The Expression Of Angiopoietins In Human Esophageal Squamous Cell Carcinoma And Their Roles In The Initiation And Progression Of Tumor

It is well known that angiogenesis, as a basic incident, participates in many pathological processes including wound healing, chronic inflammation and tumors etc. The research on the course and mechanism of angiogenesis promotes the application and development of anti-angiogenic cancer therapies. Some angiogenesis targets have used on many medicial fields, both the analysis or predication of malignant tumor biological behavior and the selection of treatment strategy.It is now known that members of the vascular endothelial growth factor and angiopoietin families induce tumor angiogenesis. The angiopoietins include a naturally occurring agonist, angiopoietin-1 (Ang-1), as well as a naturally occurring antagonist, angiopoietin-2 (Ang-2), both of which act by means of the Tie-2 receptor.To date, Angiopoietin family, as the second family of growth factors that specially act on the vascular endothelium mainly includes Ang-1, Ang-2, Ang-3 and Ang-4, which all may bind to the Tie-2 receptor and as the blood vessel stabilization signals to involve the angiogenesis of both physiological and pathological procedures. In recent years, the angiopoietins have emerged as important regulators of angiogenesis in the fields of embryonic vessel development, angiogenic remodeling, inflammation and cancer as well.Worldwide, esophageal carcinoma is a common gastrointestinal cancer with a high mortality. The incidence of adenocarcinoma of the esophagus is increasing in the western world, but squamous cell carcinoma remains dominant in the developing parts of the world. Currently, there are no optimal preventative screening programs available and most patients present with advanced or metastatic disease. To promote the diagnosis rate of early squamous cell carcinoma is of great importance.At present, more than a few studies have indicated that Ang-2 and Tie-2 receptor overexpressed in many gastrointestinal cancer such as gastric carcinoma, colorectal adenocarcinoma, hepatocellular cancer and pancreatic tumors etc. However, the research on the relationship between the expression of angiopoietin and esophageal squamous cell carcinoma (ESCC) is still very rare. Therefore, to gain a better understanding of the role of the Ang/Tie-2 system in ESCC, the expression of both proteins and genes were investigated in a series of human ESCCs. Firstly, the expression of Ang-2 protein and gene were studied in the cases of ESCC to understand the relationship between the expression and clinical pathological factors. Secondly, we studied the relationship between the expression of Ang-2/Tie-2 system and tumor angiogenesis. Thirdly, we investigated the expression of Ang-1 and Ang-2 proteins in different stages of ESCC and then evalued their roles in the initiation and progression of tumors. Moreover, in order to provide some evidence for the diagnosis of early ESCC, we also investigated the relationship between the expression of Ang-2 mRNA and endoscopic classification.Now the results are as follows:1. S-P immunohistochemistry method was used to detect the expression of Ang-2 in 85 cases of ESCC and 22 cases of normal esophageal tissue. As a result, Ang-2 was detected in 57 out of 85 (67.06%) cases of ESCC and 8 out of 22 (36.36%) cases of normal esophagus tissue (P<0.05). The positive expression rate of Ang-2 increased significantly with the increase of pathological grading and lymphatic metastasis (P<0.05).2. In situ hybridization method was performed to detect the expression of Ang-2 mRNA in the same cases. The positive AOD of Ang-2 mRNA in ESCCs was higher than in normal esophageal issues. There was remarkably difference in comparison between normal esophageal issues and ESCCs (P<0.05). In addition, the positive AOD of Ang-2 mRNA in ESCCs increased significantly with the increase of pathological grading and infiltration depth (P<0.05).3. Expression of Ang-2,Tie-2 and CD34 proteins were detected immunohistochemically in 39 cases of the differently graded squamous carcinoma of esophagus. Microvessel density (MVD) was counted according to the result of CD34 protein staining. It showed that the positive staining of both Ang-2 and Tie-2 proteins were 74.36%. The levels of the two proteins were significantly related to differentiation degree and lymphatic metastasis of tumor tissues. The MVDs of the cases of Ang-2 and Tie-2 strongly-positive staining were 42.83±7.73 and 41.62±5.83 respectively, both of which were significantly higher than those of negative staining and the MVDs were 33.70±3.34 and 35.20±3.74, (P<0.01).4. S-P immunochemical method was used to detect the expression of Ang-1 and Ang-2 in 13 cases of normal squamous epithelium, 32 cases of early ESCC and 34 cases of advanced ESCC. The findings were then analyzed compared with the pathological factors. It was found that there was not significant difference in Ang-1 expression between normal squamous epithelium group and early carcinoma group as well as advanced carcinoma group(P>0.05), but there was remarkable correlation in Ang-2 expression between normal squamous epithelium group and early carcinoma group or advanced carcinoma group(P<0.05).5. In situ hybridization method was performed to detect the expression of Ang-2 mRNA in 47 cases of early ESCC and combined with endoscopic classification, it was indicated that the expression of Ang-2 mRNA was various in different infiltration depath of endoscopic classification. There was remarkable correlation in Ang-2 gene expression between the infiltration depath of endoscopic classification(P<0.05).In conclusion, the increased expression of Ang-2 maybe occurs in the early stage of esophageal carcinomatous changes and it may be involved in the development and progression of ESCC. Ang-2 may play an important role in the iniation and progress of esophageal carcinoma. This work attempts to provide some new ways on early diagnosis and endoscopic therapy and anti-angiogenic cancer therapies.