INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 (IGFBP-3) CONCENTRATION IN CEREBROSPINAL FLUID (CSF) OF CHILDREN WITH BRAIN TUMORS OR LEUKEMIA

Abstract

The major IGFBPs in CSF are IGFBP-2 and IGFBP-4. whereas IGFBP-3 is a minor component in CSF of healthy subjects. We investigated IGFBP-3 levels in CSF from patients with brain tumors, leukemia or meningitis. IGFBP-3 was measured by radioimmuno-assay with αIGFBP-3g I, a rabbit polyclonal antibody. Further, as proteolysis of IGFBP-3 is purt of the modulation of IGF activity IGFBP-3 fragmentation was quantified by densitometric analysis of [125I]IGFBP-3 protease assays. We examined CSFs of 24 children with malignant brain tumors. 18 children with leukemia and 13 children with meningitis. CSFs of 38 children, who received a lumbal puncture in order to exclude meningitis, were used to define a normalative range for IGFBP-3 concentration and IGFBP-3 protease activity in normal CSF. Elevated IGFBP-3 concentrations were found in CSF of 17 of all 24 (71%) brain tumor patients and 7 of 8 (87%) brain tumor patients who had microscopically detectable malignant cells in CSF. 13 of 14 (93%) patients with medulloblastoma or ependymoma and all 7 medulloblasioma/ependymoma patients with malignant cells in CSF had elevated IGFBP-3 concentrations in CSF. IGFBP-3 protease activity in CSF was elevated in 15 of 17 (88%) patients with histological high grade (WIIO III°/IV°) brain tumors. 5 of 6 (83%) patients with acute leukemia and microscopically detectable malignant cells in CSF at the time of diagnosis showed elevated IGFBP-3 concentrations in CSF that normalized under chemotherapy. leukemia patients without any detectable malignant cells in the CSF had normal IGFBP-3 concentrations in CSF. We conclude that in CSF of children with high grade malignant brain tumors or CNS leukemia. IGFBP-3 is elevated. We hypothesize that this phenomenon could be caused by local production of IGFBP-3 by the brain tumor tissue and secretion into CSF or by local secretion of IGFBP-3 by malignant cells that spread into CSF. This hypothesis is supported by the observation that only 2 of 13 (15%) meningitis patients had slightly elevated IGFBP-3 concentrations in CSF while high numbers of non malignant inflammatory cells were present in all cases. Further studies will analyse the origin of elevated IGFBP-3 levels in CSF of tumor patients and will show whether these findings are of diagnostic or prognostic value.