Tumor-associated macrophages may influence tumor progression, angiogenesis and invasion. To investigate mechanisms by which macrophages interact with tumor cells, we developed an in vitro coculture model. Previously we reported that coculture enhanced invasiveness of the tumor cells in a TNF-alpha- and matrix metalloprotease-dependent manner. In this report, we studied intracellular signaling pathways and induction of inflammatory genes in malignant cells under the influence of macrophage coculture. We report that coculture of macrophages with ovarian or breast cancer cell lines led to TNF-alpha-dependent activation of JNK and NF-kappa B pathways in tumor cells, but not in benign immortalized epithelial cells. Tumor cells with increased JNK and NF-kappa B activity exhibited enhanced invasiveness. Inhibition of the NF-kappa B pathway by TNF-alpha neutralizing Abs, an NF-kappa B inhibitor, RNAi to Re1A, or overexpression of I kappa B inhibited tumor cell invasiveness. Blockade of JNK also significantly reduced invasiveness, but blockade of p38 MAPK or p42 MAPK had no effect. Cocultured tumor cells were screened for the expression of 22 genes associated with inflammation and invasion that also contained an AP-1 and NF-kappa B binding site. EMMPRIN and MIF were up-regulated in cocultured tumor cells in a JNK- and NF-kappa B-dependent manner. Knocking down either MIF or EMMPRIN by RNAi in the tumor cells significantly reduced tumor cell invasiveness and matrix metalloprotease activity in the coculture supernatant. We conclude that TNF-alpha, via NF-kappa B, and JNK induces MIF and EMMPRIN in macrophage to tumor cell cocultures and this leads to increased invasive capacity of the tumor cells.
机构:
Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Arnott, CH
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Scott, KA
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Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Scott, KA
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Moore, RJ
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Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Moore, RJ
;
Robinson, SC
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Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Robinson, SC
;
Thompson, RG
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Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Thompson, RG
;
Balkwill, FR
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Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
机构:Univ Sheffield, Sch Med, Div Genom Med, Tumor Targeting Grp, Sheffield S10 2RX, S Yorkshire, England
Bingle, L
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Brown, NJ
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机构:Univ Sheffield, Sch Med, Div Genom Med, Tumor Targeting Grp, Sheffield S10 2RX, S Yorkshire, England
Brown, NJ
;
Lewis, CE
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Univ Sheffield, Sch Med, Div Genom Med, Tumor Targeting Grp, Sheffield S10 2RX, S Yorkshire, EnglandUniv Sheffield, Sch Med, Div Genom Med, Tumor Targeting Grp, Sheffield S10 2RX, S Yorkshire, England
机构:
Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Arnott, CH
;
Scott, KA
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h-index: 0
机构:
Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Scott, KA
;
Moore, RJ
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h-index: 0
机构:
Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Moore, RJ
;
Robinson, SC
论文数: 0引用数: 0
h-index: 0
机构:
Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Robinson, SC
;
Thompson, RG
论文数: 0引用数: 0
h-index: 0
机构:
Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
Thompson, RG
;
Balkwill, FR
论文数: 0引用数: 0
h-index: 0
机构:
Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, EnglandBarts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England
机构:Univ Sheffield, Sch Med, Div Genom Med, Tumor Targeting Grp, Sheffield S10 2RX, S Yorkshire, England
Bingle, L
;
Brown, NJ
论文数: 0引用数: 0
h-index: 0
机构:Univ Sheffield, Sch Med, Div Genom Med, Tumor Targeting Grp, Sheffield S10 2RX, S Yorkshire, England
Brown, NJ
;
Lewis, CE
论文数: 0引用数: 0
h-index: 0
机构:
Univ Sheffield, Sch Med, Div Genom Med, Tumor Targeting Grp, Sheffield S10 2RX, S Yorkshire, EnglandUniv Sheffield, Sch Med, Div Genom Med, Tumor Targeting Grp, Sheffield S10 2RX, S Yorkshire, England