Carcinogenesis Advance Access originally published online on March 25, 2004
Carcinogenesis 2004 25(8):1543-1549; doi:10.1093/carcin/bgh146
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Carcinogenesis vol.25 no.8 © Oxford University Press 2004; all rights reserved.
ARTICLE |
Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-
dependent up-regulation of matrix metalloproteases
1 Department of Haematology/Oncology, Georg-August-University, Göttingen, Germany, 2 Cancer Research Institute, Departments of Laboratory Medicine, Pathology, and Comprehensive Cancer Center, University of California, San Francisco, USA and 3 Cancer Research UK Translational Oncology Laboratory, Barts and The London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, UK
4 To whom correspondence should be addressed Email: cbinder{at}med.uni-goettingen.de
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-
) 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- antibodies. Co-culture of macrophages and hTERT-HME1 did not lead to MMP induction. In the co-cultures, mRNAs for MMPs and TNF- 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- dependent MMP induction in the macrophages.
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