Kikuchi Y, Dinjens W N, Bosman F T
Institute of Pathology, Erasmus University, Rotterdam, The Netherlands.
Virchows Arch. 1997 Aug;431(2):111-7. doi: 10.1007/s004280050076.
Classically, neoplasia has been considered to be primarily a disturbance in the regulation of proliferation, but it is now clear that programmed cell death is dysregulated as well as proliferation. The genes that are implicated in the regulation of these processes, such as p53, c-myc and bcl-2, are often also altered in neoplasms. We have studied proliferation and programmed cell death in hyperplastic polyps, adenomas, carcinomas in adenomas and adenocarcinomas of the colorectum, using the MIB-1 antibody which recognizes the Ki-67 proliferation related antigen, and an in situ nick-end labelling procedure for histochemical labelling of proliferating and apoptotic cells. In addition, immunohistochemistry was used to study the expression of the p53, c-myc and bcl-2 proteins. The material studied consisted of 12 samples of normal mucosa, 8 hyperplastic polyps, 39 adenomas with different degrees of dysplasia and including 3 that carried a carcinoma, and 10 adenocarcinomas, all formalin fixed and paraffin embedded. The Ki-67 index indicated that proliferation increased progressively in hyperplasia, through different degrees of dysplasia in adenoma, to reach the highest level (Ki-67 index of 50%) in adenocarcinoma. Apoptosis also increased in hyperplastic polyps and in adenomas, but decreased significantly in adenocarcinomas. p53 Labelling was seen in 77% of the carcinomas but in only 3% of the adenomas. Expression of c-myc increased in adenomas and carcinomas. Furthermore, a shift from predominantly nuclear to predominantly cytoplasmic expression was seen in progressive neoplasms. Expression of bcl-2 was increased in an occasional hyperplastic polyp, but was increased markedly in almost all adenomas. Strikingly, in the adenomas with a carcinoma, the carcinoma showed weaker bcl-2 expression than the adenoma. In 20% of the carcinomas some bcl-2 staining was seen but this was less extensive than in the adenomas. Our findings indicate that in the progression from adenoma to carcinoma both increased proliferation and decreased apoptosis occur. This is paralleled by an increased expression of p53 and an increased and predominantly cytoplasmic expression of c-myc, but a decreased expression of bcl-2. This decreased bcl-2 expression does not lead to an increase in apoptotic activity.
传统上，肿瘤形成主要被认为是增殖调节的紊乱，但现在清楚的是，程序性细胞死亡以及增殖都存在失调。参与这些过程调节的基因，如p53、c-myc和bcl-2，在肿瘤中也常常发生改变。我们使用识别Ki-67增殖相关抗原的MIB-1抗体以及用于对增殖和凋亡细胞进行组织化学标记的原位缺口末端标记程序，研究了结直肠增生性息肉、腺瘤、腺瘤内癌和腺癌中的增殖和程序性细胞死亡。此外，采用免疫组织化学方法研究p53、c-myc和bcl-2蛋白的表达。所研究的材料包括12份正常黏膜样本、8份增生性息肉、39份不同程度发育异常的腺瘤（其中3份伴有癌）以及10份腺癌，均为福尔马林固定、石蜡包埋。Ki-67指数表明，从增生到腺瘤不同程度的发育异常，再到腺癌中增殖逐渐增加，腺癌中达到最高水平（Ki-67指数为50%）。增生性息肉和腺瘤中的凋亡也增加，但腺癌中显著减少。77%的癌中可见p53标记，但腺瘤中仅3%可见。腺瘤和癌中c-myc的表达增加。此外，在进展性肿瘤中可见从主要核表达向主要胞质表达的转变。bcl-2在偶尔的增生性息肉中表达增加，但在几乎所有腺瘤中显著增加。引人注目的是，在伴有癌的腺瘤中，癌的bcl-2表达比腺瘤弱。20%的癌中可见一些bcl-2染色，但不如腺瘤广泛。我们的研究结果表明，从腺瘤进展为癌的过程中，增殖增加而凋亡减少。这与p53表达增加、c-myc表达增加且主要为胞质表达以及bcl-2表达减少相平行。bcl-2表达的减少并未导致凋亡活性增加。
