Review. TNF/VEGF cross-talk in chronic inflammation-related cancer initiation and progression: an early target in anticancer therapeutic strategy.

In the last decade a growing body of epidemiological and clinical data has emerged to support the concept that longstanding inflammation potentiates or promotes tumor development, growth and progression. Among pro-inflammatory gene products involved in such interactions are tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and vascular endothelial growth factors (VEGFs), whose expression is mainly regulated by the transcription nuclear factor (NF)-kappaB. Clinically, several reports have detected abnormally high levels of circulating cytokines in cancer patients, and inflammation is currently being investigated as a target of anticancer therapies. To date three main groups of antiangiogenic drugs approved for clinical use and experimentation can be identified: secreted VEGF inhibitors, tyrosine kinase (TK) inhibitors (mainly VEGFR inhibitors) and drugs that inhibit angiogenesis with a complex mechanism. More recently, TNF-alpha antagonists have become available. The first clinical data on anti-TNF-alpha showed that this drug can be used in cancer patients without major sideeffects. Further investigations are needed to understand if anti-TNF-alpha or NF-kappaB inhibitors may really represent a novel approach in cancer treatment, probably as adjuvant to other therapies, such as anti-angiogenic or cytotoxic agents.