Schwann cells in neuroblastoma express erythropoietin

The glycoprotein erythropoietin (Epo) and its cognate receptor EpoR are expressed both in the central nervous system (CNS) and the peripheral nervous system (PNS) [1–3]. The importance of EpoR in the CNS was demonstrated in studies of EpoR-null mice, which shows significantly reduced number of neuronal progenitor cells, extensive apoptosis in embryonic brain, and increased sensitivity to low oxygen tension [4]. Li et al. [5] demonstrated that Epo and EpoR are expressed by Schwann cells in rat sciatic nerve and that Epo is substantially upregulated in response to chronic constriction injury. Moreover, exogenously administered Epo increases the number of Schwann cells present at chronic constriction injury site in vivo and also promotes Schwann cell proliferation in vitro. Keswani et al. [6] showed that in response to axonal injury, periaxonal Schwann cells release Epo, which via EpoR binding on neurons, prevents axonal degeneration. Moreover, in an animal model of distal axonopathy, systemic Epo administration prevents axonal degeneration. Campana and Myers [7] reported localized Epo and EpoR in the sciatic nerve and dorse root ganglion of adult rats. Their data indicated that Epo is produced in the cell bodies and axons in normal root ganglion and is up-regulated in Schwann cells after painful chronic constriction injury. Neuroblastoma (NB) is an heterogenous tumor exhibiting a large spectrum of histological features ranging from immature NBs, composed of sheets of small undifferentiated neuroblasts with scarce Schwannian stroma, to progressively mature NBs composed of larger neuroblastic/ganglion-like cells with abundant Schwannian stroma [8]. The increasing presence of Schwannian stroma and differentiating/ differentiated neuroblasts that biologically resemble ganglion cells directly correlates with tumor maturation and better prognosis. In addition to a differentiated phenotype, Schwannian stroma rich tumors also have low vascularity [9]. This association between abundant Schwannian stroma, neuronal differentiation, and decreased vascularity has led to the hypothesis that Schwann cells may influence the biology of NB tumors by producing soluble factors that are capable of inducing neuroblast differentiation and inhibiting angiogenesis [10]. It has been demonstrated that Schwann cells secrete several potent angiogenesis inhibitors, such as secreted protein acidic rich in cysteine (SPARC) and pigment epithelium-derived factor [11, 12]. Here, we demonstrated a strong cytoplasmic immunoreactivity for Epo (1:200 in TBS, Santa Cruz Biotechnology, Santa Cruz, CA, USA) in Schwann cells of surgical specimens obtained form five cases of Schwannian stroma rich NBs (ganglioneuroblastomas, intermixed by Shimada classification) (Fig. 1). Several studies have suggested that Epo might stimulate angiogenesis by acting to promote proliferation and/ or migration of endothelial cells [13, 14], inhibiting D. Ribatti (&) V. Longo Department of Human Anatomy and Histology, University of Bari Medical School, Piazza Giulio Cesare, 11 – Policlinico, Bari 70124, Italy e-mail: ribatti@anatomia.uniba.it