Chronic inflammation in cancer development

Abstract

Chronic inflammatory mediators exert pleiotropic effects in the development of cancer. On the one hand, inflammation favors carcinogenesis, malignant transformation, tumor growth, invasion, and metastatic spread; on the other hand inflammation can stimulate immune effector mechanisms that might limit tumor growth. The link between cancer and inflammation depends on intrinsic and extrinsic pathways. Both pathways result in the activation of transcription factors such as NF-κB, STAT-3, and HIF-1 and in accumulation of tumorigenic factors in tumor and microenvironment. STAT-3 and NF-κB interact at multiple levels and thereby boost tumor-associated inflammation which can suppress anti-tumor immune responses. These factors also promote tumor growth, progression, and metastatic spread. IL-1, IL-6, TNF, and PGHS-2 are key mediators of an inflammatory milieu by modulating the expression of tumor-promoting factors. In this review we concentrate on the crucial role of pro-inflammatory mediators in inflammation-driven carcinogenesis and outline molecular mechanisms of IL-1 signaling in tumors. In addition, we elucidate the dual roles of stress proteins as danger signals in the development of anti-cancer immunity and anti-apoptotic functions.

Keywords: IL-1; NF-κB; STAT-3; carcinogenesis; heat shock proteins; inflammation; tumorigenic factors.

Figure 1

IL-1 signaling in the tumor microenvironment. IL-1 is a critical molecule in inflammation-associated carcinogenesis produced directly by tumor cells or cells of the tumor microenvironment. IL-1 signal transduction is initiated by binding of either form of IL-1 to IL-1 receptor type I (IL-1RI), which undergoes a conformational change allowing the IL-1 receptor accessory protein (IL-1RAcP) to recognize the ligated IL-1RI. IL-1RAcP does not recognize IL-1 but represents an essential component in the IL-1 signaling pathway (Wesche et al., ; Radons et al., 2002). The naturally occurring IL-1 receptor antagonist (IL-1Ra) also binds to IL-1RI without leading to its activation. Ligand-mediated heterodimerization of the receptor complex leads to recruitment of dimeric myeloid differentiation protein 88 (MyD88) via its TIR domain (Muzio et al., ; Wesche et al., ; Radons et al., 2003) followed by complex formation between IRAK-4, MyD88, and IL-1RAcP and subsequent phosphorylation of IRAK-4 (Cahill and Rogers, 2008). After recruitment of IRAK-1/Tollip to the complex, IRAK-1 is initially phosphorylated by IRAK-4 (Born et al., ; Dunne and O’Neill, 2003). Subsequently, IRAK-1 (and possibly IRAK-2) becomes hyperphosphorylated and dissociates into the cytoplasm where it binds TNF receptor-associated factor 6 (TRAF-6; Cao et al., 1996). IRAK-1 interacts with membrane-bound TAK-binding protein 2 (TAB-2) as well as TAK-1/TAB-1 complex (Dower and Qwarnstrom, 2003) followed by translocation of TAB-2 from the plasma membrane to the signalosome and subsequent partial activation of TAK-1 by TAB-2. IRAK-1, presumably as dimer or oligomer, enables dimerization of TRAF-6 resulting in its ubiquitination and activation. In close proximity to TAB-2, TAK-1 is partially activated followed by complete activation through polyubiquitinated TRAF-6 (Kishimoto et al., ; Martin and Wesche, 2002) enabling activation of numerous signaling cascades. Polyubiquitination of TRAF-6 obviously occurs through IRAK-2 (Keating et al., 2007). On the one hand, TAK-1 activates certain members of the MAP kinase family leading to activation of AP-1 and ATF (Ninomiya-Tsuji et al., ; O’Neill, ; Hefler et al., ; Blanco et al., 2008) the latter augmenting NF-κB-mediated transcription via transactivation (Jefferies and O’Neill, ; Cahill and Rogers, 2008). On the other hand, TAK-1 phosphorylates and activates IKK resulting in phosphorylation and inactivation of IκBα (Wang et al., 2001). Afterward, IκBα dissociates from the complex with NF-κB and undergoes proteasomal degradation. After phosphorylation, NF-κB translocates to the nucleus and activates NF-κB-dependent gene transcription (Chen and Greene, 2004). Inhibitors of NF-κB activation are indicated that suppress the inflammatory network in cancer development. IL-1 signaling also involves recruitment of PI3-kinase (PI3K) to the IL-1 receptor complex via the p85 regulatory subunit of PI3K (Reddy et al., 1997) and subsequent activation of AKT/PKB leading to IKK-dependent activation of NF-κB and AP-1 (Cahill and Rogers, 2008). Receptor ligation can also activate numerous G proteins resulting in activation of AP-1 and ATF mediated by several MAP kinases and an IκBα-independent transactivation of NF-κB (Singh et al., ; Jefferies and O’Neill, 2000). IL-1 signaling finally regulates gene expression of a great variety of tumorigenic factors including pro-angiogenic factors (IL-8, VEGF), growth factors (IL-6, GM-CSF), anti-apoptotic factors (Bcl-X_L, c-FLIP), invasion-promoting factors (MMP-2, MMP-7, MMP-9, uPA), inflammatory enzymes (PGHS-2, LOX), prostaglandins, iNOS, chemokines (CCL2, CCL20, IL-8), and pro-inflammatory cytokines (IL-1, IL-6, IL-23, TNF, TGF-β, EGF, RANKL).

Figure 2

Interactions of inflammatory mediators in tumor cells. Schematical simplified representation of the complex intracellular signaling network in cancer. Among the tumorigenic factors produced by tumor cells or cells of the tumor microenvironment, IL-1, TNF, and IL-6 act as crucial mediators of inflammation-driven tumorigenesis. In particular IL-1 and TNF are major pleiotropic cytokines involved in tumor/host interactions. Nevertheless, these cytokines function as autocrine growth factors and modulate the expression of several tumorigenic factors at any stage of tumorigenesis not only affecting proliferation, migration, and survival of tumor cells but also angiogenesis, invasiveness, metastasis as well as chemoresistance of tumors.