Autocrine regulation of growth by insulin-like growth factor (IGF)-II mediated by type I IGF-receptor in Wilms tumor cells.

Wilms tumor is a common embryonic tumor in childhood. Two Wilms tumor-suppressor genes, WT1 and WT2, are located on chromosome 11p, WT2 at 11p15.5 close to the IGF-II gene, which is highly expressed in some Wilms tumors. We established Wilms tumor cell lines to investigate the regulation of tumor cell growth by IGF-II. We demonstrated that Wilms tumor cells produce more IGF-II than normal kidney cells. Both types I and II IGF receptors reside on these cells. In serum-free culture medium, tumor cell growth is reversibly inhibited by suramin via interfering with IGF-II binding. Wilms tumor cell growth is also arrested by IGF binding protein-3, capturing the continuously produced IGF-II, and by alpha IR-3, a type I IGF receptor-blocking antibody. Thus, we demonstrated the whole loop of elevated synthesis, secretion, receptor binding, and autocrine growth stimulation of IGF-II through type I IGF receptor in Wilms tumor cell cultures. We concluded that IGF-II plays a crucial role in the regulation of growth of this embryonic tumor. Overproduction of IGF-II by the tumor cell is the limiting step for Wilms tumor growth, supporting its important role as an embryonic growth factor.

Systemic effects of insulin-like growth factor-II produced and released from Wilms tumour tissue.

The concentration of mRNA of insulin-like growth factor-II is (IGF-II) much elevated in some embryonic tumours such as Wilms tumour (nephroblastoma). In order to prove whether or not IGF-II is produced by the tumour tissue, IGF-II was extracted from freshly frozen tissue of Wilms tumour and hepatoblastoma. Normal adjacent tissue of kidney and liver was used as a control. The total IGF-II in Wilms tumour was 548.4 +/- 77.4 ng/g (n = 7) compared to 112.8 +/- 38.2 ng/g (n = 5) in kidney. In two hepatoblastomas, it was 96.1 +/- 22.8 ng/g compared to 30.1 +/- 14.2 ng/g in normal liver. Small pieces of fresh primary tissue of several Wilms tumours were successfully transplanted into immunodeficient nude mice. In serum of tumour-bearing mice IGF-II was elevated compared to normal mice. Liver weight of tumour bearing mice was higher than that of control mice (2.29 +/- 0.4 g and 2.02 +/- 0.06 g; P < 0.005). This was also found for kidney weight (0.58 +/- 0.01 g vs. 0.51 +/- 0.01 g in controls, P < 0.001). In contrast, serum glucose (9.73 +/- 0.29 mmol/l compared to 11.80 +/- 0.42 mmol/l in controls, P < 0.0005) was decreased. However, there was no significant difference in nose-tail length of tumour-bearing compared to control mice. These results demonstrate that besides the highly increased IGF-II-mRNA, the synthesis of the peptide IGF-II and its release into circulation are also elevated in Wilms tumour transplanted into nude mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired differentiation of Schwann cells in transgenic mice with increased PMP22 gene dosage.

An intrachromosomal duplication containing the PMP22 gene is associated with the human hereditary peripheral neuropathy Charcot-Marie-Tooth disease type 1A, and PMP22 overexpression as a consequence of increased PMP22 gene dosage has been suggested as causative event in this frequent disorder of peripheral nerves. We have generated transgenic mice that carry additional copies of the pmp22 gene to prove that increased PMP22 gene dosage is sufficient to cause PNS myelin deficiencies. Mice carrying approximately 16 and 30 copies of the pmp22 gene display a severe congenital hypomyelinating neuropathy as characterized by an almost complete lack of myelin and marked slowing of nerve conductions. Affected nerves contain an increased number of nonmyelinating Schwann cells, which do not form onion bulbs but align in association with axons. The mutant Schwann cells are characterized by a premyelination-like state as indicated by the expression of embryonic Schwann cell markers. Furthermore, continued Schwann cell proliferation is observed into adulthood. We hypothesize that Schwann cells are impaired in their differentiation into the myelinating phenotype, leading to a disorder comparable to severe cases of hereditary motor and sensory neuropathies. Our findings, combined with the analysis of heterozygous and homozygous PMP22-deficient mice, indicate that aberrant pmp22 gene copy numbers cause various forms of myelination defects.