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Research of Expressions and Clinical Valuation of Pro-angiogenic Factors and Some Correlation Factors in Wilms’ Tumor

Author: NiuZhiBin
Tutor: WangChangLin
School: China Medical University
Course: Pediatrics
Keywords: Wilms’ tumor Angiogenesis VEGF angiopoietins Survivin Stat3 HIF-1α
CLC: R737.11
Type: PhD thesis
Year: 2007
Downloads: 115
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Abstract


INTRODUCTION AND OBJECTIVEWilms’s tumor is a pediatric malignancy of the kidney and one of the most common solid tumors in children. It account to 8% of all the solid tumors in children and 80% of malignant tumor in urogenital system among the children younger than fifteen years old. There may be seven cases of Wilms’ tumor among one million people in the world and it is an important disease in pediatric surgery. Despite the remarkable response to chemotherapy, 5-10% of tumours are fatal because of the occurrence of metastases and drug resistance. Therefore, it is important to find regulation mechanisms and biological characteristics of the process of growth of Wilms’ tumor to guide the research of direct treatment and new drug.Formation of the new vessels in tumor is essential for tumorous growth, angiogenesis is very important for the growth and invasion of the primartumor. It has been a hot spot of oncology research to study the relationship of angiogenesis and metastasis, development of solid tumor, it has been suggested that angiogenesis plays an important role in tumor progression and the spread of metastases through the bloodstream in solid tumors. It has been reported that several growth factors with angiogenic activity are produced by solid tumours. Vascular endothelial growth factor (VEGF) is an angiogenic factor that is highly specific for endothelium, and also functions as a vascular permeability factor. This study focus on VEGF AND study the expressions and clinical significance of VEGF and related cell factors in Wilms’ tumor, research the mechanisms of angiogenesis in Wilms’ tumor. The study may be helpful for the treatment of wilm’s tumor and provide a new way to cure the disease. MATERIALS AND METHODS1、Clinical specimens: All the specimens are from Congenital malformationslaboratory of the Ministry of Health. Wilms’ tumor specimens of 52 patients, 27 male, 25 female, aged 0.5-11 years with a mean age of 4.2 years, were confirmed by pathology; According to NWTS-5 (National Wilms Tumor Study) standards by histological anaplastic cells, there are 35 cases of good histological types and 17 cases of adverse histologic types. Nephridial tissues close to the tumors were taken immediately after surgery in which 47 cases. Another eight cases of renal tissues were drawed as control group from autopsy. Aseptic surgical specimens were treated with liquid nitrogen and stored. The specimens for RT-PCR were placed in the Eppendoff tubes which managed by DEPC and autoclaving. They were preserved in -80℃refrigerator. There were 31 cases in all the patients to be followed up for more than two years and seven cases died due to tumor recurrence and metastasis.2、Immunohistochemistry agents: Anti-ANG1, Anti-ANG1, Anti-TIE2,Anti-Survivin and Anti-Stat3 are polyclonal rabbit anti-human antibody (from the Fujian Maixin biotechnology companies). Anti-CD34, Anti-VEGF and Anti-FLT, Anti-HIF-1αare polyclonal rabbit anti-human antibody (Wuhan Boshide biotechnology companies). RT-PCR Kit, Marker (DNA Marker DL2000), Taq2 enzyme, dNTP Mixture and agarose are all from TAKARA Biotechnolgy Co.(Dalian) ; RNA lysates were purchased in TRIZOL Reagent (Total RNA isolation U.S).3、RT-PCR and immunohistochemistry staining method were used to study theexpressions of vascular endothelial growth factor (VEGF) and its receptors (FLT), and angiopoietin (Ang1, Ang2) and its receptor(Tie2) in different parts of WT specimens, CD34(the endothelial cell-specific marker) was detected by immunohistochemical staining, then the relationship of vascular density and the expressions of angiogenesis factors was analyzed.4、The expressions of Survivin and VEGF were detected by the immohistochemical staining and RT-PCR in 52 specimens from WT tissues, 47 from adjacent kidney tissues and 8 from normal kidney tissues in protein level and mRNA level. The data were analyzed combined with clinical and follow-up data.5、The expression of Stat3, HIF-1αand VEGF were detected by theimmunohistochemical staining in 52 specimens from Wilms’ tumor tissues, 47 from adjacent kidney tissues and 8 from normal kidney tissues, the expression intensity was analyzed by computer image processing of . Image-plus pro 5.1. The data were analyzed combined with clinical and follow-up data.RESULTS1、The expression levels of VEGF and Ang2 were significantly higher innephroblastoma group than the normal tissues(P<0.05), and so did the expression of CD34. The expressions of FLT and Ang1/Tie2 showed to be increased to various levels in tumor and tumor adjacent tissues as compared with normal kidney tissues. Compare with normal kidney tissue, expression of VEGF in the WT and adjacent tissues increased significantly (P <0.05). Expression of Ang2 was higher in the WT than in the adjacent tissues and kidney tissues, the difference was significant (P <0.05). Expressions of Ang1, Flt in various groups did not see significant differences (P> 0.2). But they had a trend of increase in the WT Ang1 and adjacent tissues compare to normal tissues. Increase in the number of angiogenesis, vascular disorder, intensive distorted could be seen in tumor tissues In adjacent tissues, vascular growth pattern was the expansion of invasive, much higher than the normal tissues, and it was consistency with the expressions of the vascular factors and its receptors.2、By immunohistochemical staining, Survivin was expressed in 72.9% of WTtissue samples and in 4.3% of adjacent kidney tissues; by RT-PCR, Survivin mRNA was expressed in 67.3% of WT tissue samples and 6.4% in adjacent kidney tissues, while no Survivin and mRNA expression was detected in normal kidney tissues. Incontrast, VEGF was expressed in 75% of WT tissues and 19.1% of adjacent kidney samples(P<0.05) and 12.5% in normal kidney tissues by immunochemical staining; VEGF mRNA was expressed in 71.2% of Wilms’ tumor tissues and 23.4% of adjacent kidney samples(P<0.05) and 25% in normal kidney tissues. The expression of Survivin and VEGF increased obviously in WT tissues with unfavourable prognosis and the cases with positive expressions of them were with higher mortality.3、The expressions of Stat3, HIF-1 and VEGF were significantly up-regulated inWilms’ tumor compare to that in adjacent tissues and normal kidney tissues(P<0.05). Stat3 and VEGF protein in Wilms’ tumor of clinical stage III-IV and high risk histopathology was higher than that of clinical stage I - II and low risk histopathology. The higher expression of HIF-1 in Wilms’ tumor was showed in tumors with high risk histopathology and with tumor size≥6cm.CONCLUSIONS1、In the process of growth of Wilms’ tumor, the two pathways of VEGF/FLTAngiopietins/Tie2 have both different levels of activation, but they are disharmony and make vascular tissue of Wilms’ tumor in the immature state, The results provide a scientific basis for the further development of drugs of anti-angiogenesis to inhibit growth of tumor.2、Expressions of Survivin, VEGF in Wilms’ tumor are associated with its clinicaland pathological features. Survivin plays an important part a in the middle stages of angiogenesis. Expressions of Survivin and VEGF in Wilms’ tumor have consistency. High expressions of them in Wilms’ tumor are closely related to the biological behavior, angiogenesis, apoptosis of vascular endothelial cells and stability of tumor vessels. They may affect the extent of tumor invasion, detection of them in Wilms’ tumor is helpful in the diagnosis and evaluation of prognosis.3、Increased expressions of Stat3, HIF-1 and VEGF were found in Wilms’ tumor,and may be related to the development and angiogenesis of Wilms’ tumor, may be associated with generation and invasion of the tumor. Stat3 may regulate expression of HIF-1 and VEGF, so it could be an effective target for inhibiting tumor VEGF expression and angiogenesis of Wilms’ tumor.

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CLC: > Medicine, health > Oncology > Genitourinary tumors > Urinary tumors > Kidney,renal pelvis tumor
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