Improved antitumor response to isolated limb perfusion with tumor necrosis factor after upregulation of endothelial monocyte-activating polypeptide II in soft tissue sarcoma.
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.
Lans
T E
TE
University Hospital Rotterdam-Daniel den Hoed Cancer Centre, Department of Surgical Oncology, Rotterdam, The Netherlands. lans@heel.fgg.eur.nl
ten Hagen
T L M
TL
van Horssen
R
R
Wu
P C
PC
van Tiel
S T
ST
Libutti
S K
SK
Alexander
H R
HR
Eggermont
A M M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005121:Extremities; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D012509:Sarcoma / Q000628:therapy*; D012983:Soft Tissue Neoplasms / Q000628:therapy*; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; C077219:small inducible cytokine subfamily E, member 1