Journal Article

Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-α dependent up-regulation of matrix metalloproteases

Thorsten Hagemann, Stephen C. Robinson, Matthias Schulz, Lorenz Trümper, Frances R. Balkwill and Claudia Binder

in Carcinogenesis

Volume 25, issue 8, pages 1543-1549
Published in print August 2004 | ISSN: 0143-3334
Published online August 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh146
Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-α dependent up-regulation of matrix metalloproteases

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Apart from the neoplastic cells, malignant tumours consist of the extracellular matrix (ECM) and normal cells, in particular tumour-associated macrophages (TAM). To understand the mechanisms by which TAM can influence tumour cell invasion we co-cultured the human breast cancer cell lines MCF-7, SK-BR-3 and the benign mammary epithelial cell line hTERT-HME1 with macrophages. Co-incubation enhanced invasiveness of the tumour cells, while hTERT-HME1 remained non-invasive. Addition of the broad-spectrum matrix metalloprotease (MMP)-inhibitor FN 439, neutralizing MMP-9 or tumour necrosis factor-alpha (TNF-α) antibodies reduced invasiveness to basal levels. As shown by zymography, all cell lines produced low amounts of MMP-2, -3, -7 and -9 under control conditions. Basal MMP production by macrophages was significantly higher. Upon co-incubation, supernatant levels of MMPs -2, -3, -7 and -9 increased significantly, paralleled by an increase of MMP-2 activation. MMP-2 and -9 induction could be blocked by TNF-α antibodies. Co-culture of macrophages and hTERT-HME1 did not lead to MMP induction. In the co-cultures, mRNAs for MMPs and TNF-α were significantly up-regulated in macrophages, while the mRNA concentrations in the tumour cells remained unchanged. In summary, we have found that co-cultivation of tumour cells with macrophages leads to enhanced invasiveness of the malignant cells due to TNF-α dependent MMP induction in the macrophages.

Keywords: ECM, extracellular matrix; MMP, matrix metalloprotease; TAM, tumour-associated macrophages; TNF-α, tumour necrosis factor-alpha

Journal Article.  5060 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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