TGF-BETA-1 AND TGF-BETA-2 ARE POTENTIAL GROWTH-REGULATORS FOR MEDULLOBLASTOMAS, PRIMITIVE NEUROECTODERMAL TUMORS, AND EPENDYMOMAS - EVIDENCE IN SUPPORT OF AN AUTOCRINE HYPOTHESIS

Our previous investigations of transforming growth factor types β1 and β2 (TGFβs) showed negative or positive autocrine growth regulation of gliomas in vitro. Near-diploid gliomas were inhibited by the TGFβs, whereas a stimulatory response correlated with progressive anaplasia and karyotypic divergence. We have tested the hypothesis that cytogenetic aberrations may be associated with conversion of TGFβ autoregulation from inhibitory to stimulatory among other cultured neuroectodermal tumors. Anchorage-independent growth and karyotypic aberrations supported the malignant nature in vitro of two medulloblastoma (MBL), two primitive neuroectodermal tumor (PNET), and two ependymoma (EPD) cultures. Transforming growth factor type β1 and/or TGFβ2 RNA was evident by Northern blot analysis among these cell cultures. By radioreceptor assay active TGFβ was present in conditioned medium in concentrations of 0 to 14 ng/mL, whereas the total amount of active and latent TGFβ secreted was in the range of 3 to 118 ng/mL. Expression of the TGFβ radioreceptor (TGFβ-R) types I and II was shown by cross-linking assay. Responses to exogenous TGFβ were determined by [3H]-thymidine incorporation, cell counts, and anchorage-independent clonogenicity. Exogenous TGFβ was growth inhibitory for the near-diploid MBL, PNET, and EPD in vitro, as well as antagonistic to the mitogenic effect of epidermal growth factor (EGF) and insulin. In contrast, MBL, PNET, and EPD with a hyperdiploid subpopulation were stimulated to proliferate in monolayer culture or soft agar by TGFβ1 and TGFβ2. The growth response did not correlate with TGFβ-R type. Autocrine regulation was supported by antibody neutralization experiments performed with quiescent cells in the absence of exogenous TGFβ. Anti-TGFβ antisera enhanced the growth of TGFβ-inhibited cultures, whereas the TGFβ-stimulated cultures were inhibited by the antisera. Karyotypic divergence seemed to predict response as MBL, PNET, and EPD with hyperdiploid elements exhibited autocrine TGFβ-stimulation. In contrast, the near-diploid cultures were inhibited by the TGFβs. By analogy with the gliomas, conversion of TGFβ autocrine regulation from inhibition to stimulation may be a late progression marker of anaplasia among MBL, PNET, and EPD. Secretion of this TGF, which serves both as a mitogen and immunosuppressive agent, may contribute to the adverse prognosis of hyperdiploid neuroectodermal neoplasms of the central nervous system (CNS). © 1994.