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Constitutive activation of the CD40 pathway promotes cell transformation and neoplastic growth

Abstract

CD40, a tumour necrosis factor (TNF) receptor family member, is expressed in a variety of cell types, including B lymphocytes, macrophages, fibroblasts, endothelial and epithelial cells, and this widespread expression is likely to account for its central role in normal physiology and disease pathogenesis. In this study, we provide evidence to support a role for constitutive CD40 signalling in cell transformation. We show that the ligand for CD40 (CD40L/CD154) is expressed in CD40-positive human breast tumour biopsies, suggesting that the constitutive activation of the CD40 receptor in vivo may contribute to the oncogenic process. Coexpression of CD40 and CD40L confers oncogenic effects on immortalized human epithelial cells in vitro, increasing their proliferation, motility and invasion. Expression of LMP:CD40, a hybrid molecule comprising the N-terminus and transmembrane domains of the Epstein–Barr virus-encoded latent membrane protein-1 (LMP1) fused to the cytoplasmic tail of CD40, mimics a constitutively active CD40 receptor and promotes the transformation of immortalized rodent fibroblasts in vitro and their oncogenicity in vivo. The observed effects of aberrant CD40 activation on cell transformation are largely diminished upon suppression of the oncogenic NF-κB signalling pathway. Taken together, our results suggest a role for the constitutive engagement of the CD40L/CD40/NF-κB activation pathway in cell transformation and neoplastic growth. Strategies that neutralize this pathway may therefore be useful in cancer treatment and prevention.

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Acknowledgements

We are grateful to Professor Martin Rowe (University of Cardiff, UK) for providing us with reagents, to Marie Smith and David Rowlands (University of Wolverhampton, UK) for the preparation of the breast cancer array and to Liz Hodgkins for technical assistance. This work was supported by a Cancer Research UK grant to AGE and LSY and by a University of Birmingham (UK) PhD studentship to AJB.

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Correspondence to Aristides G Eliopoulos.

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Baxendale, A., Dawson, C., Stewart, S. et al. Constitutive activation of the CD40 pathway promotes cell transformation and neoplastic growth. Oncogene 24, 7913–7923 (2005). https://doi.org/10.1038/sj.onc.1208929

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