1. ¹Department of Pediatric Hematology/Oncology, University Children's Hospital, Münster, Germany
2. ²Department of Orthopedics, 48129 Münster, Germany

Correspondence: Priv-Doz Dr med J Vormoor, Universitätsklinikum Münster, Klinik und Poliklinik für Kinderheilkunde – Pädiatrische Hämatologie/Onkologie, Albert-Schweitzer-Str. 33, 48149 Münster, Germany. E-mail: vormoor@uni-muenster.de

³These authors contributed equally to this work

Revised 4 October 2004; Accepted 15 December 2004; Published online 1 February 2005.

Abstract

While in vitro studies had shown that fibroblast growth factor 2 (FGF2) can induce cell death in Ewing tumours, it remained unclear how Ewing tumour cells survive in vivo within a FGF2-rich microenvironment. Serum- and integrin-mediated survival signals were, therefore, studied in adherent monolayer and anchorage-independent colony cell cultures. In a panel of Ewing tumour cell lines, either adhesion to collagen or exposure to serum alone only had a minor protective effect against FGF2. However, both combined led to complete resistance to 5 ng ml^-1 FGF2 in three of four FGF2-sensitive cell lines (RD-ES, RM-82 and WE-68), and to an increased survival as compared to other culture conditions in TC-71 cells. Inhibition studies with LY294002 demonstrated that the serum signal is mediated via the phosphoinositide 3-OH kinase/AKT pathway. Thus, Ewing tumour cells escape FGF2-induced cell death by modulating FGF2 signalling. The tumour microenvironment provides the necessary survival signals by integrin-mediated adhesion and soluble serum factor(s). These survival signals warrant further investigation as a potential resistance mechanism to other apoptosis-inducing agents in vivo.