Krajewska M, Fenoglio-Preiser C M, Krajewski S, Song K, Macdonald J S, Stemmerman G, Reed J C
Burnham Institute, La Jolla, California 92037, USA.
Am J Pathol. 1996 Nov;149(5):1449-57.
The apoptosis-regulating proteins Bcl-2, Bax, Bcl-X, Bak, and Mcl-1 were examined by immunohistochemical methods in 48 archival specimens of adenocarcinoma of the stomach, and the results were correlated with tumor histology (intestinal versus diffuse pattern) and clinical stage (early- versus late-stage disease, ie, stages I and II versus stage III). Tumor cells containing immunostaining for the anti-apoptotic proteins Bcl-2, Bcl-X, and Mcl-1 were present in 26 (54%), 41 (85%), and 36 (75%) of the 48 cases evaluated, respectively, whereas immunopositivity for the pro-apoptotic proteins Bax and Bak was found in 44 (92%) and 42 (88%) specimens Comparisons of these immunostaining results with tumor histology revealed statistically significant differences for Bax (P = 0.03), Bcl-X (P = 0.003), and Mcl-1 (P = 0.005), which were all more frequently immunopositive for tumors with an intestinal than a diffuse histological pattern (chi 2 analysis). In addition, the percentage of immunopositive tumor cells was significantly higher for Bcl-X (62 +/- 6% versus 45 +/- 6%, mean +/- SE, P = 0.01) and for Mcl-1 (48 +/- 6% versus 30 +/- 6%; P = 0.04) in tumors with intestinal versus diffuse histology (unpaired t-test). In contrast, the percentage of Bcl-2-immunopositive tumor cells was higher in tumors with diffuse histology compared with intestinal (32 +/- 5% versus 12 +/- 5%; P = 0.01), whereas the percentages of Bax- and Bak-immunopositive tumor cells were not significantly different between these two histological types. In 34 specimens, residual normal gastric epithelial cells (foveolar cells) were present for direct comparisons of immunointensity with tumor cells. The immunointensity for the Bcl-2, Bcl-X, and Mcl-1 proteins was stronger in tumor cells compared with normal foveolar cells in 7 (21%), 15 (44%), and 8 (2.1%) of 34 cases, respectively, whereas the immunointensity of the proapoptotic proteins Bax and Bak was reduced compared with normal cells in 8 (24%) and 24 (71%) cases. Immunointensity, however, did not correlate with histology. clinical stage was not significantly associated with the presence or absence of immunopositive tumor cells, the percentage of immunopositive cells, or immunointensity. Taken together, these results establish for the first time that several Bcl-2 family proteins are expressed in gastric adenocarcinomas and suggest that the repertoire of these proteins may differ depending on the histological type. The findings therefore support the notion that the intestinal and diffuse types of gastric cancer arise at least in part through different mechanisms.
采用免疫组化方法检测了48例胃腺癌存档标本中的凋亡调节蛋白Bcl-2、Bax、Bcl-X、Bak和Mcl-1，并将结果与肿瘤组织学类型（肠型与弥漫型）和临床分期（早期与晚期疾病，即I期和II期与III期）进行关联分析。在评估的48例病例中，分别有26例（54%）、41例（85%）和36例（75%）的肿瘤细胞出现抗凋亡蛋白Bcl-2、Bcl-X和Mcl-1免疫染色阳性，而促凋亡蛋白Bax和Bak免疫阳性则分别在44例（92%）和42例（88%）标本中发现。将这些免疫染色结果与肿瘤组织学类型进行比较，发现Bax（P = 0.03）、Bcl-X（P = 0.003）和Mcl-1（P = 0.005）存在统计学显著差异，与弥漫型组织学模式的肿瘤相比，肠型组织学模式的肿瘤中这些蛋白免疫阳性更为常见（χ2分析）。此外，肠型与弥漫型组织学肿瘤中，Bcl-X免疫阳性肿瘤细胞百分比显著更高（62±6%对45±6%，均值±标准误，P = 0.01），Mcl-1也是如此（48±6%对30±6%；P = 0.04）（非配对t检验）。相比之下，弥漫型组织学肿瘤中Bcl-2免疫阳性肿瘤细胞百分比高于肠型（32±5%对12±5%；P = 0.01），而这两种组织学类型之间Bax和Bak免疫阳性肿瘤细胞百分比无显著差异。在34例标本中，存在残余正常胃上皮细胞（小凹细胞），以便与肿瘤细胞进行免疫强度的直接比较。在34例病例中，分别有7例（21%）、15例（44%）和8例（2.1%）的肿瘤细胞中，Bcl-2、Bcl-X和Mcl-1蛋白的免疫强度强于正常小凹细胞，而在8例（24%）和24例（71%）病例中，促凋亡蛋白Bax和Bak的免疫强度与正常细胞相比降低。然而，免疫强度与组织学类型无关。临床分期与免疫阳性肿瘤细胞的有无、免疫阳性细胞百分比或免疫强度均无显著关联。综上所述，这些结果首次证实几种Bcl-2家族蛋白在胃腺癌中表达，并表明这些蛋白的表达谱可能因组织学类型而异。因此，这些发现支持了胃腺癌的肠型和弥漫型至少部分通过不同机制发生的观点。
