Author(s): Fran Balkwill [1]; Lisa M. Coussens [2]
Inflammation is central to our fight against pathogens, but if it is not ordered and timely, the resulting chronic inflammation can contribute to diseases such as arthritis, heart attacks and Alzheimer's disease. A functional link between chronic inflammation and cancer has also long been suspected [1, 2]: population-based studies show that susceptibility to cancer increases when tissues are chronically inflamed; and long-term use of non-steroidal anti-inflammatory drugs reduces the risk of several cancers [3]. Moreover, most solid tumours contain many non-malignant cells, including immune cells and blood-vessel cells, that are important in inflammation. But the crucial molecular pathways that permit communication between abnormally growing cancer cells and these inflammatory cells remain unknown. A complex network of pro-inflammatory mediators is probably involved, because deletion of certain key molecules can reduce cancer susceptibility in mice [1, 2, 4]. Two mouse models of inflammation-associated cancer now implicate the gene-transcription factor NF-κB and the inflammatory mediator known as tumour-necrosis factor-α (TNF-α) in cancer progression [5, 6].
Using a mouse model of inflammatory hepatitis that predisposes mice to liver cancers, Pikarsky <pres:italics>et al</pres:italics> . [5], writing on page 461 of this issue, present evidence that the survival of hepatocytes -- liver cells -- and their progression to malignancy are regulated by NF-κB. (NF-κB is an important transcription factor that controls cell survival by regulating programmed cell death, proliferation and growth arrest.) Moreover, Pikarsky <pres:italics>et al </pres:italics> . find that the activation state of NF-κB, and its localization in the cell, can be controlled by TNF-α produced by neighbouring inflammatory cells (known collectively as stromal cells). Greten <pres:italics>et al </pres:italics> . [6], reporting in <pres:italics>Cell</pres:italics> , come to a similar conclusion by studying a mouse colitis-associated cancer model. Their work does not directly implicate TNF-α, but instead found enhanced production of several pro-inflammatory mediators ('cytokines'), including TNF-α, in the tumour microenvironment during the development of cancer.
An important feature of both studies is that NF-κB activation was selectively ablated in different cell compartments in developing tumour masses, and at different stages of cancer development. These approaches offer new insight into the differential regulation of pre-malignant and malignant states by inflammation and NF-κB in distinct cellular compartments.
In Pikarsky and colleagues' inflammation-associated model of liver cancer [5], TNF-α, produced by stromal cells, activated NF-κB in adjacent hepatocytes that were undergoing 'transformation' into malignant cells. Selective deletion of NF-κB in hepatocytes, or inhibition...