DETECTION OF EPIDERMAL GROWTH-FACTOR AND TRANSFORMING GROWTH-FACTOR-ALPHA PROTEIN IN MENINGIOMAS AND OTHER TUMORS OF THE CENTRAL-NERVOUS-SYSTEM IN HUMAN-BEINGS

Epidermal growth factor (EGF) and transforming growth factor alpha (TG F(alpha)) are potent mitogens for normal cells of ectodermal and mesod ermal origin. Evidence is accumulating that suggests that EGF, TGF(alp ha) and their common receptor (EGF/TGF(alpha)-R) influence development and functioning of tissues of the central nervous system (CNS). To fu rther investigate the possible roles of EGF, TGF(alpha) and their rece ptor in autocrine/paracrine regulation of tumor growth in the CNS, a s eries of tumors of the CNS were analyzed for the presence of specific, high affinity EGF/TGF(alpha) receptors and for die presence of immuno reactive TGF(alpha) protein. Binding of I-125-EGF to crude membranes f rom a pool of meningiomas was competed for equally well by low concent rations of unlabeled EGF or TGF(alpha), but not by high concentrations of other protein hormones, demonstrating the high degree of specifici ty of die EGF/TGF(alpha) receptor. Specific binding of I-125-EGF was d ependent upon time and temperature, with maximum specific binding achi eved after two hours at 22 degrees C. Scatchard analysis of six tumors of the CNS large enough to permit titration analysis generated linear plots with an average kilodalton of 1.1 +/- 0.1 nanometer (+/- standa rd error of the mean), suggesting the presence of a single class of EG F/TGF(alpha)-R with high affinity. EGF also stimulated phosphorylation of a 170 kilodalton protein in membrane fraction of a meningioma, dem onstrating that the EGF/TGF(alpha)-R in this tumor retained EGF-stimul ated kinase autophosphorylating activity. Membranes for 17 additional smaller tumors of the CNS were analyzed for specific binding of I-125- EGF by single, high concentration method, and all 17 tumors were found to contain specific binding of I-125-EGF. The average level of I-125- EGF for all 23 tumors of the CNS was 46 +/- 27 femtomoles per milligra m protein with a range of 1 femtomoles per milligram for both a pituit ary adenoma and meningioma to 638 femtomoles per milligram for a gliob lastoma. A series of 13 tumors of the CNS were analyzed for EGF(alpha) with use of a specific radioinimunoassay. TGF(alpha) immunoreactive p rotein was detected in all four malignant tumors of the CNS assayed at an average level of 2.6 +/- 1.1 nanograms per milligram soluble prote in, whereas TGF(alpha) immunoreactive protein was detected in only two of nine benign tumors of the CNS. These results add support to the hy pothesis that TGF(alpha) and its receptor may act by autocrine/paracri ne mechanisms to influence growth of tumors of the CNS in vivo.