IL-6 Signaling Promotes Tumor Growth in Colorectal Cancer

Becker, Christoph; Fantini, Massimo; Wirtz, Stefan; Nikolaev, Alexei; Lehr, Hans A.; Galle, Peter R.; Rose–John, Stefan; Neurath, Markus F.

doi:10.4161/cc.4.2.1413

Cited by 226 publications

(194 citation statements)

References 28 publications

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“…In a model developed in our laboratory, the conditional deletion of the SMAD4 gene specifically in T cells leads to a progressive intestinal epithelial hyperplasia (unpublished). We observe a significant increase in T-cell production of IL-6 in vivo and in vitro in this model, consistent with the transgenic model in which T-cell resistance to TGF-b is induced by a CD2-driven dnTbRII (Becker et al, , 2005. More importantly, we also see a significant production of IL-5, a key factor in the induction, activation, and migration of eosinophils.…”

Section: Smad-dependent Signaling In T Cells Controlling Mucosal Inflsupporting

confidence: 69%

“…The broader influence of TGF-b in the immune system can in part be attributed to the interaction between intermediates in the TGF-b pathway with components downstream of both cytokine receptors and antigen receptors (Jacobsen et al, 1991), including Toll-like receptors (Moustakas and Heldin, 2003;Xiao et al, 2003), and modulation of cytokine production Roberts, 1997, 1998;Laouar et al, 2005;Lyakh et al, 2005). However, the recognition that a disruption or loss of TGF-b signaling within immune cells directly contributes to the initiation and progression of epithelial cancer highlights the role this cytokine plays in controlling cell-to-cell interactions, and the immune surveillance of cancer (Becker et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

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TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia

Letterio

2005

Oncogene

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Transforming growth factor-b (TGF-b) plays an essential role in regulating the homeostasis of cells in the lymphoid lineage. TGF-b signaling is not required for normal thymopoiesis, but is essential for regulating the expansion, activation, and effector function of the mature CD4 þ and CD8 þ T cells in the peripheral lymphoid organs and target tissues. Recent studies in both mice and humans have elucidated an important and complex role for TGF-b in regulatory T-cell biology. Disruption of TGF-b signaling in T cells impairs the maintenance of regulatory T cells, results in the expansion of activated effector T cells, and is associated with the production of cytokines that have major effects on cells in their environment. While autoimmunity and inflammation are the principal phenotypes associated with the abrogation of TGF-b signaling in T cells in mice, emerging evidence now also directly links Smad-dependent TGF-b signaling in T cells to the suppression of epithelial neoplasia. The TGF-b receptor-activated Smad3 plays a critical role in mediating many of the inhibitory effects of TGF-b signaling in T cells, and has now been established as an important suppressor of leukemogenesis. These studies are increasing our awareness of the many complex mechanisms through which TGF-b signaling controls the pathogenesis of cancer.

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Section: Smad-dependent Signaling In T Cells Controlling Mucosal Inflsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia

Letterio

2005

Oncogene

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“…The increased number of Th17 cells may aggravate inflammation and promote tumor growth by increasing IL-6 secretion (Gaffen 2008). On the other hand, IL-6 itself also has the capability to promote tumorigenesis (Becker et al 2005). Thus, we concluded that the serum IL-6 level might be a useful biomarker for predicting colorectal tumorigenesis and disease progression.…”

Section: Discussionmentioning

confidence: 90%

Colorectal Cancer Progression Is Associated with Accumulation of Th17 Lymphocytes in Tumor Tissues and Increased Serum Levels of Interleukin-6

Yan

Han

et al. 2014

Tohoku J. Exp. Med.

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Colorectal cancer is a significant worldwide health problem, and an altered immunoresponse plays an important role in colorectal tumorigenesis and cancer progression. T helper 17 (Th17) lymphocytes (a subgroup of CD4 + T cells), together with the related cytokines, such as interleukin (IL)-6 and IL-17A, participate in cancer-related immunity. In this study, we measured the percentage of Th17 cells in peripheral blood mononuclear cells (PBMCs) and the levels of IL-17A and IL-6 in serum samples or tumor tissues, prepared from 40 colorectal cancer patients (a median age of 75 years), 32 age-matched healthy controls (a median age of 74 years), and 30 young healthy controls (a median age of 26 years). The percentage of Th17 cells in PBMCs and the serum IL-6 levels were higher in cancer patients than those in elderly controls, and they were associated with tumor progression. Moreover, the percentage of Th17 cells and the serum IL-6 levels were higher in elderly healthy controls than those in young healthy controls. In contrast, serum IL-17A levels were similar in the cancer patients and the elderly controls, although its serum levels were higher than those in young controls. Importantly, Th17 cells were accumulated in the intratumor and peritumor regions. In conclusion, the percentage of Th17 cells and the serum IL-6 level are significantly increased with aging, and their higher levels are correlated with colorectal cancer progression. The percentage of Th17 cells in PBMCs and the serum IL-6 level are potential biomarkers for predicting disease progression.

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“…Furthermore, we found IL-6 and ICAM1, which are upregulated only in high-risk tumors, as the key mediators of chemosensitivity. In good correlation, IL-6 and ICAM1 were found associated with invasion, angiogenesis, tumor growth, chemoresistance, and prognosis in many cancers (29)(30)(31)(32). .…”

Section: Discussionmentioning

confidence: 99%

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

et al. 2013

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Glioblastoma (GBM) is the most common, malignant adult primary tumor with dismal patient survival, yet the molecular determinants of patient survival are poorly characterized. Global methylation profile of GBM samples (our cohort; n ¼ 44) using high-resolution methylation microarrays was carried out. Cox regression analysis identified a 9-gene methylation signature that predicted survival in GBM patients. A risk-score derived from methylation signature predicted survival in univariate analysis in our and The Cancer Genome Atlas (TCGA) cohort. Multivariate analysis identified methylation risk score as an independent survival predictor in TCGA cohort. Methylation risk score stratified the patients into low-risk and high-risk groups with significant survival difference. Network analysis revealed an activated NF-kB pathway association with high-risk group. NF-kB inhibition reversed glioma chemoresistance, and RNA interference studies identified interleukin-6 and intercellular adhesion molecule-1 as key NF-kB targets in imparting chemoresistance. Promoter hypermethylation of neuronal pentraxin II (NPTX2), a risky methylated gene, was confirmed by bisulfite sequencing in GBMs. GBMs and glioma cell lines had low levels of NPTX2 transcripts, which could be reversed upon methylation inhibitor treatment. NPTX2 overexpression induced apoptosis, inhibited proliferation and anchorage-independent growth, and rendered glioma cells chemosensitive. Furthermore, NPTX2 repressed NF-kB activity by inhibiting AKT through a p53-PTENdependent pathway, thus explaining the hypermethylation and downregulation of NPTX2 in NF-kB-activated highrisk GBMs. Taken together, a 9-gene methylation signature was identified as an independent GBM prognosticator and could be used for GBM risk stratification. Prosurvival NF-kB pathway activation characterized high-risk patients with poor prognosis, indicating it to be a therapeutic target. Cancer Res; 73(22); 6563-73. Ó2013 AACR.

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IL-6 Signaling Promotes Tumor Growth in Colorectal Cancer

Cited by 226 publications

References 28 publications

TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia

TGF-β signaling in T cells: roles in lymphoid and epithelial neoplasia

Colorectal Cancer Progression Is Associated with Accumulation of Th17 Lymphocytes in Tumor Tissues and Increased Serum Levels of Interleukin-6

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

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