Scientific article
Open access

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

Published inJournal of cell science, vol. 118, no. Pt 15, p. 3487-3500
Publication date2005

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 alpha (TNF-alpha) 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-alpha abolished contact-mediated inhibition of cell proliferation and stimulated cell growth both in the absence of exogenous mitogens and under anchorage-independent conditions. TNF-alpha induced the expression of matrix metalloproteinase 9 (MMP-9). Addition of the MMP inhibitor BB-94 abrogated TNF-alpha-induced 3D scattering. TNF-alpha also enhanced the attachment of 31EG4-2A4 cells to type-I collagen and markedly increased the expression of the alpha2 integrin subunit. Addition of a blocking antibody to beta1-integrin or of rhodocetin (a specific alpha2beta1 antagonist) to collagen-gel cultures abrogated 3D scattering. Collectively, these results demonstrate an essential role for MMPs and alpha2beta1 integrin in the invasive response of 31EG4-2A4 cells to TNF-alpha. We propose that the biological activities described in this study contribute to the ability of TNF-alpha to promote tumour progression and cancer-cell dissemination.

  • Animals
  • Cell Line
  • Cell Movement/drug effects
  • Cell Proliferation/drug effects
  • Collagen/metabolism
  • Epithelial Cells/cytology/drug effects/metabolism
  • Extracellular Matrix/metabolism
  • Integrin alpha2beta1/metabolism
  • Mammary Glands, Animal/cytology/drug effects/metabolism
  • Metalloproteases/antagonists & inhibitors/metabolism
  • Mice
  • Phenotype
  • Protease Inhibitors/pharmacology
  • Receptors, Tumor Necrosis Factor, Type I/metabolism
  • Tumor Necrosis Factor-alpha/pharmacology
Citation (ISO format)
MONTESANO, Roberto et al. Tumour necrosis factor alpha confers an invasive, transformed phenotype on mammary epithelial cells. In: Journal of cell science, 2005, vol. 118, n° Pt 15, p. 3487–3500. doi: 10.1242/jcs.02467
Main files (1)
Article (Accepted version)
ISSN of the journal0021-9533

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