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toll like receptors and pancreatic cancer

Smruti Pushalkar, Mautin Hundeyin, Donnele Daley, Constantinos P Zambirinis, Emma Kurz, Ankita Mishra, Navyatha Mohan, Berk Aykut, Mykhaylo Usyk, Luisana E Torres, Gregor Werba, Kevin Zhang, Yuqi Guo, Qianhao Li, Neha Akkad, Sarah Lall, Benjamin Wadowski, Johana Gutierrez, Juan Andres Kochen Rossi, Jeremy W Herzog, Brian Diskin, Alejandro Torres-Hernandez, Josh Leinwand, Wei Wang, Pardeep S Taunk, Shivraj Savadkar, Malvin Janal, Anjana Saxena, Xin Li, Deirdre Cohen, R Balfour Sartor, Deepak Saxena, George Miller
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation...
April 2018: Cancer Discovery
Ibtehaj Naqvi, Ruwan Gunaratne, Jessica E McDade, Angelo Moreno, Rachel E Rempel, Douglas C Rouse, Silvia Gabriela Herrera, David S Pisetsky, Jaewoo Lee, Rebekah R White, Bruce A Sullenger
Nucleic acid binding polymers (NABPs) have been extensively used as vehicles for DNA and RNA delivery. More recently, we discovered that a subset of these NABPs can also serve as anti-inflammatory agents by capturing pro-inflammatory extracellular nucleic acids and associated protein complexes that promote activation of toll-like receptors (TLRs) in diseases such as lupus erythematosus. Nucleic-acid-mediated TLR signaling also facilitates tumor progression and metastasis in several cancers, including pancreatic cancer (PC)...
February 23, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Anthony L Schwartz, Eric Dickerson, Nilesh Dagia, Ramiro Malgor, Kelly D McCall
Heightened co-expression and dysregulated signaling associated with Toll-like receptor 3 (TLR3) and Wnt5a is an integral component of solid tumors and hematological malignancies. Our previous findings in pancreatic cancer and melanoma suggest that inhibition of these pathways by a TLR3 signaling inhibitor, phenylmethimazole (C10), results in significantly decreased IL-6 levels, STAT3 phosphorylation, minimal cancer cell migration and reduced cancer cell growth in vitro and in vivo . In this study, we extended our earlier observations by performing studies in human breast cancer cells...
December 26, 2017: Oncotarget
Panagiotis Samaras, Marina Tusup, Thi Dan Linh Nguyen-Kim, Burkhardt Seifert, Helga Bachmann, Roger von Moos, Alexander Knuth, Steve Pascolo
PURPOSE: Following a previously published pre-clinical validation, this phase I study evaluated the safety, maximum tolerated dose, anti-tumour activity and immune status of a gemcitabine-chloroquine combination as a first- or late-line treatment in patients with metastatic or unresectable pancreatic cancer. METHODS: In this 3 + 3 dose escalation study, patients received a single weekly standard dose of intravenous gemcitabine, followed by single weekly oral intake of 100, 200 or 300 mg of chloroquine...
November 2017: Cancer Chemotherapy and Pharmacology
Shikhar Mehrotra, Carolyn D Britten, Steve Chin, Elizabeth Garrett-Mayer, Colleen A Cloud, Mingli Li, Gina Scurti, Mohamed L Salem, Michelle H Nelson, Melanie B Thomas, Chrystal M Paulos, Andres M Salazar, Michael I Nishimura, Mark P Rubinstein, Zihai Li, David J Cole
BACKGROUND: Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC). METHODS: We generated autologous DCs from the peripheral blood of HLA-A2+ patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV...
April 7, 2017: Journal of Hematology & Oncology
Joni Leppänen, Olli Helminen, Heikki Huhta, Joonas H Kauppila, Joel Isohookana, Kirsi-Maria Haapasaari, Petri Lehenkari, Juha Saarnio, Tuomo J Karttunen
Pancreatic cancer remains one of the deadliest malignancies in the world. Inflammatory response and tumor environment are thought to play a major role in its pathogenesis. Knowledge on TLR expression and impact on patient survival in pancreatic cancer is limited. The study's aim was to clarify the role of different TLRs in pancreatic cancer. TLR2, TLR4, and TLR9 expression was investigated in 65 surgically resected pancreatic ductal adenocarcinoma specimens by immunohistochemistry. The association between TLR expression, clinical parameters, and local inflammatory response to the tumor was assessed using chi-square test...
April 2017: Virchows Archiv: An International Journal of Pathology
Makena J Binker-Cosen, Daniel Richards, Brenda Oliver, Herbert Y Gaisano, Marcelo G Binker, Laura I Cosen-Binker
Pancreatic cancer (PC) is an aggressive malady with proclivity for early metastasis. Overexpression of toll-like receptor 4 (TLR4) in pancreatic ductal adenocarcinoma, the most common type of pancreatic malignancy, correlates to tumor size, lymph node involvement, venous invasion and pathological stage. Lipopolysaccharides (LPS) are natural TLR4 ligands that have been shown to increase the invasive ability of PC cells. However, rapid inactivation of circulating LPS and low systemic absorption of inhaled LPS from the bronchoalveolar compartment make other agonists such as saturated fatty acids more suitable to be considered for TLR4-related cell invasiveness...
February 26, 2017: Biochemical and Biophysical Research Communications
Latha B Pathangey, Dustin B McCurry, Sandra J Gendler, Ana L Dominguez, Jessica E Gorman, Girish Pathangey, Laurie A Mihalik, Yushe Dang, Mary L Disis, Peter A Cohen
Effective adoptive immunotherapy has proved elusive for many types of human cancer, often due to difficulties achieving robust expansion of natural tumor-specific T-cells from peripheral blood. We hypothesized that antigen-driven T-cell expansion might best be triggered in vitro by acute activation of innate immunity to mimic a life-threatening infection. Unfractionated peripheral blood mononuclear cells (PBMC) were subjected to a two-step culture, first synchronizing their exposure to exogenous antigens with aggressive surrogate activation of innate immunity, followed by γ-chain cytokine-modulated T-cell hyperexpansion...
February 14, 2017: Oncotarget
Tanja Grimmig, Romana Moench, Jennifer Kreckel, Stephanie Haack, Felix Rueckert, Roberta Rehder, Sudipta Tripathi, Carmen Ribas, Anil Chandraker, Christoph T Germer, Martin Gasser, Ana Maria Waaga-Gasser
Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers...
December 8, 2016: International Journal of Molecular Sciences
Hridayesh Prakash, Vinod Nadella, Sandhya Singh, Hubertus Schmitz-Winnenthal
Pancreatic cancer is the fourth major cause of cancer related deaths in the world and 5 year survival is below 5%. Among various tumor directed therapies, stimulation of Toll-like receptors (TLR) has shown promising effects in various tumor models. However, pancreatic cancer cells frequently express these receptors themselves and their stimulation (TLR 2 and/or 4 particularly) within tumor microenvironment is known to potentially enhance tumor cell proliferation and cancer progression. Consistent stimulation of tumor associated macrophages (TAMs), in particular with tumor derived TLR ligand within the tumor microenvironment promotes cancer related inflammation, which is sterile, non-immunogenic and carcinogenic in nature...
2016: Scientific Reports
Yunliang Sun, Congshan Wu, Jianxia Ma, Yu Yang, Xiaohua Man, Hongyu Wu, Shude Li
Deregulation of Toll-like receptor 4 (TLR4) is closely associated with the progression of various types of cancers, but its role in pancreatic carcinogenesis is unclear. This study aimed to investigate the role of TLR4 in the angiogenesis of pancreatic cancer and the underlying molecular mechanisms. The culture supernatant (conditioned medium) of PANC-1 cells after appropriate treatment was used for the treatment of HUVECs. The proliferation, migration and tube formation of HUVECs were assessed by MTT, Transwell and Matrigel, respectively...
October 1, 2016: Experimental Cell Research
Anthony L Schwartz, Eric Dickerson, Nilesh Dagia, Ramiro Malgor, Kelly D McCall
Heightened co-expression and dysregulated signaling associated with Toll-like receptor 3 (TLR3) and Wnt5a is an integral component of solid tumors and hematological malignancies. Our previous findings in pancreatic cancer and melanoma suggest that inhibition of these pathways by a TLR3 signaling inhibitor, phenylmethimazole (C10), results in significantly decreased IL-6 levels, STAT3 phosphorylation, minimal cancer cell migration and reduced cancer cell growth in vitro and in vivo. In this study, we extended our earlier observations by performing studies in human breast cancer cells...
July 1, 2016: Oncotarget
Lena Seifert, Gregor Werba, Shaun Tiwari, Nancy Ngoc Giao Ly, Sara Alothman, Dalia Alqunaibit, Antonina Avanzi, Rocky Barilla, Donnele Daley, Stephanie H Greco, Alejandro Torres-Hernandez, Matthew Pergamo, Atsuo Ochi, Constantinos P Zambirinis, Mridul Pansari, Mauricio Rendon, Daniel Tippens, Mautin Hundeyin, Vishnu R Mani, Cristina Hajdu, Dannielle Engle, George Miller
Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs...
April 14, 2016: Nature
Tae Heung Kang, Young Seob Kim, Seokho Kim, Benjamin Yang, Je-Jung Lee, Hyun-Ju Lee, Jaemin Lee, In Duk Jung, Hee Dong Han, Seung-Hyun Lee, Sang Seok Koh, T-C Wu, Yeong-Min Park
Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway...
September 29, 2015: Oncotarget
Bing-Bing Zou, Fang Wang, Lei Li, Feng-Wei Cheng, Rui Jin, Xin Luo, Li-Xin Zhu, Xiaoping Geng, Sheng-Quan Zhang
Pancreatic cancer is one of the most malignant types of tumor and has a poor prognosis. Toll‑like receptor 7 (TLR7) has been found to be present and have different roles in different types of cancer cells. In the present study, the roles of TLR7 in BxPC‑3 cells, a human pancreatic adenocarcinoma cell line, were investigated. The cells were treated with gardiquimod, an agonist of TLR7, following which the properties of the cells, including proliferation, migration, cell cycle and apoptosis, were analyzed...
October 2015: Molecular Medicine Reports
Tanja Grimmig, Niels Matthes, Katharina Hoeland, Sudipta Tripathi, Anil Chandraker, Martin Grimm, Romana Moench, Eva-Maria Moll, Helmut Friess, Igor Tsaur, Roman A Blaheta, Cristoph T Germer, Ana Maria Waaga-Gasser, Martin Gasser
Chronic inflammation as an important epigenetic and environmental factor for putative tumorigenesis and tumor progression may be associated with specific activation of Toll-like receptors (TLR). Recently, carcinogenesis has been suggested to be dependent on TLR7 signaling. In the present study, we determined the role of both TLR7 and TLR8 expression and signaling in tumor cell proliferation and chemoresistance in pancreatic cancer. Expression of TLR7/TLR8 in UICC stage I-IV pancreatic cancer, chronic pancreatitis, normal pancreatic tissue and human pancreatic (PANC1) cancer cell line was examined...
September 2015: International Journal of Oncology
Matteo Santoni, Kalliopi Andrikou, Valeria Sotte, Alessandro Bittoni, Andrea Lanese, Chiara Pellei, Francesco Piva, Alessandro Conti, Massimo Nabissi, Giorgio Santoni, Stefano Cascinu
Toll-like receptors (TLRs) mediate interactions between environmental stimuli and innate immunity. TLRs play a major role in the development of numerous pancreatic diseases, making these molecules attractive as potential therapeutic targets. TLR2, TLR7 and TLR9 are involved in the initiation of type 1 diabetes mellitus (T1DM), whereas TLR2 and TLR4 play a major role in the onset of type 2 diabetes mellitus (T2DM). Furthermore, TLRs cause derangements in several tumor suppressor proteins (such as p16, p21, p27, p53 and pRb), induce STAT3 activation and promote epithelial-mesenchymal transition as well as oncogene-induced senescence...
July 2015: Cancer Treatment Reviews
Sebastian Schölch, Conrad Rauber, Alexandra Tietz, Nuh N Rahbari, Ulrich Bork, Thomas Schmidt, Christoph Kahlert, Uwe Haberkorn, Mark A Tomai, Kenneth E Lipson, Rafael Carretero, Jürgen Weitz, Moritz Koch, Peter E Huber
In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer...
March 10, 2015: Oncotarget
Min Zhou, Jionghuang Chen, Liangjing Zhou, Wenchao Chen, Guoping Ding, Liping Cao
MicroRNAs (miRNAs) are aberrant in many human tumors which can be transferred to immune cells by tumor-derived exosomes. Dendritic cells (DCs) play an important role in activation of immune response. However, the effect of tumor-derived exosomes on toll-like receptor (TLR) in DCs remains unclear. We investigated the influence of pancreatic cancer derived exosomes on TLR4, and downstream cytokines via miR-203. Our results showed that miR-203 expressed in panc-1 cells and exosomes, and upregulated in exosomes-treated DCs...
November 2014: Cellular Immunology
R Chen, R Kang, X-G Fan, D Tang
Histones and their post-translational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecular pattern molecules when they are released into the extracellular space. Administration of exogenous histones to animals leads to systemic inflammatory and toxic responses through activating Toll-like receptors and inflammasome pathways. Anti-histone treatment (e.g., neutralizing antibodies, activated protein C, recombinant thrombomodulin, and heparin) protect mice against lethal endotoxemia, sepsis, ischemia/reperfusion injury, trauma, pancreatitis, peritonitis, stroke, coagulation, and thrombosis...
2014: Cell Death & Disease
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