NF-κB in Tumorigenesis, or not?

Inflammation has been implicated in tumor promotion and progression in a number of cancers. In many cases, tumorigenesis has been linked to chronic infection. For instance, HBV or HCV infection has been shown to be a major risk factor for hepatocellular carcinoma. Nuclear Factor kappaB (NF-κB) is known to play a key role in the response to infectious agents by stimulating the immune response through regulation of pro-inflammatory cytokine genes. In addition, NF-κB has been shown to regulate many genes that are implicated in cancer. Some of these genes include cell-cycle regulators, genes involved in apoptosis, and proteases which have been shown to increase metastases.

In prostate tumorigenesis, NF-κB has been shown to induce secretion of IL-1 from infiltrating macrophages. In prostate cells, IL-1 causes the conversion of androgen antagonists to agonists. Increased androgen activity in the prostate has been shown to promote tumor formation.

NF-B has also been shown to inhibit tumor progression in females. Kupffer cells (a type of macrophage) present in response to cellular damage in the liver, release IL-6 which acts as a pro-growth and inflammation signal in neighboring cells. Prolonged exposure to IL-6 in the liver has been correlated with cancer formation. In Kupffer cells, estrogen acts as a suppressor of IL-6 by activating NF-B which then down-regulates this cytokine. Therefore, pre-menopausal women that produce a fair amount of estrogen have a much lower risk of developing hepatocellular carcinoma. NF-B activation has also been shown to have antiapoptotic effects in gastric cancer cells, though the mechanism is not so clear.

NF-B can be expressed in just about every cell type and can be activated by a number of pathways. Each pathway has the ability to cause NF-κB to target different subsets of genes. The ability of different signals to induce NF-κB targeting toward pro-cancerous or anti-cancerous genes is an interesting observation and should be considered when therapeutics are designed. Most NF-κB related therapies which are currently in clinical trials, aim to inhibit its regulation, which could have profound effects on the recipients immune system. Instead of inhibiting NF-κB, should we instead try to change its targets from less favorable to more positive ones? One example is the ability of estrogen receptor (ER) to target genes through NF-κB. Estrogen receptor normally activates or represses genes by binding directly to target genes that contain estrogen response elements. When ER binds certain ligands, it can also bind to and activate NF-κB, which leads to activation of NF-κB target genes. Estrogens are thought to elicit some of their pro-inflammatory effects in this way. Is it possible that, if exploited, this ER-NF-κB interaction can lead to an overall positive outlook for cancer patients? Can some other pathway that leads to NF-κB activation give a positive outlook? Since NF-κB controls so many genes (good or bad depending on context), should it even be considered as a target for therapy?

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