Increased expression of urinary matrix metalloproteinases parallels the extent and activity of vascular anomalies.
OBJECTIVE
Matrix metalloproteinases (MMPs) and the angiogenic proteins basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been implicated in mechanisms of human cancer and metastasis. Assays were conducted on the urine of patients with vascular anomalies (tumors and malformations), relatively common and occasionally life-threatening disorders for which few therapies exist. We sought to determine whether these angiogenesis modulators are present in the urine and whether their expression is associated with the extent and clinical course of the vascular lesion.


METHODS
A total of 217 patients with vascular anomalies and 74 age-matched control subjects participated. Urinary MMP expression was determined by substrate gel electrophoresis. Urinary bFGF and VEGF levels were measured by enzyme-linked immunosorbent assay. Each patient was assigned to 1 of 2 categories (tumor or malformation) and 1 of 9 specific groups. Extent of the vascular lesion and activity were scored by a blinded clinician.


RESULTS
Urinary high molecular weight (hMW) MMPs and bFGF were significantly increased in patients with vascular tumors (53%) and vascular malformations (41%), compared with control subjects (22%). These percentages increased as a function of extent of the lesion and disease activity. hMW MMPs were increased in 4 groups: infantile hemangioma, other vascular neoplasms, lymphatic malformation and capillary-lymphaticovenous malformations, and extensive and unremitting capillary malformation and arteriovenous malformation. No significant differences among the groups were detected for low molecular weight MMPs or VEGF.


CONCLUSIONS
Expression patterns of hMW MMPs and bFGF in the urine of patients with tumors and malformations are consistent with their different clinical behavior. These data represent the first evidence that MMPs are elevated in the urine of children with vascular anomalies. These data also suggest that the increased expression of urinary MMPs parallels the extent and activity of vascular anomalies in children. In addition to tumors, vascular malformations are angiogenesis dependent, suggesting that progression of a vascular malformation might be suppressed by angiogenic inhibitors, which would target bFGF and MMPs.
Vascular Anomalies Center and Department ofSurgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA. jennifer.marler@chmcc.org
Jennifer J
JJ
Marler
Steven J
SJ
Fishman
Susan M
SM
Kilroy
Jianmin
J
Fang
Joseph
J
Upton
John B
JB
Mulliken
Patricia E
PE
Burrows
David
D
Zurakowski
Judah
J
Folkman
Marsha A
MA
Moses
D000293:Adolescent; D000328:Adult; D001808:Blood Vessels / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000652:urine; D006391:Hemangioma / Q000652:urine; D006801:Humans; D044148:Lymphatic Abnormalities / Q000652:urine; D008297:Male; D020782:Matrix Metalloproteinases / Q000652:urine*; D008970:Molecular Weight; D014652:Vascular Diseases / Q000652:urine*; D042461:Vascular Endothelial Growth Factor A / Q000652:urine; D019043:Vascular Neoplasms / Q000652:urine*
D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D020782:Matrix Metalloproteinases