Insulin-like growth factor-II (
IGF-II) is the major IGF in human cerebrospinal fluid (CSF), whereas
IGF-I is only detectable in trace amounts. The major IGFBPs in CSF are
IGFBP-2 and
IGFBP-4. Normally,
IGFBP-3 is a minor component in CSF of healthy subjects, but may be increased in pathological states. We investigated
IGF-I,
IGF-II, and
IGFBP-3 levels by specific RIAs in CSF from patients with central nervous system (CNS)
tumor or
leukemia and compared them with values in patients with
meningitis. Further, as proteolysis of
IGFBP-3 is part of the modulation of IGF activity,
IGFBP-3 fragmentation was quantified by densitometric analysis of [125I]
IGFBP-3
protease assays. We examined CSFs of 23 children with malignant CNS
tumors, 18 children with
leukemia, and 13 children with
meningitis. The CSF from 38 children who received lumbar punctures to exclude
meningitis was used to define the normal range for
IGF-I,
IGF-II,
IGFBP-3, and
IGFBP-3 protease activity in CSF. CNS
tumor and
leukemia patients had normal levels of
IGF-I and
IGF-II in CSF, whereas the
IGF-II concentration in CSF of
meningitis patients was elevated (P < 0.0001). Only 2 of 13 (15%)
meningitis patients had elevation of CSF
IGFBP-3 concentrations, despite high numbers of inflammatory cells. By comparison, elevated
IGFBP-3 concentrations were found in the CSF of 16 of 23 (70%) CNS
tumor patients and 6 of 7 (86%) CNS
tumor patients with microscopically detectable malignant cells in CSF. Twelve of 13 (92%) patients with
medulloblastoma or
ependymoma and all 7
medulloblastoma/
ependymoma patients with malignant cells in CSF had elevated
IGFBP-3 concentrations. The
IGFBP-3 protease activity in CSF was elevated in 15 of 16 (94%) patients with CNS
tumors of high grade histological
malignancy. Five of 6 patients (83%) with acute
leukemia and microscopically detectable malignant cells in CSF at the time of diagnosis showed elevated
IGFBP-3 concentrations, with normalization after
chemotherapy.
Leukemia patients without malignant cells in CSF had normal
IGFBP-3 concentrations. We conclude that in CSF of children with highly malignant CNS
tumor or CNS
leukemia,
IGFBP-3 is elevated. This phenomenon could be caused by disruption of the blood-CSF barrier and entry of
IGFBP-3 from serum, although this appears unlikely, especially for CNS
leukemia. More likely possibilities are 1) local production of
IGFBP-3 by CNS
tumor tissue and secretion into the CSF, or 2) local production of
IGFBP-3 by malignant cells within the CSF.