TITLE:
Therapy-Induced Changes of Gene Expression in a Matched Pair of Small Cell Lung Cancer (SCLC) Cell Lines
AUTHORS:
Gerhard Hamilton, Ernst Ulsperger, Klaus Geissler, Ulrike Olszewski
KEYWORDS:
Small Cell Lung Cancer; GLC14; GLC19; Chemotherapy; Chemoresistance; Gene Expression; Cancer-Initiating Cells
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.3 No.4A,
September
12,
2012
ABSTRACT: Extended stage small cell lung cancer (SCLC) responds to platinum/vepeside-based first-line chemotherapy but relapses early as drug-resistant tumor associated with a dismal prognosis. A pair of SCLC cell lines obtained from a single patient at different time points during treatment allows for the investigation of the changes in gene expression prior to (GLC14) and following cycles of chemotherapy and irradiation (GLC19). GLC19 cells were reported to reveal an increased doubling time and exhibit increased chemoresistance to doxorubicin, etoposide, melphalan and vinblastine. Upregulated transcripts in GLC19, as assessed by microarray analysis, comprised proteins involved in regulation of cellular growth (NGFRAP1/BEX3), adhesion, glutathione metabolism and, in particular, WNT/Notch pathways and the putative cancer stem cell phenotype (CD44, ALDH1A1, and AKR1C1/13). Metallothioneins, tubulins TUBA3/4 and tumor protein p53 inducible protein 11 (TP53IP11) were downregulated in this cell line compared to GLC14. Except increased expression of glutathione transferases no classical markers of chemoresistance were found, pointing to a role of altered growth control/differentiation and reduced accessibility of this SCLC tumor cells growing as multicellular spheroids. In conclusion, treatment of this single SCLC with cyclophosphamide, doxorubicin and etoposide (CDE) followed by radiotherapy ultimately resulted in an enrichment of tumor cells displaying the typical signature of tumor-initiating or cancer stem cells (CIC/CSC).