Expression of Insulin-like Growth-Factor-1 Receptor (IGF-1R) in Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1

Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disease, characterised by the development of nerve sheath tumors. NF1 is the most frequently inherited disease associated with a predisposition for cancer (in particular malignant peripheral nerve sheath tumors: MPNST). NF1 is a progressive disease with phase-like growth spurts of dermal or plexiform neurofibroma (PNF). These tumors can cause severe disfigurement of patients. Growth control of these tumors is poorly understood. The aim of this study was to identify the expression of insulin-like growth factor 1-receptor (IGF-1R) in peripheral nerve sheath tumors. Factor and receptor are involved in the growth control of numerous physiological and pathological processes, including Schwann cell development. Materials and Methods: The investigation included tumors of NF1-patients only (neurofibroma, MPNST). Sections of the specimens were immunohistochemically typed for several antigens (target antigens: IGF-1R, S-100, EMA, CD34, MIB-1), using both single and double-staining methods. Double-staining allowed the sub-typing of the IGF-1R-expressing cells in the mixed nerve sheath tumors. The expression was also investigated in Schwann cell cultures and co-cultures with fibroblasts. Results: Staining of S-100 and IGF-1R, PNF were more intensely marked than MPNST (r=-0.439, p neurofibroma. The IGF-1R-expression correlated positively with the MIB-1 index in neurofibroma (r=0.372, p=0.021, N=38). The receptor expression was higher in PNF than in dermal neurofibroma (r=0.335, p=0.040, N=38). IGF-1R was detected in Schwann cells (S-100 positive) and in perineurial cells (EMA-positive) of all nerve sheath tumors. However, the receptor was also identified in CD34-marked endothelia of neurofibromas but not in endothelia of MPNST. In Schwann cell cultures, a strong receptor-expression became evident. This expression was independent of co-cultivation of tumor cells with fibroblasts. The statistical calculations excluded the impact of gender on the receptor expression. Conclusion: This investigation provides evidence for the expression of IGF-1R in nerve sheath tumors in NF1. The expression pattern varied between the tumor types, the cell types, and between tumors of the same type. IGF and IGF- 1R are a prerequisite to maintain Schwann cell stability in the postnatal period and to prevent Schwann cell apoptosis. The first evidence for IGF-1R expression in mutated Schwann cells may indicate a tumor-type associated receptor expression in NF1. Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disease, affecting about 1 in 3000 individuals alive at birth (1). Neurofibromas, i.e. benign tumors of peripheral nerve sheath cells, are the hallmark of the disease. NF1 is a progressive disease with phase-like growth spurts of dermal or plexiform neurofibromas (PNF). These tumors can cause severe disfigurement of patients. Moreover, NF1 is the most frequently inherited disease associated with a predisposition for cancer, in particular malignant peripheral nerve sheath tumors (MPNST). Plexiform neurofibromas are judged as a precancerous lesion in NF1 patients that can give rise to the development of MPNST. Growth control of neurofibromas in NF1 is poorly understood. The aim of this study was to identify the expression of insulin-like growth factor receptor (IGF-1R) in peripheral nerve sheath tumors. Factor and receptor are involved in the growth control of numerous physiological and pathological processes, including Schwann cell development and regeneration (2-5). Signal pathways via the IGF-1R play a crucial role in the development and progression of malignant diseases (6). At present, no immunohistochemical studies have been published on IGF-1R in nerve sheath tumors in NF1.