Urinary biomarkers predict brain tumor presence and response to therapy.
OBJECTIVE
A major difficulty in treating brain tumors is the lack of effective methods of identifying novel or recurrent disease. In this study, we have evaluated the efficacy of urinary matrix metalloproteinases (MMP) as diagnostic biomarkers for brain tumors.


METHODS
Urine, cerebrospinal fluid, and tissue specimens were collected from patients with brain tumors. Zymography, ELISA, and immunohistochemistry were used to characterize the presence of MMP-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL), and vascular endothelial growth factor (VEGF). Results were compared between age- and sex-matched controls and subjected to univariate and multivariate statistical analyses.


RESULTS
Evaluation of a specific panel of urinary biomarkers by ELISA showed significant elevations of MMP-2, MMP-9, MMP-9/NGAL, and VEGF (all P < 0.001) in samples from brain tumor patients compared with controls. Multiplexing MMP-2 and VEGF provided superior accuracy compared with any other combination or individual biomarker. Receiver-operating characteristics curves for MMP-2 and VEGF showed excellent discrimination. Immunohistochemistry identified these same proteins in the source tumor tissue. A subset of patients with longitudinal follow-up revealed subsequent clearing of biomarkers after tumor resection.


CONCLUSIONS
We report, for the first time, the identification of a panel of urinary biomarkers that predicts the presence of brain tumors. These biomarkers correlate with presence of disease, decrease with treatment, and can be tracked from source tissue to urine. These data support the hypothesis that urinary MMPs and associated proteins are useful predictors of the presence of brain tumors and may provide a basis for a novel, noninvasive method to identify new brain tumors and monitor known tumors after treatment.
Smith
Edward R
ER
Department of Neurosurgery, Children's Hospital, Boston, MA 02115-5737, USA.
Zurakowski
David
D
Saad
Ali
A
Scott
R Michael
RM
Moses
Marsha A
MA
D000209:Acute-Phase Proteins / Q000134:cerebrospinal fluid / Q000652:urine*; D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000652:urine*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000628:therapy / Q000652:urine; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D000071068:Lipocalin-2; D054834:Lipocalins / Q000134:cerebrospinal fluid / Q000652:urine*; D008137:Longitudinal Studies; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000134:cerebrospinal fluid / Q000652:urine*; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid / Q000652:urine*; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000134:cerebrospinal fluid / Q000652:urine*; D042461:Vascular Endothelial Growth Factor A / Q000134:cerebrospinal fluid / Q000652:urine*
D000209:Acute-Phase Proteins; D014408:Biomarkers, Tumor; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9