Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells.

Katherine L Meyer-Siegler,Erica C Leifheit,Pedro L Vera

doi:10.1186/1471-2407-4-34

Abstract

BackgroundThe importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established. Increased expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) has previously been associated with various types of adenocarcinoma.MethodsMIF IHC was used to localize MIF in human bladder tissue. ELISA and Western blot analysis determined the synthesis and secretion of MIF by human bladder transitional cell carcinoma cells. The effects of MIF inhibitors (high molecular weight hyaluronate (HA), anti-MIF antibody or MIF anti-sense) on cell growth and cytokine expression were analyzed.ResultsHuman bladder cancer cells (HT-1376) secrete detectable amounts of MIF protein. Treatment with HA, anti-MIF antibody and MIF anti-sense reduced HT-1376 cell proliferation, MIF protein secretion, MIF gene expression and secreted inflammatory cytokines. Our evidence suggests MIF interacts with the invariant chain, CD74 and the major cell surface receptor for HA, CD44.ConclusionsThis study is the first to report MIF expression in the human bladder and these findings support a role for MIF in tumor cell proliferation. Since MIF participates in the inflammatory response and bladder cancer is associated with chronic inflammatory conditions, these new findings suggest that neutralizing bladder tumor MIF may serve as a novel therapeutic treatment for bladder carcinoma.

Highlights

The importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established
There was no significant reduction in cell proliferation in nonspecific IgG or migration inhibitory factor (MIF)-sense treated cells indicating that the reduction in cell numbers was not due to either non-specific antibody effects or the transfection protocol, respectively
HT-1376 cells secrete large amounts of hyaluronidase and various proteases [29], the effects of the various treatments on MIF expression and cytokine production were examined at 24 h so as to limit potential confounds associated with hyaluronan degradation and antibody proteolysis

Summary

Introduction

The importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established. According to 2003 estimates, urinary bladder cancer will be diagnosed in 57,400 Americans and will result in 12,500 deaths [1]. Of these new cases, 80 to 90% will originally present as tumors of the epithelium or submucosa, with the majority being transitional cell carcinomas [2,3]. Transurethral resection of bladder tumor remains the initial line of defense in treatment of superficial bladder cancer. This treatment is hardly adequate as the recurrence rate in treated patients approaches 50 to 70% and 5 to 40% of recurrent cancers progress [2,4]. The high rate of mortality associated with invasive urinary bladder cancer and the high incidence of reoccurrence after treatment demonstrate the need for a (page number not for citation purposes)

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