Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status
Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status
复制标题
DOI：
10.1007/s10585-006-9045-7
复制
发表时间：
2006-12-01
影响因子：
4
通讯作者：
Iacobuzio-Donahue, Christine A.
中科院分区：
文献类型：
--
作者：
Mudali, Shiyama V.;Fu, Baojin;Iacobuzio-Donahue, Christine A.
EphA2 是一种跨膜受体酪氨酸激酶，在细胞生长、存活、血管生成和迁移的调节中发挥作用，EphA2 靶向已被提议作为过度表达该蛋白的肿瘤的一种新型治疗策略。 EphA2 过度表达与胰腺癌细胞系的侵袭和转移能力增强相关。然而，EphA2 在人类胰腺癌和相关转移中的表达模式尚不清楚，EphA2 在这种肿瘤类型中的遗传学也是未知的。我们收集了 98 名原发性和/或转移性胰腺癌患者的临床病理数据和石蜡包埋材料，并对 EphA2 蛋白进行了免疫组织化学标记。在 219 个样本中的 207 个样本中发现了 EphA2 蛋白免疫标记（95%）。尽管在少数病例中观察到主要是膜染色，但表达主要是细胞质。当专门评估标记强度时，与良性导管和 PanIN 病变相比，原发性和转移性癌的 EphA2 阳性程度更高（分别为 P < 0.00001 和 P < 0.01），低分化癌的 EphA2 阳性程度比高分化和中分化肿瘤更强（P < 0.005）。当将没有转移性疾病的原发性癌与具有相关转移性疾病的癌进行具体比较时，晚期癌显示出相对较弱的 EphA2 阳性标记（P < 0.008）。此外，与远处淋巴结转移（P < 0.01）相比，EphA2 标记减少更常见于肝脏（P < 0.002）、肺（P < 0.004）或腹膜转移（P < 0.01）。对 22 个异种移植富集的胰腺癌样本中的 EPHA2 酪氨酸激酶结构域进行基因测序，未发现任何失活突变。然而，在与淋巴结转移相对应的 33 例胰腺癌中，有 1 例发现了 EPHA2 扩增，表明 EPHA2 基因组扩增可能是少数患者 EphA2 过度表达的基础。我们的数据证实 EphA2 在胰腺癌中过度表达，但表明 EphA2 在共存的胰腺癌转移中相对缺失，并且 EPHA2 在器官特异性转移中发挥作用。
EphA2 is a transmembrane receptor tyrosine kinase that functions in the regulation of cell growth, survival, angiogenesis, and migration and EphA2 targeting has been proposed as a novel therapeutic strategy for neoplasms that overexpress this protein. EphA2 overexpression has been correlated with increased invasive and metastatic ability in pancreatic cancer cell lines. However, the patterns of EphA2 expression in human pancreatic cancers and associated metastases is unknown, as are the genetics of EphA2 in this tumor type. We collected clinicopathologic data and paraffin-embedded materials from 98 patients with primary and/or metastatic pancreatic cancer and performed immunohistochemical labeling for EphA2 protein. EphA2 protein immunolabeling was found in 207 of 219 samples (95%). The expression was predominantly cytoplasmic, although predominant membranous staining was observed in a minority of cases. When evaluated specifically for labeling intensity, primary and metastatic carcinomas were more strongly positive compared to benign ducts and PanIN lesions (P < 0.00001 and P < 0.01, respectively) and poorly differentiated carcinomas were more strongly positive for EphA2 than well and moderately differentiated tumors (P < 0.005). When primary carcinomas without metastatic disease were specifically compared to carcinomas with associated metastatic disease, the advanced carcinomas showed relatively less strong positive labeling for EphA2 (P < 0.008). Moreover, decreased EphA2 labeling was more commonly found in liver (P < 0.002), lung (P < 0.004) or peritoneal metastases (P < 0.01) as compared to distant lymph node metastases (P < 0.01). Genetic sequencing of the tyrosine kinase domain of EPHA2 in 22 samples of xenograft enriched pancreatic cancer did not reveal any inactivating mutations. However, EPHA2 amplification was found in 1 of 33 pancreatic cancers corresponding to a lymph node metastasis, indicating EPHA2 genomic amplification may underlie EphA2 overexpression in a minority of patients. Our data confirms that EphA2 is overexpressed in pancreatic cancer, but suggests a relative loss of EphA2 in co-existent pancreatic cancer metastases as well as a role for EPHA2 in organ specific metastasis.