Association Between The Expression Of MMP-2,-9, TIMP-2,-1 And Tumor Progression In NB

Objective: Neuroblastoma(NB) is the most common extracranial malignant solid tumor of childhood and arises from the sympathetic nervous system. The outcome is connected with the age at the time of diagnosis and clinical stage. K II stage has better prognosis. IV S stage which may has distant metastasis limited to the live^ bone marrow or skin but absent in bones can regresses naturally. But advanced stage (III ^ IV stage) has high recurrence rate and mortality rate even after operation, themotherapy, radiation and bone marrow transplantation.Matrix metalloproteinases(MMPs) is a large family of Zn++-dependent neural endopeptidases with a protedytic activity for many components of the extra celluler matrix(ECM), which take part in a series of physiological and pathological process, especially in tumor invasion and metastasis. MMPs can destroy the basement membrane(BM) and regional tissue structure, promoting angiogenesis by degrade the ECM. MMPs play a important role for the tumor cells to metastasis.The activity of MMPs is controlled by a family of tissue inhibitors of metalloproteinases(TIMPs) which can form stable complexes with the active domain of MMPs and control the activation process so as to decrease the degration of ECMMMPs comprise about 20 different proteases. Among them, gelatinase A(MMP-2) and gelatinase B(MMP-9) can act at basement membrance collagens and the capability of degradation of basement membrance is far more important than other members ofMMPs. TIMP-2 and TIMP-1 can connect with MMP-2 and MMP-9 respectively, forming complexes with both latent and activated MMPs. They block the degradation of ECM and are responsible for the inhibition of tumor progression. NB always has poor prognosis, and the majority of tumor-related deaths are caused by frequent metastasis. So it is important to study the expression of MMP-2, MMP-9,TIMP-2,TIMP-1 and the relationship between their levels and clinical stage, different outcome of NB. To detect the role of them in the occurance > development of NB and the possible mechanism of tumor cells'invasion and metastasis. In order to evaluate whether they can be used as a reliable predictor for diagnosis and whether a new treatment pattern can be carried out.Method: Cryostat sections of NB tumor tissue were collected from 1990-2001.We use immunohistochemistry method to detect the stain of MMP-2,MMP-9,TIMP-2,TIMP-1 in neuroblastoma specimens, compare them with clinical stage and the age at diagnosis.Result: Positive staining of MMP-2,MMP-9 and TIMP-2, TIMP-1 were observed in all the samples, but with different intensity. In stage I , II , IV S, MMP-2 expression is about 63. 6% and in advanced stage(stage UK IV) is 91. 7%, but the strong expression(++, + + + ) is from 18.2% to 79.2% in different stage. While MMP-9 staining is from 72.7% to 87.5%,and strong staining 36.4% to 79.2%,respectively. There are nine samples show strong staining of TIMP-2 in early tumor, and ten in advanced. Under one year old, MMP-2 strong staining is found in 2 samples of 7, while in elder children, there are 19. The result of MMP-9 is 6 and 17.Conclusion: In NB, the MMP-2, MMP-9 staining is increased as the progression of tumor,while TIMP-2 expression is inverse.They are all significantly associated with clinical stages and different prognosis. But it seems that there is no effect by the age of the patients, which is also an important prognosis factor in NB. This study demonstrates that MMP-2,MMP-9 and TIMP-2 play important role to indicate the prognosis in NB. An early detection may provide information to treatment.