Mmp-9 And Timp-1, Expression Of Vegf And Cd44v6 In Non-small Cell Lung Cancer And Its Clinical Significance

Non-small cell lung cancer (NSCLC) is one of the most common cancer in the world. It is a major cause of death from malignant diseases, due to its high incidence malignant behavior and lack of major advancements in treatment. Non-small cell lung cancer has a poor prognosis due to its tendency towards local invasion and subsequent metastasis. A complex series of steps must take place to allow for a single cell to metastasize, which is mediated by multiple proteolytic enzymes, angiogenesis and cellular adhesion. Identifying factors responsible for these steps is essential to invasion and metastasis. We detected expression of matrix metalloproteinases-9(MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) , vascular endothelial growth factor (VEGF) ,and CD44 variance 6(CD44v6) by immunohistochemical method in non-small cell lung cancer. We used them to investigate mechanisms of metastasis to human non-small cell lung cancer .The aim of this study was to examine the expression levels of MMP-9, TIMP-1, VEGF and CD44v6 in non-small cell lung cancer, and to evaluate the relationship between the expression levels of MMP-1, TIMP-1, VEGF and CD44v6 and some clinicopathological parameters ,such as tumor size ,lymph nod metastasis , pathological type and TNM stage. We also analysed interrelations of MMP-9, TIMP-1, VEGF and CD44v6 in invasion and metastasis of non-small cell lung cancer and study their malignant behavior and clinical significance. Methods Immunohistochemical method was used to detect the expressions of MMP-9, TIMP-1, VEGF and CD44v6 in 91 cases of non-small cell lung cancer and 20 control subjects with normal lung tissues. Their relationships between the four biological marker and some clinicopathological parameters were analyzed. Results 1) The positive rates of MMP-9, TIMP-1, VEGF and CD44v6 in NSCLC were much higher than those in the normal lung tissues, P<0.01. Compared with squamous cell carcinoma (Sqcc), adenocarcinoma (Adc) more frequently overexpressed MMP-9, TIMP-1 and VEGF, whereas the higher frequency of CD44v6 overexpression was in Sqcc than in Adc. 2) MMP-9, TIMP-1, VEGF and CD44v6 expression positively correlated with more advanced stage disease. The expression levels of MMP-9, VEGF and CD44v6 were associated with lymph nodal metastasis. Multivariate analysis showed VEGF and MMP-9 to be the most related toTNM stage, CD44v6 to be the most related to nodal metastatisis and VEGF to be the most related to the tumor size . 3) The positive relations between MMP-9 and TIMP-1, MMP-9 and VEGF, TIMP-1 and VEGF were all statistically significant in NSCLC (P<0.05). Along with the raised expression of MMP-9, TIMP-1 and VEGF expression would be increased.4) The combined positive rate of MMP-9, TIMP-1, VEGF and CD44v6 was 36.3% in NSCLC. Their positive expression levels were higher in III stage and IV stage than in I stage and II stage. Conclusions 1) The expression and distribution suggested that MMP-9, TIMP-1,VEGF and CD44v6 might play important roles in tumor invasion and metastasis of human NSCLC. 2) MMP-9 and VEGF expression levels showed a significant correlation to TNM stage. CD44v6 may be valuable for predication of lymph nod metastasis. VEGF may play an important role in tumor angiogenesis. 3) With the increasing expression level of MMP-9, TIMP-1 expression level would be increased. This demonstrated the proportion imbalance of MMP-9 and TIMP-1 may play an important role in tumor invasion and metastasis.4) Combined overexpression of MMP-9, TIMP-1, VEGF and CD44v6 in NSCLC revealed poor prognosis. They stimulated the malignant behavior of NSCLC.5) MMP-9, TIMP-1, VEGF and CD44v6 may be good predictors of metastasis and prognostic for human NSCLC.