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Annals of Surgical Oncology 9:812-819 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Improved Antitumor Response to Isolated Limb Perfusion With Tumor Necrosis Factor After Upregulation of Endothelial Monocyte-Activating Polypeptide II in Soft Tissue Sarcoma

T. E. Lans, MD, T. L. M. ten Hagen, Dr, R. van Horssen, Ing, P. C. Wu, MD, S. T. van Tiel, Ing, S. K. Libutti, MD, H. R. Alexander, MD and A. M. M. Eggermont, MD, Prof Dr

From the University Hospital Rotterdam–Daniel den Hoed Cancer Centre, Department of Surgical Oncology (TEL, TLMtH, RvH, STvT, AMME), Rotterdam, The Netherlands; and Surgery Branch (PCW, SKL, HRA), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Correspondence: Address correspondence and reprints requests to: T. E. Lans, MD, Erasmus University Rotterdam, Laboratory for Experimental Surgical Oncology, Room Ee 110a, PO Box 1738, 3000 DR Rotterdam, The Netherlands; Fax: 00-31-104089471; E-mail: lans{at}heel.fgg.eur.nl

Background: Experiments with tumor necrosis factor {alpha} (TNF) in rodents have shown that a high dose can lead to hemorrhagic necrosis in tumors. Endothelial monocyte-activating polypeptide II (EMAP-II) is a novel tumor-derived cytokine, and its expression increases the TNF-1 receptor on tumor endothelium, enhances the induction of tissue factor on tumor endothelial cells, and has an antiangiogenic effect. It has recently been shown that in vivo sensitivity of tumor vasculature to TNF is determined by tumor production of EMAP-II.

Methods: We measured the level of EMAP-II in a TNF-resistant soft tissue sarcoma. We subsequently stabile-transfected this cell line with a retroviral construct containing the EMAP gene. In an extremity perfusion model in tumor-bearing rats, we measured response rates to TNF therapy.

Results: Functional EMAP-II production was increased after this transfection. Immunostaining of paraffin-embedded tumor tissue sections in rats showed an overexpression of human EMAP-II. Results of the TNF perfusions in rats suggest that this tumor is more sensitive to TNF therapy.

Conclusions: EMAP-II is produced in various levels. One can increase the sensitivity of tumor for TNF therapy in vivo by upregulating the EMAP-II production. This result leaves an opportunity for enhanced TNF response of tumors in future settings.

Key Words: Limb perfusion • EMAP-II • Sarcoma • TNF






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