Expression And Clinical Analyses Of Heparanase、VEGF And B-FGF In Prostate Cancer

Background:Prostate cancer(particularly for elderly males) is one of the most common malignant tumors which cause the male deaths in the world. Main treatment for prostate cancer includes surgery, hormone therapy、radiotherapy and chemotherapy. For hormone-refractory prostate cancer, there has been no effective treatment recently. Bone-metastasis is the most common manifestation for advanced Prostate cancer. To a large extent, bone metastasis is closely related to poor prognosis. Heparin-sulphate proteoglycans(HSPGs)is the basic component of the extracellular matrix and basement membrane. Heparanase is an unique endoglycosidase that degrade heparin sulfate proteoglycan family(HSPGs) by cleaving heparin sulfate side chains and remodel the extracellular matrix(ECM) and basement membrane. Heparanase also can release HS-bound biological active substances and participate in important physiological processes,such as wound healing, inflammation, angiogenesis, tumor progression.Heparanase directly stimulated the phosphatidylinositol3-kinase-dependent endothelial cell migration through protein kinase B/Akt signaling pathway. Studys have shown that heparanase can not only promote tumor angiogenesis,but also promote lymphangiogenesis. Heparanase can regulate cellular biological behavior in an enzymatic activity-independent manner, such as heparanase can promote the expression of VEGF by enhancing phosphorylation of signaling molecules Src. Recently, heparanase upregulation was documented in an variety of human carcinomas,especially in tumor invasion and metastasis, like endometrial cancer, breast cancer, esophageal cancer, stomach cancer, colon cancer, hepatoma, head and neck cancer,etc. In many cancers, heparanase expression correlated with tumor matastasis, angiogenesis and poor prognosis, but there were few reports about heparanase expression in prostate cancer, thus it is important to investigate the relationship between heparanase expression and occurrence and development of prostate cancer.Objective:To investigate the expression levers of heparanase、VEGF、b-FGF in prostate cancer(Pca) and benign prostatic hyperplasia(BPH), the relationship between heparanase and clinicopathological significance and prognosis.Materials and Methods:80cases (age,43to87years; mean,71) who were diagnosed for prostate cancer at the Institute of Pathology, Nanfang Hospital, between2003and2011were enclosed in this study.20cases of benign prostatic hyperplasia were chosen as control.All patients did not receive radiotherapy, chemotherapy, endocrine therapy and other anti-cancer treatment,and no other malignancies at the time of diagnosis were included.All patients are divided by age, gleason scores,bone matastasis,the value of serum PSA, TNM stage(according to2009UICC staging system). Two-step Immunohistochemical staining (Non-Biotin HRP Detection System) was adopted in this retrospective study. We investigate the expression levers of heparanase、VEGF、 b-FGF in prostate cancer(Pca) and benign prostatic hyperplasia(BPH), the relationship between heparanase and clinicopathological significance.Clinical follow-up data were collected. All datas were analyzed by the software SPSS13.0. The grade materials were evaluated with non-parametric rank sum test(Kruskal-Wallis H test or Mann-Whitney U test). Spearman rank correlation analysis was employed to test the correlation between variables. Kaplan-Meier survival analysis was performed for75cases with survival time, and we analyzed the prognostic factor according to Cox regression model in these cases. Result:1.The expression of Hpa, VEGF, b-FGF in the prostate cancer (Pca) and benign prostatic hyperplasia(BPH)Hpa, VEGF, b-FGF were distributed in cytoplasm of glandular epithelial cell, cytoplasm of tumor cells, Hpa was occasionally expressed in the nucleus of tumor cells. The expression rate of Hpa were80%in Pca group,25%in BPH group,there were significant differences (P<0.001). The expression rate of VEGF were85%in Pca group,35%in BPH group,there were significant differences (P<0.001). The expression rate of b-FGF were85%in Pca group,40%in BPH group,there were significant differences (P<0.001). The expression rate of Hpa, VEGF, b-FGF in the Pca group was significantly higher than in BPH group.2.The correlations between the expression of Hpa, VEGF, b-FGF and prostate cancer clinicopathological factorsThe expression of Hpa, VEGF, b-FGF in bone metastasis group was significantly higher than in non-bone metastasis group (P<0.001、P<0.01、P<0.001). The expression of Hpa, VEGF, b-FGF in T3-T4clinical stage group was significantly higher than in T1-T2clinical stage group (P<0.01、P<0.01、P<0.01). The expression of Hpa, VEGF was significantly diffent in PSA subgroups (P<0.01、P<0.01), and was positively correlated with PSA values (P<0.01、P<0.001). In the comparison between any two PSA subgroups, the results showed that the expression of Hpa, VEGF in the PSA≤20subgroup was significantly lower than in the PSA≥100subgroup (P<0.01、P<0.01), but for the adjacent PSA subgroups(between PSA≤20subgroup and20<PSA<100subgroup, between20<PSA<100subgroup and PSA≥100subgroup), the expression of Hpa was not significantly different (P>0.05).In the adjacent PSA subgroups(between PSA<20subgroup and20<PSA<100subgroup), the expression of VEGF was not significantly different (P>0.05)。The expression of b-FGF was not significantly diffent in PSA subgroups (P>0.05).The expression of Hpa, VEGF, b-FGF were not associated with age and Gleason score (P >0.05)3.The correlations between the expression of Hpa and the expression of b-FGF in prostate cancerThe expression of Hpa was positively correlated with VEGF and b-FGF expression respectively (r=0.524, p<0.001; r=0.583, p<0.001)4. Survival analysis resultsClinical follow-up data were available for75of the80patients(93.8%). Cases with bone-matastasis,T3-T4clinical stage showed a significantly shorted mean survival time in comparison with the patients with non-bone-matastasis, T1-T2clinical stage (p<0.001、p<0.01). Patients with high Hpa, VEGF, b-FGF expression showed a significantly shorted mean survival time compared with patients with low Hpa,VEGF,b-FGF expression (p<0.001, p<0.001, p<0.05).Univariate survival analysis showed that clinical stage, bone-matastasis, Hpa expression,VEGF expression,b-FGF expression were prognostic factors in prostate cancer (p<0.05). In the multivariate survival analysis, Hpa expression, VEGF expression, bone-matastasis were significant independent prognostic factors(p<0.05)。Conclusions:Hpa, VEGF, b-FGF were commonly up-regulated in prostate cancer, and they were both significantly associated with bone-matastasis, clinical stage. Hpa, VEGF were both significantly associated with PSA value also. The expression of Hpa was positively correlated with VEGF and b-FGF expression respectively. Univariate and multivariate analyses have showed that Hpa is an independent prognostic factor and played a important role in the progress and angiogenesis of prostate cancer.