Identification and clinical significance of circulating endothelial progenitor cells in human non-small cell lung cancer.
Until recently, it was generally accepted that vascularization of tumors arises exclusively from endothelial sprouting. Whether circulating bone marrow-derived endothelial progenitor cells (EPC) participate in the progression of non-small cell lung cancer (NSCLC) has not yet been evaluated. EPCs labeled with CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR2) antibodies were counted by flow cytometry in the peripheral blood of 53 NSCLC patients. Furthermore, by means of a quantitative reverse transcription-PCR approach, we measured VEGFR2, CD133, CD34, and VE-cadherin mRNA in the peripheral blood samples of the same patient population. EPCs in tumor samples were identified by confocal microscopy using CD31, CD34, CD133, and VEGFR2 antibodies. Although immunofluorescent labeling of microvessels made clear that incorporation of EPCs is a rare phenomenon in NSCLC tissue (9 of 22 cases), circulating EPC levels before therapeutic intervention were increased in NSCLC patients (P < 0.002, versus healthy controls), and high pretreatment circulating EPC numbers correlated with poor overall survival (P < 0.001). Furthermore, in the subgroup of responders to treatment, the posttreatment EPC numbers in the peripheral blood were significantly lower compared with nonresponding patients. Interestingly, pretreatment mRNA levels of CD133, VE-cadherin, and CD34 were not significantly increased in NSCLC patients, whereas VEGFR2 expression was increased by 80-fold. Moreover, posttreatment VEGFR2 mRNA level in the peripheral blood was significantly higher in the subgroup of nonresponding patients when compared with posttreatment level of patients responding to antitumor therapy. Circulating levels of bone marrow-derived EPCs are significantly increased in NSCLC patients and correlate with clinical behavior.
Dome
Balazs
B
Department of Tumor Biology, National Koranyi Institute of Pulmonology, National Koranyi Institute of Pulmonology, Budapest, Hungary. domeb@yahoo.com
Timar
Jozsef
J
Dobos
Judit
J
Meszaros
Livia
L
Raso
Erzsebet
E
Paku
Sandor
S
Kenessey
Istvan
I
Ostoros
Gyula
G
Magyar
Melinda
M
Ladanyi
Andrea
A
Bogos
Krisztina
K
Tovari
Jozsef
J
D000071916:AC133 Antigen; D015703:Antigens, CD / Q000097:blood; D018952:Antigens, CD34 / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D015820:Cadherins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000098:blood supply / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000097:blood; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000098:blood supply / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood / Q000473:pathology; D010455:Peptides / Q000097:blood; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D000099152:Cadherin 5
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D015820:Cadherins; D006023:Glycoproteins; D010455:Peptides; D012333:RNA, Messenger; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C000606023:PROM1 protein, human