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

Author:

Montesano Roberto1,Soulié Priscilla1,Eble Johannes A.2,Carrozzino Fabio1

Affiliation:

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

Abstract

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 α (TNF-α) 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-α abolished contact-mediated inhibition of cell proliferation and stimulated cell growth both in the absence of exogenous mitogens and under anchorage-independent conditions. TNF-α induced the expression of matrix metalloproteinase 9 (MMP-9). Addition of the MMP inhibitor BB-94 abrogated TNF-α-induced 3D scattering. TNF-α also enhanced the attachment of 31EG4-2A4 cells to type-I collagen and markedly increased the expression of the α2 integrin subunit. Addition of a blocking antibody to β1-integrin or of rhodocetin (a specific α2β1 antagonist) to collagen-gel cultures abrogated 3D scattering. Collectively, these results demonstrate an essential role for MMPs and α2β1 integrin in the invasive response of 31EG4-2A4 cells to TNF-α. We propose that the biological activities described in this study contribute to the ability of TNF-α to promote tumour progression and cancer-cell dissemination.

Publisher

The Company of Biologists

Subject

Cell Biology

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