Increased expression of ABC transporter genes in lung cancer CD133-positive cells

Drug resistance represents a major obstacle towards the cure of different tumor types including non‐small cell lung cancer (NSCLC), being one of the main causes of failure of antitumor therapy. Tumor cells frequently exhibit simultaneous resistance to multiple structurally unrelated drugs, a phenotype known as multidrug resistance (MDR). A major cause of the MDR phenotype is the over‐expression of members of a conserved family of transmembrane proteins (ABC transporters). Different structurally unrelated compounds, including conventional cytotoxic and target‐specific agents are substrates for ABC transporters. Cancer stem cells (CSC) refer to a subset of tumor cells with the ability to self‐renew and generate the diverse cells that comprise tumors. At present, the mechanisms contributing to the drug‐resistant phenotype of CSC are poorly understood. Some lines of evidence support that specific ABC transporters may be expressed in CSC and may be relevant therapeutic targets. The aim of the present study was to examine the pattern of expression of ABC transporter genes in spheres derived from human lung tumors, which we found enriched for CD133 (prominin‐1), a surface glycoprotein described as a marker of cancer‐initiating cells in different tumor types. To better define the molecular features of cancer cells endowed with stem‐like features with respect to cellular defence mechanisms, using TaqMan MicroFluidic cards we analyzed the mRNA levels of transporters of the ABC superfamily in CD133+ and CD133− cell populations sorted from lung tumor cell lines grown as spheres. With this approach, we found that around 70% of the 50 human ABC transporters were expressed at detectable levels in floating spheres obtained from human lung cancer A549 adherent cell line and in the corresponding sorted populations. When compared to the CD133− raction, CD133+ cells exhibited a marked increased expression of different components of the ABCC family which are known to be involved in the MDR phenotype (i.e., ABCC1). The level of ABCG2 mRNA was also enhanced. Similar results were obtained in CD133+ cells isolated from a cell line established from a human primary lung tumor growing as floating spheres. Thus, CD133+ cells expressed ABCG2 and additional ABC transporters that may contribute to determine a drug‐resistant phenotype. A better knowledge of the pattern of expression of ABC transporters in lung cancer CD133+ cells may lead to develop approaches that will circumvent drug resistance in NSCLC and is expected to contribute to optimization of therapy, based on targeting of ABC transporters. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A59.