Tamoxifen-resistant glioma-cell sub-populations are characterized by increased migration and proliferation

Multifocal tumor recurrence of glioblastomas occurs in up to 14% of patient s. In a parallel phase-II-study investigating post-operative treatment with tamoxifen (TAM), carboplatin and radiation therapy for glioblastomas, 16 o f 49 patients (33%) showed multifocal recurrence, which developed after a m ean of 46 weeks, raising the question of an association with therapy. We st udied the interrelation of proliferation and migration in the presence of d ifferent protein-kinase-C(PKC) inhibitors (TAM, staurosporine, hypericin) i n 2 glioma cell lines. In addition, 3 cell lines were selected for TAM resi stance by repeated cycles of treatment with sub-lethal concentrations of TA M. The proliferative capacity and the invasive potential of selected sub-po pulations were assessed using growth-curve experiments, monolayer migration , and cell-adhesion assays. Treatment with all PKC inhibitors tested result ed in a dose-dependent decrease of proliferation, while motility was altere d only at significantly higher doses. Resistance to TAM occurred in all 3 s elected cell lines. The TAM-resistant sub-populations showed significantly increased proliferation, migration and adhesion as compared with the parent al (non-selected) cell line. The higher incidence of multifocal disease aft er TAM treatment was paralleled by increased migratory potential of TAM-tre ated cells in vitro. Int. J. Cancer 86:468-473, 2000. (C) 2000 Wiley-Liss, Inc.