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toll like receptors and gastrointestinal cancer

Kanae Echizen, Hiroko Oshima, Mizuho Nakayama, Masanobu Oshima
Accumulating evidence has indicated that the inflammatory response is important for tumor promotion. However, the mechanisms underlying the induction of the inflammatory response in cancer tissues and how it promotes tumorigenesis remain poorly understood. We constructed several mouse models that develop inflammation-associated gastric and intestinal tumors and examined the in vivo mechanisms of tumorigenesis. Of note, the activation of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2 ) pathway and Toll-like receptor (TLR)/MyD88 signaling cooperatively induced the generation of an inflammatory microenvironment, which is required for early-stage tumorigenesis...
February 5, 2018: Advances in Biological Regulation
Juan J Ortiz de Urbina, Beatriz San-Miguel, Alfonso Vidal-Casariego, Irene Crespo, Diana I Sánchez, José L Mauriz, Jesús M Culebras, Javier González-Gallego, María J Tuñón
Background and Aims: Abdominal radiotherapy (RT) causes harm to the mid gastrointestinal mucosa by release of pro-inflammatory cytokines and promotes autophagic changes in tumor cells. This study was aimed to measure the effect of glutamine administration on markers of inflammation and autophagy in cancer patients treated with RT. Methods: In this double-blind, randomized, controlled pilot trial 43 patients under abdominal RT diagnosed of pelvic or abdominal malignancies receiving glutamine (30 g/d) or placebo (casein, 30 g/d)...
2017: International Journal of Medical Sciences
Evagelia Spanou, Polyxeni Kalisperati, Ioannis S Pateras, Alexandros Papalampros, Alexandra Barbouti, Athanasios G Tzioufas, Athanassios Kotsinas, Stavros Sougioultzis
The fundamental role of human Toll-like receptors (TLRs) and NOD-like receptors (NLRs), the two most studied pathogen recognition receptors (PRRs), is the protection against pathogens and excessive tissue injury. Recent evidence supports the association between TLR/NLR gene mutations and susceptibility to inflammatory, autoimmune, and malignant diseases. PRRs also interfere with several cellular processes, such as cell growth, apoptosis, cell proliferation, differentiation, autophagy, angiogenesis, cell motility and migration, and DNA repair mechanisms...
2017: Frontiers in Genetics
Ilia A Toshkov, Anatoli S Gleiberman, Vadim L Mett, Alan D Hutson, Anurag K Singh, Andrei V Gudkov, Lyudmila G Burdelya
Radiation treatment of head and neck cancer frequently causes severe collateral damage to normal tissues including mouth mucosa, salivary glands and skin. This toxicity limits the radiation dose that can be delivered and affects the patient's quality of life. Previous studies in mice and nonhuman primates showed that entolimod, a toll-like receptor 5 (TLR5) agonist derived from bacterial flagellin, effectively reduced radiation damage to hematopoietic and gastrointestinal tissues in both total-body and local irradiation scenarios, with no protection of tumors...
May 2017: Radiation Research
Heikki Huhta, Olli Helminen, Joonas H Kauppila, Tuula Salo, Katja Porvari, Juha Saarnio, Petri P Lehenkari, Tuomo J Karttunen
Toll-like receptors (TLRs) are innate immune receptors expressed in all parts of the alimentary tract. However, analyses comparing expression in different segments and data on germ-free animals are lacking. Alimentary tract cancers show increased TLR expression. According to the field effect concept, carcinogenetic factors induce subtle cancer predisposing alterations in the whole organ. We studied TLR1 to TLR9 expression in all segments of the alimentary tract from cancer patients' tumor-adjacent normal mucosa, healthy organ donors, and conventional and germ-free mice by using immunohistochemistry and quantitative PCR...
August 2016: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Elke Cario
PURPOSE OF REVIEW: Intestinal mucositis represents a common complication and dose-limiting toxicity of cancer chemotherapy. So far chemotherapy-induced intestinal mucositis remains poorly treatable resulting in significant morbidity and reduced quality of life in cancer patients. This review discusses recent insights into the pathophysiology of chemotherapy-induced intestinal mucositis. Novel mechanisms linking gut microbiota, host innate immunity and anticancer drug metabolism are highlighted...
June 2016: Current Opinion in Supportive and Palliative Care
Adi Binder Gallimidi, Stuart Fischman, Brurya Revach, Raanan Bulvik, Alina Maliutina, Ariel M Rubinstein, Gabriel Nussbaum, Michael Elkin
Oral squamous cell carcinoma (OSCC) is a lethal disease whose incidence is increasing. Epidemiologic studies demonstrate an association between periodontitis and oral cancer, and periodontal pathogens are implicated in the pathogenesis of numerous disorders, including rheumatoid arthritis, cardiovascular diseases, diabetes and gastrointestinal malignancies. Nevertheless, a causal role for periodontal pathogens in OSCC has not been shown, partly due to the lack of an appropriate animal model. Here, utilizing a newly-established murine model of periodontitis-associated oral tumorigenesis, we report that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect...
September 8, 2015: Oncotarget
Simona Frosali, Danilo Pagliari, Giovanni Gambassi, Raffaele Landolfi, Franco Pandolfi, Rossella Cianci
The gut is able to maintain tolerance to microbial and food antigens. The intestine minimizes the number of harmful bacteria by shaping the microbiota through a symbiotic relationship. In healthy human intestine, a constant homeostasis is maintained by the perfect regulation of microbial load and the immune response generated against it. Failure of this balance may result in various pathological conditions. Innate immune sensors, such as Toll-like receptors (TLRs), may be considered an interface among intestinal epithelial barrier, microbiota, and immune system...
2015: Journal of Immunology Research
Alison C West, Brendan J Jenkins
Collectively, cancers of the gastrointestinal (GI) tract (including the esophagus, stomach, duodenum, colon, rectum, liver, gall bladder and bile ducts) are the most prevalent and deadly worldwide. A common denominator in the pathogenesis of these GI tract cancers is chronic inflammation, as evidenced by the fact that sufferers of inflammatory bowel disease (IBD) are significantly more susceptible to colon cancer than healthy individuals. However, since only a relatively small proportion of individuals with chronic inflammatory conditions such as IBD go on to develop cancer, research has focused on identifying discrepancies in the host immune system that may be responsible for promoting carcinogenesis in inflamed tissue...
2015: Current Pharmaceutical Design
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
Hannah R Wardill, Ysabella Z A Van Sebille, Kimberley A Mander, Rachel J Gibson, Richard M Logan, Joanne M Bowen, Stephen T Sonis
Regimen-related toxicities remain a priority concern within the field of supportive care in cancer. Despite this, many forms of toxicity are under reported and consequently poorly characterised. Although there have been significant improvements in our understanding of regimen-related toxicities, symptom management continues to occur independently raising concerns such as drug interactions and the tendency to emphasise management of a single symptom at the expense of others. This review focuses on two important toxicities induced by chemotherapy; neuropathy/pain and gastrointestinal toxicity, introducing the Toll-like receptor (TLR) 4 pathway as a common component of their pathobiology...
February 2015: Cancer Treatment Reviews
Imtiyaz Thagia, Elisabeth J Shaw, Emily Smith, Kathryn J Else, Rachael J Rigby
A single layer of intestinal epithelial cells (IEC) lines the entire gastrointestinal tract and provides the first line of defense and barrier against an abundance of microbial stimuli. IEC homeostasis and repair are mediated through microbe-sensing Toll-like receptor (TLR)-induced inflammatory pathways. Increasing evidence supports a role of suppressor of cytokine signaling 3 (SOCS3) as a modulator of IEC turnover, balancing controlled repair and replenishment with excessive IEC proliferation predisposing to dysplasia and cancer...
January 1, 2015: American Journal of Physiology. Gastrointestinal and Liver Physiology
Janet K Coller, Imogen A White, Richard M Logan, Jonathan Tuke, Alison M Richards, Kelly R Mead, Christos S Karapetis, Joanne M Bowen
PURPOSE: Severe chemotherapy-induced gastrointestinal toxicity (CIGT) is common and results in treatment delays, dose reductions, and potential premature treatment discontinuation. Currently, there is no diagnostic marker to predict CIGT. Proinflammatory cytokines, produced via toll-like receptor signaling, are key mediators of this toxicity. Hence, this pilot study investigated the association between immune genetic variability and severe CIGT risk. METHODS: Genomic DNA from 34 patients (10 with severe CIGT) who had received 5-fluoruracil-based chemotherapy regimens was analyzed for variants of IL-1B, IL-2, IL-6, IL-6R, IL-10, TNF-a, TGF-b, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE, and OPRM1...
May 2015: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
Manon D Schulz, Ciğdem Atay, Jessica Heringer, Franziska K Romrig, Sarah Schwitalla, Begüm Aydin, Paul K Ziegler, Julia Varga, Wolfgang Reindl, Claudia Pommerenke, Gabriela Salinas-Riester, Andreas Böck, Carl Alpert, Michael Blaut, Sara C Polson, Lydia Brandl, Thomas Kirchner, Florian R Greten, Shawn W Polson, Melek C Arkan
Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development. However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined...
October 23, 2014: Nature
Bojidar M Kojouharov, Craig M Brackett, Jean M Veith, Christopher P Johnson, Ilya I Gitlin, Ilia A Toshkov, Anatoli S Gleiberman, Andrei V Gudkov, Lyudmila G Burdelya
Myelosuppression and gastrointestinal damage are common side effects of cancer treatment limiting efficacy of DNA-damaging chemotherapeutic drugs. The Toll-like receptor 5 (TLR5) agonist Entolimod has demonstrated efficacy in mitigating damage to hematopoietic and gastrointestinal tissues caused by radiation. Here, using 5-Fluorouracil (5-FU) treated mice as a model of chemotherapy-induced side effects, we demonstrated significant reduction in the severity of 5-FU-induced morbidity and increased survival accompanied by the improved integrity of intestinal tissue and stimulated the restoration of hematopoiesis...
February 15, 2014: Oncotarget
Qi Lu, Hao Ding, Weiping Li
Toll-like receptors (TLRs) serve as specific pattern recognition molecules that bind to microbial components to activate innate immunity and instruct and modulate adaptive immunity in the face of immunological danger. Accumulating evidence supports that TLR signaling pathway responses to luminal microbes participate in the development of gastrointestinal malignancies. This review summarizes current knowledge on the roles of TLR in microbiota-associated gastrointestinal cancer metastasis, focusing on TLR recognition of microbiota ligands, initiating inflammation, and promoting tumorigenesis, as well as the therapeutic strategies to target TLR...
November 2013: Journal of Cancer Research and Therapeutics
Hannah R Wardill, Rachel J Gibson, Richard M Logan, Joanne M Bowen
Chemotherapy-induced gut toxicity is a major clinical and economic burden to oncology practice. The mechanisms responsible for its development are ill defined, hampering the development of therapeutic interventions. In light of newly published research foci and clinical practice guidelines in supportive care in cancer, there has been renewed interest in the role tight junctions play in the pathobiology of chemotherapy-induced gut toxicity. Several preclinical studies have identified molecular defects in intestinal tight junctions following chemotherapy...
December 1, 2014: International Journal of Cancer. Journal International du Cancer
Shashank Saran, Doan D H Tran, Sabine Klebba-Färber, Patricia Moran-Losada, Lutz Wiehlmann, Alexandra Koch, Himpriya Chopra, Oliver Pabst, Andrea Hoffmann, Robert Klopfleisch, Teruko Tamura
BACKGROUND: THO (Suppressors of the transcriptional defects of hpr1 delta by overexpression) complex 5 (THOC5), an mRNA export protein, is involved in the expression of only 1% of all genes. Using an interferon inducible knockout mouse system, we have previously shown that THOC5 is an essential element in the maintenance of hematopoietic stem cells and cytokine-mediated hematopoiesis in adult mice. Here we interrogate THOC5 function in cell differentiation beyond the hematopoietic system and study pathological changes caused by THOC5 deficiency...
2013: BMC Cell Biology
Chun Wai Mai, Yew Beng Kang, Mallikarjuna Rao Pichika
Toll-like receptor 4 (TLR-4) is well known for its host innate immunity. Despite the fact that TLR-4 activation confers antitumor responses; emerging evidence suggests that TLR-4 is associated with tumor development and progression. It is now clear that overactivation of TLR-4, through various immune mediators, may cause immune response dysfunction, resulting in tumorigenesis. Different cancers could have different extents of TLR-4 involvement during tumorigenesis or tumor progression. In this review, we focus on infection- and inflammation-related TLR-4 activation in noncancer and cancer cells, as well as on the current evidence about the role of TLR-4 in ten of the most common cancers, viz, head and neck cancer, lung cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, skin cancer, breast cancer, ovarian cancer, cervical cancer, and prostate cancer...
2013: OncoTargets and Therapy
Hiroyuki Marusawa, Brendan John Jenkins
Gastrointestinal cancers collectively rank as the most lethal cancers worldwide, and are strongly linked with chronic inflammation. Despite advances over the last decade into our understanding of the etiology of these malignancies, both from a host perspective and with respect to environmental factors, current treatment strategies comprising surgery, chemotherapy and/or radiotherapy are still associated with unacceptably poor patient survival rates. Accordingly, there is a pressing need to identify new molecular targets which can underpin the development of next-generation treatment strategies to improve patient outcomes, and serve as biomarkers for early disease detection...
April 10, 2014: Cancer Letters
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