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First published online August 3, 2005
doi: 10.1242/10.1242/jcs.02467

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Tumour necrosis factor confers an invasive, transformed phenotype on mammary epithelial cells

¹ Department of Cell Physiology and Metabolism, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland
² Institute of Physiological Chemistry and Pathobiochemistry, Münster University Hospital, Münster 48149, Germany

^* Author for correspondence (e-mail: roberto.montesano{at}medecine.unige.ch)

Accepted 3 May 2005

Although loss of cell-cell adhesion and gain of invasive properties play a crucial role in the malignant progression of epithelial tumours, the molecular signals that trigger these processes have not been fully elucidated. In light of the well-established relationship between chronic inflammation and cancer, we hypothesized that pro-inflammatory cytokines disrupt epithelial-cell adhesion and promote cell migration. To test this hypothesis, we used an in vitro model in which 31EG4-2A4 mouse mammary epithelial cells grown in a collagen gel form compact spheroidal colonies. Among the several cytokines examined, tumour necrosis factor (TNF-) caused a pronounced 3D scattering of preformed epithelial-cell colonies and induced 31EG4-2A4 cells grown on top of a collagen gel to invade the underlying matrix. In addition, TNF- abolished contact-mediated inhibition of cell proliferation and stimulated cell growth both in the absence of exogenous mitogens and under anchorage-independent conditions. TNF- induced the expression of matrix metalloproteinase 9 (MMP-9). Addition of the MMP inhibitor BB-94 abrogated TNF--induced 3D scattering. TNF- also enhanced the attachment of 31EG4-2A4 cells to type-I collagen and markedly increased the expression of the 2 integrin subunit. Addition of a blocking antibody to ß1-integrin or of rhodocetin (a specific 2ß1 antagonist) to collagen-gel cultures abrogated 3D scattering. Collectively, these results demonstrate an essential role for MMPs and 2ß1 integrin in the invasive response of 31EG4-2A4 cells to TNF-. We propose that the biological activities described in this study contribute to the ability of TNF- to promote tumour progression and cancer-cell dissemination.

Key words: Cytokine, Migration, Invasion, Transformation, Integrin