Interleukin-6 Stimulation Of Growth Of Prostate Cancer In Vitro And In Vivo Through Activation Of The Androgen Receptor

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 19 Jan 2009 - 3:00 PDT

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UroToday.com - Among scientists and urologists, there is considerable interest in ligand-independent activation of the androgen receptor (AR), which was first described 14 years ago. Remarkably, many studies were published with cell lines that were transfected with a reporter gene and, in some cases, with AR cDNA and stimulated with growth factors, neuropeptides, and interleukins (IL). It is known that these compounds increase transcriptional activity of the AR in a ligand-independent or synergistic manner.

However, the consequences of these findings for a scientist engaged in translational research are still unclear. It has been assumed that increased expression of AR in many patients with advanced prostate cancer is a result of adaptation to conditions with reduced androgenic concentrations. The most important question that should be answered in this context is whether enhanced AR activation through non-steroidal compounds contributes to tumor growth. It was demonstrated that ErbB2, a molecule that is related to the epidermal growth factor receptor, causes tumor growth in vivo through activation of the AR. The situation with AR-mediated regulation of prostate cancer cells by alternative ligands is rather complex since it is known that some compounds that activate the receptor display multifunctional properties.

Urologists are interested in the role of IL-6 in prostate cancer. IL-6 activation of the AR was first described in LNCaP cells, in which a mutated receptor is expressed. In these cells, IL-6 caused a growth inhibition and induction of expression of prostate-specific antigen. How representative are LNCaP cells for the human prostate cancer? There is no doubt that many experiments with these cells yielded useful information as to hormonal regulation of prostate cancer cell growth. With regard to heterogenity of prostate cancer, it is reasonable to investigate the role of IL-6 in other AR-positive prostate cells, such as LAPC-4 or MDA PCa 2b. LAPC-4 cells express the wild-type AR and MDA PCa 2b the mutated one. The results published by the Culig´s laboratory show that MDA PCa 2b cells respond to IL-6 by growth stimulation and that this effect could be inhibited by bicalutamide.

So there are important clinical implications on the basis of this article; one could assume that selected prostate cancer cells get additional growth stimulation through the IL-6/AR interaction. At present, we can unfortunately not discriminate between patients who will benefit from anti-IL-6 therapy in AR-positive cells and those in whom such treatment is contraindicated. Therefore, we should continue with investigations on IL-6 signalling in prostate cancer. Scientists are beginning to understand the reasons why in some cells there is a specific activation of one of the signalling pathways typical for IL-6. Importantly, a group of endogenous inhibitors of IL-6 signalling, SOCS (suppressors of cytokine signalling), are expressed in most prostate cancer cells. They inhibit signal transduction through the pathway of Janus kinases/signal transducers and activators of transcription, thus preventing chronic inflammation. Interestingly, in prostate cancer these proteins may have a different role, such as inhibition of cAMP- induced apoptosis.

Obviously, the IL-6 network in prostate cancer is very complex and additional studies are required to establish a basis for a more efficient anti-IL-6 therapy. It was demonstrated that the anti-IL-6 antibody CNTO328 has an anti-tumor effect in some prostate cancer xenografts. The findings published by Malinowska and associates may therefore have therapeutic relevance.

Written by Zoran Culig, MD as part of Beyond the Abstract on UroToday.com

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