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toll like receptors and gastrointestinal cancer

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
Hugo Lagunes-Servin, Javier Torres, Carmen Maldonado-Bernal, Martha Pérez-Rodríguez, Sara Huerta-Yépez, Armando Madrazo de la Garza, Leopoldo Muñoz-Pérez, Lourdes Flores-Luna, Guillermo Ramón-García, Margarita Camorlinga-Ponce
BACKGROUND AND AIM: Helicobacter pylori infection is mainly acquired during childhood, and establishes a chronic infection that may lead to peptic ulcer or gastric cancer during adulthood. Toll-like receptors (TLRs) are expressed by distinct cell types throughout the gastrointestinal tract, and play an important role in regulation of the innate immune response. Few works have addressed TLRs expression in gastric epithelia of adults, and scarce studies have done it in children. The aim of this work was to analyze the expression of TLR2, TLR4, TLR5, TLR9, and IL-8, IL-10 and TNF-α in the gastric mucosa of children with and without H...
December 2013: Helicobacter
Hazel Tye, Brendan J Jenkins
Inflammation-associated malignancies of the gastrointestinal tract (GI), including those of the stomach and colon, collectively rank as the highest cause of cancer-related deaths worldwide. It has been well documented that the deregulated activation of the archetypal pro-inflammatory and oncogenic transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription (STAT)3 is a common feature of GI cancers that invariably correlates with poor prognosis. Signal transducer and activator of transcription 3 and NF-κB are key downstream signal transducers of the interleukin (IL)-6 cytokine and toll-like receptor (TLR) families, respectively, and until recently, the potential involvement of these two families in the pathogenesis of cancer has been investigated in isolation...
September 2013: Cancer Science
Shirin Moossavi, Hongyu Zhang, Jun Sun, Nima Rezaei
Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are the major diseases of the lower gastrointestinal tract. The intestinal epithelium plays a critical role in the host's interactions with the large communities of resident luminal bacteria. Epithelial cells recognize the bacterial components via pattern-recognition receptors. Toll-like receptors (TLRs) are a major class of pattern-recognition receptors that are present on intestinal epithelial cells, including putative stem cells. Stem cells are responsible for tissue homeostasis and regeneration after injury including IBD...
May 2013: Expert Review of Clinical Immunology
Klara Klimesova, Miloslav Kverka, Zuzana Zakostelska, Tomas Hudcovic, Tomas Hrncir, Renata Stepankova, Pavel Rossmann, Jakub Ridl, Martin Kostovcik, Jakub Mrazek, Jan Kopecny, Koichi S Kobayashi, Helena Tlaskalova-Hogenova
BACKGROUND: Microbial sensing by Toll-like receptors (TLR) and its negative regulation have an important role in the pathogenesis of inflammation-related cancer. In this study, we investigated the role of negative regulation of Toll-like receptors signaling and gut microbiota in the development of colitis-associated cancer in mouse model. METHODS: Colitis-associated cancer was induced by azoxymethane and dextran sodium sulfate in wild-type and in interleukin-1 receptor-associated kinase M (IRAK-M)-deficient mice with or without antibiotic (ATB) treatment...
May 2013: Inflammatory Bowel Diseases
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