Receptor tyrosine kinases expressed in endothelial cells are potential targets for therapy with specific tyrosine kinase inhibitors. Endothelial cell KIT expression has not been systematically evaluated in human cancer. In the present study, endothelial cell KIT expression was assessed in 345 tumours consisting of 34 different histological types using a tissue microarray technique. Marked KIT expression occurred in the tumour endothelial cells only in primary glioblastomas in the microarray. Moderate to strong KIT and phosphorylated KIT expression was detected in the tumour endothelial cells in six (16%) and seven (19%) of the 37 primary glioblastomas examined, respectively. In whole tissue sections, KIT and phosphorylated KIT were expressed in tumour endothelial cells in 13 (59%) and 11 (50%) of the 22 glioblastomas examined, respectively. RNA in situ hybridization showed KIT mRNA expression in most glioblastomas both in tumour vessel endothelial cells and in perinecrotic palisading glioblastoma cells, whereas little KIT mRNA was found in the endothelial cells of colon or pancreatic carcinomas. Phosphorylated KIT, its ligand stem cell factor, and the downstream signalling molecules phosphorylated Akt and mTOR were often expressed in glioblastoma cells located in the perinecrotic tumour areas that often also contained abundant HIF-1alpha. It is concluded that marked KIT and phosphorylated KIT expression is frequently present in the endothelial cells of glioblastomas, which are known to harbour florid microvascular proliferation with characteristic morphological features. Glioblastomas also express phosphorylated KIT and its activated downstream signalling molecules in the tumour cells. Lower levels of KIT and phosphorylated KIT are present in endothelial cells of other tumour types and in normal tissues. Endothelial cell and tumour cell expression of activated KIT might explain in part the responsiveness of glioblastomas to the combination of imatinib (an inhibitor of KIT) and hydroxyurea.
Copyright (c) 2007 Pathological Society of Great Britain and Ireland.