Inflammation and cancer: role of nuclear factor-kappaB activation

Abstract

It has been thought that there is a strong relationship between inflammation and carcinogenesis so that the development of cancer occurs with chronic inflammation in many organs. An in-depth understanding of the mechanism by which inflammation can lead to carcinogenesis may enable the development of drugs targeted at important molecules, providing a powerful tool for preventing cancer development. In this review, we focused on a signal transduction system, the nuclear factor-kappaB (NF-kappaB) pathway, which is thought to play a role in the process leading from inflammation to carcinogenesis, and may thus serve as a candidate for targeted intervention.

Figure 1

Nuclear factor‐kappaB (NF‐κB) signaling pathways. BAFF, B cell activating factor belonging to the TNF family; IKK, I kappa B kinase; IL, interleukin; LPS, lipopolysaccharide; LT, lymphotoxin; NIK, NF‐κB‐inducing kinase; TNF, tumor necrosis factor.

Figure 2

Participation of the nuclear factor‐kappaB (NF‐κB) activation in carcinogenesis. NF‐κB activation participates in many processes in carcinogenesis by the expression of various factors controlling inflammation or growth factors. IKK, I kappa B kinase; IL, interleukin; VEGF, vascular endothelial growth factor.

Figure 3

Participation of the nuclear factor‐kappaB (NF‐κB) activation in the Helicobacter pylori (H. pylori) infection and dextran sulfate sodium salt (DSS) colitis models. (a) Hematoxylin–eosin (HE) and phospho‐IκBα stainings of the antrum part 25 weeks after H. pylori infection are shown. By the infection of cag PAI‐negative H. pylori (Δcag) without the activation ability of NF‐κB, degree of the chronic gastritis and phospho‐IκBα staining are extremely slight in comparison with the infection of the wild‐type (WT) (magnification 40 ×). (b) Hematoxylin–eosin (HE) and phospho‐IκBα stainings of the colonic part 10 days after DSS administration are shown. By the treatment of NF‐κB essential modulator (NEMO)‐binding domain (NBD) peptides which inhibit NF‐κB activity, degree of the colitis and phospho‐IκBα staining are extremely slight compared with the absence of NBD peptides (magnification 10 × in HE and 40 × in phospho‐IκBα staining).

Figure 4

Relationship of nuclear factor‐kappaB (NF‐κB) activation to an inflammation cell and a neoplastic cell. NF‐κB‐regulated factors, which are growth factors, inflammatory cytokines, and angiogenic factors are produced in an inflammation cell around the neoplastic cell by bacteria factor, various cytokines, or stress, leading to the proliferation and progression of the neoplastic cell. Furthermore, NF‐κB activation in the neoplastic cell controls expression of antiapoptotic, cell‐cycle associated genes and participates in further malignancy. IKK, I kappa B kinase.