Expression of the putative stem cell marker Musashi-1 in Barrett's esophagus and esophageal adenocarcinoma
Expression of the putative stem cell marker Musashi-1 in Barrett's esophagus and esophageal adenocarcinoma
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DOI：
10.1111/j.1442-2050.2010.01061.x
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发表时间：
2010-09-01
影响因子：
2.6
通讯作者：
Lord, R. V. N.
中科院分区：
文献类型：
--
作者：
Bobryshev, Y. V.;Freeman, A. K.;Lord, R. V. N.
癌症干细胞理论认为，癌症中含有肿瘤形成细胞，这些细胞具有自我更新的能力，并能产生分化细胞。肿瘤干细胞已在几种实体瘤中被鉴定，但在正常人食管或Barrett食管或腺癌中的干细胞尚未报道。Musashi-1由被鉴定为肠干细胞的隐窝基底柱状细胞表达。在其他胃肠道疾病中，图尼卡粘膜的局部炎症可能是休眠干细胞所在的局灶性组织“壁龛”改变的起始因素。本研究探讨Musashi-1是否在食管中表达及其与Barrett食管和食管腺癌粘膜免疫炎症的关系。共对41例患者的41例食管组织标本进行了研究。其中，15例为食管腺癌，17例为Barrett食管（10例肠上皮化生和7例异型增生），9例为来自无食管病理学患者的正常鳞状食管组织标本。使用Musashi-1抗体和一组细胞类型特异性标志物进行免疫组织化学。多重串联聚合酶链反应方法用于测量Musashi-1和特定树突状细胞标志物树突状细胞特异性细胞间分子-3（ICAM-3）-抓取非整合素的相对mRNA表达水平。免疫组织化学显示，在无Barrett食管患者的活检组织中，少量Musashi-1+细胞分散在结缔组织基质和贲门型腺体上皮内。Musashi-1表达存在于Barrett肠化生和发育不良的Barrett中，其中个体腺体中的大多数上皮细胞表达该抗原。Musashi-1在食管腺癌中的表达最高，在腺癌形成早期的腺体中表达最强。相反，Musashi-1染色水平在显示晚期腺癌特征的腺体中较弱。增殖细胞核抗原的双重免疫染色显示绝大多数Musashi-1+细胞的增殖较低。Musashi-1 mRNA在食管腺癌中的表达水平显著高于正常食管或Barrett食管组织。树突状细胞特异性细胞间分子-3（ICAM-3）-抓取非整合素（DC-SIGN）mRNA表达水平在Barrett组织和腺癌组织中均显著增加。推定的干细胞标记物Musashi-1的表达在正常鳞状上皮中不存在，在食管贲门型腺体和Barrett食管中弱，并且在腺癌中显著增加，特别是在显示早期癌症发展特征的腺体中。Musashi-1表达细胞在Barrett食管和腺癌的病因学中可能是重要的，甚至可能是这种疾病的起源细胞。我们推测发生在Barrett食管的免疫炎症改变了粘膜微环境，有利于激活休眠的干细胞。
P>The cancer stem cell theory states that cancers contain tumor-forming cells that have the ability to self-renew as well as give rise to cells that differentiate. Cancer stem cells have been identified in several solid tumors, but stem cells in normal human esophagus or in Barrett's esophagus or adenocarcinoma have not been reported. Musashi-1 is expressed by the crypt base columnar cells identified as intestinal stem cells. In other diseases of the gastrointestinal tract, local inflammation of the tunica mucosa may be an initiating factor of alteration of focal tissue 'niches,' where dormant stem cells locate. The present study investigated whether Musashi-1 is expressed in the esophagus and its relation to immune inflammation of the mucosa in Barrett's esophagus and esophageal adenocarcinoma. A total of 41 esophageal tissue specimens from 41 patients were studied. Of these, 15 were esophageal adenocarcinoma, 17 were Barrett's esophagus (10 intestinal metaplasia and 7 dysplasia), and 9 were normal squamous esophagus tissue specimens from patients without esophageal pathology. Immunohistochemistry was performed using antibodies to Musashi-1 and to a set of cell type-specific markers. A multiplexed tandem polymerase chain reaction method was used to measure the relative mRNA expression levels of Musashi-1 and the specific dendritic cell marker dendritic cell-specific intercellular molecule-3 (ICAM-3)-grabbing nonintegrin. Immunohistochemistry demonstrated the presence of small numbers of Musashi-1+ cells scattered in the connective tissue stroma and within the epithelium in cardiac-type glands in biopsies from patients without Barrett's esophagus. Musashi-1 expression was present in Barrett's intestinal metaplasia and in dysplastic Barrett's in which the majority of epithelial cells in individual glands expressed this antigen. Expression of Musashi-1 was highest in esophageal adenocarcinoma, where it was most intense in glands that displayed features of early stages of adenocarcinoma formation. In contrast, Musashi-1 staining level was weaker in glands that displayed features of advanced adenocarcinoma. Double immunostaining with proliferating cell nuclear antigen showed low proliferation in the vast majority of Musashi-1+ cells. Musashi-1 mRNA expression levels were significantly higher in esophageal adenocarcinoma than in normal esophagus or Barrett's esophagus tissues. Dendritic cell-specific intercellular molecule-3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) mRNA expression levels were significantly increased in both Barrett's tissues and adenocarcinoma tissues. Expression of the putative stem cell marker Musashi-1 is absent in normal squamous epithelium, weak in esophageal cardiac-type glands and Barrett's esophagus, and markedly increased in adenocarcinoma, especially in glands displaying features of early cancer development. Musashi-1 expressing cells may be significant in the etiology of Barrett's esophagus and adenocarcinoma, and perhaps even a cell of origin for this disease. We speculate that immune inflammation occurring in Barrett's esophagus alters the mucosal microenvironment in a manner which is favorable to the activation of dormant stem cells.