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 beta 1 and beta 2 (TGF beta s) showed negative or positive autocrine growth regulation of gliomas in vitro. Near-diploid gliomas were inhibited by the TGF beta s, 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 TGF beta 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 beta 1 and/or TGF beta 2 RNA was evident by Northern blot analysis among these cell cultures. By radioreceptor assay active TGF beta was present in conditioned medium in concentrations of 0 to 14 ng/mL, whereas the total amount of active and latent TGF beta secreted was in the range of 3 to 118 ng/mL. Expression of the TGF beta radioreceptor (TGF beta-R) types I and II was shown by cross-linking assay. Responses to exogenous TGF beta were determined by [3H]-thymidine incorporation, cell counts, and anchorage-independent clonogenicity. Exogenous TGF beta 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 TGF beta 1 and TGF beta 2. The growth response did not correlate with TGF beta-R type. Autocrine regulation was supported by antibody neutralization experiments performed with quiescent cells in the absence of exogenous TGF beta. Anti-TGF beta antisera enhanced the growth of TGF beta-inhibited cultures, whereas the TGF beta-stimulated cultures were inhibited by the antisera. Karyotypic divergence seemed to predict response as MBL, PNET, and EPD with hyperdiploid elements exhibited autocrine TGF beta-stimulation. In contrast, the near-diploid cultures were inhibited by the TGF beta s. By analogy with the gliomas, conversion of TGF beta 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).
Jennings
M T
MT
Department of Neurology, Vanderbilt University, Nashville, TN 37232-3375.
Kaariainen
I T
IT
Gold
L
L
Maciunas
R J
RJ
Commers
P A
PA
D000906:Antibodies; D001932:Brain Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004806:Ependymoma / Q000473:pathology*; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D008527:Medulloblastoma / Q000473:pathology*; D018242:Neuroectodermal Tumors, Primitive / Q000473:pathology*; D011869:Radioligand Assay; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000906:Antibodies; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D006131:Growth Inhibitors; D016212:Transforming Growth Factor beta