Eerola A K, Ruokolainen H, Soini Y, Raunio H, Pääkkö P
University of Oulu, Department of Pathology Kajaanintie 52 D, Oulu, FIN-90401, Finland.
Pathol Oncol Res. 1999;5(3):179-86. doi: 10.1053/paor.1999.0198.
In order to test the hypothesis that increased apoptotic activity is connected with neuroendocrine differentiation and low differentiation degree in large cell carcinoma (LCLC) and is regulated by bcl-2 family proteins, we analysed the extent of apoptosis and tumor necrosis and their relation to the expression of bcl-2, bax, bak and mcl-1 in 35 LCLCs, of which 20 were classified as large cell neuroendocrine lung carcinomas (LCNEC) and 15 as large cell non-neuroendocrine lung carcinomas (LCNNEC). The extent of apoptosis was determined by detecting and counting the relative and absolute numbers of apoptotic cells and bodies using in situ 3 -end labelling of the apoptotic DNA. The extent and intensity of expression of the bcl-2, bax, bak and mcl-1 proteins were studied by immunohistochemistry. Also the relative volume density of necrosis was evaluated and correlated with the other parameters. Finally, all the parameters were evaluated as prognostic markers and correlated with data on the survival of the patients. Relatively high apoptotic indices were seen in both tumor types (average for both 2.53%, range 0.09 27.01%). Significantly higher bcl-2 and bak indices were detected more often in LCNECs than in LCNNECs. Immunohistochemically detected bax, bcl-2 and bak expression was independent of apoptotic index in both tumor types, while there was a statistically significant positive association between mcl-1 expression and apoptotic index in LCNNEC but not in LCNEC. There was a statistically significant association between high apoptotic index and shortened survival in LCLC. However, no association was found between tumor stage and apoptosis. The patients with LCNEC and low bcl-2 protein expression had a significantly shorter survival time than those with high bcl-2 indices. There was also a clear association between shortened survival and necrotic LCNNEC. LCLCs show relatively high apoptotic activity, which is associated with shortened survival. The expression of bcl-2, bak and mcl- 1 is associated with neuroendocrine differentiation in LCLC. Finally, our results support some previous reports suggesting that bcl-2 expression in combination with some other markers involved in apoptosis and/or proliferation may be of prognostic value in cases of lung carcinoma with neuroendocrine differentiation.
凋亡活性增加与大细胞癌（LCLC）中的神经内分泌分化及低分化程度相关，并受bcl-2家族蛋白调控，我们分析了35例LCLC中凋亡和肿瘤坏死的程度及其与bcl-2、bax、bak和mcl-1表达的关系，其中20例被归类为大细胞神经内分泌肺癌（LCNEC），15例为大细胞非神经内分泌肺癌（LCNNEC）。通过使用凋亡DNA的原位3'-末端标记检测并计数凋亡细胞和凋亡小体的相对及绝对数量来确定凋亡程度。采用免疫组织化学研究bcl-2、bax、bak和mcl-1蛋白的表达程度和强度。同时评估坏死的相对体积密度并与其他参数进行关联分析。最后，将所有参数作为预后标志物进行评估，并与患者的生存数据进行关联。在两种肿瘤类型中均观察到相对较高的凋亡指数（两者平均为2.53%，范围为0.09%至27.01%）。LCNEC中检测到的bcl-2和bak指数明显高于LCNNEC。免疫组织化学检测到的bax、bcl-2和bak表达在两种肿瘤类型中均与凋亡指数无关，而在LCNNEC中mcl-1表达与凋亡指数之间存在统计学上显著的正相关，在LCNEC中则无此相关性。在LCLC中，高凋亡指数与生存期缩短之间存在统计学上显著的关联。然而，未发现肿瘤分期与凋亡之间存在关联。LCNEC且bcl-2蛋白表达低的患者生存期明显短于bcl-2指数高的患者。坏死的LCNNEC与生存期缩短之间也存在明显关联。LCLC显示出相对较高的凋亡活性，这与生存期缩短相关。LCLC中bcl-2、bak和mcl-1的表达与神经内分泌分化相关。最后，我们的结果支持了一些先前的报道，表明bcl-2表达与其他一些参与凋亡和/或增殖的标志物相结合可能对神经内分泌分化的肺癌病例具有预后价值。
