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Discuss tumor necrosis factor and its role in cancer chemotherapy.
Scientific research often advances with serendipitous observations that lead to entirely new avenues of discovery. The story of Alexander Fleming’s discovery of lysozyme is a classic example. The path of discovery of tumor necrosis factor (TNF) began over a century ago, with the observation by Brunes that some of his cancer patients showed a spontaneous regression of tumors after they had acute bacterial infections. After decades of study, this compelling observation led to the discovery of TNF: a multifunctional signaling molecule with important roles in inflammation and apoptosis.
TNF is composed of three identical protein chains. The trimeric shape of TNF is the key to its activity. As shown in Figure 1, TNF brings three copies of the TNF receptor together, initiating a cascade of signaling interactions inside the target cell. TNF is found in two forms. When synthesized, TNF is bound to the cell membrane through a short transmembrane segment. It is then released by a membrane-bound metalloproteinase to give the soluble form. Both forms are active, so signals may be passed locally from cell to cell using TNF anchored to the cell surface, or more widely, by release of the soluble form.
Nearly all human cells display receptors for TNF on their surfaces. Their responses to TNF, however, can be very different, depending on the current state of each cell. In some cases, TNF signaling is used for defense against infection. TNF can direct a virus-infected cell to destroy itself by apoptosis, and the presence of lipopolysaccharide on bacterial surfaces stimulates blood cells to release TNF, which promotes an inflammatory response to fight the infection. In other cases, TNF signaling is used for the day-to-day remodeling of tissues. For instance, TNF on blood cell surfaces, through direct contact between cells, promotes the proliferation of lymphocytes in some cases and, in other cases, forces them into apoptosis. Because TNF plays such diverse and often contradictory roles, a careful balance must be kept at all times to ensure that TNF is applied only when and where it is needed. When this control is lost, it can lead to severe inflammatory illnesses such as septic shock and arthritis.2367
The multiple roles played by TNF have lead to an unusual medical paradox: in some cases, the desired treatment requires an overactive TNF, and in other cases, the treatment inhibits its action. Because it plays a pivotal role in inflammation, inhibitors of TNF are effective for the treatment of diseases like Crohn’s disease and rheumatoid arthritis. In these cases, an antibody or a soluble form of the receptor is used to block the signaling pathway, reducing the inflammatory response. In cancer therapy, however, the goal is to kill tumor cells, and we seek to enhance the apoptotic signals carried by TNF. Application of soluble TNF leads to the reduction of tumors by directly attacking tumor cells and through damage of tumor blood vessels. Unfortunately, TNF is far too toxic to be administered as a systemic drug.
TNF is part of a large family of cytokines. Like TNF, they are trimeric proteins that bring together three receptor molecules to initiate their signals. Most, however, have far more focused activities, specializing in one type of signal. Some, such as lymphotoxin, are involved in the development of blood cells. Others, such as TNF-related apoptosis-inducing ligand (TRAIL) (Fig. 2) and FasL, specialize in apoptosis. New therapies are being designed using these specialist molecules to attack cancer cells while sparing normal tissues and reducing dangerous side effects.
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The author indicates no potential conflicts of interest.
ADDITIONAL READING
1 Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2002;2:420–430.
2 Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001;11:372–377.
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