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

Abstract

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-alpha) 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-alpha antibodies. Co-culture of macrophages and hTERT-HME1 did not lead to MMP induction. In the co-cultures, mRNAs for MMPs and TNF-alpha 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-alpha dependent MMP induction in the macrophages.

• Authors: Thorsten Hagemann, Stephen C Robinson, Matthias Schulz, Lorenz Trümper, Frances R Balkwill, Claudia Binder
• Journal: Carcinogenesis (Carcinogenesis) Vol. 25 Issue 8 Pg. 1543-9 (Aug 2004) ISSN: 0143-3334 [Print] England
• PMID: 15044327 (Publication Type: Journal Article)

Chemical References

• Drug Combinations
• Laminin
• Lipopolysaccharides
• Proteoglycans
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• matrigel
• RNA
• Collagen
• Matrix Metalloproteinases
• Matrix Metalloproteinase 3
• Matrix Metalloproteinase 7
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Breast Neoplasms (pathology)
• Cell Line
• Cell Line, Tumor
• Coculture Techniques
• Collagen (pharmacology)
• Densitometry
• Down-Regulation
• Drug Combinations
• Enzyme-Linked Immunosorbent Assay
• Humans
• Laminin (pharmacology)
• Lipopolysaccharides (metabolism)
• Macrophages (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 3 (biosynthesis)
• Matrix Metalloproteinase 7 (biosynthesis)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinases (biosynthesis)
• Neoplasm Invasiveness
• Proteoglycans (pharmacology)
• RNA (metabolism)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Necrosis Factor-alpha (biosynthesis)
• Up-Regulation