Premium
Intratumoural expression of TNF‐R1 and EMAP‐II in relation to response of patients treated with TNF‐based isolated limb perfusion
Author(s) -
van Horssen Remco,
Rens Joost A.P.,
Brunstein Flavia,
Guns Veronique,
van Gils Marjon,
Hagen Timo L.M. ten,
Eggermont Alexander M.M.
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21973
Subject(s) - tumor necrosis factor alpha , melanoma , medicine , cd68 , cd31 , downregulation and upregulation , necrosis , sarcoma , pathology , cancer research , immunohistochemistry , monocyte , immunology , biology , gene , biochemistry
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. © 2006 Wiley‐Liss, Inc.