Carcinogenesis Advance Access published online on March 25, 2004
Carcinogenesis, doi:10.1093/carcin/bgh146
© 2004 by Oxford University Press
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CARCINOGENESIS
1 Dept of Haematology/Oncology, Georg-August-University, Göttingen, Germany
* Corresponding author. E-mail: cbinder{at}med.uni-goettingen.de.
Received 25 December 2003
; revised 2 March 2004
; accepted 7 March 2004
Apart from the neoplastic cells, malignant tumours consist of the extracellular matrix 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 TNF-® antibodies reduced invasiveness to basal levels. As shown by zymography, all cell lines produced low amounts of MMP-2, -3, -7, -9 under control conditions. Basal MMP production by macrophages was significantly higher. Upon co-incubation, supernatant levels of MMPs-2, -3, -7, -9 increased significantly, paralleled by an increase of MMP-2 activation. MMP-2, -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 upregulated 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.
invasion, tumour associated macrophages, breast cancer, co-culture, matrix metalloproteases, TNF-®
Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-® dependent upregulation of matrix metalloproteases
2 Cancer Research Institute, Depts of Laboratory Medicine, Pathology, and Comprehensive Cancer Center, University of California, San Francisco, USA
3 Cancer Research UK Translational Oncology Laboratory, Barts and The London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London, UK
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