¹Department of Haematology and Oncology, Centre for Internal Medicine, University Hospital, Philipps-Universität Marburg, D35033 Marburg, Germany

²Department of Radiotherapy and Radio-oncology, University Hospital, Philipps-Universität Marburg, D35033 Marburg, Germany

³Department of Neuropathology, University Hospital, Philipps-Universität Marburg, D35033 Marburg, Germany

⁴Institute for Molecular Biology and Tumour Research, University Hospital, Philipps-Universität Marburg, D35033 Marburg, Germany

Correspondence to: M Schuermann, Zentrum fuer Innere Medizin, Klinikum der Philipps-Universität, Baldingerstrasse, D-35033 Marburg, Germany; E-mail: schuermann@mailer.uni-marburg.de

Most small cell lung cancer (SCLC) patients relapse within 12 months of starting combination chemotherapy plus radio-therapy, due to the development of acquired chemo- and radio-resistance. This phenomenon relates to the induction of tumour differentiation, resulting in apoptosis-resistant, morphologically variant (v-SCLC) cells, which lack the neuroendocrine expression of classic (c-) SCLC cells. In this study spontaneously adherent SCLC sublines were shown by differential gene expression analysis to provide an in vitro model of variant differentiation in SCLC, with down-regulation of neuroendocrine markers and up-regulation of epithelial differentiation markers cyclin D1, endothelin, the cell adhesion molecules CD 44 and integrin subunits 2, 3 and 4. The sensitivity of adherent SCLC sublines to etoposide, cyclophosphamide and gamma radiation was significantly diminished relative to parent suspension cell lines. Western blot analysis using phosphorylation-specific antibodies to Akt and MAP kinase revealed markedly elevated activation in adherent SCLC sublines, paralleled by increased levels of phosphorylated Bad protein and activated NF-B. Subcultivation of the adherent sublines on uncoated surfaces reversed their adherent phenotype immediately and under these conditions Akt activity reverted to low levels. These results suggest that c-SCLC cells can differentiate spontaneously to v-SCLC and that the associated cellular adhesion may trigger Akt-dependent inhibition of apoptosis in SCLC cells, thus leading to acquired chemo- and radio-resistance.

Oncogene (2002) 21, 8683-8695. doi:10.1038/sj.onc.1205939

lung cancer; Akt; chemoresistance; radio-resistance; adhesion