elastin and Astrocytoma

Elastin has been identified within the meninges and the microvasculature of the normal human brain. However, the role that elastin plays in either facilitating astrocytoma cell attachment to these structures or modulating astrocytoma invasion has not been previously characterized. We have recently shown that astrocytoma cell lines and specimens produce tropoelastin, and express the 67 kDa elastin binding protein (EBP). In the present report, we have established that astrocytoma cells attach to elastin as a substrate in vitro. The U87 MG astrocytoma cell line demonstrated the greatest degree of adhesion. In addition, all astrocytoma cell lines examined were capable of penetrating and migrating through an intact elastin membrane, and of degrading tritiated-elastin, a process that could be prevented by the pre-incubation of astrocytoma cells with EDTA, but not with alpha1-antitrypsin. Astrocytoma cells were also capable of penetrating 1 mm sections of human brain tissue maintained as organotypic cultures. Interestingly, the invasive potential of cultured astrocytoma cells plated on organotypic cultures of human brain was significantly increased after exposure to elastin degradation products (kappa-elastin), which interact with astrocytoma cell surface EBP. Our data show that astrocytoma cells express a functional 67 kDa EBP, enabling them to potentially recognize and attach to elastin as a substrate. These data also suggest that this elastin receptor may be involved in processes which regulate regional astrocytoma invasion.

Topics: alpha 1-Antitrypsin; Astrocytoma; Blotting, Western; Brain; Brain Neoplasms; Cell Adhesion; Cell Movement; Chelating Agents; Edetic Acid; Elastin; Humans; Immunohistochemistry; Membranes; Organ Culture Techniques; Trypsin Inhibitors; Tumor Cells, Cultured

Expression of tropoelastin, the precursor of insoluble elastin and a major component of elastic fibers, has not yet been demonstrated in astrocytomas nor has it been linked to their proliferation. Here we report that human astrocytoma cell lines (U87 MG, U251 MG, U343 MG-A, U373 MG, SF 126, SF188, SF 539), as well as surgical specimens of malignant human astrocytomas, express intracellular tropoelastin. The tropoelastin produced by astrocytoma cells is, however, susceptible to proteolytic trimming to the extent that it cannot be assembled into extracellular elastic fibers. Astrocytoma cells also express the cell surface 67-kDa elastin binding protein (EBP), which binds elastin degradation products, leading to the upregulation of cyclin A and cdk2 and increased incorporation of [3H]-thymidine. The elastin-dependent mitogenic response of astrocytoma cells is abolished by lactose and chondroitin sulfate, factors which cause shedding of this 67-kDa elastin receptor from the cell surface and by blocking anti-EBP antibody. We therefore suggest that, in astrocytomas, endogenous tropoelastin degradation products bind to EBP and generate signals leading to cell cycle progression in an autocrine or paracrine manner. This is the first report implicating elastin-derived peptides as possible mitogens in malignant astrocytomas.

Topics: Astrocytoma; Blotting, Northern; Brain Neoplasms; CDC2 Protein Kinase; Cell Division; Cyclin A; Elastin; Humans; Iodine Radioisotopes; Receptors, Cell Surface; Signal Transduction; Tropoelastin; Tumor Cells, Cultured