¹Department of Haematology, Royal Liverpool University Hospital, Level 2 Ducan Building, Prescot Street, Liverpool, Merseyside L7 8XP, UK

Correspondence: AR Pettitt, E-mail: andrew.pettitt@rlbuht.nhs.uk

Received 7 March 2005; Revised 31 May 2005; Accepted 3 June 2005; Published online 15 August 2005.

Abstract

p53 is the most frequently inactivated gene in human cancers, reflecting its pivotal role in maintaining genomic integrity. The present study was conducted to explore the possibility that tumour cells with no intrinsic defects of the p53 pathway might nevertheless acquire p53 dysfunction through extrinsic suppression of the pathway by microenvironmental factors. Neoplastic cells from patients with chronic lymphocytic leukaemia (CLL) were cultured in the presence or absence of basic fibroblast growth factor (bFGF) and exposed to ionizing radiation (IR) to induce p53 accumulation. bFGF is greatly increased in the plasma of CLL patients and can suppress p53 activation in some experimental models. IR induced a marked increase in p53 levels in 28 samples from 24 patients. bFGF inhibited IR-induced p53 accumulation to some extent in most of these samples and by more than 50% in seven samples from seven patients. Suppression of p53 activation by bFGF was frequently but not always accompanied by upregulation of the p53-inhibitory protein MDM2 and/or phosphorylation of MDM2 at serine 166, and was associated with impaired transcriptional activation of the p53 target gene p21. These observations provide the first demonstration in human cancer cells that the p53 pathway can be suppressed by factors in the tumour-cell microenvironment.