INSULIN-LIKE GROWTH FACTORS IN GROWTH, INVASIVENESS AND MOTILITY OF BRAIN TUMORS

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Primary CNS neoplasms account for 20% of all pediatric malignancies and are the most common solid tumors in children. Insulin-like growth factor I and II (IGF-I and IGF-II) have been demonstrated to influence growth, development and differentiation in numerous peripheral tissues and in primary cultures of astroglial and neuronal cells from fetal brain. The endogenous production of IGFs and their binding proteins as well as the presence of IGF receptors in the brain suggests that these peptides may regulate proliferation, development and differentiation of brain cells (1,2). In addition, IGFs have been shown to act by endocrine, autocrine or paracrine pathways in the growth regulation of several human malignancies (3-5). We have recently reported that IGF-II is an autocrine growth factor for human rhabdomyosarcomas, and is an autocrine and/or paracrine growth factor for neuroblastomas (4-5). Recent studies have identified the presence of IGF receptors and specific mRNA for IGF-I and II in some human brain tumors (6,7). Therefore, we hypothesize that IGFs play an active role in the growth regulation of human brain malignancies. We recently reported that IGF-II stimulates cell motility in human rhabdomyosarcomas (9). Malignant gliomas and medulloblastomas are characterized by a high degree of local invasiveness. Since tumor invasion requires active locomotion, we hypothesize that IGFs play a key role in modulating tumor cell locomotion and, hence, invasion. We speculate that these functions may be mediated by the type II receptor, in analogy to what we have shown in rhabdomyosarcoma (9). Therefore, we will characterize IGFs, IGF receptors, and IGF binding proteins in human brain tumor cells and analyze their relationship to tumor growth, motility, and invasion.