Abstract
BackgroundThe urokinase plasminogen activator (uPA) and its receptor (uPAR/CD87) are major regulators of extracellular matrix degradation and are involved in cell migration and invasion under physiological and pathological conditions. The uPA/uPAR system has been of great interest in cancer research because it is involved in the development of most invasive cancer phenotypes and is a strong predictor of poor patient survival. However, little is known about the role of uPA/uPAR in small cell lung cancer (SCLC), the most aggressive type of lung cancer. We therefore determined whether uPA and uPAR are involved in generation of drug resistant SCLC cell phenotype.Methods and FindingsWe screened six human SCLC cell lines for surface markers for putative stem and cancer cells. We used fluorescence-activated cell sorting (FACS), fluorescence microscopy and clonogenic assays to demonstrate uPAR expression in a subpopulation of cells derived from primary and metastatic SCLC cell lines. Cytotoxic assays were used to determine the sensitivity of uPAR-positive and uPAR-negative cells to chemotherapeutic agents. The uPAR-positive cells in all SCLC lines demonstrated multi-drug resistance, high clonogenic activity and co-expression of CD44 and MDR1, putative cancer stem cell markers.ConclusionsThese data suggest that uPAR-positive cells may define a functionally important population of cancer cells in SCLC, which are resistant to traditional chemotherapies, and could serve as critical targets for more effective therapeutic interventions in SCLC.
Highlights
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer and has a uniformly poor prognosis
Increased levels of uPAR are correlated with higher mortality in patients with squamous cell and non-small cell lung cancer [15,16], little is known about the role of urokinase plasminogen activator (uPA)/uPAR expression in SCLC
All six SCLC cell lines were positive for CD29 (20–99%), CD44 (8–98%), CD105 (3–34%), CD166 (85–98%), and negative for CD90, and CXCR4. uPAR (CD87) was the only cell surface antigen expressed on a small subpopulation of cells (1–4%) in each of the six SCLC cell lines, when analyzed by fluorescence-activated cell sorting (FACS) using anti-uPAR-FITC antibody (Figure 1, lower panels)
Summary
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer and has a uniformly poor prognosis. Increased levels of uPAR are correlated with higher mortality in patients with squamous cell and non-small cell lung cancer [15,16], little is known about the role of uPA/uPAR expression in SCLC. The urokinase plasminogen activator (uPA) and its receptor (uPAR/CD87) are major regulators of extracellular matrix degradation and are involved in cell migration and invasion under physiological and pathological conditions. The uPA/ uPAR system has been of great interest in cancer research because it is involved in the development of most invasive cancer phenotypes and is a strong predictor of poor patient survival. The uPAR-positive cells in all SCLC lines demonstrated multi-drug resistance, high clonogenic activity and coexpression of CD44 and MDR1, putative cancer stem cell markers. These data suggest that uPAR-positive cells may define a functionally important population of cancer cells in SCLC, which are resistant to traditional chemotherapies, and could serve as critical targets for more effective therapeutic interventions in SCLC
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