Telomerase,matrix metalloproteinases and their tissue inhibitory proteins activities in neuroblastoma

Background & Aim: The mechanisms underlying biological and prognostic heterogeneity of neuroblastomas still remain unknown. To investigate the significance of parameters which may play a role in this heterogeneity, we studied telomerase activity, matrix metalloproteinase 2 (MMP-2) and tissue inhibitory matrix metalloproteinase 3 (TIMP-3) expressions in neuroblastoma.Material and Method: The study included 50 primary neuroblastoma cases treated under standard protocol. Hematoxylen & Eosin stained tumor sections were reviewed to determine neuroblastic differentiation and mitotic-karyorexis index (MKI) and to categorize Shimada histological groups combining with age and NMYC status. 1 p deletion status, stage, survival, metastasis and recurrence were obtained from patients? records. Tumor sections were stained with MMP-2, TIMP-3 and telomerase antibodies to analyze the statistical relation between these protein expressions and established prognostic factors for neuroblastoma.Results: The median age was 48 months (range: 40 days-16 years). Of 50 cases, 29 (58%) were boy. Histologically, 19 (38%) cases were undifferentiated, 14 (28%) poor differentiated and 17 (34%) well differentiated. MKI was low in 23 (46%) cases, moderate in 13 (26%) and high in 14 (28%). Sixteen (32%) cases showed MYCN amplification (>10 copies). Based on Shimada classification, 34 (68%) cases were of poor histology group. Of 46 cases, 16 (34.7%) showed 1 p deletion. Twelve (41.3%) of overall 29 cases with standard clinical follow-up were in low risk category, three (10.3%) in moderate risk and 14 (48.4%) in high risk. Of 50 cases, 22 (44%) cases showed MMP-2 immunopositivity in tumor stroma, whereas both tumor cells and the stroma were positive in 46 (92%) cases for TIMP-3 antibody. Strong MMP-2 immunopositivity was significantly related with undifferantiation, poor histology, advanced tumor stage and metastatic disease (p>0.05). However, none of morphological, genetical and clinical parameters showed significant relation with TIMP-3 immunostaining. Thirty-one (62%) cases showed higher telomerase activity ( positivity in >90% tumor cells) with statistical relation to high MKI and advanced stage.Conclusion: We think that significant relation between strong MMP-2 expression and neuroblastic undifferentiation can explain why these cases were of poor histology group. The established role of MMP-2 in tumor invasion and angiogenesis is in concordance with advanced tumor stage and metastatic risk. In addition, telomerase activity is significantly increased in advanced stage neuroblastoma. Thus it may be an indicator of poor prognosis in neuroblastoma. However, based on our findings, TIMP-3 does not appear a prognosticator for this tumor.Keywords: matrix metelloproteinase - MMP-2 ? neuroblastoma- telomerase - TIMP-3 - tissue inhibitory matrix metelloproteinase