Signal transduction of inflammatory cytokines and tumor development

Abstract

It has been estimated that >20% of all malignancies are initiated or exacerbated by inflammation. Until recently, the molecular basis of this process has not been clarified. However, recent studies have uncovered the molecular mechanism of intracellular signaling pathways of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and interleukin (IL)-6. Three major transcription factors including NF-kappaB, STAT1 and STAT3 have been shown to play major roles in transmitting inflammatory cytokine signals to the nucleus. One function of NF-kappaB and STAT3 in tumor cells is the promotion of cell growth and cell survival through the induction of target genes, whose products promote cell division and inhibit apoptosis. In addition, NF-kappaB and STAT1 are important transcription factors that induce inflammatory mediators from inflammatory cells, especially macrophages, while STAT3 often antagonizes this process. STAT1 is generally believed to be an anti-oncogene because it promotes apoptosis through p53, but it could promote inflammation-mediated tumor development by enhancing tissue injury, remodeling, fibrosis and inflammation. Hence, the inhibition of NF-kappaB and STATs offers a strategy for treatment of a variety of malignancies and can convert inflammation-induced tumor growth into inflammation-induced tumor regression.

Figure 1

Role of inflammatory cells on tumor development.

Figure 2

Signal transduction pathways of proinflammatory cytokines.

Figure 3

Role of inflammatory transcription factors on tumor development and the mechanism of tumor regression by blocking of NF‐kB or STAT3. (a) Tumor progression state with tumor‐associated inflammation and suppression of antitumor immunity. In tumor cells, STAT3 and NF‐kB are activated via cytokines from myeloid cells and support proliferation and antiapoptosis. This is associated with reduced expression of suppressors of cytokine signaling (SOCS)1 and SOCS3. Reduced STAT1 activation is often associated with highly malignant tumors. In myeloid cells, for growth promoting factor production, NF‐kB, STAT1 and STAT3 usually work positively, while SOCS1 and SOCS3 work negatively. However, in the status of the suppression of antitumor immunity, STAT3 is activated and suppresses NF‐kB and STAT1. Enhanced SOCS1 and reduced SOCS3 expression is associated with this situation. (b) When the NF‐kB pathway is blocked, cytokine production from myeloid cells is blocked and tumor cell apoptosis is accelerated. However, NF‐kB blockage may weaken antitumor immunity. (c) When STAT3 is blocked, tumor cell apoptosis is enhanced and antitumor immunity is reinforced by increasing chemokine production from tumor cells and by enhancing dendritic activation and cytotoxic T cells (CTL) activation. However, this may enhance inflammation which supplies tumor‐promoting factors.