Intratumoural expression of TNF-R1 and EMAP-II in relation to response of patients treated with TNF-based isolated limb perfusion.

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.
AuthorsRemco van Horssen, Joost A P Rens, Flavia Brunstein, Veronique Guns, Marjon van Gils, Timo L M Ten Hagen, Alexander M M Eggermont
JournalInternational journal of cancer. Journal international du cancer (Int J Cancer) Vol. 119 Issue 6 Pg. 1481-90 (Sep 15 2006) ISSN: 0020-7136 [Print] United States
PMID16615114 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Cytokines
  • Neoplasm Proteins
  • RNA-Binding Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • small inducible cytokine subfamily E, member 1
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents (administration & dosage)
  • Chemotherapy, Cancer, Regional Perfusion (methods)
  • Cytokines (metabolism)
  • Extremities
  • Female
  • Humans
  • Male
  • Melanoma (secondary, therapy)
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Neoplasm Proteins (metabolism)
  • Perfusion
  • RNA-Binding Proteins (metabolism)
  • Receptors, Tumor Necrosis Factor, Type I (metabolism)
  • Sarcoma (therapy)
  • Skin Neoplasms (secondary, therapy)
  • Transfection (methods)
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha (administration & dosage)
  • Up-Regulation

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