Identification of uPAR-positive chemoresistant cells in small cell lung cancer.
BACKGROUND
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. 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.


RESULTS
We 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.


CONCLUSIONS
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.
Gutova
Margarita
M
Division of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, United States of America. mgutova@coh.org
Najbauer
Joseph
J
Gevorgyan
Anna
A
Metz
Marianne Z
MZ
Weng
Yehua
Y
Shih
Chu-Chih
CC
Aboody
Karen S
KS
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000737:chemistry / Q000473:pathology / Q000556:secondary; D001932:Brain Neoplasms / Q000737:chemistry / Q000473:pathology / Q000556:secondary; D018288:Carcinoma, Small Cell / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D002945:Cisplatin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D008175:Lung Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D009363:Neoplasm Proteins / Q000032:analysis* / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000187:drug effects; D010641:Phenotype; D055293:Receptors, Urokinase Plasminogen Activator / Q000032:analysis* / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D055293:Receptors, Urokinase Plasminogen Activator; D005047:Etoposide; D014568:Urokinase-Type Plasminogen Activator; D002945:Cisplatin; D005472:Fluorouracil