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      Chronic Inflammation in Cancer Development

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          Chronic inflammatory mediators exert pleiotropic effects in the development of cancer. On the one hand, inflammation favors carcinogenesis, malignant transformation, tumor growth, invasion, and metastatic spread; on the other hand inflammation can stimulate immune effector mechanisms that might limit tumor growth. The link between cancer and inflammation depends on intrinsic and extrinsic pathways. Both pathways result in the activation of transcription factors such as NF-κB, STAT-3, and HIF-1 and in accumulation of tumorigenic factors in tumor and microenvironment. STAT-3 and NF-κB interact at multiple levels and thereby boost tumor-associated inflammation which can suppress anti-tumor immune responses. These factors also promote tumor growth, progression, and metastatic spread. IL-1, IL-6, TNF, and PGHS-2 are key mediators of an inflammatory milieu by modulating the expression of tumor-promoting factors. In this review we concentrate on the crucial role of pro-inflammatory mediators in inflammation-driven carcinogenesis and outline molecular mechanisms of IL-1 signaling in tumors. In addition, we elucidate the dual roles of stress proteins as danger signals in the development of anti-cancer immunity and anti-apoptotic functions.

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          Most cited references 200

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          NF-kappaB in cancer: from innocent bystander to major culprit.

          Nuclear factor of kappaB (NF-kappaB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-KB in immunity is undisputed, recent evidence indicates that NF-kappaB and the signalling pathways that are involved in its activation are also important for tumour development. NF-kappaB should therefore receive as much attention from cancer researchers as it has already from immunologists.
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            Molecular chaperones in cellular protein folding.

            The folding of many newly synthesized proteins in the cell depends on a set of conserved proteins known as molecular chaperones. These prevent the formation of misfolded protein structures, both under normal conditions and when cells are exposed to stresses such as high temperature. Significant progress has been made in the understanding of the ATP-dependent mechanisms used by the Hsp70 and chaperonin families of molecular chaperones, which can cooperate to assist in folding new polypeptide chains.
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              Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.

              TNFalpha is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear. We now show that TNFalpha-induced ROS, whose accumulation is suppressed by mitochondrial superoxide dismutase, cause oxidation and inhibition of JNK-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This results in sustained JNK activation, which is required for cytochrome c release and caspase 3 cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevents H(2)O(2) accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevents TNFalpha-mediated fulminant liver failure without affecting liver regeneration.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immun.
                Frontiers in Immunology
                Frontiers Research Foundation
                12 January 2012
                : 2
                1Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München Munich, Germany
                2Clinical Cooperation Group Innate Immunity in Tumor Biology, Helmholtz Zentrum München Munich, Germany
                3multimmune GmbH Munich, Germany
                Author notes

                Edited by: Cristina Bonorino, Pontificia Universidade Catolica do Rio Grande do Sul, Brazil

                Reviewed by: Lidija Klampfer, Montefiore Medical Center and Albert Einstein Cancer Center, USA; Ana Paula Souza, Pontificia Universidade Católica do Rio Grande do Sul, Brazil

                *Correspondence: Gabriele Multhoff, Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, D-81675 Munich, Germany. e-mail: gabriele.multhoff@ 123456lrz.tu-muenchen.de

                This article was submitted to Frontiers in Inflammation, a specialty of Frontiers in Immunology.

                Copyright © 2012 Multhoff, Molls and Radons.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 253, Pages: 17, Words: 17718
                Review Article


                heat shock proteins, inflammation, carcinogenesis, nf-κb, il-1, stat-3, tumorigenic factors


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