Elastin Peptides and Elastin Receptor Control Proliferation of Human Gliomas

摘要

Elastin is unique among mammalian matrix proteins in lhat expression of its gene is temporally related to a brief period in late fetal life which extends into the early postnatal period. However, in response to injury, physical stress, growth factors, and cytokines, elastogenesis can resume. In the central nervous system, elastin is typically localized to the leptomeninges and the cerebral vasculature. There have been no previous reports of elastin production by cells of brain tumors of neuronal or glial origin. Our recent data indicate that rapidly proliferating glioma cell lines, as well as surgical specimens of malignant human gliomas, express abundant intracellular tropoelastin and the 67-kDa elastin receptor. We have also established that exposure of cultured glioma cells to elastin degradation products causes upregulation of cyclin A and cdk2 expression and a significant increase in their incorporation of [3H]-thymidine and that elastin peptides-dependent mitogenic response of glioma cells was abolished by an antibody to the elastin receptor or in the presence of galactosugars which cause shedding of elastin receptor from the cell surface. These results suggest that tropoelastin produced by glioma cells is not used as a structural component of the ECM. Rather, after proteolytic trimming, tropoelastin-derived peptides bind to the cell surface elastin receptor, which in turn generates signals leading to DNA replication and cell division. We have also established that suramin, a popular anticancer drug, stimulated accumulation of elastin receptor molecules on the cell surface of glioma cells and amplified the elastin-derived signals leading to their progression through the cell cycle. Thus, suramin should not be used in the therapy of malignant gliomas.-