Inflammation Amplifier, a New Paradigm in Cancer Biology

Atsumi, Toru; Singh, Rajeev; Sabharwal, Lavannya; Bando, Hidenori; Meng, Jie; Arima, Yasunobu; Yamada, Moe; Harada, Masaya; Jiang, Jingjing; Kamimura, Daisuke; Ogura, Hideki; Hirano, Toshio; Murakami, Masaaki

doi:10.1158/0008-5472.can-13-2322

Cited by 179 publications

(153 citation statements)

References 29 publications

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“…One mechanism associated with this development and specific to nonimmune cells, such as synovial cells, fibroblasts, and endothelial cells, is an NF-kB activator, the inflammation amplifier (formerly IL-6 amplifier) (15), which is activated by a simultaneous stimulation of NF-kB and STAT3. The main functional molecules of the inflammation amplifier are chemokines and growth factors, which deregulate local homeostasis via an accumulation of various immune cells and proliferate various regional cells, whereas IL-6 mainly acts as fuel to maintain the activation of STAT3 (16,17). We have shown that the amplifier is activated in the affected tissues of several disease models and clinical samples (17)(18)(19) and that its blockade suppressed these models (17,19).…”

Section: B Reakpoint Cluster Region (Bcr) Protein Is a Unique Kinasementioning

confidence: 87%

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Meng

Jiang

Atsumi

et al. 2016

The Journal of Immunology

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The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the α subunit of casein kinase II (CK2α), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-κB activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography–tandem mass spectrometry analysis showed that CK2α associated with BCR. We found the BCR functions are mediated by CK2α. Indeed, CK2α associated with adaptor molecules of TNF-αR and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-α stimulation. Notably, p65 S529 phosphorylation by CK2α creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2α, and the BCR–CK2α complex could be a novel therapeutic target for various inflammatory diseases.

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Section: B Reakpoint Cluster Region (Bcr) Protein Is a Unique Kinasementioning

confidence: 87%

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Meng

Jiang

Atsumi

et al. 2016

The Journal of Immunology

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“…TLRs are actually considered as major actors implicated in chronic inflammatory-driven carcinogenesis [28,29]. In the present study, we hypothesized that a functional TLR pathway may exist in IBCs, particularly in the TNC subtype and be activated by both epithelial cancer cells and stromal cells.…”

Section: Discussionmentioning

confidence: 88%

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Meseure

Vacher

Alsibai

et al. 2016

Cancer Microenvironment

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Toll-like receptors (TLRs) are pattern recognition receptors mainly expressed by cells of the immune system but also by epithelial tumor cells. Little is known about expression patterns of TLR genes in breast tumors, and their clinical significance is unclear. The aim of our study was to investigate expression of TLRs pathway components in pre-invasive breast lesions and invasive breast carcinomas (IBCs). We used RT-PCR assays to quantify mRNA levels of the 10 TLR genes and genes involved in TLR pathways in 350 breast tumors from patients with known clinical/pathological status and long-term outcome. Sets of 158 breast samples were also analyzed by immunochemistry including; 40 early noninvasive breast lesions, 38 IBCs and 80 triple negative carcinomas subtype (TNCs). We identified TLR9 as the major TLR gene family member upregulated in breast tumors and more particularly in TNCs. Immunohistochemical studies demonstrated that TLR9 protein was expressed in tumor epithelial and stromal cells of the TLR9 mRNA-overexpressing tumors. TLR9 overexpression appears very early during breast carcinogenesis. High TLR9 levels were associated with favorable outcome in the TNC sub-group. TLR9 overexpression was associated with alterations of down-stream components of the TLR9 signaling pathway, epithelio-mesenchymal transition (EMT) induction and EGFR pathway deregulation. TNCs with TLR9 overexpression were significantly correlated with development of a fibrous and inflammatory microenvironment with variable status of nuclear phosphoSTAT3. Our results suggest that TLR9 could play a role in TNC carcinogenesis and could be useful as predictive biomarker and therapeutic target.Keywords Toll-like receptor 9 . Breast cancer subtypes .

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“…During the last 2 decades, TNF has been implicated in numerous diseases such as arthritis, 17 Alzheimer disease, 28 cancer, 29 major depression, 30 septic shock, 31 and inflammatory bowel disease. 32 Therefore, anti-TNF therapy has been used in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

The Physiological Role of Tumor Necrosis Factor in Human Immunity and Its Potential Implications in Spinal Manipulative Therapy: A Narrative Literature Review

Zhang

Yao

2016

Journal of Chiropractic Medicine

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Objective: Although tumor necrosis factor (TNF) is a well-known inflammatory cytokine in the pathological development of various human diseases, its physiological roles are not widely understood nor appreciated. The molecular mechanisms underlying spinal manipulation therapy (SMT) remain elusive. The relationship between TNF and SMT is unclear. Thus, we performed this literature review to better understand TNF physiology and its potential relationship with SMT, and we propose a novel mechanism by which SMT may achieve clinical benefits by using certain beneficial features of TNF. Methods: We searched several databases for relevant articles published between 1975 and 2015 and then reexamined the studies from current immunophysiological perspectives. Results: The history and recent progresses in TNF physiology research were explored. Conflicting reports on the relationship between TNF and SMT were identified. Based on the newly discovered interaction between TNF and regulatory T cells, we proposed a putative biphasic TNF response to SMT, which may resolve the conflicts in the reported observations and interpretations. Conclusion: The current literature about TNF informed our discussion of new physiological roles for TNF, which may help to better understand the physiological effects of SMT. (J Chiropr Med 2016;15:190-196)

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Inflammation Amplifier, a New Paradigm in Cancer Biology

Cited by 179 publications

References 29 publications

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

The Physiological Role of Tumor Necrosis Factor in Human Immunity and Its Potential Implications in Spinal Manipulative Therapy: A Narrative Literature Review

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