Interaction of transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) in human glioma cells

Gliomas are characterized by a deregulation of growth factor production and growth factor receptors expression, e.g. overproduction of the cytokine transforming growth factor-beta (TGF-beta) and overexpression/constitutive activation of receptors for the epidermal growth factor (EGF). Potential interactions of such growth factors and their signaling cascades could enhance the malignancy of these tumors. Therefore, we investigated the effects of TGF-beta and EGF alone and in combination on the proliferation of glioma cells cultivated from eight solid human WHO grade IV gliomas and one glioma cell line, analyzed the expression and intactness of the TGF-beta-signaling molecules Samd-4 and -2, and the phosphorylation of the EGF-signaling kinases ERK 1/2. The effects were divergent and complex: Whereas EGF mostly stimulated glioma cell proliferation, TGF-beta either enhanced, inhibited or had no significant effect on proliferation. In combination, co-stimulation and inhibition of the EGF-induced mitogenic activity could be observed. Smad-4/-2 were expressed in all glioma cells, one point mutation at base 1595 in Smad-4 did not affect its protein sequence. In part of the glioma cells, reduced phosphorylation of ERK 1/2 and expression of cyclin-dependent kinase inhibitor 1 or p21 was observed in co-stimulation experiments. These experiments show that TGF-beta can inhibit EGF-mediated effects only in some gliomas, whereas it enhances it in others. The interaction of both factors is very complex and varies between different gliomas.