Panelos John, Batistatou Anna, Paglierani Milena, Zioga Aikaterini, Maio Vincenza, Santi Raffaella, Pimpinelli Nicola, De Giorgi Vincenzo, Santucci Marco, Massi Daniela
Department of Human Pathology and Oncology, University of Florence, Florence, Italy.
Mod Pathol. 2009 Jul;22(7):959-68. doi: 10.1038/modpathol.2009.55. Epub 2009 Apr 24.
Increasing evidence indicates that Notch signaling contributes to physiological processes, including development and differentiation, as well as tumorigenesis, either as a tumor promoter or suppressor, depending on cellular context, expression levels and cross talk with other signaling systems. Recent studies reported absent or minimal Notch-1 expression in neuroendocrine tumors of the lung and gastrointestinal tract, suggesting a tumor-suppressor function of Notch-1. Merkel cell carcinoma is a rare and highly aggressive primary cutaneous neuroendocrine carcinoma. Because no information is available on Notch-1 expression in this tumor, we have investigated a series of 31 Merkel cell carcinoma for Notch-1 immunoreactivity. Immunoreactivities for E-cadherin and beta-catenin were also analyzed. All but 1 Merkel cell carcinoma (30 of 31) retained cytoplasmic and membrane Notch-1 expression in more than 50% of cells. beta-Catenin displayed a prevalent membrane-associated staining in 30 of 31 cases, and 22 cases showed more than 50% of immunoreactive cells whereas nuclear beta-catenin was seen only in 2 of 31 cases. E-cadherin membranous expression was remarkably low, as only 1 of 26 cases was found positive in more than 50% of cells. In contrast with neuroendocrine tumors in other tissues, evident Notch-1 expression was found in Merkel cell carcinoma. This finding does not support a tumor-suppressor function of Notch-1 in Merkel cell carcinoma. Downregulation of E-cadherin and diffuse membranous beta-catenin expression suggest a dysregulation of the E-cadherin/beta-catenin complex in Merkel cell carcinoma. This may contribute to local invasion and distant metastasis.
越来越多的证据表明，Notch信号通路参与生理过程，包括发育和分化，以及肿瘤发生，其作用取决于细胞环境、表达水平以及与其他信号系统的相互作用，既可以作为肿瘤促进因子，也可以作为肿瘤抑制因子。最近的研究报道，在肺和胃肠道神经内分泌肿瘤中Notch-1表达缺失或极少，提示Notch-1具有肿瘤抑制功能。默克尔细胞癌是一种罕见且侵袭性很强的原发性皮肤神经内分泌癌。由于尚无关于该肿瘤中Notch-1表达的信息，我们对31例默克尔细胞癌进行了研究，检测其Notch-1免疫反应性。同时也分析了E-钙黏蛋白和β-连环蛋白的免疫反应性。31例默克尔细胞癌中，除1例之外（30/31），超过50%的细胞中保留了细胞质和膜性Notch-1表达。β-连环蛋白在31例中的30例显示为普遍的膜相关染色，22例中免疫反应性细胞超过50%，而核β-连环蛋白仅在31例中的2例可见。E-钙黏蛋白的膜性表达非常低，26例中仅1例超过50%的细胞呈阳性。与其他组织中的神经内分泌肿瘤不同，在默克尔细胞癌中发现了明显的Notch-1表达。这一发现不支持Notch-1在默克尔细胞癌中的肿瘤抑制功能。E-钙黏蛋白的下调和弥漫性膜性β-连环蛋白表达提示默克尔细胞癌中E-钙黏蛋白/β-连环蛋白复合物失调。这可能有助于局部侵袭和远处转移。
