This Article Full Text Full Text (PDF) eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Horssen, R. Articles by Eggermont, A. M. M. Search for Related Content PubMed PubMed Citation Articles by van Horssen, R. Articles by Eggermont, A. M. M.

Sarcomas

TNF- in Cancer Treatment: Molecular Insights, Antitumor Effects, and Clinical Utility

Department of Surgical Oncology, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

Key Words. Cancer • TNF- • TNFR-1 • Tumor vasculature • Isolated limb perfusion

Correspondence: Alexander M. M. Eggermont, M.D., Ph.D., Erasmus MC–Daniel den Hoed Cancer Center, Department of Surgical Oncology, 301 Groene Hilledijk, 3075 EA Rotterdam, The Netherlands. Telephone: 31-0-10-439-1911; Fax: 31-0-10-439-1011; e-mail: a.m.m.eggermont{at}erasmusmc.nl

Tumor necrosis factor alpha (TNF-), isolated 30 years ago, is a multifunctional cytokine playing a key role in apoptosis and cell survival as well as in inflammation and immunity. Although named for its antitumor properties, TNF has been implicated in a wide spectrum of other diseases. The current use of TNF in cancer is in the regional treatment of locally advanced soft tissue sarcomas and metastatic melanomas and other irresectable tumors of any histology to avoid amputation of the limb. It has been demonstrated in the isolated limb perfusion setting that TNF- acts synergistically with cytostatic drugs. The interaction of TNF- with TNF receptor 1 and receptor 2 (TNFR-1, TNFR-2) activates several signal transduction pathways, leading to the diverse functions of TNF-. The signaling molecules of TNFR-1 have been elucidated quite well, but regulation of the signaling remains unclear. Besides these molecular insights, laboratory experiments in the past decade have shed light upon TNF- action during tumor treatment. Besides extravasation of erythrocytes and lymphocytes, leading to hemorrhagic necrosis, TNF- targets the tumor-associated vasculature (TAV) by inducing hyperpermeability and destruction of the vascular lining. This results in an immediate effect of selective accumulation of cytostatic drugs inside the tumor and a late effect of destruction of the tumor vasculature. In this review, covering TNF- from the molecule to the clinic, we provide an overview of the use of TNF- in cancer starting with molecular insights into TNFR-1 signaling and cellular mechanisms of the antitumor activities of TNF- and ending with clinical response. In addition, possible factors modulating TNF- actions are discussed.

This article has been cited by other articles:

				M. J. Duffy, E. McKiernan, N. O'Donovan, and P. M. McGowan Role of ADAMs in Cancer Formation and Progression Clin. Cancer Res., February 15, 2009; 15(4): 1140 - 1144. [Abstract] [Full Text] [PDF]

				J. Jiang, R. Goel, M. A. Iftekhar, R. Visaria, J. D. Belcher, G. M. Vercellotti, and J. C. Bischof Tumor necrosis factor-{alpha}-induced accentuation in cryoinjury: mechanisms in vitro and in vivo Mol. Cancer Ther., August 1, 2008; 7(8): 2547 - 2555. [Abstract] [Full Text] [PDF]

				L. Crippa, A. Gasparri, A. Sacchi, E. Ferrero, F. Curnis, and A. Corti Synergistic Damage of Tumor Vessels with Ultra Low-Dose Endothelial-Monocyte Activating Polypeptide-II and Neovasculature-Targeted Tumor Necrosis Factor-{alpha} Cancer Res., February 15, 2008; 68(4): 1154 - 1161. [Abstract] [Full Text] [PDF]

				P. Hohenberger and W. M. Wysocki Neoadjuvant Treatment of Locally Advanced Soft Tissue Sarcoma of the Limbs: Which Treatment to Choose? Oncologist, February 1, 2008; 13(2): 175 - 186. [Abstract] [Full Text] [PDF]

				R. Goel, D. Swanlund, J. Coad, G. F. Paciotti, and J. C. Bischof TNF-{alpha}-based accentuation in cryoinjury--dose, delivery, and response Mol. Cancer Ther., July 1, 2007; 6(7): 2039 - 2047. [Abstract] [Full Text] [PDF]

				S. Mena, M. Benlloch, A. Ortega, J. Carretero, E. Obrador, M. Asensi, I. Petschen, B. D. Brown, and J. M. Estrela Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease Clin. Cancer Res., May 1, 2007; 13(9): 2658 - 2666. [Abstract] [Full Text] [PDF]

				F. J. Lejeune and A. M.M. Eggermont Hyperthermic Isolated Limb Perfusion With Tumor Necrosis Factor Is a Useful Therapy for Advanced Melanoma of the Limbs J. Clin. Oncol., April 10, 2007; 25(11): 1449 - 1450. [Full Text] [PDF]

				J. W. Barrett, J. Sypula, F. Wang, L. R. Alston, Z. Shao, X. Gao, T. S. Irvine, and G. McFadden M135R Is a Novel Cell Surface Virulence Factor of Myxoma Virus J. Virol., January 1, 2007; 81(1): 106 - 114. [Abstract] [Full Text] [PDF]