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Pancreatic Neoplasms: HELP
Articles by Alexandr V. Bazhin
Based on 18 articles published since 2009
(Why 18 articles?)
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Between 2009 and 2019, A. V. Bazhin wrote the following 18 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Two immune faces of pancreatic adenocarcinoma: possible implication for immunotherapy. 2014

Bazhin, Alexandr V / Shevchenko, Ivan / Umansky, Viktor / Werner, Jens / Karakhanova, Svetlana. ·Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 156, 69120, Heidelberg, Germany, alexandr.bazhin@med.uni-heidelberg.de. ·Cancer Immunol Immunother · Pubmed #24129765.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms, having extremely poor prognosis with a 5-year survival rate of <1 % and a median survival of 6 months. In contrast to other malignancies, pancreatic cancer is highly resistant to chemotherapy and targeted therapy. Therefore, new treatment options are urgently needed to improve the survival of patients with PDAC. Based on our data showing that patients with higher CD8+ T cell tumour infiltration exhibited prolonged overall and disease-free survival compared to patients with lower or without CD8+ T cell tumour infiltration, we suggested that immunotherapy could be a promising treatment option for PDAC. However, clinical data from the chemoradioimmunotherapy with interferon-α (IFN) trial did not point to an improved efficiency of chemoradiation combined with IFN as compared to chemoradiotherapy alone, suggesting an important role of the immune suppression induced by PDAC and/or unspecific immune stimulation. In support of this hypothesis, we found that the PDAC patients and experimental mice had an increased number of regulatory T cells and myeloid-derived suppressor cells. These results allowed us to conclude that PDAC provokes not only an anti-tumour immune response, but also strong immune suppression. Thus, we supposed that new immunotherapeutical strategies should involve not only stimulation of the immune system of PDAC patients, but also exert control over the tumour immune suppressive milieu.

2 Clinical Trial Prognostic and predictive value of immunological parameters for chemoradioimmunotherapy in patients with pancreatic adenocarcinoma. 2015

Karakhanova, S / Ryschich, E / Mosl, B / Harig, S / Jäger, D / Schmidt, J / Hartwig, W / Werner, J / Bazhin, A V. ·Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. · 1] Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany [2] National Centre for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany. · National Centre for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany. · 1] Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany [2] General and Visceral Surgery Center, 8002 Zurich, Switzerland. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, 81377 Munich, Germany. · 1] Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany [2] Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, 81377 Munich, Germany. ·Br J Cancer · Pubmed #25742476.

ABSTRACT: BACKGROUND: Chemoradioimmunotherapy of patients with pancreatic adenocarcinoma from the CapRI trial did not show any benefit of interferon-α in addition to a 5-fluorouracil (5FU)-based treatment. The aim of this study was to identify immunological parameters in patients from this trial to be used for predictive and/or prognostic purposes. METHODS: The following methods were used: tumour immunohistology, FACS analyses, cytokine measurement, as well as cytotoxicity and ELIspot. Immunological parameters were correlated with patients' survival using the Kaplan-Meier method. RESULTS: Irrespective of therapy type, high lymphocyte accumulation in tumours and frequencies of NK cells and effector (eff) CD8(+) T cells in peripheral blood of the patients were associated with patients' survival. Amount of CD3(+) and effector-memory CD8(+) blood lymphocytes, expression of CD152 and interleukin (IL)-2 serum level showed a predictive value for chemoradioimmunotherapy. Tumoural accumulation of CD3(+) and CD8(+) cells was predictive for outcome of chemotherapy alone. Besides, we identified the frequencies of CD3(+) lymphocytes, effCD8(+) T cells and NK cells in the peripheral blood of the patients, and IL-10 amount in serum, to be predictive values for 5FU-based chemotherapy. CONCLUSIONS: Immunological parameters, identified in this trial as possible markers, may be of interest in personalized medicine towards the improvement of the treatment and prognosis of pancreatic carcinoma patients.

3 Clinical Trial Influence of interferon-alpha combined with chemo (radio) therapy on immunological parameters in pancreatic adenocarcinoma. 2014

Karakhanova, Svetlana / Mosl, Beate / Harig, Sabine / von Ahn, Katharina / Fritz, Jasmin / Schmidt, Jan / Jäger, Dirk / Werner, Jens / Bazhin, Alexandr V. ·Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. Svetlana.karakhanova@med.uni-heidelberg.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. beate.mosl@med.uni-heidelberg.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. Dirk.Jaeger@med.uni-heidelberg.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. katharinavonahn@hotmail.com. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. jasminfritz@web.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. Jan.Schmidt@hirslanden.ch. · National Centre for Tumor Disease, University Hospital Heidelberg, 69120 Heidelberg, Germany. Dirk.Jaeger@med.uni-heidelberg.de. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, 81377 Munich, Germany. jens.werner@med.uni-heidelberg.de. · Department of General Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany. Alexandr.bazhin@med.uni-heidelberg.de. ·Int J Mol Sci · Pubmed #24608924.

ABSTRACT: Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy.

4 Article Differential MicroRNA Expression Profiles as Potential Biomarkers for Pancreatic Ductal Adenocarcinoma. 2019

Zhu, Y / Wang, J / Wang, F / Yan, Z / Liu, G / Ma, Y / Zhu, W / Li, Y / Xie, L / Bazhin, A V / Guo, X. ·Department of Oncology, International Joint Laboratory for Cell Medical Engineering of Henan Province, Henan University Huaihe Hospital, Kaifeng, Henan, 475000, P. R. China. celltransplant@163.com. · Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450014, P. R. China. wj68happy@hotmail.com. · Department of Preventive Medicine, Cell Signal Transduction Laboratory, Joint National Laboratory for Antibody Drug Engineering, Institute of Biomedical Informatics, Medical School, Henan University, Kaifeng, Henan, 475004, P. R. China. · Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450014, P. R. China. · College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, Tianjin, 300353, P. R. China. mayonggang@nankai.edu.cn. · Department of Anesthesia, Stanford University, CA 94305, USA. wan.zhu@stanford.edu. · Department of General, Visceral, and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, 81377, Germany. alexandr.bazhin@med.uni-muenchen.de. · Department of Preventive Medicine, Cell Signal Transduction Laboratory, Joint National Laboratory for Antibody Drug Engineering, Institute of Biomedical Informatics, Medical School, Henan University, Kaifeng, Henan, 475004, P. R. China. xqguo@henu.edu.cn. ·Biochemistry (Mosc) · Pubmed #31234772.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge due to its poor prognosis. Therefore, the early diagnosis of PDAC is extremely important for achieving a cure. MicroRNAs (miRNAs) could serve as a potential biomarker for the early detection and prognosis of PDAC. In this work we analyzed plasma samples from healthy persons and PDAC patients to assess differential miRNA expression profiles by next generation sequencing technology and bioinformatics analysis. In this way, 165 mature miRNAs were found to be significantly deregulated in the patient group, of which 75 and 90 mature miRNAs were up- and down-regulated compared with healthy individuals, respectively. Furthermore, 1029 novel miRNAs were identified. In conclusion, plasma miRNA expression profiles are different between healthy individuals and patients with PDAC. These data provide a possibility for use of miRNA as diagnostic and prognostic biomarkers of PDAC.

5 Article Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma. 2018

Mahajan, Ujjwal Mukund / Langhoff, Eno / Goni, Elisabetta / Costello, Eithne / Greenhalf, William / Halloran, Christopher / Ormanns, Steffen / Kruger, Stephan / Boeck, Stefan / Ribback, Silvia / Beyer, Georg / Dombroswki, Frank / Weiss, Frank-Ulrich / Neoptolemos, John P / Werner, Jens / D'Haese, Jan G / Bazhin, Alexandr / Peterhansl, Julian / Pichlmeier, Svenja / Büchler, Markus W / Kleeff, Jörg / Ganeh, Paula / Sendler, Matthias / Palmer, Daniel H / Kohlmann, Thomas / Rad, Roland / Regel, Ivonne / Lerch, Markus M / Mayerle, Julia. ·Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. · Department of Medicine III, University Hospital, LMU Munich, Germany. · Department of Pathology, University Medicine Greifswald, Greifswald, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther University Halle-Wittenberg, Halle, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Department of Community Medicine, University Medicine Greifswald, Greifswald, Germany. · Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. Electronic address: julia.mayerle@med.uni-muenchen.de. ·Gastroenterology · Pubmed #30092175.

ABSTRACT: BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.

6 Article Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting. 2018

Cheung, Phyllis F / Neff, Florian / Neander, Christian / Bazarna, Anna / Savvatakis, Konstantinos / Liffers, Sven-Thorsten / Althoff, Kristina / Lee, Chang-Lung / Moding, Everett J / Kirsch, David G / Saur, Dieter / Bazhin, Alexandr V / Trajkovic-Arsic, Marija / Heikenwalder, Mathias F / Siveke, Jens T. ·Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. · Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina. · Medical Department, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians University, Munich, Germany. · German Caner Consortium (DKTK), Partner Site Munich, Germany. · Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. j.siveke@dkfz.de. ·Cancer Res · Pubmed #29844119.

ABSTRACT: Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multilayered tumor microenvironment. In this study, we employed a dual recombinase-based

7 Article MiRNAs are Unlikely to be Involved in Retinoid Receptor Gene Regulation in Pancreatic Cancer Cells. 2017

Yin, Shuai / Bleul, Tim / Zhu, Yifan / Isayev, Orkhan / Werner, Jens / Bazhin, Alexandr V. ·Department of General, Visceral, and Transplantation Surgery, University Hospital of the LMU, Munich, Germany. · Department of Oncology, Henan University Huaihe Hospital, Kai Feng, China. · International Joint Research Laboratory for Cell Medical Engineering of Henan, Zhengzhou, China. · Department of Histology, Embryology and Cytology, Azerbaijan Medical University, Baku, Azerbaijan. · German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. ·Cell Physiol Biochem · Pubmed #29169171.

ABSTRACT: BACKGROUND/AIMS: Retinoid receptors and retinoic acid were reported to be down-regulated in pancreatic duct adenocarcinoma (PDAC) compared to normal pancreas. Yet the mechanism of the down-regulation of retinoid receptors is not well defined. The aim of this study was to find out whether selected dysregulated miRNAs in PDAC are responsible for the decreased level of retinoid receptors. METHODS: Bioinformatics, real-time PCR, western blot analysis as well as molecular manipulation with miRNA in cells of PDAC were carried out. RESULTS: We first performed bioinformatics research to identify conserved target sequences for deregulated miRNAs within the 3'UTR region of retinoid receptor mRNA. This research revealed binding sites for miR-138, -27a, -27b, -206, -613, -9-5p, -27a/b-3p and -27a. Next, we investigated the expression of selected retinoid receptors and miRNAs in PDAC cell lines and in the Human Pancreatic Duct Epithelial (HPDE) cell line. Further, we investigated the effects of modifying expression levels of selected miRNAs using miRNA inhibitors or mimics. We demonstrated that none of these miRNAs can target the selected retinoid receptors in vitro. CONCLUSIONS: miR-27a, miR-27b, miR-9, miR10a and miR-10b were up-regulated in PDAC cells compared to HPDE cells. The up-regulation of these miRNAs was not responsible for the down-regulation of RARα, RARβ, RXRα and RXRβ in PDAC cells.

8 Article A marginal anticancer effect of regorafenib on pancreatic carcinoma cells in vitro, ex vivo, and in vivo. 2017

Mayer, Barbara / Karakhanova, Svetlana / Bauer, Nathalie / Liu, Li / Zhu, Yifan / Philippov, Pavel P / Werner, Jens / Bazhin, Alexandr V. ·Department of General, Visceral, and Transplantation Surgery, University Hospital of the LMU, Marchioninistr. 15, 81377, Munich, Germany. · Section Surgical Research, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Oncology, Henan University Huaihe Hospital, Kai Feng, People's Republic of China. · International Joint Research Laboratory for Cell Medical Engineering of Henan, Zhengzhou, People's Republic of China. · Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia. · Department of General, Visceral, and Transplantation Surgery, University Hospital of the LMU, Marchioninistr. 15, 81377, Munich, Germany. alexandr.bazhin@med.uni-muenchen.de. ·Naunyn Schmiedebergs Arch Pharmacol · Pubmed #28779210.

ABSTRACT: Activation of receptor tyrosine kinases is recognized as a hallmark of cancer. Vascular endothelial growth factor (VEGF) and its receptor VEGFR are the prominent players in the induction of tumor neoangiogenesis. Strategies to inhibit VEGF and VEGFR are under intensive investigation in preclinical and clinical settings. Regorafenib is a multikinase inhibitor targeting some VEGFR and other receptor kinases. Preclinical results led to the FDA approval of regorafenib for treatment of metastatic colorectal cancer patients. Effects of this drug in pancreatic ductal adenocarcinoma (PDAC) have not been investigated yet. Gene expression was assessed with real-time PCR analysis. In vitro cell viability, proliferation, apoptosis, necrosis, migration, and invasion of the PDAC cells were assessed after regorafenib treatment. Ex vivo anti-tumor effects of regorafenib were investigated in a spheroid model of PDAC. In vivo anti-tumor effects of the drug were evaluated in a fertilized chicken egg model. In this work, we have demonstrated only a marginal anticancer effect of regorafenib in PDAC in vitro and ex vivo. However, in the egg model of PDAC, this drug reduced tumor volume. Besides, regorafenib is capable of modulating the expression of cancer stem cell (CSC) markers and epithelial-to-mesenchymal transition (EMT) markers on PDAC cells. We found out that effects of regorafenib on the expression of CSC and EMT markers are very heterogeneous and depend obviously on original expression of these markers. We concluded that regorafenib might be a potential drug for PDAC and it should be investigated in future clinical trials.

9 Article The novel mitochondria-targeted antioxidant SkQ1 modulates angiogenesis and inflammatory micromilieu in a murine orthotopic model of pancreatic cancer. 2016

Bazhin, Alexandr V / Yang, Yuhui / D'Haese, Jan G / Werner, Jens / Philippov, Pavel P / Karakhanova, Svetlana. ·Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, LMU Munich, Germany. · Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. · Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia. · Department of General Surgery, University Hospital Heidelberg, Germany. ·Int J Cancer · Pubmed #26914404.

ABSTRACT: Our understanding in the last few years about reactive oxygen species (ROS) has changed from being harmful substances to crucial intra- and extracellular messengers as well as important regulators controlling a wide spectrum of signaling pathways, including those in cancer immunology. Therefore, these multiple essential roles of ROS and especially of mitochondria-derived ROS in malignant transformation and cancer progression make them a promising target for anticancer therapy. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. A link between ROS, antioxidants and the PDAC development and progression has been recently established. Therefore, usage of specific highly efficient antioxidants could bring an option for treatment and/or prevention of PDAC. 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) is a new antioxidant with the highest mitochondrion membrane penetrating ability and potent antioxidant capability. In this work, we investigated an impact of SkQ1 on tumor angiogenesis, immune micromilieu, and oncological parameters in the orthotopic Panc02 murine model of PDAC. We showed that in this model SkQ1 treatment leads to the elevation of pro-angiogenic factors and to building of mainly an anti-inflammatory cytokine milieu. On the cellular level we showed an increase in a percentage of memory T cells and a decrease in frequency on natural killer T (NKT) cells. At the same time, SkQ1 was ineffective in the improvement of oncological parameters of PDAC-bearing mice. New studies are needed to clarify the absence of therapeutic and/or prophylactic benefits of the antioxidant.

10 Article In vitro immunomodulatory properties of gemcitabine alone and in combination with interferon-alpha. 2015

Fritz, Jasmin / Karakhanova, Svetlana / Brecht, Ramona / Nachtigall, Ines / Werner, Jens / Bazhin, Alexandr V. ·Department of General Surgery, University Hospital Heidelberg, Germany. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Germany. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Germany. Electronic address: alexandr.bazhin@med.uni-muenchen.de. ·Immunol Lett · Pubmed #26450014.

ABSTRACT: In general, conventional chemotherapy is associated with significant toxicity leading to immunosuppression manifesting mainly in the lymphocyte depletion. This immunosuppression promotes tumor growth and elicits the tumor cell dissemination. However, chemotherapy can be immune stimulative especially in combination with an immunotherapy. In this work, we investigated in vitro effects of gemcitabine alone and in combination with interferon-alpha on splenocytes obtained from healthy and pancreatic carcinoma bearing mice. We showed that gemcitabine alone depletes the regulatory T cells in the splenocyte culture. Gemcitabine in combination with interferon-alpha demonstrated some immunomodulatory features, but these effects were interferon-alpha dependent. We concluded that combination of both drugs induces rather cumulative effects, supposing that these therapeutic could be applied together for a chemo-immunotherapy.

11 Article Anti-tumor properties of the cGMP/protein kinase G inhibitor DT3 in pancreatic adenocarcinoma. 2015

Soltek, Sabine / Karakhanova, Svetlana / Golovastova, Marina / D'Haese, Jan G / Serba, Susanne / Nachtigall, Ines / Philippov, Pavel P / Werner, Jens / Bazhin, Alexandr V. ·Department of General Surgery, University Hospital Heidelberg, Heidelberg,, Germany. · Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich,, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich,, Germany. alexandr.bazhin@med.uni-muenchen.de. ·Naunyn Schmiedebergs Arch Pharmacol · Pubmed #26105003.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Therefore, new therapeutic options are urgently needed to improve the survival of PDAC patients. Protein kinase G (PKG) conducts the interlude of cGMP signaling which is important for healthy as well as for cancer cells. DT3 is a specific inhibitor of PKG, and it has been shown to possess an anti-tumor cytotoxic activity in vitro. The main aim of this work was to investigate anti-tumor effects of DT3 upon PDAC in vivo.Expression of PKG was assessed with real-time PCR analysis in the normal and tumor pancreatic cells. In vitro cell viability, proliferation, apoptosis, necrosis, migration, and invasion of the murine PDAC cell line Panc02 were assessed after DT3 treatment. In vivo anti-tumor effects of DT3 were investigated in the murine Panc02 orthotopic model of PDAC. Western blot analysis was used to determine the phosphorylation state of the proteins of interest.Functional PKGI is preferentially expressed in PDAC cells. DT3 was capable to reduce viability, proliferation, and migration of murine PDAC cells in vitro. At the same time, DT3 treatment did not change the viability of normal epithelial cells of murine liver. In vivo, DT3 treatment reduced the tumor volume and metastases in PDAC-bearing mice, but it was ineffective to prolong the survival of the tumor-bearing animals. In addition, DT3 treatment decreased phosphorylation of GSK-3, P38, and CREB in murine PDAC.Inhibition of PKG could be a potential therapeutic strategy for PDAC treatment which should be carefully validated in future pre-clinical studies.

12 Article Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer. 2015

Zhang, Yiyao / Liu, Li / Fan, Pei / Bauer, Nathalie / Gladkich, Jury / Ryschich, Eduard / Bazhin, Alexandr V / Giese, Nathalia A / Strobel, Oliver / Hackert, Thilo / Hinz, Ulf / Gross, Wolfgang / Fortunato, Franco / Herr, Ingrid. ·Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Section Surgical Research, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China. ·Oncotarget · Pubmed #25846752.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis. An inflammatory microenvironment triggers the pronounced desmoplasia, the selection of cancer stem-like cells (CSCs) and therapy resistance. The anti-inflammatory drug aspirin is suggested to lower the risk for PDA and to improve the treatment, although available results are conflicting and the effect of aspirin to CSC characteristics and desmoplasia in PDA has not yet been investigated. We characterized the influence of aspirin on CSC features, stromal reactions and gemcitabine resistance. Four established and 3 primary PDA cell lines, non-malignant cells, 3 patient tumor-derived CSC-enriched spheroidal cultures and tissues from patients who did or did not receive aspirin before surgery were analyzed using MTT assays, flow cytometry, colony and spheroid formation assays, Western blot analysis, antibody protein arrays, electrophoretic mobility shift assays (EMSAs), immunohistochemistry and in vivo xenotransplantation. Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling. Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine. This was associated with a decreased expression of markers for progression, inflammation and desmoplasia. These findings were confirmed in tissue samples obtained from patients who had or had not taken aspirin before surgery. Importantly, aspirin sensitized cells that were resistant to gemcitabine and thereby enhanced the therapeutic efficacy. Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice. These results highlight aspirin as an effective, inexpensive and well-tolerated co-treatment to target inflammation, desmoplasia and CSC features PDA.

13 Article Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival. 2015

Bleul, Tim / Rühl, Ralph / Bulashevska, Svetlana / Karakhanova, Svetlana / Werner, Jens / Bazhin, Alexandr V. ·Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Biochemistry and Molecular Biology, Medical and Health Science Center, Debrecen, Hungary. · Paprika Bioanalytics BT, Debrecen, Hungary. · Department of Life Science Informatics, B-IT, University of Bonn, Bonn, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich, Germany. ·Mol Carcinog · Pubmed #24729540.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. All-trans retinoic acid (ATRA) is the major physiologically active form of vitamin A, regulating expression of many genes. Disturbances of vitamin A metabolism are prevalent in some cancer cells. The main aim of this work was to investigate deeply the components of retinoid signaling in PDAC compared to in the normal pancreas and to prove the clinical importance of retinoid receptor expression. For the study, human tumor tissues obtained from PDAC patients and murine tumors from the orthotopic Panc02 model were used for the analysis of retinoids, using high performance liquid chromatography mass spectrometry and real-time RT-PCR gene expression analysis. Survival probabilities in univariate analysis were estimated using the Kaplan-Meier method and the Cox proportional hazards model was used for the multivariate analysis. In this work, we showed for the first time that the ATRA and all-trans retinol concentration is reduced in PDAC tissue compared to their normal counterparts. The expression of RARα and β as well as RXRα and β are down-regulated in PDAC tissue. This reduced expression of retinoid receptors correlates with the expression of some markers of differentiation and epithelial-to-mesenchymal transition as well as of cancer stem cell markers. Importantly, the expression of RARα and RXRβ is associated with better overall survival of PDAC patients. Thus, reduction of retinoids and their receptors is an important feature of PDAC and is associated with worse patient survival outcomes.

14 Article Inhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine. 2014

Isayev, Orkhan / Rausch, Vanessa / Bauer, Nathalie / Liu, Li / Fan, Pei / Zhang, Yiyao / Gladkich, Jury / Nwaeburu, Clifford C / Mattern, Jürgen / Mollenhauer, Martin / Rückert, Felix / Zach, Sebastian / Haberkorn, Uwe / Gross, Wolfgang / Schönsiegel, Frank / Bazhin, Alexandr V / Herr, Ingrid. ·Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; General and Transplantation Surgery, University Hospital Heidelberg, Germany. ·Oncotarget · Pubmed #25015789.

ABSTRACT: According to the cancer stem cell (CSC) hypothesis, the aggressive growth and early metastasis of pancreatic ductal adenocarcinoma (PDA) is due to the activity of CSCs, which are not targeted by current therapies. Otto Warburg suggested that the growth of cancer cells is driven by a high glucose metabolism. Here, we investigated whether glycolysis inhibition targets CSCs and thus may enhance therapeutic efficacy. Four established and 3 primary PDA cell lines, non-malignant cells, and 3 patient-tumor-derived CSC-enriched spheroidal cultures were analyzed by glucose turnover measurements, MTT and ATP assays, flow cytometry of ALDH1 activity and annexin positivity, colony and spheroid formation, western blotting, electrophoretic mobility shift assay, xenotransplantation, and immunohistochemistry. The effect of siRNA-mediated inhibition of LDH-A and LDH-B was also investigated. The PDA cells exhibited a high glucose metabolism, and glucose withdrawal or LDH inhibition by siRNA prevented growth and colony formation. Treatment with the anti-glycolytic agent 3-bromopyruvate almost completely blocked cell viability, self-renewal potential, NF-κB binding activity, and stem cell-related signaling and reverted gemcitabine resistance. 3-bromopyruvate was less effective in weakly malignant PDA cells and did not affect non-malignant cells, predicting minimal side effects. 3-bromopyruvate inhibited in vivo tumor engraftment and growth on chicken eggs and mice and enhanced the efficacy of gemcitabine by influencing the expression of markers of proliferation, apoptosis, self-renewal, and metastasis. Most importantly, primary CSC-enriched spheroidal cultures were eliminated by 3-bromopyruvate. These findings propose that CSCs may be specifically dependent on a high glucose turnover and suggest 3-bromopyruvate for therapeutic intervention.

15 Article Interlude of cGMP and cGMP/protein kinase G type 1 in pancreatic adenocarcinoma cells. 2014

Karakhanova, Svetlana / Golovastova, Marina / Philippov, Pavel P / Werner, Jens / Bazhin, Alexandr V. ·From the *Department of General Surgery, University Hospital Heidelberg, Germany; and †Department of Cell Signalling, Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia. ·Pancreas · Pubmed #24826884.

ABSTRACT: OBJECTIVE: cAMP and cGMP signaling is important both for normal and cancer cells. This signaling is controlled by adenylyl and guanylyl cyclases and cyclic nucleotide phosphodiesterases. One of the direct targets for cGMP is protein kinase G (PKG). The main aim of this work was to investigate cGMP and PKG signaling in pancreatic adenocarcinoma (PDAC) cells. METHODS: The PKG activity, cGMP, and calcium level were measured with the CycLex Cyclic GMP dependent protein kinase (cGK) Assay Kit, the DetectX Cyclic GMP Colorimetric EIA Kit, and the Fluo-4 NW Calcium Assay Kit, respectively. The Proteome Profiler Array was done using Human Phospho-Kinase Array and Human Phospho-MAPK Array Kits. RESULTS: This study shows for the first time that functional PKG1 is expressed in PDAC cells. It demonstrates that the specific PKG1 inhibitor, DT3, induces cytotoxicity through necrosis and reduces proliferation and migration of PDAC cells. Moreover, ERK1/2 and p38 can be considered as potential targets for PKG1 in PDAC cells. In addition, the study shows that phosphodiesterases and nitric oxide-guanylyl cyclases regulate the cGMP level in PDAC cells, affecting the proliferation of the cells. CONCLUSIONS: The cGMP and PKG signaling may be a target for developing new therapeutic approaches for PDAC.

16 Article Influence of interferon-α on the expression of the cancer stem cell markers in pancreatic carcinoma cells. 2014

Zhu, Yifan / Karakhanova, Svetlana / Huang, Xiaolun / Deng, Shao Ping / Werner, Jens / Bazhin, Alexandr V. ·Cell Transplantation Center, Research Institute for Organ Transplantation, Sichuan Academy of Medical Science & Sichuan Provincial People׳s Hospital, Chengdu, China. · Department of General Surgery, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich, Germany. · Department of General Surgery, University of Heidelberg, Heidelberg, Germany; Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich, Germany. Electronic address: alexandr.bazhin@med.uni-heidelberg.de. ·Exp Cell Res · Pubmed #24726912.

ABSTRACT: The cytokine interferon-α (IFNα) belongs to the group of type I interferons already used in cancer therapy. This drug possesses radio- and chemo-sensitizing, and shows anti-angiogenic properties. Cancer stem cells (CSC) are a unique population of tumor cells that initiate secondary tumors, and are responsible for metastasis formation. Patients with pancreatic ductal adenocarcinoma (PDAC) have an especially poor prognosis, with 5-year survival rates of only ~1% and median survival of 4-6 months. PDAC is characterized by the presence of CSC. In this work we demonstrate for the first time that IFNα up-regulates the expression of the CSC markers CD24, CD44 and CD133 in in vitro and in vivo models of PDAC. We showed the IFNα effects on the migration and invasion of PDAC cells, which is associated with the level of the CSC marker expression. In vivo, this drug inhibits tumor growth but promotes metastasis formation in the early stage of tumor growth. We propose that IFNα may enhance the enrichment of CSC in PDAC tumors. Additionally we also suggest that in combination therapy of solid tumors with IFNα, this drug should be given to patients prior to chemotherapy to achieve the CSC activation.

17 Article Low-dose gemcitabine depletes regulatory T cells and improves survival in the orthotopic Panc02 model of pancreatic cancer. 2013

Shevchenko, Ivan / Karakhanova, Svetlana / Soltek, Sabine / Link, Julia / Bayry, Jagadeesh / Werner, Jens / Umansky, Viktor / Bazhin, Alexandr V. ·Department of General Surgery, University of Heidelberg, Germany. ·Int J Cancer · Pubmed #23233419.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplasms with extremely poor prognosis and a low survival rate. Immunosuppressive cell populations, e.g. regulatory T cells (Treg), appear to be important in PDAC, contributing to patient's poor prognosis. Therefore, we investigated the PDAC microenvironment with a focus on conventional and regulatory T cells in view of their potential therapeutic importance. We found that tumors from the murine Panc02 orthotopic model of PDAC were infiltrated with high numbers of Treg. Remarkably, these cells exhibited the effector/memory phenotype, suggesting their enhanced suppressive activity and higher proliferation capacity. Although we observed a steady increase in transforming growth factor-β (TGF-β) levels in the tumors, treatment with a specific inhibitor of TGF-β receptor I kinase failed to abrogate Treg accumulation. A CCR4 antagonist did not affect Treg percentage in the tumor either. However, intense Treg cell division in the tumor microenvironment was demonstrated, suggesting local proliferation as a major mechanism of Treg accumulation in PDAC. Notably, this accumulation was reduced by low-dose gemcitabine administration, resulting in a modestly increased survival of PDAC mice. Our results provide an insight into mechanisms of immunosuppression in PDAC, suggesting an important role for proliferative expansion of effector/memory Treg. Low-dose gemcitabine therapy selectively depletes Treg, providing a basis for new modalities of PDAC therapy.

18 Minor Relationship Between All-trans-13,14-Dihydro Retinoic Acid and Pancreatic Adenocarcinoma. 2016

Bazhin, Alexandr V / Bleul, Tim / de Lera, Angel R / Werner, Jens / Rühl, Ralph. ·Department of General, Visceral and Transplant Surgery Ludwig-Maximilians-Universität München, Germany and Department of General Surgery University Hospital Heidelberg Heidelberg, Germany alexandr.bazhin@med.uni-muenchen.de Department of General Surgery University Hospital Heidelberg Heidelberg, Germany Organic Chemistry Department University of Vigo Vigo, Spain Department of General, Visceral and Transplant Surgery Ludwig-Maximilians-Universität München, Germany Paprika Bioanalytics BT Debrecen, Hungary MTA-DE Public Health Research Group of the Hungarian Academy of Sciences Faculty of Public Health and Department of Biochemistry and Molecular Biology, University Debrecen Debrecen, Hungary. ·Pancreas · Pubmed #27295537.

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