Cytoplasmic expression of fibroblast growth factor receptor-4 in human pituitary adenomas: Relation to tumor type, size, proliferation, and invasiveness
Cytoplasmic expression of fibroblast growth factor receptor-4 in human pituitary adenomas: Relation to tumor type, size, proliferation, and invasiveness
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DOI：
10.1210/jc.2003-031489
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发表时间：
2004-04-01
影响因子：
5.8
通讯作者：
Ezzat, S
中科院分区：
文献类型：
--
作者：
Qian, ZR;Sano, T;Ezzat, S
垂体腺瘤的发病机制仍不清楚。成纤维细胞生长因子受体-4（ptd-FGFR 4）的垂体肿瘤衍生（ptd）亚型与肿瘤过程有关。为了进一步了解FGFR 4在散发性垂体腺瘤中的表达，我们研究了137例不同类型的垂体腺瘤，（102例来自日本患者的腺瘤和35例来自加拿大患者的腺瘤）和10例非肿瘤性垂体，使用识别FGFR 4 C末端的多克隆抗血清，分析FGFR 4表达、患者国籍、肿瘤类型、大小、侵袭性、以及使用MIB-1抗体的增殖标记Ki-67的标记指数。FGFR 4蛋白在日本和加拿大病例中的胞浆表达率分别为57.8%和62.8%。在所有10个正常的腺垂体组织检查FGFR 4反应是不存在的。垂体腺瘤中FGFR 4的表达主要局限于细胞质，与转染人ptd-FGFR 4的大鼠垂体细胞中观察到的模式相似，但与转染野生型FGFR 4的细胞不同，后者显示染色膜定位。来自原发性人腺瘤的蛋白质作为65-kDa物质迁移，与预测的ptd-FGFR 4大小一致。FGFR 4蛋白表达常见于含有GH、ACTH或FSH/LH的腺瘤中，也见于空细胞腺瘤中，但在日本和加拿大组中，含有催乳素的腺瘤中反应性相对罕见。FGFR 4蛋白在大腺瘤中的表达强于微腺瘤（P = 0.02），大腺瘤中FGFR 4蛋白的高表达（中等或更高密度染色）多于微腺瘤（P < 0.05）。高水平的FGFR 4表达也与增殖标志物Ki-67显著相关（P = 0.002），并且倾向于（但不显著）在侵袭性肿瘤中发现。这些数据与ptd-FGFR 4在大多数人垂体腺瘤中垂体肿瘤发生中的作用一致。此外，FGFR 4细胞质染色的检测可能提供一个辅助诊断工具，在垂体腺瘤的诊断，特别是在可疑的情况下。
The pathogenesis of pituitary adenomas remains unknown. A pituitary tumor-derived (ptd) isoform of fibroblast growth factor receptor-4 (ptd-FGFR4) has been implicated in the neoplastic process. To further understand the expression of FGFR4 in sporadic human pituitary adenomas, we studied 137 pituitary adenomas of various types (102 adenomas from Japanese patients and 35 adenomas from Canadian patients) and 10 nontumorous pituitaries using a polyclonal antiserum that recognizes the C terminus of FGFR4 and analyzed possible relationships among expression of FGFR4, patient nationality, tumor type, size, invasion, and the labeling index of the proliferation marker Ki-67 using the MIB-1 antibody. Cytoplasmic expression of FGFR4 protein was observed in 57.8% of Japanese cases and 62.8% of Canadian cases. FGFR4 reactivity was absent in all 10 normal adenohypophysial tissues examined. FGFR4 expression in pituitary adenomas was restricted mainly to the cytoplasm, a pattern similar to that seen in rat pituitary cells transfected with human ptd-FGFR4 but different from that of cells transfected with wild-type FGFR4, which displayed membrane localization of staining. Protein from primary human adenomas migrated as a 65-kDa species consistent with the predicted size of ptd-FGFR4. FGFR4 protein expression was frequently found in adenomas containing GH, ACTH, or FSH/LH and was also found in null cell adenomas, but reactivity was relatively rare in prolactin-containing adenomas in both Japanese and Canadian groups. The expression of FGFR4 protein was stronger in macroadenomas than in microadenomas (P = 0.02) and high levels of FGFR4 expression (moderate or greater density staining) were more frequently observed in macroadenomas than in microadenomas (P < 0.05). High levels of FGFR4 expression also correlated significantly with the proliferation marker Ki-67 (P = 0.002) and tended (but not significantly) to be found in invasive tumors. These data are consistent with a role for ptd-FGFR4 in pituitary tumorigenesis in a majority of human pituitary adenomas. Moreover, detection of FGFR4 cytoplasmic staining may provide an ancillary diagnostic tool in the diagnosis of pituitary adenoma, particularly in equivocal cases.