The Relationship Between Pathological Grade And Cathepsin B As Well As Cystatin C Expression In Hunman Gliomas

Background and Objective: Gliomas are the most common of all brain tumors, contributing to more than half of their incidence. Migration and invasion of tumor cells are important for the infiltrative and destructive growth patterns of malignant gliomas.Tumor cells often infiltrate several millimeters beyond any obviously defined tumor margin, often preventing complete tumor resection and contributing to the high incidence of recurrence,which is the main cause of death from gliomas. Therefore, it is urgent and significant to elucidate the molecular mechanisms underlying glomas cell migration and invasion, inhibit the growth of gliomas and improve survival and prognosis for gliomas patients. .Invasion of tumor involves multiple steps and factors. In central nervous system, proteolytic enzymes related to infiltration of gliomas are classified as followings: ( 1) matrix metalloproteinases(MMPs);( 2)urokinase-type plasminogen activator(uPA), tissue-type plasminogen activator(tPA), plasminogen activator inhibitor(PAIs); ( 3) cathepsin. Cysteine cathepsins are papain-like proteases.Cathepsin is normally localized to lysosomes, including cathepsin B,cathepsin D, cathepsin H, cathepsin L and cathepsin S. During the invasion and progression of gliomas cells into adjacent brain tissues, cathepsins can either directly degrade extracellular matrix(ECM) and matrix barriers or indirectly activate related proteolytic enzymes to facilitate the invasive spread of tumor cells. Among them, cathepsin B is considered ashousekeeping gene and is responsible for progression of tumor. It has been reported that cathepsin B has abnormally high expression in lung cancer, stomach cancer, colon cancer,liver cancer, breast cancer and prostate cancer. In addition, the intensity of cathepsin B expression is associated with the differentiation, histological type and invasion of tumors.Recent studies have shown proteolytic enzymes possess their corresponding inhibitors. The activity of the cysteine cathepsins can be regulated at various levels, ultimately by their endogenous inhibitors. According to molecular structures, cystatin family can be classified into following types: cystatin A and B which are intracellular proteins; cystatin C and cystatin S which are secret proteins. In general, the proteolytic enzymes and their inhibitors maintain a balance to prevent cells from being degraded by proteolytic enzymes. Cystatin C is the strongest inhibitor of cathepsin B, also inhibits other cathepsins.So far, the role of cystatin family in invasiveness of tumors has not been reported in China, but other investigators have revealed that cathepsin B and cystatin C participate in invasion and metastasis of lung cancer, colon cancer, breast cancer and ovarian cancer. However, knowledge of cathepsin B and cystatin C participation in the progression of gliomas is limited.Methods: In the present study, immunohistochemical method was used to detect the expression of cathepsin B and cystatin C and investigate their association with the pathologic grade of 27 gliomas. The aim is to provide useful information to inhibit the growth and invasion of gliomas.Results: 1. The expression of cathepsin B in gliomas Cathepsin B was expressed in the cytoplasm and on the cell membrane of gliomas cells as well as in some extracellular matrix. No expression was apparent in the nuclei. The expression of cathepsin B was detected in all 27 gliomas. Low-grade( WHO gradesⅠ-Ⅱ) gliomas tended to have low percentage of cathepsin B positive expression and weak staining intensity(1.4±0.7).With increased tumor grade, the percentage of cathepsin B positive expression cells and immunochemical staining intensity were increased. The expression of cathepsin B in high-grade (WHO gradesⅢ—Ⅳ) was significantly higher than in low-grade(2.5±0.5, p=0.003). 2. The expression of cystatin C in gliomas The expression of cystatin C was spreadin the cytoplasm and extracellular matrix. It was found that the percentage of cystatin C positive expression was 100%(27/27). The expression of cystatin C in low-grade (2.9±1.2)was significantly higher than in high-grade ( 1.3±0.7, p =0.001 ) .3. The correlation between cathepsin B and cystatin C The expression of cathepsin B was inversely correlated with cystatin C (r=-0.454,p =0.01).The ration of cathepsin B to cystatin C in gradeⅠ-Ⅱ(1.3±2.7) was lower than gradeⅢ—Ⅳ(3.1±2.6, p=0.1).Conclusions With increased gliomas grade, the expression of cathepsin B was increased and the expression of cystatin C was decreased. The expression of cathepsin B was inversely correlated with cystatin C. implying their expressions are closely associated with differentiation and invasion of gliomas. The combining detection of cathepsin B and cystatin C is useful to evaluate maglinant degree of gliomas.