Griffioen A W, Coenen M J, Damen C A, Hellwig S M, van Weering D H, Vooys W, Blijham G H, Groenewegen G
Department of Internal Medicine and Medical Oncology, University Hospital Utrecht, The Netherlands.
Blood. 1997 Aug 1;90(3):1150-9.
CD44 is described to be an activation molecule in a number of different cell types. We investigated the role of CD44 on human endothelial cells (EC) and in tumor angiogenesis. Using flow cytometry we showed that EC from the vasculature of human solid tumors display an enhanced expression of CD44 as compared to EC from normal tissue. This finding was confirmed by immunohistochemical studies on frozen tissue sections. Because tumors are dependent on angiogenesis, the role of angiogenic stimuli in the enhanced CD44 expression was investigated. We found that basic fibroblast growth factor (bFGF) and vascular endothelial growth factor were able to efficiently upregulate CD44 expression on cultured human EC. The upregulation reached maximal levels after treatment for 3 days with 10 ng/mL bFGF. The physiological impact of this upregulation was shown by the enhanced binding of EC to hyaluronate after pretreatment with bFGF. In a next set of studies that were designed to unravel the regulation of CD44 expression on EC we concluded that CD44 is an activation antigen on human EC since (1) human umbilical vein derived endothelial cells, which in vivo do not express CD44, begin to express CD44 when plated and cultured, (2) CD44 expression is enhanced after subculture of confluent cultures, (3) CD44 is predominantly expressed on the BrdU incorporating subset of cultured EC. The specific expression of CD44 on activated and tumor EC prompted us to study the usefulness of CD44 as an endothelial target for therapy with immunotoxins. In vitro experiments showed that EC are efficiently killed after targeting immunotoxin to CD44.
CD44被描述为在多种不同细胞类型中的一种激活分子。我们研究了CD44在人内皮细胞（EC）及肿瘤血管生成中的作用。通过流式细胞术，我们发现与来自正常组织的EC相比，人实体瘤脉管系统中的EC显示出CD44表达增强。这一发现通过对冷冻组织切片的免疫组织化学研究得到了证实。由于肿瘤依赖血管生成，因此研究了血管生成刺激因素在CD44表达增强中的作用。我们发现碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子能够有效上调培养的人EC上的CD44表达。用10 ng/mL bFGF处理3天后，上调达到最高水平。bFGF预处理后EC与透明质酸结合增强，显示了这种上调的生理影响。在接下来一组旨在阐明EC上CD44表达调控的研究中，我们得出结论，CD44是人类EC上的一种激活抗原，因为（1）体内不表达CD44的人脐静脉来源的内皮细胞在接种和培养时开始表达CD44，（2）汇合培养物传代培养后CD44表达增强，（3）CD44主要表达于培养的EC中掺入BrdU的亚群。CD44在活化的和肿瘤性EC上的特异性表达促使我们研究CD44作为免疫毒素治疗的内皮靶点的实用性。体外实验表明，将免疫毒素靶向CD44后，EC能被有效杀伤。
