The I kappa B kinase - a bridge between inflammation and cancer

A potential link between inflammation and cancer has been suspected for over a century, but the exact molecular mechanisms connecting the two remained nebulous. We proposed that NF-kappa B transcription factors regulated via the I kappa B kinase (IKK) complex play a critical role in coupling inflammation and cancer and have set out to test this hypothesis in mouse models of cancer. Using mice bearing mutations in the genes coding for the IKK beta and IKK alpha catalytic subunits we obtained evidence supporting a critical role for IKK beta in tumor promotion and more recently identified the involvement of IKK alpha in metastatogenesis. Whereas the major pro-tumorigenic function of IKK beta is mediated via NF-kappa B, the pro-metastatic function of IKK alpha is NF-kappa B-independent. In addition to illustrating the critical roles of the two IKK molecules in linking inflammation and cancer and providing an explanation for increased cancer risk in response to persistent infections and inflammation, these results also identify new targets for development of novel anti-cancer therapies and preventive strategies. Instead of targeting the cancer cell itself, as done by conventional anti-cancer drugs, the new therapeutics will target processes that occur within inflammatory cells that are essential for cancer development and progression. Unlike cancer cells, inflammatory cells retain a normal and stable genome and therefore are unlikely to become genetically resistant to therapeutic intervention.