Pelosi Giuseppe, Scarpa Aldo, Veronesi Giulia, Spaggiari Lorenzo, Del Curto Barbara, Moore Patrick S, Maisonneuve Patrick, Sonzogni Angelica, Masullo Michele, Viale Giuseppe
Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan School of Medicine, Milan, Italy.
Virchows Arch. 2005 Dec;447(6):969-77. doi: 10.1007/s00428-005-0044-x. Epub 2005 Sep 13.
Nuclear translocation of beta-catenin has been correlated with epidermal growth factor receptor (EGFR) overexpression/activation in non-small cell lung cancer. Less is known on beta-catenin transactivation in high-grade pulmonary neuroendocrine tumors and on the status of beta-catenin activating EGFR and human epidermal growth factor receptor 2 (HER-2) or beta-catenin target genes cyclin D1 and matrix metalloproteinase-7 (MMP-7). beta-catenin immunoreactivity was evaluated in 51 large-cell neuroendocrine carcinomas (LCNEC) and 45 small-cell lung carcinomas (SCLC). Nineteen cases were assessed for beta-catenin gene exon 3 mutations, expression of MMP-7, and expression/gene amplification of EGFR, HER-2, and cyclin D1. beta-catenin was expressed in all 96 high-grade neuroendocrine tumors, the vast majority (94%) showing >50% immunopositive cells. A disarrayed immunoreactivity, however, was commonly encountered consisting in variably altered membrane-associated patterns of staining along with progressive accumulation of cytoplasmic immunoreactivity. In LCNEC, but not in SCLC, the disarrayed patterns correlated with EGFR and HER-2 protein expression. beta-catenin nuclear accumulation was found in nine tumors, including seven LCNEC and two SCLC, and was always associated with disarrayed immunoreactivity and increased MMP-7, but not cyclin D1 expression. These cases, however, did not show beta-catenin gene mutations or EGFR and HER-2 gene amplification or expression. No association was found between nuclear beta-catenin and any clinicopathological variable including patients' survival. The subcellular compartmentalization of beta-catenin is profoundly altered in high-grade pulmonary neuroendocrine tumors. A minor subset of these tumors shows beta-catenin nuclear accumulation in association with increased expression of MMP-7, but not of cyclin D1, independent of EGFR and HER-2 gene amplification or expression.
β-连环蛋白的核转位与非小细胞肺癌中表皮生长因子受体（EGFR）的过表达/激活相关。关于高级别肺神经内分泌肿瘤中β-连环蛋白的反式激活以及β-连环蛋白激活EGFR和人表皮生长因子受体2（HER-2）或β-连环蛋白靶基因细胞周期蛋白D1和基质金属蛋白酶-7（MMP-7）的状态，人们了解较少。对51例大细胞神经内分泌癌（LCNEC）和45例小细胞肺癌（SCLC）进行了β-连环蛋白免疫反应性评估。对19例病例评估了β-连环蛋白基因外显子3突变、MMP-7的表达以及EGFR、HER-2和细胞周期蛋白D1的表达/基因扩增情况。β-连环蛋白在所有96例高级别神经内分泌肿瘤中均有表达，绝大多数（94%）显示免疫阳性细胞>50%。然而，常见的是免疫反应性紊乱，表现为膜相关染色模式的可变改变以及细胞质免疫反应性的逐渐积累。在LCNEC中，但不在SCLC中，这种紊乱模式与EGFR和HER-2蛋白表达相关。在9个肿瘤中发现了β-连环蛋白核积累，包括7例LCNEC和2例SCLC，并且总是与免疫反应性紊乱和MMP-7表达增加相关，但与细胞周期蛋白D1表达无关。然而，这些病例未显示β-连环蛋白基因突变或EGFR和HER-2基因扩增或表达。未发现核β-连环蛋白与任何临床病理变量（包括患者生存率）之间存在关联。在高级别肺神经内分泌肿瘤中，β-连环蛋白的亚细胞区室化发生了深刻改变。这些肿瘤的一小部分显示β-连环蛋白核积累，与MMP-7表达增加相关，但与细胞周期蛋白D1表达无关，且与EGFR和HER-2基因扩增或表达无关。
