Elevated insulin-like growth factor (IGF) binding protein (IGFBP)-2 and IGFBP-4 expression of leukemic T-cells is affected by autocrine/paracrine IGF-II action but not by IGF type I receptor expression

Paediatric Endocrinology, University Children's Hospital, Tuebingen, Germany.

We recently found evidence indicating that the source of elevated serum insulin-like growth factor binding protein (IGFBP)-2 in leukemia was the leukemic T-cells. Here we report that locally produced IGF-II affects IGFBP-2 expression and growth of leukemic cells through the IGF type I receptor. We measured IGFBP-2, -4 and IGF type I receptor (IGF-I-R) mRNA by RT-PCR, cell growth and IGFBP-2 secretion (per 10(6) cells). IGF-I-R binding sites were assessed by 125I-IGF replacement studies. Inhibition using an IGF-II antibody showed that tumor cell-derived IGF-II accounts for a significant 25% (P < 0.001) increase in IGFBP-2 secretion and enhanced growth (P < 0.01) of leukemic T-cells after 7 days in culture. IGFBP-2 secretion, but not IGFBP-2 mRNA was specifically increased by IGFs, while no specific effect of insulin was detectable. The addition of 100 ng/ml IGF-II enhanced the IGFBP-2 secretion 2.8-fold, while the use of IGF-I only enhanced IGFBP-2 secretion 1.7-fold, although IGF-I enhanced IGF-II action. Through inhibition using JB1, a peptide inhibiting the IGF signal transduction by blocking the IGF-I-R, we demonstrated the involvement of the IGF-I-R in IGFBP-2 and -4 expression and leukemic cell growth. However, only slight differences in the IGF-I-R mRNA expression were seen for T- and B-cells compared with the differences found for the IGFBP-2 and -4 mRNA or IGFBP-2 secretion. Thus, although IGF-I-R mediates the autocrine/paracrine effects of the IGFs, IGF-I-R mRNA expression is most probably not involved in the differential IGFBP-2/IGFBP-4 expression in leukemic cells.

This article has been cited by other articles:

				P. Vorwerk, K. Mohnike, H. Wex, F.-W. Rohl, M. Zimmermann, W. F. Blum, and U. Mittler Insulin-Like Growth Factor Binding Protein-2 at Diagnosis of Childhood Acute Lymphoblastic Leukemia and the Prediction of Relapse Risk J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3022 - 3027. [Abstract] [Full Text] [PDF]

				A. Hoeflich, R. Reisinger, H. Lahm, W. Kiess, W. F. Blum, H. J. Kolb, M. M. Weber, and E. Wolf Insulin-like Growth Factor-binding Protein 2 in Tumorigenesis: Protector or Promoter? Cancer Res., December 1, 2001; 61(24): 8601 - 8610. [Full Text] [PDF]

				M. W. Elmlinger, M. H. Deininger, B. S. Schuett, R. Meyermann, F. Duffner, E. H. Grote, and M. B. Ranke In Vivo Expression of Insulin-Like Growth Factor-Binding Protein-2 in Human Gliomas Increases with the Tumor Grade Endocrinology, April 1, 2001; 142(4): 1652 - 1658. [Abstract] [Full Text]

				W. Zumkeller and S. Burdach The Insulin-Like Growth Factor System in Normal and Malignant Hematopoietic Cells Blood, December 1, 1999; 94(11): 3653 - 3657. [Full Text] [PDF]