Inflammatory signaling and cellular senescence

Abstract

Inflammation acts as a double-edged sword in the pathogenesis of cancer. Inflammatory responses play a key role in eliminating potentially cancerous cells; however, an inflammatory microenvironment also promotes the development of cancer. Proinflammatory cytokines, the key mediators of inflammation, also play a dual role in oncogenesis. While they can promote neoplastic progression, recent studies have revealed an unexpected function of the inflammatory pathways in inhibiting cancer development. These studies demonstrate that cells undergoing senescence, a cellular program serving as a barrier to cancer development, produce increased amount of inflammatory cytokines. These inflammatory cytokines play an essential role in the initiation and maintenance of cellular senescence, and are responsible for triggering an innate immune response that clears the senescent tumor cells in vivo. The purpose of the present review is to discuss the dual roles of the inflammatory cytokines produced by senescent cells in the pathogenesis of cancer, and the signaling pathway mediating their role in cellular senescence.

Fig. 1

Signaling pathways mediating the dual roles of senescence-associated inflammatory cytokines in cancer development. The senescence stimuli, such as telomere attrition, activated oncogenes, DNA damage, initially activate C/EBPβ, NF-κB, and p38 through mechanisms yet to be identified, leading to increased expression of IL-6. IL-6 in turn induces the expression levels of other inflammatory cytokines and chemokines including those binding to the CXCR2 receptor. The senescence signals also induce the expression level of CXCR2, which is activated in the presence of the increased amount of CXCR2 ligands. The induced CXCR2 activates the senescence effectors, such as p15^INK4B, p16^INK4A and the p53/p21^WAF1 circuit, triggering cellular senescence. Within the pathway, C/EBPβ and IL-6 form a positive feedback loop, as C/EBPβ mediates the increased expression of TL-6, and the induction of C/EBPβ requires TL-6. Moreover, C/EBPβ directly stimulates the transcription of not only IL-6, but also the cytokines that are induced by IL-6. While the function of IL-6 in the execution of senescence is mainly mediated by an autocrine effect, a paracrine pathway at least partly contributes to the role of IL-8 and other CXCR2 ligands in senescence. The inflammatory cytokines secreted to the extracellular compartment by senescent cells also have paracrine functions. They mediate the clearance of tumors by recruiting host immune cells to tumor tissues. In addition, the inflammatory cytokines provide a cancer-promoting microenvironment for nearby tumors by enhancing angiogenesis, tumor cell proliferation and survival, and tumor invasion and metastasis.