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The Oncologist, Vol. 11, No. 1, 83-84, January 2006; doi:10.1634/theoncologist.11-1-83
© 2006 AlphaMed Press

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Fundamentals of Cancer Medicine

The Molecular Perspective: Tumor Necrosis Factor

David S. Goodsell

Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Web site: http://www.scripps.edu/pub/goodsell

Received November 10, 2005; accepted for publication November 10, 2005.


   LEARNING OBJECTIVE
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 Learning Objective
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After completing this course, the reader will be able to:

  1. Discuss tumor necrosis factor and its role in cancer chemotherapy.

Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com

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 1Go, 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.



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  		Figure 1. TNF (red) is composed of three identical chains. It brings together three receptor proteins (blue), initiating the cascade of signals inside the cell. The intracellular portion of the receptor contains a "death domain," which interacts with the death domain of the protein TRADD (light blue). This, in turn, recruits multiple proteins such as TRAF2 (green), which together decide on the proper response: apoptosis, inflammation, or survival. Three crystallographic structures from the PDB (http://www.pdb.org) were used in this illustration: PDB entry 1 tnr for TNF and the extracellular part of the receptor, PDB entry 1f3v for TRADD and TRAF2, and PDB entry 1d2z to show the interaction between two death domains. Abbreviations: PDB, Protein Data Bank; TNF, Tumor necrosis factor; TRADD, TNF receptor-associated death domain; TRAF2, TNF receptor-associated factor 2.

 
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.

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. 2Go) 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.



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  		Figure 2. TRAIL (right, in red) and tumor necrosis factor (left, in red) are both composed of three subunits. TRAIL binds to three separate copies of the death receptor (blue), initiating the apoptosis cascade inside the target cell. Atomic coordinates were taken from Protein Data Bank entries 1tnr and 1d0g. Abbreviation: TRAIL, Tumor necrosis factor-related apoptosis-inducing ligand.

 

   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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The author indicates no potential conflicts of interest.


   ADDITIONAL READING
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 Learning Objective
 Disclosure of Potential...
 Additional Reading
 

    1 Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2002;2:420–430.[CrossRef][Medline]

    2 Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001;11:372–377.[CrossRef][Medline]

    3 Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science 2002;296:1634–1635.[Abstract/Free Full Text]





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