【作者】 张婉媛；

【导师】 吴强；

【作者基本信息】 安徽医科大学 ， 病理学与病理生理学， 2009， 硕士

【摘要】 背景:胃肠道间质瘤(gastrointestinal stromal tumor, GIST)是常见消化道的间叶源性肿瘤,认为其起源与胃肠道肌层的Cajal细胞有关。现在多数学者倾向于按侵袭危险性分类,即按照肿瘤的大小、核分裂的多少,将其分为极低危险性,低度危险性,中度危险性和高度危险性。影响GIST侵袭性的分子机制尚不清楚,目前肿瘤外细胞基质与肿瘤侵袭性的关系成为研究的热点之一,内皮细胞特异性分子-1( endothelial cell-specific moelecule-1, ESM-1) ,基质金属蛋白酶( matrix metalloproteinases,MMPs)及基质金属蛋白酶抑制因子tissue inhabitors of metalloproteinasrs-1,TIMPs)引起重视。ESM-1是近年发现的一种新颖的内皮细胞分泌的特异性分子,研究表明ESM-1的表达与某些肿瘤如肺癌、肾癌、结直肠癌等的发生、发展相关。ESM-1表达水平和肿瘤的侵袭性和多血管程度呈正相关。MMPs是一个蛋白水解酶大家族,可分为胶原酶、明胶酶、基质降解素以及膜型MMPs等,其中胶原酶尤为重要。越来越多的研究表明,胶原酶在肿瘤侵袭转移中起着重要的作用,而且此作用不仅仅限于它有利于细胞外基质的降解,还对肿瘤微环境的维持和促进肿瘤生长起着重要作用。TIMPs是MMPs的抑制剂,可抑制所有胶原酶的活性。ESM-1在GIST中的是否存在表达,是否与GIST肿瘤性质、生物学行为相关,及其与胶原酶及组织抑制因子的关系,国内外尚未见报道。值得进一步研究。目的:检测GIST中ESM-1及胶原酶与组织抑制因子的表达,分析它们与各病理参数的关系,探讨GIST组织中ESM-1的表达及其与胶原酶及组织抑制因子的关系,为预测该肿瘤的侵袭潜能提供理论依据和可能的预测指标,以指导临床的治疗和预后。方法:应用组织芯片平台,采用免疫组织化学技术检测69例GIST组织ESM-1、MMP-1、MMP-3和TIMP-1的表达,分析各项指标与GIST临床病理特征的关系及其相互之间的关系。结果:(1)免疫组化描述本组实验结果ESM-1在GIST组织中的表达呈弥漫性分布,阳性信号主要定位于细胞质。在69例GIST组织中,除1例外,其余68例均有不同程度的ESM-1表达,阳性表达率为98.5%,其中有63例为强阳性(高表达),高表达率为91.3%(63/69)。并随着GIST生物学行为恶性度的增高,其表达出现递增趋势,差异有显著性意义(P<0.05)。(2)ESM-1表达在GIST病理学形态上皮细胞型与梭形细胞型相比,统计略有增高趋势,但无统计学意义;(3) MMP-1、MMP-3和TIMP-1的表达率分别为89.9%,89.9%和84.1%,且与ESM-1的表达呈正相关。结论:(1)ESM-1在GIST中存在广泛高表达,与GIST的生物学行为密切相关。并对判断GIST生物学行为具有潜在意义,为预测该肿瘤的侵袭潜能提供理论依据和可能的预测指标。(2)胶原酶及组织抑制因子在GIST存在广泛表达,并与ESM-1共同作用于GIST的生物学行为。更多还原

【Abstract】 Background:Gastrointestinal stromal tumor (GIST) , one of the most common sarcoma of the alimentary tract, is considered as deriving from the interstitial cells of Cajal (ICCs). Presently, many scholars tend to classify GIST into four types: extremely low risk,low risk, moderate risk and high risk, which is on the basis of its invasive chanciness according to the the size and the degree of karyokinesis of tumors. The underlying molecular mechanisms that exist in the invasive chanciness of GIST is still unclear. But more and more attention was paid to the relation between tumor extracellular matrix and tumor invasive chanciness, including endothelial-cell-specific moelecule-1 (ESM-1), matrix metalloproteinases (MMPs) , and tissue inhabitors of metalloproteinasrs-1(TIMPs). Endothelial-cell-specific molecule 1 (ESM-1) is a recently identified human endothelial cell-specific molecule. Studies have demonstrated that the expression of ESM-1 is correlated with certain tumors, such as the origin and development of lung cancer and renal carcinoma. Positive correlation has been found between the expression of ESM-1 and the degree of tumor invasiveness and its multivessel . Matrix metalloproteinases (MMPs) is a big family of proteolytic enzymes , including collagenase, gelatinase and membrane-MMPs , of which collagenase is the most important . Numerous studies have shown that collagenase plays essential roles in the invasion and metastasis of tumor , in a way that it not only contributes to the degradation of the extracellular matrix but also to the tumor microenvironment maintainence and growth of tumor. TIMPs are the inhibitors of MMPs. which could suppress the activation of all collagenases. Whether there is the expression of ESM-1 in GIST, and whether ESM-1 is related to the character and biological behavior of tumour, and whether there is close relations between collagenases and TIMP-1, are still unknown and deserve further study. Objective:To detect the expression level of ESM-1,MMP-1,MMP-3 and TIMP-1 in GIST, and to analyze their relation to respective clinical pathology data. To study the expression of ESM-1 and probe its relation to collagenase and tissue inhibitive factor and to find theory basis for the indicator of tumor invasion for the sake of clinical treatment and prognosis.Methods: Tissue microarry was used to detected the expression of ESM-1, MMP-1,MMP-3 and TIMP-1 in 69 cases of GIST by immunohistochemistry. The relation of ESM-1 expression to the clinical pathologic data, collagenase and tissue inhibitive factor was investigated .Results:(1)The expression of ESM-1 in the gastrointestinal stromal tumor is diffusely distributed and ESM-1 is mainly positive in the cytoplasm. ESM-1 is expressed in 68 cases of the 69 cases and the expression rate reaches to 98.5% (68/69). Of the 68 cases 63 cases are strong positive with a high expression rate of 91.3% ( 63/69). Along with increased degree of malignant GIST , the expression of ESM-1 increases with statistical significance (P<0.05). (2)In the form of pathological morphology , compared with the expression level of ESM-1 in spindle cells there is a trend that ESM-1 expression level in epithelial cells increases but with no statistical significance. ( 3 ) The expression rate of MMP-1,MMP-3 and TIMP-1 in the gastrointestinal stromal tumor reaches to 89.9%, 89.9% and 84.1% respectively. And they are positively correlated with ESM-1 expression. Conclusions:(1)ESM-1 is widely expressed in the gastrointestinal stromal tumor (GIST) with a high rate , and is closely related with the biological behavior of GIST , which might be a potential indicator of biological behaviour of GIST. (2)There is also a wide expression of collagenase and tissue inhibitive factor in GIST and they are both relate to the biological behavior of GIST as ESM-1 .更多还原