Interleukin-6 and prostate cancer: Current developments and unsolved questions

https://doi.org/10.1016/j.mce.2017.03.012Get rights and content

Highlights

  • IL-6 exerts oncogenic effects in most prostate cancers and activates multiple signaling pathways.

  • Therapeutic intervention is based on inhibition of IL-6 itself or the STAT3 pathway.

  • Translation of experimental therapy studies has a very limited success.

  • Future experimental anti-IL-6 and anti-STAT3 therapies may target stem cells.

Abstract

Interleukin (IL)-6 is a pro-inflammatory cytokine that is expressed in prostate tumors and in the stromal tumor micro-enviroment. It is known to regulate proliferation, apoptosis, angiogenesis, and differentiation. The signaling pathway of Janus kinase and signal transducer and activator of transcription (STAT)3, which is activated by IL-6, is in the focus of scientific investigations for improved treatment approaches. Different effects of IL-6 and/or STAT3 on tumor cell growth have been observed in human and murine prostate cancer (PCa) models. Experimental therapies have been proposed in order to block the IL-6/STAT3 signaling pathway. In this context, the anti-IL-6 antibody siltuximab (CNTO 328) has been demonstrated to inhibit growth of prostate tumors in vitro and in vivo and delays progression towards castration resistance. However, clinically, the anti-IL-6 antibody was not successful as a monotherapy in phase II studies in patients with metastatic PCa. IL-6 is implicated in regulation of cellular stemness by increasing phosphorylation of STAT3. The cytokine has also a role in development of resistance to the non-steroidal anti-androgen enzalutamide. Endogenous inhibitors of IL-6 are suppressors of cytokine signaling and protein inhibitors of activated STAT. Although they inhibit signal transduction through STAT3, they may also exhibit anti-apoptotic effects. On the basis of complexity of IL-6 action in PCa, an individualized approach is needed to identify patients who will benefit from anti-IL-6 therapy in combination with standard treatments.

Introduction

Recent investigations have resulted in identification of a large number of potential targets for prostate cancer (PCa) therapy. Although established therapies target the androgen receptor (AR) or elements of the AR signaling pathway, it is clear that several molecules regulated by cytokines contribute to growth at different stages of prostate carcinogenesis. The oncogenic role of inflammatory cytokines has been studied in PCa in different human and animal models and experimental settings. In most studies, signal transduction and effects on proliferation and apoptosis by interleukin (IL)-6, −8, and −4 have been investigated. The role of IL-6 in PCa is particularly interesting because of its association with multiple signaling pathways, as well as different regulation of proliferative and apoptotic responses. Thus, there is great potential for therapeutic intervention. Although results of preclinical research have provided encouraging data related to potential anti-IL-6 strategies, translation of these findings into clinical practice is still associated with considerable difficulties. Recent studies have therefore focused on the role of endogenous inhibitors of cytokine signaling in PCa. In this review, these topics will be primarily addressed and discussed. Basic knowledge of IL-6 signal transduction and regulation of cellular events in PCa have been summarized previously (Culig and Puhr, 2012). A central role in regulation of the inflammatory responses in PCa could be attributed to signal transducer and activator of transcription (STAT) factor-3. It is regulated not only in response to IL-6, but also by other cytokines such as IL-11 and epidermal growth factor (EGF) in the tumor and in the tumor micro-environment. In this updated review, we analyze recent developments in the field and discuss problems as well as perspectives of IL-6 targeted PCa therapies.

Section snippets

IL-6: a therapeutic target or tumor suppressor in PCa

Prostate carcinogenesis and progression are determined by the presence and activation status of the AR. Its activation in normal and pathological conditions can be potentiated by numerous co-activators that interact with one or more domains of the receptor. AR expression is increased in castration resistant PCa (CRPC) due to gene amplification or protein stabilization. Mutant receptors may be activated by various steroids and anti-hormones, thus contributing to accelerated tumor growth.

IL-6 and AR activation

PCa progression is dependent on an active role of the AR. For example, a derivative of LNCaP, C4-2 cells, exhibit high levels of AR although they cannot be regulated by androgenic hormones. Many investigators focused on expression and activation of truncated AR which is constitutively active thus contributing to failure of treatment with inhibitors of androgen synthesis and 2nd generation anti-androgens. Among other mechanisms, ligand-independent activation of the AR has been intensively

IL-6 in regulation of PCa stemness

It is widely accepted that tumor-initiating cells with stem cell characteristics are associated with therapy resistance, as they can not be targeted by conventional endocrine, chemo- or radiotherapies. Their function has to be analyzed in appropriate cellular models, some of which are being developed. Because of a rare appearance of stem or “stem cell like” cells, it is difficult to precisely quantify them in tumor samples. In prostate and in other malignancies, the signaling pathway of Janus

Translational anti-IL-6 therapies in PCa

Therapeutic approaches in PCa could be focused on IL-6 itself, the JAK/STAT3 pathway, or specifically STAT3. The outcome of these different therapies may not necessarily be the same and depends on interaction with other pathways as well as on drug pharmacokinetics and pharmacodynamics.

Several laboratories tested the monoclonal antibody CNTO 328 (siltuximab) for a potential anti-IL-6 approach so far. PC3 and DU145 cells, which express high levels of the cytokine, could be inhibited in vitro and

Endogenous inhibitors of cytokine signaling

Persistent activation of STAT3 in target tissues could be prevented by endogenous inhibitors of cytokine signaling. They are known as suppressors of cytokine signaling (SOCS) or protein inhibitors of activated STAT (PIAS). SOCS are rapidly induced by cytokines and may achieve their action at different levels. There are substantial differences in SOCS3 expression between AR-positive and –negative cells. In AR-negative cells, a high expression of SOCS3 could be explained by endogenous IL-6

Challenges for future research

Although results of preclinical studies with the anti-IL-6 antibody siltuximab suggested that IL-6 and downstream signaling pathways should be targeted in PCa, translation of these findings in clinic has been associated with difficulties. Several issues have to be addressed in order to improve IL-6 targeted therapy. Biomarkers that may allow selection of patients who may benefit are still not available. Critical issues related to this novel therapy are appropriate selection of patients and

Declaration of interest

The authors do not have a conflict of interest in relation to preparation of this article.

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