title: Intratumoural expression of TNF-R1 and EMAP-II in relation to response of patients treated with TNF-based isolated limb perfusion.
abstract: Tumour necrosis factor-alpha (TNF) has been used in the clinic for more than 10 years in an isolated limb perfusion (ILP). However, intra-tumoural expression of TNF receptor-1 (TNF-R1) and TNF-R1 upregulating factors are unknown. We determined the expression of TNF-R1, proEMAP and endothelial monocyte-activating polypeptide-II (EMAP-II) before and after ILP and evaluated this against clinical response. Tumour biopsies were taken before and after ILP of patients (n = 27) with advanced sarcoma or metastatic melanoma. Biopsies were randomly analysed by western blotting for proEMAP/EMAP-II and TNF-R1 expression. Appropriate melanoma biopsies were stained for EMAP-II, TNF-R1, CD31 and CD68. For melanomas we found that an up-regulation of EMAP-II, in contrast to proEMAP or TNF-R1, directly after ILP significantly correlated with a complete tumour response. No correlation was found for sarcoma patients. In a comparative analysis we found that the overall proEMAP and EMAP-II expression was higher in melanoma as compared to sarcoma cases and measurements in cell lines revealed high proEMAP expression by melanoma cells. We report high EMAP-II expression by endothelial cells and association with macrophages. In addition, macrophages are recruited to vessel-remnants after ILP. An upregulation of EMAP-II directly after ILP of melanoma patients correlates with and might predict a complete response to TNF-based ILP. The association of macrophages with EMAP-II expression and vascular damage suggests a role for EMAP-II in regulating the TNF-based anti-tumour effects observed with an ILP. Analysis of EMAP-II expression in melanoma biopsies should be implemented in the ILP procedure.
authors.affiliation: Department of Surgical Oncology, Laboratory for Experimental Surgical Oncology, Erasmus MC -- Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands. r.vanhorssen@erasmusmc.nl
authors.forename: Remco
authors.initials: R
authors.lastname: van Horssen
authors.forename: Joost A P
authors.initials: JA
authors.lastname: Rens
authors.forename: Flavia
authors.initials: F
authors.lastname: Brunstein
authors.forename: Veronique
authors.initials: V
authors.lastname: Guns
authors.forename: Marjon
authors.initials: M
authors.lastname: van Gils
authors.forename: Timo L M Ten
authors.initials: TL
authors.lastname: Hagen
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods; D016207:Cytokines / Q000378:metabolism*; D005121:Extremities; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D010477:Perfusion; D016601:RNA-Binding Proteins / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D012509:Sarcoma / Q000628:therapy; D012878:Skin Neoplasms / Q000556:secondary / Q000628:therapy; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C077219:small inducible cytokine subfamily E, member 1