Immunohistochemical expression of MMP-2, MMP-9, and TIMP-2 in neuroblastoma: association with tumor progression and clinical outcome.
OBJECTIVE
The matrix metalloproteinases (MMPs) are responsible for degradation of the extracellular matrix. The MMPs and their specific tissue inhibitor metalloproteinases (TIMP) have been associated with tumor cell invasion and metastasis in a number of adult tumors. This study was carried out to detect their expression pattern in neuroblastoma and to evaluate whether they have any association with tumor progression and clinical outcome.


METHODS
Cryostat sections of tumor tissues were collected from 31 patients with neuroblastoma, and immunohistochemical staining of MMP-2, MMP-9 and TIMP-2 with specific antibodies was performed according to labelled streptavidin-biotin method.


RESULTS
MMP-2 and MMP-9 were coexpressed in neuroblastoma and exhibited an intratumor variability of staining intensity. MMP-2 and MMP-9 staining were confined mostly to the peritumoral stromal tissues rather than tumor cells and found positive in 80.6% cases and 71.0% cases, respectively. MMP-2 and MMP-9 immunoreactivity had no association with mass screened cases or with age of the patients. Increased expression of MMP-2 in stromal tissues of neuroblastoma had significant association with advanced clinical stages (chi2 test, P < .05). However, the expression of MMP-9 in neuroblastoma had no association with clinical stages and prognosis. However, TIMP-2 staining was confined mostly to the neoplastic cell cytoplasm, stromal tissue, and to the endothelial cells and accounted for 58.0% positivity. Decreased expression of TIMP-2 also had significant relationship with advanced clinical stages (chi2 test, P < .05). Kaplan-Meier survival curve showed that either increased expression of MMP-2 or decreased expression of TIMP-2 had relationship with poor clinical outcome.


CONCLUSIONS
In neuroblastoma, stromal tissues are actively involved in the complex interaction between MMP-2 and TIMP-2 in extracellular matrix degradation during tumor progression, and TIMP-2 expression is inversely correlated with the corresponding MMP-2. An early detection of their expression pattern by immunohistochemistry in neuroblastoma may provide prognostic informations in clinical practice.
Department of Pediatric Surgery, Osaka University Medical School, Suita City, Japan.
T
T
Ara
M
M
Fukuzawa
T
T
Kusafuka
Y
Y
Komoto
T
T
Oue
M
M
Inoue
A
A
Okada
D014408:Biomarkers, Tumor / Q000032:analysis*; D001707:Biopsy, Needle; D002675:Child, Preschool; D017364:Collagenases / Q000032:analysis*; D046508:Culture Techniques; D005260:Female; D018093:Gelatinases / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000032:analysis*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000556:secondary; D011379:Prognosis; D011480:Protease Inhibitors / Q000032:analysis*; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D015996:Survival Rate; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis*
D014408:Biomarkers, Tumor; D011480:Protease Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9