Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction

Lin, Chieh Yu; Lin, Chien Jung; Chen, Kuo Hsing; Wu, Jiann Chun; Huang, Shifeng; Wang, Seu Mei

doi:10.1016/j.febslet.2006.04.049

Cited by 69 publications

(63 citation statements)

References 45 publications

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“…Our results have shown that culturing activated macrophages with A549 cells in the absence of TGF-β1 does not drive EMT however culturing activated macrophages with A549 cells in the presence of TGF-β1 accentuates TGF-β1 driven EMT. The results are in agreement with previously published reports demonstrating that conditioned media from activated tumour associated macrophages (TAMs) induced EMT and stimulated the migratory and invasive activities of hepatoma cells [49]. Furthermore, decreasing the number of TAMs markedly suppressed tumour growth and metastasis in breast cancer [50] suggesting that targeting TAMs in lung cancer may limit EMT and provide a novel therapeutic target.…”

Section: Discussionsupporting

confidence: 82%

Transforming Growth Factor-β1 (TGF-β1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor α (TNFα) via Crosstalk Between the SMAD and NF-κB Pathways

Borthwick

Gardner

Soyza

et al. 2011

Cancer Microenvironment

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process by which an epithelial cell alters its phenotype to that of a mesenchymal cell and plays a critical role in embryonic development, tumour invasion and metastasis and tissue fibrosis. Transforming growth factor-β1 (TGF-β1) continues to be regarded as the key growth factor involved in driving EMT however recently tumour necrosis factor α (TNFα) has been demonstrated to accentuate TGF-β1 driven EMT. In this study we investigate how various signalling pathways contribute to this accentuated effect. A549 cells were treated with TGF-β1 (10 ng/ml), TNFα (20 ng/ml) or a combination of both for 72 h and EMT assessed. The effect of selective inhibition of the SMAD, MAPK and NF-κB pathways on EMT was assessed. A549 cells treated with TGF-β1 downregulate the expression of epithelial markers, increase the expression of mesenchymal markers, secrete matrix-metalloproteinases and become invasive. Significantly, TGF-β1 driven EMT is accentuated by co-treatment with TNFα. SMAD 3 inhibition attenuated effect of TNFα. However, inhibiting IKKβ blocked both TGF-β1 driven EMT and the accentuating action of TNFα. Inhibiting p38 and ERK signalling had no effect on EMT. TNFα accentuates TGF-β1 driven EMT in A549 cells via a SMAD 2/3 independent mechanism involving the NF-κB pathway independent of p38 and ERK 1/2 activation.

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Section: Discussionsupporting

confidence: 82%

Transforming Growth Factor-β1 (TGF-β1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor α (TNFα) via Crosstalk Between the SMAD and NF-κB Pathways

Borthwick

Gardner

Soyza

et al. 2011

Cancer Microenvironment

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“…It is also important to note that a number of studies have analyzed the response of human cells to murine RAW 264.7 cells, with results that frequently replicate key features of disease pathology. [85][86][87][88][89][90][91][92][93] Future studies will use primary human macrophages to further develop this coculture system. Eventual testing of new therapeutics, particularly those targeting macrophage activation, using our developed coculture system will also be a key focus of future work.…”

Section: Discussionmentioning

confidence: 99%

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

Samavedi

Díaz‐Rodríguez

Erndt-Marino

et al. 2017

Tissue Engineering Part A

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The goal of the present study was to develop a fully three-dimensional (3D) coculture system that would allow for systematic evaluation of the interplay between activated macrophages (AMs) and chondrocytes in osteoarthritic disease progression and treatment. Toward this end, our coculture system was first validated against existing in vitro osteoarthritis models, which have generally cultured healthy normal chondrocytes (NCs)-in two-dimensional (2D) or 3D-with proinflammatory AMs in 2D. In this work, NCs and AMs were both encapsulated within poly(ethylene glycol) diacrylate hydrogels to mimic the native 3D environments of both cell types within the osteoarthritic joint. As with previous studies, increases in matrix metalloproteinases (MMPs) and proinflammatory cytokines associated with the early stages of osteoarthritis were observed during NC-AM coculture, as were decreases in protein-level Aggrecan and collagen II. Thereafter, the coculture system was extended to osteoarthritic chondrocytes (OACs) and AMs to evaluate the potential effects of AMs on pre-existing osteoarthritic phenotypes. OACs in coculture with AMs expressed significantly higher levels of MMP-1, MMP-3, MMP-9, MMP-13, IL-1b, TNF-a, IL-6, IL-8, and IFN-g compared to OACs in mono-culture, indicating that proinflammatory macrophages may intensify the abnormal matrix degradation and cytokine secretion already associated with OACs. Likewise, AMs cocultured with OACs expressed significantly more IL-1b and VEGF-A compared to AM mono-culture controls, suggesting that OACs may intensify abnormal macrophage activation. Finally, OACs cultured in the presence of nonactivated macrophages produced lower levels of MMP-9 and proinflammatory cytokines IL-1b, TNF-a, and IFN-g compared to OACs in the OAC-AM system, results that are consistent with anti-inflammatory agents temporarily reducing certain OA symptoms. In summary, the 3D coculture system developed herein captures several key features of inflammatory OA and may prove useful in future screening of therapeutic agents and/or assessment of disease progression mechanisms.

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“…In EMT there is a de-stabilization of adherent junctions [98] and the cells develop more invasive properties [93] .…”

Section: Hepatocarcinogenesis and Tumormicroenviromentmentioning

confidence: 99%

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

Severi¹,

Malenstein²,

Verslype³

et al. 2010

Acta Pharmacol Sin

157

125

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Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction

Cited by 69 publications

References 45 publications

Transforming Growth Factor-β1 (TGF-β1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor α (TNFα) via Crosstalk Between the SMAD and NF-κB Pathways

Transforming Growth Factor-β1 (TGF-β1) Driven Epithelial to Mesenchymal Transition (EMT) is Accentuated by Tumour Necrosis Factor α (TNFα) via Crosstalk Between the SMAD and NF-κB Pathways

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

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