V-ERBA ONCOGENE INDUCES INVASIVENESS AND ANCHORAGE-INDEPENDENT GROWTHIN CULTURED GLIAL-CELLS BY MECHANISMS INVOLVING PLATELET-DERIVED GROWTH-FACTOR

The v-erbA oncogene coding for a mutated form of the thyroid hormone ( T-3) receptor (TR alpha 1) increased the invasion capacity of the mous e B3.1 glial cell line, This effect was mediated by the induction of p latelet-derived growth factor (c-sis/PDGF B), as shown by its inhibiti on using an anti-PDGF BB antibody. Also, the low invasion capacity of parental B3.1 and c-erbA-expressing cells (B3.1 + TR alpha 1) was enha nced by exogenously added PDGF BB. This effect was independent of the growth-promoting activity of PDGF and unrelated to the secretion of me talloproteinases, All three cell types (parental B3.1, B3.1 + v-erbA, and B3.1 + TR alpha 1) secreted similar high levels of the M(r) 72,000 collagenase IV (A) independently of PDGF. Anchorage-independent cell growth was also enhanced by v-erbA; B3.1 + v-erbA cells but neither pa rental B3.1 nor B3.1 + TR alpha 1 cells formed foci in soft agar, The effect of v-erbA only happened in the presence of serum, suggesting th at some serum factor(s) cooperate with PDGF to overcome the anchorage dependence of B3.1 + v-erbA cells, Supporting this, high doses of exog enous PDGF were much less efficient than serum, and the addition of an anti-PDGF BE antibody blocked only partially the effect of serum, Bas ic fibroblast: growth factor was found to cooperate with PDGF to aboli sh anchorage dependence, Moreover, B3.1 + v-erbA cells detached and gr ew in suspension when cultured on plastic dishes, Interestingly, the t ransformation-competent c-jun and fra-1 oncogenes were induced by v-er bA in serum-free medium and are candidates to mediate v-erba effects. In summary, our results show that v-erbA induces transformation parame ters in the glial B3.1 cell line via an increase in c-sis/PDGF B and p robably other mechanisms, suggesting a role for (autocrine) PDGF stimu lation in glial cell transformation.