The Clinical Study Of Endothelin-1 Expression In Prostate Cancer

Prostate carcinoma(PCa) is one of the most common malignances among the urological neoplasms and the incidence of Pca is getting higher and higher in China today with the aging and the diet habit changing.However,the patients with Pca in China are quite different from that in the western countries.For example,Chinese patients are often diagnosed as the advanced Pca in the outpatient department who have lost the opportunity of radical surgery,which leads to the poor prognosis.For those patients,how to inhibit the proliferation,invasiveness and metastasis of the tumor is of the most importance. A lot of studies have focused on this field,in which the endothelin(ET) axis is an important one of the focuses.In 1988,a graduate student in Japan,published a paper in the journal Nature about the isolation and characterization of a new,21-reside peptide prodced by porcine aortic endothelial cells as the most potent vasoconstrictor,called endothelin.The vasoconstrctor activity of endothelin was one of the most potent reported.This peptide,now termed endothelin-1,was part of a family of endothelins,which includes ET-2 and ET-3. The biologic activity of ET-1 is the most potent among the three peptides. The family ligands and the ET receptors(ETA and ETB) are termed the ET axis.As a biologic mediator ,ET-1 is ubiquitous.It is produced by a large variety of cells from a wide range of mmmalian species. ET contributes to a great many body functions and a great deal of diseases including many tumors.The tumor development, progression and metastasis are quite complicated process involved in a series of pathologic physiology aspects such as the proliferation and differentiation of the malignancies and vascular proliferation of tumor tissue. Previous research showed that the ET axis plays an important physiological role, as transcription of proto-oncogene, modulator of vascular tone, tissue differentiation, development of cell proliferation. The role of ET axis in mitogeneses, apoptosis inhibition, invaseveness, angiogenesis and bone remodeling provides evidences of the importance of ET axis in cancer. It's reported that ET participates in the growth and progression of a variety of tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, brain tumors, melanoma, and bone metastases, suggesting endothelin receptors as novel targets in tumor therapy.Until present,many research have shown that the expression level of ET-1 in the tissues and plasma of many kinds of tumors is pretty high,implicating that ET-1 may become a promising molecule marker to predict the prognoses in those kinds the tumors.To the best of our knowledge,there are still many different opinions about the clinical significance of the plasma concentrations of ET-1 in tumors,the localization of ET-1 in BPH and PCa tissues and its respective sense.Our study aimed to find out the relationship of ET-1 plasma levels and between BPH and PCa,the exact localization of ET-1 in BPH and PCa tissues,the relationship between the ET-1 expression and the PCa,and the relationship between the ET-1 and the VEGF in PCa from the following five aspects:1. Using the technique of the radioimmunoassay to investigate plasma ET-1 level in patients,we found that there were no significance among the BPH group,non-HRPC group and HRPC group, between bone metastasis(BM) and non- BM, between high and middling differentiation prostate cancer, among different PSA level groups (P>0.05).But the ET-1 level in low differentiation prostate cancer was significantly lower than the high and middling(P<0.05).The study suggests that detecting plasma ET-1 level might not be a useful method to determine the development and the prognosis of prostate cancer.The cilinical significance to evaluating prostate cancer is uncertain.2. Using the technique of the radioimmunoassay to investigate plasma ET-1 level and the ET-1 quantity in tissues of BPH patients and normal person, we found that there were no significance of plasma ET-1 level between the BPH and normal group (P>0.05), but the ET-1 quantity in tissues of BPH is significantly higher than that of normal group. The study suggests that the abnormal ET-1 expression may be related to the development of BPH,but the variation of plasma ET-1 level compared with normal tissues could not be detectived.3. Using the technique of the radioimmunoassay to investigate the effects of DRE and transrectsl prostatic biopsy on plasma ET-1 levels.We found there are no significant differences in the plasma ET-1 levels before and after DRE or transrectsl prostatic biopsy(P>0.05). The study shows that such operations as DRE or transrectsl prostatic biopsy do not cause the variation of plasma ET-1 level because of not resulting in body's alarm reaction or changing of endothelial system all over the body.4. Using the technique of the immunohistochemistry(Elivision? plus method) to examine the expression of ET-1,we found that: the positive immunoreactivety was found in BPH and PCa,and the positive ratio reach 100%;Positive staining was localized mostly in the cytoplasm of glandular epithelium and smooth muscle cells of both BPH and PCa;Stroma vascular endothelial cells are all positive ataening;There are no significances in the intensity of positive staining of ET-1 between BPH and PCa group(P>0.05), between bone metastasis(BM) and non-BM group(P>0.05) and between high and middling differentiation prostate cancer(P>0.05), but the staining intensity of ET-1 in low differentiation prostate cancer was significantly higher than the high and middling(P<0.01). The study shows that ET-1 has a high expression both in BPH and in PCa,but the functions are different in the two diseases. ET-1 sevices as a paracrine factor in charge of construction of stroma smooth muscle,playing a important role in BOO. ET-1 should not be regarded as a carcinogenic factor.The effects of ET-1 on the development and progression of tumor depend on the type of ETR distributed over the tumor tissues.5. Using the technique of the immunohistochemistry(Elivision? plus method) to examine the expression of ET-1 and VEGF,we found that:ET-l was stained mainly in the cytoplasm of tumour cells and weakly in vascular endothelial cells;the stainingintensity of VEGF in PCa was significantly higher than in the BPH(P<0.01), in low differentiation prostate cancer hinger than the high and middling group(/*<0.01), in bone metastasis(BM) higher than non-BM group(P<0.01).The expression of ET-1 correlated directly with the expression of VEGF(rs=0.780,, P<0.0\). The study indicates that VEGF is relevant to the development,progression and metastasis of malignant tumors. The expression of ET-1 and VEGF genes and their functions are interactive.lt may be a novel efficiently way to inhibit both ET-1 and VEGF simultaneously.Nowadays there are still a lot of unresolved problems about the relationship between the ET-1 and the development or progression of tumor in PCa. First, whether or how the ET-1 downregulates apoptosis of tumors;Second, the relationship between the ET-1 and other genes or factors .related to proliferation and inhibition of tumors is still unknown;Third, the relationship between the ETR antagonists and the up-today therapies such as hormone therapy and radiotherapy is also unknownjFourth, the study of subtype of ETR and its special antagonists may be a promising orientationl;Fifth, there are still no follow-up data about the long-term therapeutic effects and side effects of ETR antagonists.