spin echo images were evaluated about detectability of the lesion. All images were classified into three groups of detectability of the lesion ; good, fair, and poor. On T 1 weighted image, 23% of cases were 'good' and 48% were evaluated as 'fair'. On the other hand, on dynamic MRI, 62% of cases were 'good' and 33% of cases were evaluated as 'fair'. Both T 2 weighted image and enhanced T 1 weighted image were not useful for depiction of the lesion. Direct comparison between T 1 weighted image and dynamic MRI was also done. In 55% of cases, dynamic MRI was superior to T 1 weighted image and in 40% of cases, dynamic MRI was equal to T 1 weighted image. Thus, dynamic MRI was superior to conventional spin echo images for detection of duct cell carcinoma. In 17 patients of duct cell carcinoma who underwent FLASH3D, contrast/noise ratio (CNR) was calculated before and after injection of gadopentetate dimeglumine. The absolute value of CNR became significantly larger by injection of contrast material. In nine resectable pancreatic carcinomas, two cases of INF α and two cases of medullary type were well depicted. It was concluded that dynamic MRI was useful for evaluation of pancreatic carcinoma. (author)

  13. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    International Nuclear Information System (INIS)

    Abe, Michio; Kortylewicz, Zbigniew P.; Enke, Charles A.; Mack, Elizabeth; Baranowska-Kortylewicz, Janina

    2011-01-01

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy

  14. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Michio [Minamata City Hospital and Medical Center, Minamata City, Kumamoto 867 (Japan); Kortylewicz, Zbigniew P.; Enke, Charles A.; Mack, Elizabeth; Baranowska-Kortylewicz, Janina, E-mail: jbaranow@unmc.edu [Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, NE 68198 (United States)

    2011-05-25

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy.

  15. Current and Future Intraoperative Imaging Strategies to Increase Radical Resection Rates in Pancreatic Cancer Surgery

    Directory of Open Access Journals (Sweden)

    Henricus J. M. Handgraaf

    2014-01-01

    Full Text Available Prognosis of patients with pancreatic cancer is poor. Even the small minority that undergoes resection with curative intent has low 5-year survival rates. This may partly be explained by the high number of irradical resections, which results in local recurrence and impaired overall survival. Currently, ultrasonography is used during surgery for resectability assessment and frozen-section analysis is used for assessment of resection margins in order to decrease the number of irradical resections. The introduction of minimal invasive techniques in pancreatic surgery has deprived surgeons from direct tactile information. To improve intraoperative assessment of pancreatic tumor extension, enhanced or novel intraoperative imaging technologies accurately visualizing and delineating cancer cells are necessary. Emerging modalities are intraoperative near-infrared fluorescence imaging and freehand nuclear imaging using tumor-specific targeted contrast agents. In this review, we performed a meta-analysis of the literature on laparoscopic ultrasonography and we summarized and discussed current and future intraoperative imaging modalities and their potential for improved tumor demarcation during pancreatic surgery.

  16. Developmental history of the extent of lymph node dissection in pancreatic cancer surgery

    Directory of Open Access Journals (Sweden)

    GOU Shanmiao

    2017-01-01

    Full Text Available Pancreatic cancer is one of the digestive malignant tumors with the worst prognosis and has an overall 5-year survival rate as low as 5%. Even though radical resection is performed, the 5-year survival rate is only about 20%. Recurrence and metastasis are the most important influencing factors for the postoperative survival of patients with pancreatic cancer. Lymph node metastasis is an important feature of pancreatic cancer, and the extent of lymph node dissection has always been a hot topic in radical surgery for pancreatic cancer. This article summarizes the history and current status of the extent of lymph node dissection in pancreatic cancer and points out that standardized lymph node dissection is a key factor for improving patients′ prognosis after pancreatic cancer surgery.

  17. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of {beta}-catenin

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Il-Rae [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Koh, Sang Seok [Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333 (Korea, Republic of); Department of Functional Genomics, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Malilas, Waraporn; Srisuttee, Ratakorn; Moon, Jeong [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Choi, Young-Whan [Department of Horticultural Bioscience, Pusan National University, Miryang 627-706 (Korea, Republic of); Horio, Yoshiyuki [Department of Pharmacology, Sapporo Medical University, Sapporo 060-8556 (Japan); Oh, Sangtaek [Department of Advanced Fermentation Fusion Science and Technology, Kookmin University, Seoul 136-702 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of)

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer SIRT1 inhibits protein levels of {beta}-catenin and its transcriptional activity. Black-Right-Pointing-Pointer Nuclear localization of SIRT1 is not required for the decrease of {beta}-catenin expression. Black-Right-Pointing-Pointer SIRT1-mediated degradation of {beta}-catenin is not required for GSK-3{beta} and Siah-1 but for proteosome. Black-Right-Pointing-Pointer SIRT1 activation inhibits proliferation of pancreatic cancer cells expressing PAUF. -- Abstract: Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of {beta}-catenin, we postulated that {beta}-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target {beta}-catenin in a colon cancer model, suppresses {beta}-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of {beta}-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced {beta}-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of {beta}-catenin. Treatment with MG132, a proteasomal inhibitor, restored {beta}-catenin protein levels, suggesting that SIRT1-mediated degradation of {beta}-catenin requires proteasomal activity. It was reported that inhibition of GSK-3{beta} or Siah-1 stabilizes {beta}-catenin in colon cancer cells, but suppression of GSK-3{beta} or Siah-1 using siRNA in the presence of resveratrol instead diminished {beta}-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3{beta} and Siah-1 are not involved in SIRT1

  18. Intestinal mucosa is a target tissue for pancreatic polypeptide

    International Nuclear Information System (INIS)

    Gilbert, W.R.; Kramer, J.L.; Frank, B.H.; Gingerich, R.L.

    1986-01-01

    Studies were carried out to identify mammalian tissues capable of specifically binding mammalian pancreatic polypeptide (PP). Bovine PP (bPP) radiolabeled with 125 I was purified by HPLC to yield [ 125 I]iodo-(Tyr-27) bPP. The label was injected into three pairs of fasted littermate dogs and allowed to circulate for 5 min. One of the dogs was a control which received an excess of unlabeled porcine PP to provide competition for receptor binding. Unbound bPP was removed by perfusion with Krebs-Ringer bicarbonate and the tissue fixed in situ with Karnovsky's fixative. Tissue samples from various organs were removed, weighed, and counted. The entire gastrointestinal tract demonstrated high levels of 125 I after injection of the labeled peptide. The duodenum, jejunum, ileum, and colon were the only tissues to exhibit specific binding of bPP. These tissues (mucosal and muscle layers) from experimental animals exhibited 31-76% higher binding than the corresponding tissues from the control animals. Sections of the gastrointestinal tract were scraped to separate the mucosal layer from the underlying muscle layer. The mucosal layer of the duodenum, jejunum, and ileum exhibited 145-162% increases in binding compared to the control animals. The muscle layer of these tissues demonstrated no significant increase. These findings demonstrate that mucosal layer of the small intestine is a target tissue for mammalian PP

  19. Laparoscopic surgery of pancreatic cancer: state of the art.

    Science.gov (United States)

    Croce, Enrico; Olmi, Stefano; Bertolini, Aimone; Magnone, Stefano

    2005-01-01

    The use of laparoscopy in pancreatic cancer offers a significant contribution to the diagnosis and treatment of this disease. Both laparoscopic staging and treatment of pancreatic cancer have proved feasible and effective. This paper reviews the literature on this topic, by a Medline search using the words laparoscopy and pancreas. Various aspects are considered: staging, treatment and palliation. Cross-references from the articles retrieved were reviewed. The efficacy and safety of diagnostic laparoscopy and ultrasonography, lowering the rate of useless laparotomies, is evident in most studies. Moreover laparoscopic resection of the body and tail of the pancreas, as well as palliation of digestive obstruction has been demonstrated as feasible. Controversy exists on feasibility of pancreatoduodenectomy. Laparoscopic gastric outlet obstruction bypass and laparoscopic biliary decompression have been reported with good results compared to open surgical procedures. Randomized controlled trials are required to validate promising results coming from the reported series, mainly retrospective.

  20. Remote partial gastrectomy as a risk factor for pancreatic cancer: potential for preventive strategies

    NARCIS (Netherlands)

    van Rees, B. P.; Tascilar, M.; Hruban, R. H.; Giardiello, F. M.; Tersmette, A. C.; Offerhaus, G. J.

    1999-01-01

    Pancreatic cancer is the fifth leading cause of cancer death mainly because of an advanced disease stage at the time of diagnosis. Patients with a remote partial gastrectomy for benign ulcer disease may constitute a high risk group for pancreatic cancer; an increased index of suspicion could

  1. p-[123I]iodo-l-phenylalanine for detection of pancreatic cancer: basic investigations of the uptake characteristics in primary human pancreatic tumour cells and evaluation in in vivo models of human pancreatic adenocarcinoma

    International Nuclear Information System (INIS)

    Samnick, Samuel; Hellwig, Dirk; Kirsch, Carl-Martin; Romeike, Bernd F.M.; Feiden, Wolfgang; Kubuschok, Boris; Amon, Michaela; Menger, Michael D.

    2004-01-01

    Pancreatic cancer is associated with the worst 5-year survival rate of any human cancer. This high mortality is due, in part, to difficulties in establishing early and accurate diagnosis. Because most tumours share the ability to accumulate amino acids more effectively than normal tissues and any other pathology, assessment of amino acid transport in tumour cells using radiolabelled amino acids has become one of the most promising tools for tumour imaging. This study investigated the potential of p-[ 123 I]iodo-l-phenylalanine (IPA) for detection of pancreatic cancer by single-photon emission tomography. IPA affinity for pancreatic tumour was investigated in human pancreatic adenocarcinoma PaCa44 and PanC1 cells, followed by analysis of the underlying mechanisms of tracer accumulation in neoplastic cells. Thereafter, IPA was evaluated for targeting of pancreatic tumours using SCID mice engrafted with primary human pancreatic adenocarcinoma cells, as well as in acute inflammation models in immunocompetent mice and rats. IPA accumulated intensively in human pancreatic tumour cells. Radioactivity accumulation in tumour cells following a 30-min incubation at 37 C/pH 7.4 varied from 41% to 58% of the total loaded activity per 10 6 cells. The cellular uptake was temperature and pH dependent and predominantly mediated by specific carriers for neutral amino acids, namely the sodium-independent and l-leucine-preferring (L-system) transporter and the alanine-, serine- and cysteine-preferring (ASC-system) transporter. Protein incorporation was less than 8%. Biodistribution studies showed rapid localization of the tracer to tumours, reaching 10%±2.5% to 15%±3% of the injected dose per gram (I.D./g) in heterotopic tumours compared with 17%±3.5% to 22%±4.3% I.D./g in the orthotopic tumours, at 60 and 240 min post injection of IPA, respectively. In contrast, IPA uptake in the gastrointestinal tract and areas of inflammation remained moderate and decreased with time. Excellent

  2. Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion

    International Nuclear Information System (INIS)

    Ji, S.Q.; Cao, J.; Zhang, Q.Y.; Li, Y.Y.; Yan, Y.Q.; Yu, F.X.

    2013-01-01

    To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3±10.7 and 97.6±7.6 vs 18.3±1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis

  3. Adipose tissue-derived stem cells promote pancreatic cancer cell proliferation and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Ji, S.Q.; Cao, J. [Department of Liver Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai (China); Zhang, Q.Y.; Li, Y.Y. [Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou (China); Yan, Y.Q. [Department of Liver Surgery I, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai (China); Yu, F.X. [Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou (China)

    2013-09-27

    To explore the effects of adipose tissue-derived stem cells (ADSCs) on the proliferation and invasion of pancreatic cancer cells in vitro and the possible mechanism involved, ADSCs were cocultured with pancreatic cancer cells, and a cell counting kit (CCK-8) was used to detect the proliferation of pancreatic cancer cells. ELISA was used to determine the concentration of stromal cell-derived factor-1 (SDF-1) in the supernatants. RT-PCR was performed to detect the expression of the chemokine receptor CXCR4 in pancreatic cancer cells and ADSCs. An in vitro invasion assay was used to measure invasion of pancreatic cancer cells. SDF-1 was detected in the supernatants of ADSCs, but not in pancreatic cancer cells. Higher CXCR4 mRNA levels were detected in the pancreatic cancer cell lines compared with ADSCs (109.3±10.7 and 97.6±7.6 vs 18.3±1.7, respectively; P<0.01). In addition, conditioned medium from ADSCs promoted the proliferation and invasion of pancreatic cancer cells, and AMD3100, a CXCR4 antagonist, significantly downregulated these growth-promoting effects. We conclude that ADSCs can promote the proliferation and invasion of pancreatic cancer cells, which may involve the SDF-1/CXCR4 axis.

  4. Definitive concurrent chemoradiotherapy in locally advanced pancreatic cancer

    International Nuclear Information System (INIS)

    Kwak, Yoo Kang; Lee, Jong Hoon; Lee, Myung Ah; Chun, Hoo Geun; Kim, Dong Goo; You, Young Kyoung; Hong, Tae Ho; Jang, Hong Seok

    2014-01-01

    Survival outcome of locally advanced pancreatic cancer has been poor and little is known about prognostic factors of the disease, especially in locally advanced cases treated with concurrent chemoradiation. This study was to analyze overall survival and prognostic factors of patients treated with concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic cancer. Medical records of 34 patients diagnosed with unresectable pancreatic cancer and treated with definitive CCRT, from December 2003 to December 2012, were reviewed. Median prescribed radiation dose was 50.4 Gy (range, 41.4 to 55.8 Gy), once daily, five times per week, 1.8 to 3 Gy per fraction. With a mean follow-up of 10 months (range, 0 to 49 months), median overall survival was 9 months. The 1- and 2-year survival rates were 40% and 10%, respectively. Median and mean time to progression were 5 and 7 months, respectively. Prognostic parameters related to overall survival were post-CCRT CA19-9 (p = 0.02), the Eastern Cooperative Oncology Group (ECOG) status (p < 0.01), and radiation dose (p = 0.04) according to univariate analysis. In multivariate analysis, post-CCRT CA19-9 value below 180 U/mL and ECOG status 0 or 1 were statistically significant independent prognostic factors associated with improved overall survival (p < 0.01 and p = 0.02, respectively). Overall treatment results in locally advanced pancreatic cancer are relatively poor and few improvements have been accomplished in the past decades. Post-treatment CA19-9 below 180 U/mL and ECOG performance status 0 and 1 were significantly associated with an improved overall survival.

  5. The inflammatory milieu within the pancreatic cancer microenvironment correlates with clinicopathologic parameters, chemoresistance and survival

    OpenAIRE

    Delitto, Daniel; Black, Brian S.; Sorenson, Heather L.; Knowlton, Andrea E.; Thomas, Ryan M.; Sarosi, George A.; Moldawer, Lyle L.; Behrns, Kevin E.; Liu, Chen; George, Thomas J.; Trevino, Jose G.; Wallet, Shannon M.; Hughes, Steven J.

    2015-01-01

    Background The tumor microenvironment impacts pancreatic cancer (PC) development, progression and metastasis. How intratumoral inflammatory mediators modulate this biology remains poorly understood. We hypothesized that the inflammatory milieu within the PC microenvironment would correlate with clinicopathologic findings and survival. Methods Pancreatic specimens from normal pancreas (n = 6), chronic pancreatitis (n = 9) and pancreatic adenocarcinoma (n = 36) were homogenized immediately upon...

  6. Quality of Online Resources for Pancreatic Cancer Patients.

    Science.gov (United States)

    De Groot, Lauren; Harris, Ilene; Regehr, Glenn; Tekian, Ara; Ingledew, Paris-Ann

    2017-10-18

    The Internet is increasingly a source of information for pancreatic cancer patients. This disease is usually diagnosed at an advanced stage; therefore, timely access to high-quality information is critical. Our purpose is to systematically evaluate the information available to pancreatic cancer patients on the internet. An internet search using the term "pancreatic cancer" was performed, with the meta-search engines "Dogpile", "Yippy" and "Google". The top 100 websites returned by the search engines were evaluated using a validated structured rating tool. Inter-rater reliability was evaluated using kappa statistics and results were analyzed using descriptive statistics. Amongst the 100 websites evaluated, etiology/risk factors and symptoms were the most accurately covered (70 and 67% of websites). Prevention, treatment and prognosis were the least accurate sections (55, 55 and 43% of websites). Prevention and prognosis were also the least likely to be covered with 63 and 51 websites covering these, respectively. Only 40% of websites identified an author. Twenty-two percent of websites were at a university reading level. The majority of online information is accurate but incomplete. Websites may lack information on prognosis. Many websites are outdated and lacked author information, and readability levels are inappropriate. This knowledge can inform the dialogue between healthcare providers and patients.

  7. Stereotactic Body Radiation Therapy Boost in Locally Advanced Pancreatic Cancer

    International Nuclear Information System (INIS)

    Seo, Young Seok; Kim, Mi-Sook; Yoo, Sung Yul; Cho, Chul Koo; Yang, Kwang Mo; Yoo, Hyung Jun; Choi, Chul Won; Lee, Dong Han; Kim, Jin; Kim, Min Suk; Kang, Hye Jin; Kim, YoungHan

    2009-01-01

    Purpose: To investigate the clinical application of a stereotactic body radiation therapy (SBRT) boost in locally advanced pancreatic cancer patients with a focus on local efficacy and toxicity. Methods and Materials: We retrospectively reviewed 30 patients with locally advanced and nonmetastatic pancreatic cancer who had been treated between 2004 and 2006. Follow-up duration ranged from 4 to 41 months (median, 14.5 months). A total dose of 40 Gy was delivered in 20 fractions using a conventional three-field technique, and then a single fraction of 14, 15, 16, or 17 Gy SBRT was administered as a boost without a break. Twenty-one patients received chemotherapy. Overall and local progression-free survival were calculated and prognostic factors were evaluated. Results: One-year overall survival and local progression-free survival rates were 60.0% and 70.2%, respectively. One patient (3%) developed Grade 4 toxicity. Carbohydrate antigen 19-9 response was found to be an independent prognostic factor for survival. Conclusions: Our findings indicate that a SBRT boost provides a safe means of increasing radiation dose. Based on the results of this study, we recommend that a well controlled Phase II study be conducted on locally advanced pancreatic cancer.

  8. Treatment of Pancreatic Cancer: What Can We Really Predict Today?

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste Bachet

    2011-02-01

    Full Text Available Managing pancreatic cancer remains a big challenge due to its worse course and prognosis. However, therapeutic options and multimodal strategies are increasing nowadays, including new agents, new regimens and chemoradiation. Recently, the FOLFIRINOX regimen has been reported to be more active than gemcitabine in selected metastatic patients. In this setting, it will be of utmost interest to guide our therapeutic choice not only on clinical and pathological findings, but also on specific biomarkers that will predict tumor behavior and patient outcome (prognostic markers, and benefit from specific agents or regimens (predictive markers. In the near future, we will have to build both our therapeutic interventions and our clinical research based on an accurate patients’ clinical selection and on biomolecular markers. In this review, we aimed to highlight and discuss some of the recent results reported on biomarkers in pancreatic cancer that may predict, i.e., preferential metastatic diffusion after surgery, like CXCR4, or predict gemcitabine efficacy in an adjuvant setting as well as in advanced disease, like hENT1. An important effort for translational research in pancreatic cancer research is thus required to validate such markers, while some important questions concerning tissue availability and processing, methodology of analysis, and design of future prospective trials, need to be addressed.

  9. Treatment of pancreatic cancer: what can we really predict today?

    Science.gov (United States)

    Bachet, Jean-Baptiste; Marechal, Raphael; Van Laethem, Jean-Luc

    2011-02-17

    Managing pancreatic cancer remains a big challenge due to its worse course and prognosis. However, therapeutic options and multimodal strategies are increasing nowadays, including new agents, new regimens and chemoradiation. Recently, the FOLFIRINOX regimen has been reported to be more active than gemcitabine in selected metastatic patients. In this setting, it will be of utmost interest to guide our therapeutic choice not only on clinical and pathological findings, but also on specific biomarkers that will predict tumor behavior and patient outcome (prognostic markers), and benefit from specific agents or regimens (predictive markers). In the near future, we will have to build both our therapeutic interventions and our clinical research based on an accurate patients' clinical selection and on biomolecular markers. In this review, we aimed to highlight and discuss some of the recent results reported on biomarkers in pancreatic cancer that may predict, i.e., preferential metastatic diffusion after surgery, like CXCR4, or predict gemcitabine efficacy in an adjuvant setting as well as in advanced disease, like hENT1. An important effort for translational research in pancreatic cancer research is thus required to validate such markers, while some important questions concerning tissue availability and processing, methodology of analysis, and design of future prospective trials, need to be addressed.

  10. Pancreatic Cancer: What the Oncologist Can Offer for Palliation

    Directory of Open Access Journals (Sweden)

    Malcolm J Moore

    2002-01-01

    Full Text Available Because pancreatic cancer has a poor survival rate and only 20% of patients present with potentially resectable disease, a key goal of therapy is to provide palliation. The poor medical condition of many patients interferes with their ability to tolerate traditional chemotherapy. Recently, however, a nucleoside analogue, gemcitabine, has been developed. This drug is more effective than 5-fluorouracil (5-FU, can be used in patients who fail to respond to 5-FU and has only modest toxicity. Combination therapies including gemcitabine and other agents are being tested. Local radiotherapy seems to provide pain relief, but gastrointestinal toxicity is significant. The effect of combined modality therapy (5-FU with radiotherapy on survival is unclear, and it does not prevent local disease progression. Some novel biological agents, including angiogenesis inhibitors, matrix metalloproteinase inhibitors, antisense compounds, inhibitors of cell signalling such as epidermal growth factor and vascular endothelial growth factor, and inhibitors of oncogene activation, are undergoing phase II and III trials in patients with pancreatic cancer. Among the most promising are farnesyl protein transferase inhibitors, which modulate K-ras function. Such an approach is promising for the treatment of pancreatic cancer because this tumour frequently exhibits mutation of the ras gene.

  11. The Challenging Diagnosis of Pancreatic Masses: Not All Tumors Are Cancers

    Directory of Open Access Journals (Sweden)

    Alessandro Morotti

    2015-01-01

    Full Text Available In the elderly patients, where biopsy-induced complications could outweigh the benefit, the identification of pancreatic masses is generally referred to as a synonymous of pancreatic cancer and patients are dismissed with no further options than palliative and supportive care. Notwithstanding, not all pancreatic tumors are cancers and therefore alternative diagnoses need to be investigated, especially when patients are unfit for invasive diagnostic procedures. Here, we report a case of an aged patient that was admitted to an internal medicine division for a previously diagnosed pancreatic cancer. The reassessment of the diagnosis has allowed identifying the pancreatic mass as a manifestation of focal pancreatitis in the context of an IgG4-related disease. Accordingly, patient was treated with steroids with rapid clinical improvement. This clinical case suggests that autoimmune diseases should always be considered in the differential diagnosis of pancreatic masses of the elderly.

  12. Characterization and Management of Interfractional Anatomic Changes for Pancreatic Cancer Radiotherapy

    International Nuclear Information System (INIS)

    Liu Feng; Erickson, Beth; Peng Cheng; Li, X. Allen

    2012-01-01

    Purpose: To quantitatively characterize interfractional anatomic variations in pancreatic cancer radiotherapy (RT) and to study dosimetric advantages for using an online adaptive replanning scheme to account for these variations. Methods and Materials: Targets and organs at risk (OAR) were delineated by autosegmentation based on daily computed tomography (CT) images acquired using a respiration-gated in-room CT during daily image-guided RT (IGRT) for 10 pancreatic cancer patients. Various parameters, including the maximum overlap ratio (MOR) between the volumes based on planning and daily CTs for a structure, while the overlapping volumes were maximized, were used to quantify the interfractional organ deformation with the intrafractional variations largely excluded. An online adaptive RT (ART) was applied to these daily CTs. To evaluate the dosimetric benefits of ART, the dose distributions from the online ART were compared to those from the repositioning in the current standard IGRT practice. Results: The interfractional anatomic variations, particularly the organ deformation, are significant during pancreas irradiation. For the patients studied, the average MORs of all daily CTs were 80.2%, 61.7%, and 72.2% for pancreatic head, duodenum, and stomach, respectively. The online ART leads to improved dosimetric plan with better target coverage and/or OAR sparing than IGRT repositioning. For the patients studied, the mean V 50.4Gy (volume covered by 50.4 Gy) for the duodenum was reduced from 43.4% for IGRT to 15.6% for the online ART scheme. Conclusions: The online adaptive RT scheme can effectively account for the significant interfractional anatomic variations observed in pancreas irradiation. The dosimetric advantages with the online ART may enable safe dose escalation in radiation therapy for pancreatic cancer.

  13. Animal models of pancreatic cancer for drug research.

    Science.gov (United States)

    Kapischke, Matthias; Pries, Alexandra

    2008-10-01

    The operative and conservative results of therapy in pancreatic ductal adenocarcinoma remain appallingly poor. This underlines the demand for further research for effective anticancer drugs. The various animal models remain the essential method for the determination of efficacy of substances during preclinical phase. Unfortunately, most of these tested substances showed a good efficacy in pancreatic carcinoma in the animal model but were not confirmed during the clinical phase. The available literature in PubMed, Medline, Ovid and secondary literature was searched regarding the available animal models for drug testing against pancreatic cancer. The models were analyzed regarding their pros and cons in anticancer drug testing. The different modifications of the orthotopic model (especially in mice) seem at present to be the best model for anticancer testing in pancreatic carcinoma. The value of genetically engineered animal model (GEM) and syngeneic models is on debate. A good selection of the model concerning the questions supposed to be clarified may improve the comparability of the results of animal experiments compared to clinical trials.

  14. Targeted nanotechnology for cancer imaging.

    Science.gov (United States)

    Toy, Randall; Bauer, Lisa; Hoimes, Christopher; Ghaghada, Ketan B; Karathanasis, Efstathios

    2014-09-30

    Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit significant advantages including increased contrast sensitivity, binding avidity and targeting specificity. Considering the various nanoparticle designs and their adjustable ability to target a specific site and generate detectable signals, nanoparticles can be optimally designed in terms of biophysical interactions (i.e., intravascular and interstitial transport) and biochemical interactions (i.e., targeting avidity towards cancer-related biomarkers) for site-specific detection of very distinct microenvironments. This review seeks to illustrate that the design of a nanoparticle dictates its in vivo journey and targeting of hard-to-reach cancer sites, facilitating early and accurate diagnosis and interrogation of the most aggressive forms of cancer. We will report various targeted nanoparticles for cancer imaging using X-ray computed tomography, ultrasound, magnetic resonance imaging, nuclear imaging and optical imaging. Finally, to realize the full potential of targeted nanotechnology for cancer imaging, we will describe the challenges and opportunities for the clinical translation and widespread adaptation of targeted nanoparticles imaging agents. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Targeted Nanotechnology for Cancer Imaging

    Science.gov (United States)

    Toy, Randall; Bauer, Lisa; Hoimes, Christopher; Ghaghada, Ketan B.; Karathanasis, Efstathios

    2014-01-01

    Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit significant advantages including increased contrast sensitivity, binding avidity and targeting specificity. Considering the various nanoparticle designs and their adjustable ability to target a specific site and generate detectable signals, nanoparticles can be optimally designed in terms of biophysical interactions (i.e., intravascular and interstitial transport) and biochemical interactions (i.e., targeting avidity towards cancer-related biomarkers) for site-specific detection of very distinct microenvironments. This review seeks to illustrate that the design of a nanoparticle dictates its in vivo journey and targeting of hard-to-reach cancer sites, facilitating early and accurate diagnosis and interrogation of the most aggressive forms of cancer. We will report various targeted nanoparticles for cancer imaging using X-ray computed tomography, ultrasound, magnetic resonance imaging, nuclear imaging and optical imaging. Finally, to realize the full potential of targeted nanotechnology for cancer imaging, we will describe the challenges and opportunities for the clinical translation and widespread adaptation of targeted nanoparticles imaging agents. PMID:25116445

  16. The Mouse Model of Pancreatic Cancer Atlas (MMPCA for classification of pancreatic cancer lesions: A large histological investigation of the Ptf1aCre/+;LSL-KrasG12D/+ transgenic mouse model of pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Michelle J Veite-Schmahl

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is one of the leading forms of cancer related deaths in the United States. With limited treatment options and unreliable diagnostic methods, long-term survival rates following a diagnosis of pancreatic cancer remain poor. Pancreatic intraepithelial neoplasia (PanIN are precancerous lesions that precede progression towards PDAC. PanIN occur in increasing complexity as the disease progresses and the description of PanIN plays a critical role in describing, staging and diagnosing PDAC. Inconsistencies in PanIN classifications exist even amongst leading pathologists. This has led to debate and confusion among researchers and pathologists involved in pancreatic cancer research, diagnosis and treatment. We have sought to initiate a discussion with leading pathologists with a goal of increasing consensus in the interpretation of PanIN and associated structures within the precancerous pancreas. Toward achieving this goal, we are in the process of conducting an extensive study of over 1000 male and female pancreata in varying stages of PanIN progression isolated from the Ptf1aCre/+;LSL-KrasG12D/+ transgenic mouse model of pancreatic cancer. Using this extensive database, we have established the Mouse Model of Pancreatic Cancer Atlas (MMPCA to serve as a platform for meaningful and interactive discussion among researchers and pathologists who study pancreatic disease. We hope that the MMPCA will be an effective tool for promoting a more consistent and accurate consensus of PanIN classifications in the future.

  17. Molecular biology of pancreatic cancer: how useful is it in clinical practice?

    Science.gov (United States)

    Sakorafas, George H; Smyrniotis, Vasileios

    2012-07-10

    During the recent two decades dramatic advances of molecular biology allowed an in-depth understanding of pancreatic carcinogenesis. It is currently accepted that pancreatic cancer has a genetic component. The real challenge is now how these impressive advances could be used in clinical practice. To critically present currently available data regarding clinical application of molecular biology in pancreatic cancer. Reports about clinical implications of molecular biology in patients with pancreatic cancer were retrieved from PubMed. These reports were selected on the basis of their clinical relevance, and the data of their publication (preferentially within the last 5 years). Emphasis was placed on reports investigating diagnostic, prognostic, and therapeutic implications. Molecular biology can be used to identify individuals at high-risk for pancreatic cancer development. Intensive surveillance is indicated in these patients to detect pancreatic neoplasia ideally at a preinvasive stage, when curative resection is still possible. Molecular biology can also be used in the diagnosis of pancreatic cancer, with molecular analysis on samples of biologic material, such as serum or plasma, duodenal fluid or preferentially pure pancreatic juice, pancreatic cells or tissue, and stools. Molecular indices have also prognostic significance. Finally, molecular biology may have therapeutic implications by using various therapeutic approaches, such as antiangiogenic factors, purine synthesis inhibitors, matrix metalloproteinase inhibitors, factors modulating tumor-stroma interaction, inactivation of the hedgehog pathway, gene therapy, oncolytic viral therapy, immunotherapy (both passive as well as active) etc. Molecular biology may have important clinical implications in patients with pancreatic cancer and represents one of the most active areas on cancer research. Hopefully clinical applications of molecular biology in pancreatic cancer will expand in the future, improving the

  18. Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer.

    Science.gov (United States)

    Song, Dongweon; Chaerkady, Raghothama; Tan, Aik Choon; García-García, Elena; Nalli, Anuradha; Suárez-Gauthier, Ana; López-Ríos, Fernando; Zhang, Xian Feng; Solomon, Anna; Tong, Jeffrey; Read, Margaret; Fritz, Christian; Jimeno, Antonio; Pandey, Akhilesh; Hidalgo, Manuel

    2008-10-01

    Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose- and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

  19. Loss of stromal caveolin-1 expression: a novel tumor microenvironment biomarker that can predict poor clinical outcomes for pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Tao Shan

    Full Text Available AIMS: Cancer development and progression is not only associated with the tumor cell proliferation but also depends on the interaction between tumor cells and the stromal microenvironment. A new understanding of the role of the tumor microenvironment suggests that the loss of stromal caveolin-1 (Cav-1 as a key regulator may become a potential therapy target. This study aims to elucidate whether stromal Cav-1 expression in pancreatic cancer can be a strong prognosis biomarker. METHODS: Tissue samples from 45 pancreatic cancer patients were studied. Parenchyma and stroma were separated and purified using laser capture microdissection. Stromal Cav-1 expression was measured from pancreatic cancer, paraneoplastic, and normal tissue using immunohistochemistry. We analyzed the correlation of stromal Cav-1 expression with clinicopathologic features and prognostic indicators, such as tumor marker HER-2/neu gene. RESULTS: Specimens from six patients (13.3% showed high levels of stromal Cav-1 staining, those from eight patients (17.8% showed a lower, intermediate level of staining, whereas those from 31 patients (68.9% showed an absence of staining. Cav-1 expression in cancer-associated fibroblasts was lower than that in paracancer-associated and in normal fibroblasts. Stromal Cav-1 loss was associated with TNM stage (P = 0.018, lymph node metastasis (P = 0.014, distant metastasis (P = 0.027, and HER-2/neu amplification (P = 0.007. The relationships of age, sex, histological grade, and tumor size with stromal Cav-1 expression were not significant (P>0.05. A negative correlation was found between circulating tumor cells and stromal Cav-1 expression (P<0.05. CONCLUSION: The loss of stromal Cav-1 in pancreatic cancer was an independent prognostic indicator, thus suggesting that stromal Cav-1 may be an effective therapeutic target for patients with pancreatic cancer.

  20. Pathogenic mechanisms of pancreatitis

    Science.gov (United States)

    Manohar, Murli; Verma, Alok Kumar; Venkateshaiah, Sathisha Upparahalli; Sanders, Nathan L; Mishra, Anil

    2017-01-01

    Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for

  1. Genome-Wide analysis of the role of copy-number variation in pancreatic cancer risk

    Directory of Open Access Journals (Sweden)

    Jason eWillis

    2014-02-01

    Full Text Available Although family history is a risk factor for pancreatic adenocarcinoma, much of the genetic etiology of this disease remains unknown. While genome-wide association studies have identified some common single nucleotide polymorphisms (SNPs associated with pancreatic cancer risk, these SNPs do not explain all the heritability of this disease. We hypothesized that copy number variation (CNVs in the genome may play a role in genetic predisposition to pancreatic adenocarcinoma. Here, we report a genome-wide analysis of CNVs in a small hospital-based, European ancestry cohort of pancreatic cancer cases and controls. Germline CNV discovery was performed using the Illumina Human CNV370 platform in 223 pancreatic cancer cases (both sporadic and familial and 169 controls. Following stringent quality control, we asked if global CNV burden was a risk factor for pancreatic cancer. Finally, we performed in silico CNV genotyping and association testing to discover novel CNV risk loci. When we examined the global CNV burden, we found no strong evidence that CNV burden plays a role in pancreatic cancer risk either overall or specifically in individuals with a family history of the disease. Similarly, we saw no significant evidence that any particular CNV is associated with pancreatic cancer risk. Taken together, these data suggest that CNVs do not contribute substantially to the genetic etiology of pancreatic cancer, though the results are tempered by small sample size and large experimental variability inherent in array-based CNV studies

  2. Serum Metabolomic Profiles for Human Pancreatic Cancer Discrimination

    Directory of Open Access Journals (Sweden)

    Takao Itoi

    2017-04-01

    Full Text Available This study evaluated the clinical use of serum metabolomics to discriminate malignant cancers including pancreatic cancer (PC from malignant diseases, such as biliary tract cancer (BTC, intraductal papillary mucinous carcinoma (IPMC, and various benign pancreaticobiliary diseases. Capillary electrophoresismass spectrometry was used to analyze charged metabolites. We repeatedly analyzed serum samples (n = 41 of different storage durations to identify metabolites showing high quantitative reproducibility, and subsequently analyzed all samples (n = 140. Overall, 189 metabolites were quantified and 66 metabolites had a 20% coefficient of variation and, of these, 24 metabolites showed significant differences among control, benign, and malignant groups (p < 0.05; Steel–Dwass test. Four multiple logistic regression models (MLR were developed and one MLR model clearly discriminated all disease patients from healthy controls with an area under receiver operating characteristic curve (AUC of 0.970 (95% confidential interval (CI, 0.946–0.994, p < 0.0001. Another model to discriminate PC from BTC and IPMC yielded AUC = 0.831 (95% CI, 0.650–1.01, p = 0.0020 with higher accuracy compared with tumor markers including carcinoembryonic antigen (CEA, carbohydrate antigen 19-9 (CA19-9, pancreatic cancer-associated antigen (DUPAN2 and s-pancreas-1 antigen (SPAN1. Changes in metabolomic profiles might be used to screen for malignant cancers as well as to differentiate between PC and other malignant diseases.

  3. Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes.

    Science.gov (United States)

    Rouanet, Marie; Lebrin, Marine; Gross, Fabian; Bournet, Barbara; Cordelier, Pierre; Buscail, Louis

    2017-06-08

    A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials.

  4. Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes

    Directory of Open Access Journals (Sweden)

    Marie Rouanet

    2017-06-01

    Full Text Available A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral, molecular tools (interference RNA, genome editing and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes. The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy. Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials.

  5. Alterations in integrin expression modulates invasion of pancreatic cancer cells.

    LENUS (Irish Health Repository)

    Walsh, Naomi

    2009-01-01

    BACKGROUND: Factors mediating the invasion of pancreatic cancer cells through the extracellular matrix (ECM) are not fully understood. METHODS: In this study, sub-populations of the human pancreatic cancer cell line, MiaPaCa-2 were established which displayed differences in invasion, adhesion, anoikis, anchorage-independent growth and integrin expression. RESULTS: Clone #3 displayed higher invasion with less adhesion, while Clone #8 was less invasive with increased adhesion to ECM proteins compared to MiaPaCa-2. Clone #8 was more sensitive to anoikis than Clone #3 and MiaPaCa-2, and displayed low colony-forming efficiency in an anchorage-independent growth assay. Integrins beta 1, alpha 5 and alpha 6 were over-expressed in Clone #8. Using small interfering RNA (siRNA), integrin beta1 knockdown in Clone #8 cells increased invasion through matrigel and fibronectin, increased motility, decreased adhesion and anoikis. Integrin alpha 5 and alpha 6 knockdown also resulted in increased motility, invasion through matrigel and decreased adhesion. CONCLUSION: Our results suggest that altered expression of integrins interacting with different extracellular matrixes may play a significant role in suppressing the aggressive invasive phenotype. Analysis of these clonal populations of MiaPaCa-2 provides a model for investigations into the invasive properties of pancreatic carcinoma.

  6. Interventional EUS for the diagnosis and treatment of locally advanced pancreatic cancer.

    Science.gov (United States)

    Al-Haddad, Mohammad; Eloubeidi, Mohamad A

    2010-01-08

    Endoscopic ultrasound (EUS) evolved as the diagnostic test of choice evaluating suspected pancreatic tumors. Coupled with fine needle aspiration (FNA), EUS provides high accuracy for the diagnosis and staging of pancreatic cancer. Novel EUS based techniques have emerged as a safe minimally invasive alternative to the surgical or radiological approaches. By allowing better pain control, delivering antitumor therapies or draining obstructed bile ducts, such techniques hold a big promise to improve the quality of life of patients with unresectable pancreatic cancer. In this review, we will discuss the role EUS-FNA plays in the diagnosis, staging and treatment of patients with locally advanced pancreatic cancer.

  7. Angiotensin converting enzyme-independent, local angiotensin II-generation in human pancreatic ductal cancer tissues.

    Science.gov (United States)

    Ohta, Tetsuo; Amaya, Kohji; Yi, Shuangqin; Kitagawa, Hirohisa; Kayahara, Masato; Ninomiya, Itasu; Fushida, Sachio; Fujimura, Takashi; Nishimura, Gen-Ichi; Shimizu, Koichi; Miwa, Koichi

    2003-09-01

    Hypovascularity is an outstanding characteristic of pancreatic ductal cancer by diagnostic imaging: most pancreatic ductal cancers are hypovascular or avascular, and tumor vessels are seldom seen on angiography. However, we found that the vasculature was not always poor on angiography of surgically resected specimens of locally advanced pancreatic ductal cancers. To elucidate these controversial findings, we focused on angiotensin II, a vasoconstrictor which is directly produced from angiotensinogen at acidic pH by active trypsin. We examined whether a local angiotensin II-generating system exists in pancreatic ductal cancer tissue. We measured angiotensin II concentration and angiotensin converting enzyme (ACE) activity in tissues from normal pancreas, pancreatic ductal cancers, colon cancers, and hepatocellular carcinomas. After surgically resected specimens were homogenized, angiotensin II concentration and ACE activity in tissues were measured using the florisil method and the Kasahara method, respectively. Tissue angiotensin II levels in pancreatic ductal cancer (n=13) were significantly higher than those of normal pancreas (n=7), colon cancers (n=7), or hepatocellular carcinomas (n=7). However, there was no significant difference in the ACE activity in tissue between them. This study provides in vivo evidence of an ACE-independent, angiotensin II-generating system in pancreatic ductal cancer tissues and suggests that locally formed angiotensin II may act on the pre-existing pancreatic arteries around the tumor, leading to formation of hypovascular or avascular regions.

  8. KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment

    Directory of Open Access Journals (Sweden)

    Daniel Zeitouni

    2016-04-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is among the deadliest cancers with a dismal 7% 5-year survival rate and is projected to become the second leading cause of cancer-related deaths by 2020. KRAS is mutated in 95% of PDACs and is a well-validated driver of PDAC growth and maintenance. However, despite comprehensive efforts, an effective anti-RAS drug has yet to reach the clinic. Different paths to inhibiting RAS signaling are currently under investigation in the hope of finding a successful treatment. Recently, direct RAS binding molecules have been discovered, challenging the perception that RAS is an “undruggable” protein. Other strategies currently being pursued take an indirect approach, targeting proteins that facilitate RAS membrane association or downstream effector signaling. Unbiased genetic screens have identified synthetic lethal interactors of mutant RAS. Most recently, metabolic targets in pathways related to glycolytic signaling, glutamine utilization, autophagy, and macropinocytosis are also being explored. Harnessing the patient’s immune system to fight their cancer is an additional exciting route that is being considered. The “best” path to inhibiting KRAS has yet to be determined, with each having promise as well as potential pitfalls. We will summarize the state-of-the-art for each direction, focusing on efforts directed toward the development of therapeutics for pancreatic cancer patients with mutated KRAS.

  9. Tissue proteomics in pancreatic cancer study: discovery, emerging technologies and challenges

    Science.gov (United States)

    Pan, Sheng; Brentnall, Teresa A.; Kelly, Kimberly; Chen, Ru

    2013-01-01

    Pancreatic cancer is a highly lethal disease that is difficult to diagnose and treat. The advances of proteomics technology, especially quantitative proteomics, have stimulated a great interest to apply this technology for pancreatic cancer study. A variety of tissue proteomics approaches have been applied to investigate pancreatic cancer and the associated diseases. These studies were carried out with various goals, aiming to better understand the molecular mechanisms underlying pancreatic tumorigenesis, to improve therapeutic treatment and to identify cancer associated protein signatures, signaling events as well as interactions between cancer cells and tumor microenvironment. Here, we provide an overview on the tissue proteomics studies of pancreatic cancer reported in the past few years in light of discovery and technology development. PMID:23125171

  10. CD271⁺ subpopulation of pancreatic stellate cells correlates with prognosis of pancreatic cancer and is regulated by interaction with cancer cells.

    Directory of Open Access Journals (Sweden)

    Kenji Fujiwara

    Full Text Available Pancreatic stellate cells (PSCs play a crucial role in the aggressive behavior of pancreatic cancer. Although heterogeneity of PSCs has been identified, the functional differences remain unclear. We characterized CD271⁺ PSCs in human pancreatic cancer. Immunohistochemistry for CD271 was performed for 31 normal pancreatic tissues and 105 pancreatic ductal adenocarcinomas (PDACs. We performed flow cytometry and quantitative RT-PCR, and assessed CD271 expression in PSCs isolated from pancreatic tissues and the changes in CD271 expression in PSCs cocultured with cancer cells. We also investigated the pattern of CD271 expression in a SCID mouse xenograft model. In the immunohistochemical analyses, the CD271-high staining rates in pancreatic stroma in normal pancreatic tissues and PDACs were 2/31 (6.5% and 29/105 (27.6%, respectively (p = 0.0069. In PDACs, CD271⁺ stromal cells were frequently observed on the edge rather than the center of the tumors. Stromal CD271 high expression was associated with a good prognosis (p = 0.0040. Flow cytometric analyses demonstrated CD271-positive rates in PSCs were 0-2.1%. Quantitative RT-PCR analyses revealed that CD271 mRNA expression was increased in PSCs after coculture with pancreatic cancer cells. However, the level of CD271 mRNA expression subsequently decreased after the transient increase. Furthermore, CD271 mRNA expression was decreased in PSCs migrating toward pancreatic cancer cells through Matrigel. In the xenograft model, CD271⁺ PSCs were present at tumor margins/periphery and were absent in the tumor core. In conclusion, CD271 was expressed in PSCs around pancreatic tumors, but not in the center of the tumors, and expression decreased after long coculture with pancreatic cancer cells or after movement toward pancreatic cancer cells. These findings suggest that CD271⁺ PSCs appear at the early stage of pancreatic carcinogenesis and that CD271 expression is significantly correlated with a

  11. Chinese herb derived-Rocaglamide A is a potent inhibitor of pancreatic cancer cells

    OpenAIRE

    Wang, Baochun; Li, Yixiong; Tan, Fengbo; Xiao, Zhanxiang

    2016-01-01

    Pancreatic cancer ranks No.1 in mortality rate worldwide. This study aims to identify the novel anti-pancreatic cancer drugs. Human pancreatic carcinoma cell lines were purchased from ATCC. CPE-based screening assay was used to examine the cell viability. Patient derived tumor xenografts in SCID mice was established. The Caspase-3 and 7 activities were measured using the Caspase Glo 3/7 Assay kit. Soft agar colony formation assay was used to evaluate the colony formation. Wound healing assay ...

  12. An iPSC Line from Human Pancreatic Ductal Adenocarcinoma Undergoes Early to Invasive Stages of Pancreatic Cancer Progression

    Directory of Open Access Journals (Sweden)

    Jungsun Kim

    2013-06-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC carries a dismal prognosis and lacks a human cell model of early disease progression. When human PDAC cells are injected into immunodeficient mice, they generate advanced-stage cancer. We hypothesized that if human PDAC cells were converted to pluripotency and then allowed to differentiate back into pancreatic tissue, they might undergo early stages of cancer. Although most induced pluripotent stem cell (iPSC lines were not of the expected cancer genotype, one PDAC line, 10–22 cells, when injected into immunodeficient mice, generated pancreatic intraepithelial neoplasia (PanIN precursors to PDAC that progressed to the invasive stage. The PanIN-like cells secrete or release proteins from many genes that are known to be expressed in human pancreatic cancer progression and that predicted an HNF4α network in intermediate-stage lesions. Thus, rare events allow iPSC technology to provide a live human cell model of early pancreatic cancer and insights into disease progression.

  13. Functional annotation of rare gene aberration drivers of pancreatic cancer | Office of Cancer Genomics

    Science.gov (United States)

    As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC).

  14. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer.

    Science.gov (United States)

    Villarroel, Maria C; Rajeshkumar, N V; Garrido-Laguna, Ignacio; De Jesus-Acosta, Ana; Jones, Siân; Maitra, Anirban; Hruban, Ralph H; Eshleman, James R; Klein, Alison; Laheru, Daniel; Donehower, Ross; Hidalgo, Manuel

    2011-01-01

    Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here, we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long-lasting (36+ months) tumor response. Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy, tailored to the genetic environment of the patient's tumor, and identification of a new biomarker of drug response in a lethal cancer. ©2010 AACR.

  15. Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Rémy Nicolle

    2017-11-01

    Full Text Available Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively. Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

  16. File list: InP.Pan.20.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  17. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

    NARCIS (Netherlands)

    Campa, Daniele; Pastore, Manuela; Gentiluomo, Manuel; Talar-Wojnarowska, Renata; Kupcinskas, Juozas; Malecka-Panas, Ewa; Neoptolemos, John P.; Niesen, Willem; Vodicka, Pavel; Delle Fave, Gianfranco; Bueno-de-Mesquita, H. Bas; Gazouli, Maria; Pacetti, Paola; Di Leo, Milena; Ito, Hidemi; Klüter, Harald; Soucek, Pavel; Corbo, Vincenzo; Yamao, Kenji; Hosono, Satoyo; Kaaks, Rudolf; Vashist, Yogesh; Gioffreda, Domenica; Strobel, Oliver; Shimizu, Yasuhiro; Dijk, Frederike; Andriulli, Angelo; Ivanauskas, Audrius; Bugert, Peter; Tavano, Francesca; Vodickova, Ludmila; Zambon, Carlo Federico; Lovecek, Martin; Landi, Stefano; Key, Timothy J.; Boggi, Ugo; Pezzilli, Raffaele; Jamroziak, Krzysztof; Mohelnikova-Duchonova, Beatrice; Mambrini, Andrea; Bambi, Franco; Busch, Olivier; Pazienza, Valerio; Valente, Roberto; Theodoropoulos, George E.; Hackert, Thilo; Capurso, Gabriele; Cavestro, Giulia Martina; Pasquali, Claudio; Basso, Daniela; Sperti, Cosimo; Matsuo, Keitaro; Büchler, Markus; Khaw, Kay-Tee; Izbicki, Jakob; Costello, Eithne; Katzke, Verena; Michalski, Christoph; Stepien, Anna; Rizzato, Cosmeri; Canzian, Federico

    2016-01-01

    The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter

  18. File list: InP.Pan.10.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

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  19. File list: InP.Pan.05.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

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  20. File list: NoD.Pan.50.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

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  1. File list: NoD.Pan.10.AllAg.Pancreatic_cancer_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available NoD.Pan.10.AllAg.Pancreatic_cancer_cells mm9 No description Pancreas Pancreatic cancer... cells http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/NoD.Pan.10.AllAg.Pancreatic_cancer_cells.bed ...

  2. Snail recruits Ring1B to mediate transcriptional repression and cell migration in pancreatic cancer cells.

    Science.gov (United States)

    Chen, Jiangzhi; Xu, Hong; Zou, Xiuqun; Wang, Jiamin; Zhu, Yi; Chen, Hao; Shen, Baiyong; Deng, Xiaxing; Zhou, Aiwu; Chin, Y Eugene; Rauscher, Frank J; Peng, Chenghong; Hou, Zhaoyuan

    2014-08-15

    Transcriptional repressor Snail is a master regulator of epithelial-mesenchymal transition (EMT), yet the epigenetic mechanism governing Snail to induce EMT is not well understood. Here, we report that in pancreatic ductal adenocarcinoma (PDAC), elevated levels of the ubiquitin E3 ligase Ring1B and Snail, along with elevated monoubiquitination of H2A at K119 (H2AK119Ub1), are highly correlated with poor survival. Mechanistic investigations identified Ring1B as a Snail-interacting protein and showed that the carboxyl zinc fingers of Snail recruit Ring1B and its paralog Ring1A to repress its target promoters. Simultaneous depletion of Ring1A and Ring1B in pancreatic cancer cells decreased Snail binding to the target chromatin, abolished H2AK119Ub1 modification, and thereby compromised Snail-mediated transcriptional repression and cell migration. We found that Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. Collectively, our results unravel an epigenetic mechanism underlying transcriptional repression by Snail, suggest Ring1A/B as a candidate therapeutic target, and identify H2AK119Ub1 as a potential biomarker for PDAC diagnosis and prognosis. ©2014 American Association for Cancer Research.

  3. Susceptibility of pancreatic cancer stem cells to reprogramming.

    Science.gov (United States)

    Noguchi, Kozo; Eguchi, Hidetoshi; Konno, Masamitsu; Kawamoto, Koichi; Nishida, Naohiro; Koseki, Jun; Wada, Hiroshi; Marubashi, Shigeru; Nagano, Hiroaki; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi

    2015-09-01

    Previous reports have indicated that reprogramming technologies may be useful for altering the malignant phenotype of cancer cells. Although somatic stem cells in normal tissues are more sensitive to reprogramming induction than differentiated cells, it remains to be elucidated whether any specific subpopulations are sensitive to reprogramming in heterogeneous tumor tissues. Here we examined the susceptibility of pancreatic cancer stem cells (CSC) and non-CSC to reprogramming. To characterize CSC populations, we focused on c-Met signaling, which has been identified as a marker of CSC in mouse experiments in vivo. Cells that expressed high levels of c-Met showed higher CSC properties, such as tumor-initiating capacity, and resistance to gemcitabine. Real-time reverse transcription-polymerase chain reaction in cells expressing high levels of c-Met revealed endogenous expression of reprogramming factors, such as OCT3/4, SOX2, KLF4 and cMYC. Introduction of these four factors resulted in higher alkaline phosphatase staining in cells with high c-Met expression than in controls. Therefore, the study results demonstrate that cellular reprogramming may be useful for extensive epigenetic modification of malignant features of pancreatic CSC. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  4. Anthropometry and pancreatic cancer risk: An illustration of the importance of microscopic verification

    NARCIS (Netherlands)

    Verhage, B.A.J.; Schouten, L.J.; Goldbohm, R.A.; Brandt, P.A. van den

    2007-01-01

    Using data collected of a large population-based cohort study, we studied the association between anthropometric factors and the risk of pancreatic cancer. Furthermore, we investigated whether these associations differ among microscopically confirmed pancreatic cancer (MCPC) cases and non-MCPC

  5. Dairy products and pancreatic cancer risk: A pooled analysis of 14 cohort studies

    NARCIS (Netherlands)

    Genkinger, J.M.; Wang, M.; Li, R.; Albanes, D.; Anderson, K.E.; Bernstein, L.; Brandt, P.A. van den; English, D.R.; Freudenheim, J.L.; Fuchs, C.S.; Gapstur, S.M.; Giles, G.G.; Goldbohm, R.A.; Håkansson, N.; Horn-Ross, P.L.; Koushik, A.; Marshal, J.R.; McCullough, M.L.; Miller, A.B.; Robien, K.; Rohan, T.E.; Schairer, C.; Silverman, D.T.; Stolzenberg-Solomon, R.Z.; Virtamo, J.; Willett, W.C.; Wolk, A.; Ziegler, R.G.; Smith-Warner, S.A.

    2014-01-01

    Pancreatic cancer has few early symptoms, is usually diagnosed at late stages, and has a high case-fatality rate. Identifying modifiable risk factors is crucial to reducing pancreatic cancer morbidity and mortality. Prior studies have suggested that specific foods and nutrients, such as dairy

  6. Which patients with resectable pancreatic cancer truly benefit from oncological resection: is it destiny or biology?

    Science.gov (United States)

    Zheng, Lei; Wolfgang, Christopher L

    2015-01-01

    Pancreatic cancer has a dismal prognosis. A technically perfect surgical operation may still not provide a survival advantage for patients with technically resectable pancreatic cancer. Appropriate selection of patients for surgical resections is an imminent issue. Recent studies have provided an important clue on what serum biomarkers may be used to select out the patients who would unlikely benefit from the surgical resection.

  7. DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer

    NARCIS (Netherlands)

    Yu, Rui; Albarenque, Stella Maris; Cool, Robbert H.; Quax, Wim J.; Mohr, Andrea; Zwacka, Ralf M.

    2014-01-01

    Current treatment modalities for pancreatic carcinoma afford only modest survival benefits. TRAIL, as a potent and specific inducer of apoptosis in cancer cells, would be a promising new treatment option. However, since not all pancreatic cancer cells respond to TRAIL, further improvements and

  8. Targeted Cancer Therapies

    Science.gov (United States)

    ... some cancers, the malignant cells are stimulated to divide continuously without being prompted to do so by ... use this content on your website or other digital platform? Our syndication services page shows you how. ...

  9. Targeted nanoparticles for colorectal cancer

    DEFF Research Database (Denmark)

    Cisterna, Bruno A.; Kamaly, Nazila; Choi, Won Il

    2016-01-01

    Colorectal cancer (CRC) is highly prevalent worldwide, and despite notable progress in treatment still leads to significant morbidity and mortality. The use of nanoparticles as a drug delivery system has become one of the most promising strategies for cancer therapy. Targeted nanoparticles could...

  10. Synergistic activity of troxacitabine (Troxatyl™ and gemcitabine in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Leblond Lorraine

    2007-07-01

    Full Text Available Abstract Background Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl™ is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials. Methods The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1 tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired t test using GraphPad prism software. Results Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth. The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of

  11. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis.

    Science.gov (United States)

    Xiao, Yuan; Yuan, Wentao; Yu, Bo; Guo, Yan; Xu, Xu; Wang, Xinqiong; Yu, Yi; Yu, Yi; Gong, Biao; Xu, Chundi

    2017-12-01

    To identify causal mutations in certain genes in children with acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP). After patients were enrolled (CP, 55; ARP, 14) and their clinical characteristics were investigated, we performed next-generation sequencing to detect nucleotide variations among the following 10 genes: cationic trypsinogen protease serine 1 (PRSS1), serine protease inhibitor, Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator gene (CFTR), chymotrypsin C (CTRC), calcium-sensing receptor (CASR), cathepsin B (CTSB), keratin 8 (KRT8), CLAUDIN 2 (CLDN2), carboxypeptidase A1 (CPA1), and ATPase type 8B member 1 (ATP8B1). Mutations were searched against online databases to obtain information on the cause of the diseases. Certain novel mutations were analyzed using the SIFT2 and Polyphen-2 to predict the effect on protein function. There were 45 patients with CP and 10 patients with ARP who harbored 1 or more mutations in these genes; 45 patients had at least 1 mutation related to pancreatitis. Mutations were observed in the PRSS1, SPINK1, and CFTR genes in 17 patients, the CASR gene in 5 patients, and the CTSB, CTRC, and KRT8 genes in 1 patient. Mutations were not found in the CLDN, CPA1, or ATP8B1 genes. We found that mutations in SPINK1 may increase the risk of pancreatic duct stones (OR, 11.07; P = .003). The patients with CFTR mutations had a higher level of serum amylase (316.0 U/L vs 92.5 U/L; P = .026). Mutations, especially those in PRSS1, SPINK1, and CFTR, accounted for the major etiologies in Chinese children with CP or ARP. Children presenting mutations in the SPINK1 gene may have a higher risk of developing pancreatic duct stones. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Histone deacetylase inhibitors and pancreatic cancer: are there any promising clinical trials?

    Science.gov (United States)

    Koutsounas, Ioannis; Giaginis, Constantinos; Theocharis, Stamatios

    2013-02-28

    Pancreatic cancer, although not very frequent, has an exceptionally high mortality rate, making it one of the most common causes of cancer mortality in developed countries. Pancreatic cancer is difficult to diagnose, allowing few patients to have the necessary treatment at a relatively early stage. Despite a marginal benefit in survival, the overall response of pancreatic cancer to current systemic therapy continues to be poor, and new therapies are desperately needed. Histone deacetylase (HDAC) enzymes play an important role in the development and progression of cancer and HDAC inhibitors (HDACIs) have been shown to induce differentiation and cell cycle arrest, activate the extrinsic or intrinsic pathways of apoptosis, and inhibit invasion, migration and angiogenesis in different cancer cell lines. As a result of promising preclinical data, various HDACIs are being tested as either monotherapeutic agents or in combination regimens for both solid and hematological malignancies. Vorinostat was the first HDACI approved by the Food and Drug Administration for patients with cutaneous T-cell lymphoma. The use of HDACIs in clinical trials, in pretreated and relapsed patients suffering from advanced pancreatic cancer is discussed. Unfortunately, clinical data for HDACIs in patients with pancreatic cancer are inadequate, because only a few studies have included patients suffering from this type of neoplasm and the number of pancreatic cancer patients that entered HDACIs phase II/III trials, among others with advanced solid tumors, is very limited. More studies recruiting patients with pancreatic cancer remain to determine the efficiency of these therapies.

  13. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Ishan Roy

    Full Text Available Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

  14. Pancreatic cancer planning: Complex conformal vs modulated therapies

    International Nuclear Information System (INIS)

    Chapman, Katherine L.; Witek, Matthew E.; Chen, Hongyu; Showalter, Timothy N.; Bar-Ad, Voichita; Harrison, Amy S.

    2016-01-01

    To compare the roles of intensity-modulated radiation therapy (IMRT) and volumetric- modulated arc therapy (VMAT) therapy as compared to simple and complex 3-dimensional chemoradiotherpy (3DCRT) planning for resectable and borderline resectable pancreatic cancer. In all, 12 patients who received postoperative radiotherapy (8) or neoadjuvant concurrent chemoradiotherapy (4) were evaluated retrospectively. Radiotherapy planning was performed for 4 treatment techniques: simple 4-field box, complex 5-field 3DCRT, 5 to 6-field IMRT, and single-arc VMAT. All volumes were approved by a single observer in accordance with Radiation Therapy Oncology Group (RTOG) Pancreas Contouring Atlas. Plans included tumor/tumor bed and regional lymph nodes to 45 Gy; with tumor/tumor bed boosted to 50.4 Gy, at least 95% of planning target volume (PTV) received the prescription dose. Dose-volume histograms (DVH) for multiple end points, treatment planning, and delivery time were assessed. Complex 3DCRT, IMRT, and VMAT plans significantly (p < 0.05) decreased mean kidney dose, mean liver dose, liver (V 30 , V 35 ), stomach (D 10 %), stomach (V 45 ), mean right kidney dose, and right kidney (V 15 ) as compared with the simple 4-field plans that are most commonly reported in the literature. IMRT plans resulted in decreased mean liver dose, liver (V 35 ), and left kidney (V 15 , V 18 , V 20 ). VMAT plans decreased small bowel (D 10 %, D 15 %), small bowel (V 35 , V 45 ), stomach (D 10 %, D 15 %), stomach (V 35 , V 45 ), mean liver dose, liver (V 35 ), left kidney (V 15 , V 18 , V 20 ), and right kidney (V 18 , V 20 ). VMAT plans significantly decreased small bowel (D 10 %, D 15 %), left kidney (V 20 ), and stomach (V 45 ) as compared with IMRT plans. Treatment planning and delivery times were most efficient for simple 4-field box and VMAT. Excluding patient setup and imaging, average treatment delivery was within 10 minutes for simple and complex 3DCRT, IMRT, and VMAT treatments. This article

  15. Overexpression and biological function of MEF2D in human pancreatic cancer.

    Science.gov (United States)

    Song, Zhiwang; Feng, Chan; Lu, Yonglin; Gao, Yong; Lin, Yun; Dong, Chunyan

    2017-01-01

    To explore the expression, clinical significance, biological function, and potential mechanism of MEF2D in pancreatic cancer, the expression of MEF2D in human pancreatic cancer tissues and corresponding adjacent normal tissues was analyzed through immunohistochemical staining. The association between MEF2D expression, clinicopathological parameters, overall survival, and disease-free survival was evaluated. Human pancreatic cancer cell lines BxPC-1 and SW1990 were selected to investigate the effect of MEF2D knockdown on cell proliferation, migration, and invasion. Western blot analysis was used to assess the effect of MEF2D expression on the Akt/GSK pathway, as well as the protein expression of cyclin B1, cyclin D1, matrix metalloprotein (MMP)-2, and MMP-9. Our results revealed that the expression of MEF2D was increased in pancreatic cancer tissues compared to adjacent normal tissues and the increased expression of MEF2D was associated with tumor size, histological differentiation, and TNM stage of pancreatic cancer patients. Moreover, the expression of MEF2D was an independent prognostic indicator for pancreatic cancer patients. In addition, knockdown of MEF2D in pancreatic cancer cells inhibited cell proliferation, migration, and invasion by down-regulating the protein expression of cyclin B1, cyclin D1, MMP-2, and MMP-9. Knockdown of MEF2D reduced the levels of phosphorylated Akt and GSK-3β. Our data indicated that MEF2D expression was increased in pancreatic cancer and was an independent molecular prognostic factor for pancreatic cancer patients. Furthermore, we showed that MEF2D controlled cell proliferation, migration, and invasion abilities in pancreatic cancer via the Akt/GSK-3β signaling pathway.

  16. Opium Use and Risk of Pancreatic Cancer: A Prospective Cohort Study

    Science.gov (United States)

    Moossavi, Shirin; Mohamadnejad, Mehdi; Pourshams, Akram; Poustchi, Hossein; Islami, Farhad; Sharafkhah, Maryam; Mirminachi, Babak; Nasseri-Moghaddam, Siavosh; Semnani, Shahryar; Shakeri, Ramin; Etemadi, Arash; Merat, Shahin; Khoshnia, Masoud; Dawsey, Sanford M.; Pharoah, Paul D.; Brennan, Paul; Abnet, Christian C.; Boffetta, Paolo; Kamangar, Farin; Malekzadeh, Reza

    2018-01-01

    Background We examined the association between opium consumption and pancreatic cancer incidence in a large-scale prospective cohort of the general population in Northeast of Iran. Methods A total of 50,045 adults were systematically followed-up (median of 7.4 years) and incident cases of pancreatic cancer were identified. Self-reported data on opium consumption was collected at baseline. Cumulative use (-year) was defined as number of nokhods (a local unit, approximately 0.2 g) of opium consumed per day multiplied by number of years consuming. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between opium consumption and pancreatic cancer were calculated using Cox proportional hazards regression models. Results Overall, 54 confirmed cases of pancreatic cancer were identified. Opium use of more than 81 nokhod-years (high cumulative use), compared to never use, was strongly associated with pancreatic cancer even after adjustments for multiple potential confounding factors [HR=3.01; 95% CI 1.25-7.26]. High cumulative consumption of opium was significantly associated with risk of pancreatic cancer after adjusting for cumulative dose of cigarette smoking [HR=3.56; 95% CI 1.49-8.50]. In a sensitivity analysis, we excluded participants (including 2 pancreatic cancer cases) who were recruited within the first 5 years of starting opium consumption; high cumulative use of opium was still associated with pancreatic cancer risk [HR=2.75; 95% CI 1.14-6.64]. Conclusion Our results showed a positive association between opium consumption and pancreatic cancer. Impact This is the first prospective large-scale study to show the association of opium consumption with pancreatic cancer as a risk factor. PMID:29263189

  17. Neoadjuvant preoperative chemoradiation in patients with pancreatic cancer

    International Nuclear Information System (INIS)

    Magnin, Valerie; Moutardier, Vincent; Giovannini, Marie-Helene; Lelong, Bernard; Giovannini, Marc; Viret, Frederic; Monges, Genevieve; Bardou, Valerie-Jeanne; Alzieu, Claude; Delpero, Jean-Robert

    2003-01-01

    Purpose: To assess the toxicity and efficacy of preoperative chemoradiation in pancreatic cancer. Methods and Materials: Between November 1996 and December 2001, 32 patients with biopsy-proven pancreatic adenocarcinoma (28 head; 4 body) were treated by chemoradiation consisting of either split-course therapy (two courses of 15 Gy separated by a 2-week break, n = 10) or standard-fractionation therapy (45 Gy during 5 weeks, n 22). Concurrent chemotherapy included continuous infusion of 5-fluorouracil and a cisplatin bolus. Pancreatic resection was scheduled for 4-6 weeks after completion of chemoradiation treatment. Results: All 32 patients completed the chemoradiation protocol. Only 2 cases of Grade 3 toxicity (weight loss, vomiting) and one fatal Grade 4 infection occurred. Of the 32 patients, 19 underwent curative resection. Two patients had a complete pathologic response. One patient died 36 months after diagnosis of late treatment-related toxicity (acute superior mesenteric artery thrombosis) with no evidence of disease. The 2-year overall survival rate for the entire group and the resected patients was 37.3% (95% confidence interval 18.2-56.4%) and 59.3% (95% confidence interval 34.1-84.9%), respectively. Conclusion: Preoperative chemoradiation with 5-fluorouracil and cisplatin is feasible and promising

  18. Stereotactic Body Radiotherapy and Gemcitabine for Locally Advanced Pancreatic Cancer

    International Nuclear Information System (INIS)

    Mahadevan, Anand; Jain, Sanjay; Goldstein, Michael; Miksad, Rebecca; Pleskow, Douglas; Sawhney, Mandeep; Brennan, Darren M.D.; Callery, Mark; Vollmer, Charles

    2010-01-01

    Purpose: Patients with nonmetastatic locally advanced unresectable pancreatic cancer have a dismal prognosis. Conventional concurrent chemoradiotherapy requires 6 weeks of daily treatment and can be arduous. We explored the safety and effectiveness of a 3-day course of hypofractionated stereotactic body radiotherapy (SBRT) followed by gemcitabine in this population. Patients and Methods: A total of 36 patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with ≥12 months of follow-up were included. They received three fractions of 8, 10, or 12 Gy (total dose, 24-36 Gy) of SBRT according to the tumor location in relation to the stomach and duodenum, using fiducial-based respiratory motion tracking on a robotic radiosurgery system. The patients were then offered gemcitabine for 6 months or until tolerance or disease progression. Results: With an overall median follow-up of 24 months (range, 12-33), the local control rate was 78%, the median overall survival time was 14.3 months, the median carbohydrate antigen 19-9-determined progression-free survival time was 7.9 months, and the median computed tomography-determined progression-free survival time was 9.6 months. Of the 36 patients, 28 (78%) eventually developed distant metastases. Six patients (17%) were free of progression at the last follow-up visit (range, 13-30 months) as determined by normalized tumor markers with stable computed tomography findings. Nine Grade 2 (25%) and five Grade 3 (14%) toxicities attributable to SBRT occurred. Conclusion: Hypofractionated SBRT can be delivered quickly and effectively in patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with acceptable side effects and minimal interference with gemcitabine chemotherapy.

  19. Palliative Interventional and Surgical Therapy for Unresectable Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Assfalg, Volker; Hüser, Norbert; Michalski, Christoph; Gillen, Sonja; Kleeff, Jorg; Friess, Helmut, E-mail: friess@chir.med.tu-muenchen.de [Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, D-81675 Munich (Germany)

    2011-02-14

    Palliative treatment concepts are considered in patients with non-curatively resectable and/or metastasized pancreatic cancer. However, patients without metastases, but presented with marginally resectable or locally non-resectable tumors should not be treated by a palliative therapeutic approach. These patients should be enrolled in neoadjuvant radiochemotherapy trials because a potentially curative resection can be achieved in approximately one-third of them after finishing treatment and restaging. Within the scope of best possible palliative care, resection of the primary cancer together with excision of metastases represents a therapeutic option to be contemplated in selected cases. Comprehensive palliative therapy is based on treatment of bile duct or duodenal obstruction for certain locally unresectable or metastasized advanced pancreatic cancer. However, endoscopic or percutaneous stenting procedures and surgical bypass provide safe and highly effective therapeutic alternatives. In case of operative drainage of the biliary tract (biliodigestive anastomosis), the prophylactic creation of a gastro-intestinal bypass (double bypass) is recommended. The decision to perform a surgical versus an endoscopic procedure for palliation depends to a great extent on the tumor stage and the estimated prognosis, and should be determined by an interdisciplinary team for each patient individually.

  20. Palliative Interventional and Surgical Therapy for Unresectable Pancreatic Cancer

    International Nuclear Information System (INIS)

    Assfalg, Volker; Hüser, Norbert; Michalski, Christoph; Gillen, Sonja; Kleeff, Jorg; Friess, Helmut

    2011-01-01

    Palliative treatment concepts are considered in patients with non-curatively resectable and/or metastasized pancreatic cancer. However, patients without metastases, but presented with marginally resectable or locally non-resectable tumors should not be treated by a palliative therapeutic approach. These patients should be enrolled in neoadjuvant radiochemotherapy trials because a potentially curative resection can be achieved in approximately one-third of them after finishing treatment and restaging. Within the scope of best possible palliative care, resection of the primary cancer together with excision of metastases represents a therapeutic option to be contemplated in selected cases. Comprehensive palliative therapy is based on treatment of bile duct or duodenal obstruction for certain locally unresectable or metastasized advanced pancreatic cancer. However, endoscopic or percutaneous stenting procedures and surgical bypass provide safe and highly effective therapeutic alternatives. In case of operative drainage of the biliary tract (biliodigestive anastomosis), the prophylactic creation of a gastro-intestinal bypass (double bypass) is recommended. The decision to perform a surgical versus an endoscopic procedure for palliation depends to a great extent on the tumor stage and the estimated prognosis, and should be determined by an interdisciplinary team for each patient individually

  1. Retrospective Evaluation of the Pancreatic Cancer Patients Who Received Chemoradiotherapy

    Directory of Open Access Journals (Sweden)

    Feryal Karaca

    2016-01-01

    Full Text Available Aim: Pancreatic cancer is a highly lethal malignancy and in locally advanced disease, chemotherapy (CT or chemoradiotherapy (CRT are implemented. The aim of this retrospective study was to investigate the general characteristics and survival of our patients receiving CRT. Material and Method: Between the years 2009-2013, 62 pancreatic cancer patients were taken into study who admitted to Van Training and Research Hospital. Eight patients who had whipple operation received radiotherapy (RT with concurrent CT. Fifty-four patients who were considered to be inoperable underwent CRT. As adjuvant treatment dose, 45 Gy (1,8 Gy/fx/day radiotherapy was administered to pancreas and regional lymph nodes. In patients who had taken definitive CRT, average 50.4 Gy (1.8 Gy/fx/day dose was given. Statistical analysis was carried out using SPSS 19 software package; Kaplan-Meier analysis method was used for survival and log-range test for comparisons. Results: Twenty-four patients (38.7% were female and 38 (61.3% were male. Eleven patients (17.7% were at stage IA, 16 (25.8% were stage IB, 13 (20.9% were stage IIA, 8 (12.9% were stage IIB and 14 (22.5% were staged as stage III. Two-year disease free survival (DFS; time from the date of biopsy until the date of recurrence was approximately 436 days and the median DFS was found to be 362 days. The average overall survival (OS time; time from the date of biopsy until the date of death were found to be approximately 854 days, the median survival time was found to be 916 days. Survival due to tumor localization (head, body and tail showed no significant difference statistically (log-range chi-square=0.366;p=0.833. Discussion: According to our single center experience, our data in pancreatic cancer patients were parallel with international data. In preclinical experiments, effective drug therapies for curative modalities are under investigation for pancreatic cancer patients.

  2. Intraoperative radiotherapy in resected pancreatic cancer: feasibility and results

    International Nuclear Information System (INIS)

    Coquard, Regis; Ayzac, Louis; Gilly, Francois-Noeel; Romestaing, Pascale; Ardiet, Jean-Michel; Sondaz, Chrystel; Sotton, Marie-Pierre; Sentenac, Irenee; Braillon, Georges; Gerard, Jean-Pierre

    1997-01-01

    Background and purpose: To evaluate the impact of intraoperative radiotherapy (IORT) combined with postoperative external beam irradiation in patients with pancreatic cancer treated with curative surgical resection. Materials and methods: From January 1986 to April 1995 25 patients (11 male and 14 female, median age 61 years) underwent a curative resection with IORT for pancreatic adenocarcinoma. The tumour was located in the head of the pancreatic gland in 22 patients, in the body in two patients and in the tail in one patient. The pathological stage was pT1 in nine patients, pT2 in nine patients, pT3 in seven patients, pN0 in 14 patients and pN1 in 11 patients. All the patients were pM0. A pancreaticoduodenectomy was performed in 22 patients, a distal pancreatectomy was performed in two patients and a total pancreatectomy was performed in one patient. The resection was considered to be complete in 20 patients. One patient had microscopic residual disease and gross residual disease was present in four patients. IORT using electrons with a median energy of 12 MeV was performed in all the patients with doses ranging from 12 to 25 Gy. Postoperative EBRT was delivered to 20 patients (median dose 44 Gy). Concurrent chemotherapy with 5-fluorouracil was given to seven patients. Results: The overall survival was 56% at 1 year, 20% at 2 years and 10% at 5 years. Nine local failures were observed. Twelve patients developed metastases without local recurrence. Twenty patients died from tumour progression and two patients died from early post-operative complications. Three patients are still alive; two patients in complete response at 17 and 94 months and one patient with hepatic metastases at 13 months. Conclusion: IORT after complete resection combined with postoperative external beam irradiation is feasible and well tolerated in patients with pancreatic adenocarcinoma

  3. Targeting Trypsin-Inflammation Axis for Pancreatitis Therapy in a Humanized Pancreatitis Model

    Science.gov (United States)

    2016-10-01

    2015. This task required: (a) Preparation and final approval of an MTA between the two institutions; (b) administrative coordination between the...the funding period, we also initiated studies to measure the effects of alcohol and the smoking compounds NNK (a nicotine derivative) and cigarette...trypsinogen activation) using rodent models, human pancreatic primary acinar cells. Overlap: There are no administrative , financial or scientific overlaps

  4. Development of improved therapeutic mesothelin-based vaccines for pancreatic cancer.

    Science.gov (United States)

    White, Michael; Freistaedter, Andrew; Jones, Gwendolyn J B; Zervos, Emmanuel; Roper, Rachel L

    2018-01-01

    Pancreatic cancer is the 5th leading cause of cancer deaths, and there are no effective treatments. We developed a poxvirus platform vaccine with improved immunogenicity and inserted the mesothelin gene to create an anti-mesothelin cancer vaccine. Mesothelin expression is mostly restricted to tumors in adult mammals and thus may be a good target for cancer treatment. We show here that the modified vaccinia virus Ankara (MVA) virus expressing mesothelin and the enhanced MVA virus missing the immunosuppressive A35 gene and expressing mesothelin were both safe in mice and were able to induce IFN-gamma secreting T cells in response to mesothelin expressing tumor cells. In addition, the MVA virus has oncolytic properties in vitro as it can replicate in and kill Panc02 pancreatic adenocarcinoma cell line tumor cells, even though it is unable to replicate in most mammalian cells. Deletion of the A35 gene in MVA improved T cell responses as expected. However, we were unable to demonstrate inhibition of Panc02 tumor growth in immunocompetent mice with pre-vaccination of mice, boosts, or even intratumoral injections of the recombinant viruses. Vaccine efficacy may be limited by shedding of mesothelin from tumor cells thus creating a protective screen from the immune system.

  5. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

    Science.gov (United States)

    Klein, Alison P; Wolpin, Brian M; Risch, Harvey A; Stolzenberg-Solomon, Rachael Z; Mocci, Evelina; Zhang, Mingfeng; Canzian, Federico; Childs, Erica J; Hoskins, Jason W; Jermusyk, Ashley; Zhong, Jun; Chen, Fei; Albanes, Demetrius; Andreotti, Gabriella; Arslan, Alan A; Babic, Ana; Bamlet, William R; Beane-Freeman, Laura; Berndt, Sonja I; Blackford, Amanda; Borges, Michael; Borgida, Ayelet; Bracci, Paige M; Brais, Lauren; Brennan, Paul; Brenner, Hermann; Bueno-de-Mesquita, Bas; Buring, Julie; Campa, Daniele; Capurso, Gabriele; Cavestro, Giulia Martina; Chaffee, Kari G; Chung, Charles C; Cleary, Sean; Cotterchio, Michelle; Dijk, Frederike; Duell, Eric J; Foretova, Lenka; Fuchs, Charles; Funel, Niccola; Gallinger, Steven; M Gaziano, J Michael; Gazouli, Maria; Giles, Graham G; Giovannucci, Edward; Goggins, Michael; Goodman, Gary E; Goodman, Phyllis J; Hackert, Thilo; Haiman, Christopher; Hartge, Patricia; Hasan, Manal; Hegyi, Peter; Helzlsouer, Kathy J; Herman, Joseph; Holcatova, Ivana; Holly, Elizabeth A; Hoover, Robert; Hung, Rayjean J; Jacobs, Eric J; Jamroziak, Krzysztof; Janout, Vladimir; Kaaks, Rudolf; Khaw, Kay-Tee; Klein, Eric A; Kogevinas, Manolis; Kooperberg, Charles; Kulke, Matthew H; Kupcinskas, Juozas; Kurtz, Robert J; Laheru, Daniel; Landi, Stefano; Lawlor, Rita T; Lee, I-Min; LeMarchand, Loic; Lu, Lingeng; Malats, Núria; Mambrini, Andrea; Mannisto, Satu; Milne, Roger L; Mohelníková-Duchoňová, Beatrice; Neale, Rachel E; Neoptolemos, John P; Oberg, Ann L; Olson, Sara H; Orlow, Irene; Pasquali, Claudio; Patel, Alpa V; Peters, Ulrike; Pezzilli, Raffaele; Porta, Miquel; Real, Francisco X; Rothman, Nathaniel; Scelo, Ghislaine; Sesso, Howard D; Severi, Gianluca; Shu, Xiao-Ou; Silverman, Debra; Smith, Jill P; Soucek, Pavel; Sund, Malin; Talar-Wojnarowska, Renata; Tavano, Francesca; Thornquist, Mark D; Tobias, Geoffrey S; Van Den Eeden, Stephen K; Vashist, Yogesh; Visvanathan, Kala; Vodicka, Pavel; Wactawski-Wende, Jean; Wang, Zhaoming; Wentzensen, Nicolas; White, Emily; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Kraft, Peter; Li, Donghui; Chanock, Stephen; Obazee, Ofure; Petersen, Gloria M; Amundadottir, Laufey T

    2018-02-08

    In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10 -8 ). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10 -14 ), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10 -10 ), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10 -8 ), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10 -8 ). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

  6. Mechanisms Regulating Acid-Base Transporter Expression in Breast- and Pancreatic Cancer

    DEFF Research Database (Denmark)

    Gorbatenko, Andrej

    Breast cancer is the most commonly diagnosed cancer in women, and the second most frequent cause of death from cancer in women. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer with only a 5% 5-year survival rate. Both types of cancer form solid tumors...

  7. STAT5b as Molecular Target in Pancreatic Cancer—Inhibition of Tumor Growth, Angiogenesis, and Metastases

    Directory of Open Access Journals (Sweden)

    Christian Moser

    2012-10-01

    Full Text Available The prognosis of patients suffering from pancreatic cancer is still poor and novel therapeutic options are urgently needed. Recently, the transcription factor signal transducer and activator of transcription 5b (STAT5b was associated with tumor progression in human solid cancer. Hence, we assessed whether STAT5b might serve as an anticancer target in ductal pancreatic adenocarcinoma (DPAC. We found that nuclear expression of STAT5b can be detected in approximately 50% of DPAC. Blockade of STAT5b by stable shRNA-mediated knockdown showed no effects on tumor cell growth in vitro. However, inhibition of tumor cell motility was found even in response to stimulation with epidermal growth factor or interleukin-6. These findings were paralleled by a reduction of prometastatic and proangiogenic factors in vitro. Subsequent in vivo experiments revealed a strong growth inhibition on STAT5b blockade in subcutaneous and orthotopic models. These findings were paralleled by impaired tumor angiogenesis in vivo. In contrast to the subcutaneous model, the orthotopic model revealed a strong reduction of tumor cell proliferation that emphasizes the meaning of assessing targets in an appropriate microenvironment. Taken together, our results suggest that STAT5b might be a potential novel target for human DPAC.

  8. Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of Pancreatic Adenocarcinoma.

    Science.gov (United States)

    2015-10-01

    The SCAN pancreatic cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. Five international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2014), the European Society of Medical Oncology (2012), Cancer Care Ontario (2013), the Japan Pancreas Society (2013) and the British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, and the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (2005). Recommendations on the management of resected, borderline resectable, locally advanced and metastatic pancreatic adenocarcinoma were developed. These adapted guidelines form the SCAN Guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore.

  9. Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case–Control Consortium (PanC4)

    Science.gov (United States)

    Bosetti, C.; Lucenteforte, E.; Bracci, P. M.; Negri, E.; Neale, R. E.; Risch, H. A.; Olson, S. H.; Gallinger, S.; Miller, A. B.; Bueno-de-Mesquita, H. B.; Talamini, R.; Polesel, J.; Ghadirian, P.; Baghurst, P. A.; Zatonski, W.; Fontham, E.; Holly, E. A.; Gao, Y. T.; Yu, H.; Kurtz, R. C.; Cotterchio, M.; Maisonneuve, P.; Zeegers, M. P.; Duell, E. J.; Boffetta, P.; La Vecchia, C.

    2013-01-01

    Background Peptic ulcer and its treatments have been associated to pancreatic cancer risk, although the evidence is inconsistent. Methods We pooled 10 case–control studies within the Pancreatic Cancer Case–control Consortium (PanC4), including 4717 pancreatic cancer cases and 9374 controls, and estimated summary odds ratios (OR) using multivariable logistic regression models. Results The OR for pancreatic cancer was 1.10 [95% confidence interval (CI) 0.98–1.23] for history of ulcer (OR = 1.08 for gastric and 0.97 for duodenal ulcer). The association was stronger for a diagnosis within 2 years before cancer diagnosis (OR = 2.43 for peptic, 1.75 for gastric, and 1.98 for duodenal ulcer). The OR was 1.53 (95% CI 1.15–2.03) for history of gastrectomy; however, the excess risk was limited to a gastrectomy within 2 years before cancer diagnosis (OR = 6.18, 95% CI 1.82–20.96), while no significant increased risk was observed for longer time since gastrectomy. No associations were observed for pharmacological treatments for ulcer, such as antacids, H2-receptor antagonists, or proton-pump inhibitors. Conclusions This uniquely large collaborative study does not support the hypothesis that peptic ulcer and its treatment materially affect pancreatic cancer risk. The increased risk for short-term history of ulcer and gastrectomy suggests that any such association is due to increased cancer surveillance. PMID:23970016

  10. Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

    Science.gov (United States)

    Bosetti, C; Lucenteforte, E; Bracci, P M; Negri, E; Neale, R E; Risch, H A; Olson, S H; Gallinger, S; Miller, A B; Bueno-de-Mesquita, H B; Talamini, R; Polesel, J; Ghadirian, P; Baghurst, P A; Zatonski, W; Fontham, E; Holly, E A; Gao, Y T; Yu, H; Kurtz, R C; Cotterchio, M; Maisonneuve, P; Zeegers, M P; Duell, E J; Boffetta, P; La Vecchia, C

    2013-11-01

    Peptic ulcer and its treatments have been associated to pancreatic cancer risk, although the evidence is inconsistent. We pooled 10 case-control studies within the Pancreatic Cancer Case-control Consortium (PanC4), including 4717 pancreatic cancer cases and 9374 controls, and estimated summary odds ratios (OR) using multivariable logistic regression models. The OR for pancreatic cancer was 1.10 [95% confidence interval (CI) 0.98-1.23] for history of ulcer (OR = 1.08 for gastric and 0.97 for duodenal ulcer). The association was stronger for a diagnosis within 2 years before cancer diagnosis (OR = 2.43 for peptic, 1.75 for gastric, and 1.98 for duodenal ulcer). The OR was 1.53 (95% CI 1.15-2.03) for history of gastrectomy; however, the excess risk was limited to a gastrectomy within 2 years before cancer diagnosis (OR = 6.18, 95% CI 1.82-20.96), while no significant increased risk was observed for longer time since gastrectomy. No associations were observed for pharmacological treatments for ulcer, such as antacids, H2-receptor antagonists, or proton-pump inhibitors. This uniquely large collaborative study does not support the hypothesis that peptic ulcer and its treatment materially affect pancreatic cancer risk. The increased risk for short-term history of ulcer and gastrectomy suggests that any such association is due to increased cancer surveillance.

  11. Targeted Therapies in Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Selen Dogan

    2014-04-01

    Full Text Available Endometrial cancer is the most common genital cancer in developed world. It is generally diagnosed in early stage and it has a favorable prognosis. However, advanced staged disease and recurrences are difficult to manage. There are some common genetic alterations related to endometrial carcinogenesis in similar fashion to other cancers. Personalized medicine, which means selection of best suited treatment for an individual, has gain attention in clinical care of patients in recent years. Targeted therapies were developed as a part of personalized or %u201Ctailored%u201D medicine and specifically acts on a target or biologic pathway. There are quite a number of molecular alteration points in endometrial cancer such as PTEN tumor suppressor genes, DNA mismatch repair genes, PI3K/AKT/mTOR pathway and p53 oncogene which all might be potential candidates for tailored targeted therapy. In recent years targeted therapies has clinical application in ovarian cancer patients and in near future with the advent of new agents these %u201Ctailored%u201D drugs will be in market for routine clinical practice in endometrial cancer patients, in primary disease and recurrences as well.

  12. Opium use, cigarette smoking, and alcohol consumption in relation to pancreatic cancer.

    Science.gov (United States)

    Shakeri, Ramin; Kamangar, Farin; Mohamadnejad, Mehdi; Tabrizi, Reza; Zamani, Farhad; Mohamadkhani, Ashraf; Nikfam, Sepideh; Nikmanesh, Arash; Sotoudeh, Masoud; Sotoudehmanesh, Rasoul; Shahbazkhani, Bijan; Ostovaneh, Mohammad Reza; Islami, Farhad; Poustchi, Hossein; Boffetta, Paolo; Malekzadeh, Reza; Pourshams, Akram

    2016-07-01

    Although several studies have suggested opium as a risk factor for cancers of the esophagus, stomach, larynx, lung, and bladder, no previous study has examined the association of opium with pancreatic cancer. We aimed to study the association between opium use and risk of pancreatic cancer in Iran, using a case-control design. We also studied the association of cigarette smoking and alcohol consumption with pancreatic cancer, for which little information was available from this population. Cases and controls were selected from patients who were referred to 4 endoscopic ultrasound centers in Tehran, Iran. We recruited 316 histopathologically (all adenocarcinoma) and 41 clinically diagnosed incident cases of pancreatic cancer, as well as 328 controls from those with a normal pancreas in enodosonography from January 2011 to January 2015. We used logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs). After adjustment for potential confounders, opium use (OR 1.91; 95% CI 1.06-3.43) and alcohol consumption (OR 4.16; 95% CI 1.86-9.31) were significantly associated with an increased risk of pancreatic cancer. We did not find an association between ever tobacco smoking and pancreatic cancer risk (OR 0.93; 95% CI 0.62-1.39). In our study, opium use and alcohol consumption were associated with an increased risk of pancreatic cancer, whereas cigarette smoking was not.

  13. Translational research in pancreatic cancer. Highlights from the "44th ASCO Annual Meeting". Chicago, IL, USA. May 30 - June 3, 2008.

    Science.gov (United States)

    Saif, Muhammad Wasif

    2008-07-10

    Pancreatic cancer is an international problem because of its increasing incidence worldwide. The incidence and age-adjusted mortality rates are almost equal, underscoring the aggressive nature of the disease. Although efforts are being made to unveil the principles governing the initiation and progression of this cancer, and to identify the factors that confer its particular aggressiveness, the exact succession of molecular events underlying the development of this devastating malignancy has remained unsolved. The management of pancreatic cancer is, therefore, an ongoing challenge. Many translational studies were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) this year. The author summarizes few of them including: polymorphisms of genes involved in gemcitabine metabolism correlate with prognosis in patients receiving neoadjuvant therapy for pancreatic cancer, diagnostic performance of MUC1 for pancreatic ductal adenocarcinoma, and use of whole genome expression analysis of pancreatic adenocarcinoma to predict prognosis after surgery. Pancreatic cancer remains a dismal disease and early diagnostic markers and therapeutic targets are urgently needed.

  14. Solitary pancreatic metastasis from breast cancer: case report and review of literature

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    Márcio Apodaca-Rueda

    2017-11-01

    Full Text Available ABSTRACT CONTEXT: Pancreatic metastases from primary malignant tumors at other sites are rare, constituting about 2% of the neoplasms that affect the pancreas. Pancreatic metastasis from breast cancer is extremely rare and difficult to diagnose, because its clinical and radiological presentation is similar to that of a primary pancreatic tumor. CASE REPORT: A 64-year-old female developed a lesion in the pancreatic tail 24 months after neoadjuvant therapy, surgery and adjuvant radiation therapy for right-side breast cancer (ductal carcinoma. She underwent distal pancreatectomy with splenectomy and left adrenalectomy, and presented an uneventful outcome. The immunohistochemical analysis on the surgical specimen suggested that the lesion originated from the breast. CONCLUSION: In cases of pancreatic lesions detected in patients with a previous history of breast neoplasm, the possibility of pancreatic metastasis should be carefully considered.

  15. Preclinical evaluation of a novel CEA-targeting near-infrared fluorescent tracer delineating colorectal and pancreatic tumors.

    Science.gov (United States)

    Boonstra, Martin C; Tolner, Berend; Schaafsma, Boudewijn E; Boogerd, Leonora S F; Prevoo, Hendrica A J M; Bhavsar, Guarav; Kuppen, Peter J K; Sier, Cornelis F M; Bonsing, Bert A; Frangioni, John V; van de Velde, Cornelis J H; Chester, Kerry A; Vahrmeijer, Alexander L

    2015-10-15

    Surgery is the cornerstone of oncologic therapy with curative intent. However, identification of tumor cells in the resection margins is difficult, resulting in nonradical resections, increased cancer recurrence and subsequent decreased patient survival. Novel imaging techniques that aid in demarcating tumor margins during surgery are needed. Overexpression of carcinoembryonic antigen (CEA) is found in the majority of gastrointestinal carcinomas, including colorectal and pancreas. We developed ssSM3E/800CW, a novel CEA-targeted near-infrared fluorescent (NIRF) tracer, based on a disulfide-stabilized single-chain antibody fragment (ssScFv), to visualize colorectal and pancreatic tumors in a clinically translatable setting. The applicability of the tracer was tested for cell and tissue binding characteristics and dosing using immunohistochemistry, flow cytometry, cell-based plate assays and orthotopic colorectal (HT-29, well differentiated) and pancreatic (BXPC-3, poorly differentiated) xenogeneic human-mouse models. NIRF signals were visualized using the clinically compatible FLARE™ imaging system. Calculated clinically relevant doses of ssSM3E/800CW selectively accumulated in colorectal and pancreatic tumors/cells, with highest tumor-to-background ratios of 5.1 ± 0.6 at 72 hr postinjection, which proved suitable for intraoperative detection and delineation of tumor boarders and small (residual) tumor nodules in mice, between 8 and 96 hr postinjection. Ex vivo fluorescence imaging and pathologic examination confirmed tumor specificity and the distribution of the tracer. Our results indicate that ssSM3E/800CW shows promise as a diagnostic tool to recognize colorectal and pancreatic cancers for fluorescent-guided surgery applications. If successfully translated clinically, this tracer could help improve the completeness of surgery and thus survival. © 2015 UICC.

  16. The correlation between FDG uptake and biological molecular markers in pancreatic cancer patients

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    Kaida, Hayato, E-mail: kaida@med.kindai.ac.jp [Department of Radiology, Kindai University Faculty of Medicine, Osakasayama City, Osaka, 589-8511 (Japan); Azuma, Koichi [Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume City, Fukuoka, 830-0011 (Japan); Kawahara, Akihiko [Department of Diagnostic Pathology, Kurume University Hospital, Kurume City, Fukuoka, 830-0011 (Japan); Yasunaga, Masafumi; Kitasato, Yuhei [Department of Surgery, Kurume University School of Medicine, Kurume City, Fukuoka, 830-0011 (Japan); Hattori, Satoshi [Biostatic Center, Kurume University School of Medicine, Kurume City, Fukuoka, 830-0011 (Japan); Taira, Tomoki [Department of Diagnostic Pathology, Kurume University Hospital, Kurume City, Fukuoka, 830-0011 (Japan); Ureshino, Hiroki [Department of Surgery, Kurume University School of Medicine, Kurume City, Fukuoka, 830-0011 (Japan); Kage, Masayoshi [Department of Diagnostic Pathology, Kurume University Hospital, Kurume City, Fukuoka, 830-0011 (Japan); Ishii, Kazunari; Murakami, Takamichi [Department of Radiology, Kindai University Faculty of Medicine, Osakasayama City, Osaka, 589-8511 (Japan); Ishibashi, Masatoshi [Division of Nuclear Medicine, PET Center, and Department of Radiology, Fukuoka Tokushukai Hospital, Kasuga City, Fukuoka, 816-0864 (Japan)

    2016-10-15

    Purpose: We examined whether fluorine-18 fluorodeoxyglucose (FDG) uptake is related to the mammalian target of rapamycin (mTOR) signal pathway and its related proteins in pancreatic cancer patients. Methods: We retrospectively studied 53 pancreatic cancer patients who underwent FDG positron emission tomography (PET) or FDG PET/CT, and complete curative surgical resection. The SUV max, the tumor to nontumor activity of pancreas [T/N (P)] ratio and the T/N of liver [T/N (L)] ratio were calculated. The expressions of glucose transporter-1(Glut-1) and mTOR pathway proteins in pancreas cell lines were examined by immune blots. Excised tumor tissue was analyzed by immunohistochemistry using monoclonal antibodies for Glut-1, epidermal growth factor receptor (EGFR), mTOR, p70S6kinase (p70S6) and S6 ribosomal protein (S6). Results: The expressions of Glut-1, EGFR and p70S6 were significantly correlated with the SUV max, T/N (P) ratio and T/N (L) ratio. The expressions of mTOR and S6 were not correlated with all parameters. The expression of Glut-1 was positively correlated with the expressions of EGFR and p70S6, but not with mTOR or S6. S6 was positively correlated with p70S6. Conclusions: Glut-1, EGFR and p70S6 expressions are associated with the FDG uptake mechanism of pancreatic cancer. FDG uptake may predict the levels of EGFR and p70S6 expressions, and FDG uptake reflects glucose metabolism and cancer progression.

  17. Nonlinear optical microscopy for histology of fresh normal and cancerous pancreatic tissues.

    Directory of Open Access Journals (Sweden)

    Wenyan Hu

    Full Text Available BACKGROUND: Pancreatic cancer is a lethal disease with a 5-year survival rate of only 1-5%. The acceleration of intraoperative histological examination would be beneficial for better management of pancreatic cancer, suggesting an improved survival. Nonlinear optical methods based on two-photon excited fluorescence (TPEF and second harmonic generation (SHG of intrinsic optical biomarkers show the ability to visualize the morphology of fresh tissues associated with histology, which is promising for real-time intraoperative evaluation of pancreatic cancer. METHODOLOGY/PRINCIPAL FINDINGS: In order to investigate whether the nonlinear optical imaging methods have the ability to characterize pancreatic histology at cellular resolution, we studied different types of pancreatic tissues by using label-free TPEF and SHG. Compared with other routine methods for the preparation of specimens, fresh tissues without processing were found to be most suitable for nonlinear optical imaging of pancreatic tissues. The detailed morphology of the normal rat pancreas was observed and related with the standard histological images. Comparatively speaking, the preliminary images of a small number of chemical-induced pancreatic cancer tissues showed visible neoplastic differences in the morphology of cells and extracellular matrix. The subcutaneous pancreatic tumor xenografts were further observed using the nonlinear optical microscopy, showing that most cells are leucocytes at 5 days after implantation, the tumor cells begin to proliferate at 10 days after implantation, and the extracellular collagen fibers become disordered as the xenografts grow. CONCLUSIONS/SIGNIFICANCE: In this study, nonlinear optical imaging was used to characterize the morphological details of fresh pancreatic tissues for the first time. We demonstrate that it is possible to provide real-time histological evaluation of pancreatic cancer by the nonlinear optical methods, which present an

  18. Heme oxygenase is not involved in the anti-proliferative effects of statins on pancreatic cancer cells

    International Nuclear Information System (INIS)

    Vanova, K.; Boukalova, S.; Gbelcova, H.; Muchova, L.; Neuzil, J.; Gurlich, R.; Ruml, T.; Vitek, L.

    2016-01-01

    Pancreatic cancer is recognized as one of the most fatal tumors due to its aggressiveness and resistance to therapy. Statins were previously shown to inhibit the proliferation of cancer cells via various signaling pathways. In healthy tissues, statins activate the heme oxygenase pathway, nevertheless the role of heme oxygenase in pancreatic cancer is still controversial. The aim of this study was to evaluate, whether anti-proliferative effects of statins in pancreatic cancer cells are mediated via the heme oxygenase pathway. In vitro effects of various statins and hemin, a heme oxygenase inducer, on cell proliferation were evaluated in PA-TU-8902, MiaPaCa-2 and BxPC-3 human pancreatic cancer cell lines. The effect of statins on heme oxygenase activity was assessed and heme oxygenase-silenced cells were used for pancreatic cancer cell proliferation studies. Cell death rate and reactive oxygen species production were measured in PA-TU-8902 cells, followed by evaluation of the effect of cerivastatin on GFP-K-Ras trafficking and expression of markers of invasiveness, osteopontin (SPP1) and SOX2. While simvastatin and cerivastatin displayed major anti-proliferative properties in all cell lines tested, pravastatin did not affect the cell growth at all. Strong anti-proliferative effect was observed also for hemin. Co-treatment of cerivastatin and hemin increased anti-proliferative potential of these agents, via increased production of reactive oxygen species and cell death compared to individual treatment. Heme oxygenase silencing did not prevent pancreatic cancer cells from the tumor-suppressive effect of cerivastatin or hemin. Cerivastatin, but not pravastatin, protected Ras protein from trafficking to the cell membrane and significantly reduced expressions of SPP1 (p < 0.05) and SOX2 (p < 0.01). Anti-proliferative effects of statins and hemin on human pancreatic cancer cell lines do not seem to be related to the heme oxygenase pathway. While hemin triggers reactive

  19. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.

    Science.gov (United States)

    Aggarwal, Gaurav; Ramachandran, Vijaya; Javeed, Naureen; Arumugam, Thiruvengadam; Dutta, Shamit; Klee, George G; Klee, Eric W; Smyrk, Thomas C; Bamlet, William; Han, Jing Jing; Rumie Vittar, Natalia B; de Andrade, Mariza; Mukhopadhyay, Debabrata; Petersen, Gloria M; Fernandez-Zapico, Martin E; Logsdon, Craig D; Chari, Suresh T

    2012-12-01

    New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer. Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls). Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice

  20. Clinical and pathologic features of familial pancreatic cancer.

    Science.gov (United States)

    Humphris, Jeremy L; Johns, Amber L; Simpson, Skye H; Cowley, Mark J; Pajic, Marina; Chang, David K; Nagrial, Adnan M; Chin, Venessa T; Chantrill, Lorraine A; Pinese, Mark; Mead, R Scott; Gill, Anthony J; Samra, Jaswinder S; Kench, James G; Musgrove, Elizabeth A; Tucker, Katherine M; Spigelman, Allan D; Waddell, Nic; Grimmond, Sean M; Biankin, Andrew V

    2014-12-01

    Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of predisposition remains unexplained in a high proportion of patients with familial PC (FPC). Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had ≥1 affected first-degree relatives; otherwise, they were classified with sporadic PC (SPC). The prevalence of FPC in this cohort was 8.9%. In FPC families with an affected parent-child pair, 71% in the subsequent generation were 12.3 years younger at diagnosis. Patients with FPC had more first-degree relatives who had an extrapancreatic malignancy (EPM) (42.6% vs 21.2; P2 years) was associated with poor survival in both groups. FPC represents 9% of PC, and the risk of malignancy in kindred does not appear to be confined to the pancreas. Patients with FPC have more precursor lesions and include fewer active smokers, but other clinicopathologic factors and outcome are similar to those in patients with SPC. Furthermore, some FPC kindreds may exhibit anticipation. A better understanding of the clinical features of PC will facilitate efforts to uncover novel susceptibility genes and the development of early detection strategies. © 2014 American Cancer Society.

  1. Surgical palliation of unresectable pancreatic head cancer in elderly patients

    Science.gov (United States)

    Hwang, Sang Il; Kim, Hyung Ook; Son, Byung Ho; Yoo, Chang Hak; Kim, Hungdai; Shin, Jun Ho

    2009-01-01

    AIM: To determine if surgical biliary bypass would provide improved quality of residual life and safe palliation in elderly patients with unresectable pancreatic head cancer. METHODS: Nineteen patients, 65 years of age or older, were managed with surgical biliary bypass (Group A). These patients were compared with 19 patients under 65 years of age who were managed with surgical biliary bypass (Group B). In addition, the results for group A were compared with those obtained from 17 patients, 65 years of age or older (Group C), who received percutaneous transhepatic biliary drainage to evaluate the quality of residual life. RESULTS: Five patients (26.0%) in Group A had complications, including one intraabdominal abscess, one pulmonary atelectasis, and three wound infections. One death (5.3%) occurred on postoperative day 3. With respect to morbidity, mortality, and postoperative hospitalization, no statistically significant difference was noted between Groups A and B. The number of readmissions and the rate of recurrent jaundice were lower in Group A than in Group C, to a statistically significant degree (P = 0.019, P = 0.029, respectively). The median hospital-free survival period and the median overall survival were also significantly longer in Group A (P = 0.001 and P < 0.001, respectively). CONCLUSION: Surgical palliation does not increase the morbidity or mortality rates, but it does increase the survival rate and improve the quality of life in elderly patients with unresectable pancreatic head cancer. PMID:19248198

  2. Results of diagnosis of pancreatic cancer by computed tomography (CT)

    Energy Technology Data Exchange (ETDEWEB)

    Kimura, K.; Okuaki, K.; Ito, M.; Katakura, T.; Suzuki, K. (Fukushima Medical Coll. (Japan))

    1981-08-01

    Results of examination of pancreatic diseases, especially pancreatic cancer, conducted by CT during the past 3 years are summarized. The EMI CT Type 5000 or 5005 were used. During the 3 years from September 1976 to August 1979, a total of 1961 patients were examined by CT, and the upper abdomen was examined in 772 of these patients. In 97 patients, positive findings were obtained in the CT image of the pancreas. In 52 of these patients, the findings were confirmed operatively or by autopsy. Though cancer of the pancreas was diagnosed by CT in 30 patients, it was confirmed in 20 by surgical operation and in 1 by autopsy. Of the 9 misdiagnosed cases, 4 were cases of infiltration of the pancreas by carcinoma of the stomach or bile duct, and the other 5 were one case each of lipoma of the abdominal wall, normal pancreas, hyperplasia of Langerhans's islets of the pancreas tail, abscess between the pancreas and the posterior wall of the stomach, and choledocholithiasis. A case diagnosed by CT as cholelithiasis was a carcinoma measuring 5 x 5 x 6 cm located on the head of the pancreas, complicated by choledocholithiasis. The 22 patients with carcinoma of the pancreas were 9 with lesions less than 3.5 x 3.0 x 3.0 cm in size who could be radically operated, 6 who underwent exploratory laparotomy or autopsy, and 7 in whom operation was impossible. False negative and false positive CT results are also discussed.

  3. Results of diagnosis of pancreatic cancer by computed tomography (CT)

    International Nuclear Information System (INIS)

    Kimura, Kazue; Okuaki, Koji; Ito, Masami; Katakura, Toshihiko; Suzuki, Kenji

    1981-01-01

    Results of examination of pancreatic diseases, especially pancreatic cancer, conducted by CT during the past 3 years are summarized. The EMI CT Type 5000 or 5005 were used. During the 3 years from September 1976 to August 1979, a total of 1961 patients were examined by CT, and the upper abdomen was examined in 772 of these patients. In 97 patients, positive findings were obtained in the CT image of the pancreas. In 52 of these patients, the findings were confirmed operatively or by autopsy. Though cancer of the pancreas was diagnosed by CT in 30 patients, it was confirmed in 20 by surgical operation and in 1 by autopsy. Of the 9 misdiagnosed cases, 4 were cases of infiltration of the pancreas by carcinoma of the stomach or bile duct, and the other 5 were one case each of lipoma of the abdominal wall, normal pancreas, hyperplasia of Langerhans's islets of the pancreas tail, abscess between the pancreas and the posterior wall of the stomach, and choledocholithiasis. A case diagnosed by CT as cholelithiasis was a carcinoma measuring 5 x 5 x 6 cm located on the head of the pancreas, complicated by choledocholithiasis. The 22 patients with carcinoma of the pancreas were 9 with lesions less than 3.5 x 3.0 x 3.0 cm in size who could be radically operated, 6 who underwent exploratory laparotomy or autopsy, and 7 in whom operation was impossible. False negative and false positive CT results are also discussed. (author)

  4. Progress in cancer genetics: lessons from pancreatic cancer

    NARCIS (Netherlands)

    Goggins, M.; Kern, S. E.; Offerhaus, J. A.; Hruban, R. H.

    1999-01-01

    In the near future advances in the molecular basis of cancer are expected to facilitate cancer diagnosis, to rationalize treatment, to facilitate screening, and to identify individuals requiring cancer prevention strategies. The literature was reviewed concerning the genetic alterations that

  5. From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers.

    Science.gov (United States)

    Kyrochristos, Ioannis D; Glantzounis, Georgios K; Ziogas, Demosthenes E; Gizas, Ioannis; Schizas, Dimitrios; Lykoudis, Efstathios G; Felekouras, Evangelos; Machairas, Anastasios; Katsios, Christos; Liakakos, Theodoros; Cho, William C; Roukos, Dimitrios H

    2017-01-18

    Hepatobiliary and pancreatic (HBP) cancers are associated with high cancer-related death rates. Surgery aiming for complete tumor resection (R0) remains the cornerstone of the treatment for HBP cancers. The current progress in the adjuvant treatment is quite slow, with gemcitabine chemotherapy available only for pancreatic ductal adenocarcinoma (PDA). In the advanced and metastatic setting, only two targeted drugs have been approved by the Food & Drug Administration (FDA), which are sorafenib for hepatocellular carcinoma and erlotinib for PDA. It is a pity that multiple Phase III randomized control trials testing the efficacy of targeted agents have negative results. Failure in the development of effective drugs probably reflects the poor understanding of genome-wide alterations and molecular mechanisms orchestrating therapeutic resistance and recurrence. In the post-ENCODE (Encyclopedia of DNA Elements) era, cancer is referred to as a highly heterogeneous and systemic disease of the genome. The unprecedented potential of next-generation sequencing (NGS) technologies to accurately identify genetic and genomic variations has attracted major research and clinical interest. The applications of NGS include targeted NGS with potential clinical implications, while whole-exome and whole-genome sequencing focus on the discovery of both novel cancer driver genes and therapeutic targets. These advances dictate new designs for clinical trials to validate biomarkers and drugs. This review discusses the findings of available NGS studies on HBP cancers and the limitations of genome sequencing analysis to translate genome-based biomarkers and drugs into patient care in the clinic.

  6. From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers

    Directory of Open Access Journals (Sweden)

    Ioannis D. Kyrochristos

    2017-01-01

    Full Text Available Hepatobiliary and pancreatic (HBP cancers are associated with high cancer-related death rates