Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status

Abstract

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.

Overexpression of Ephrin A2 receptors in cancer stromal cells is a prognostic factor for the relapse of gastric cancer

“…EphA2 is highly expressed in a variety of cancers, including breast, lung, prostate, urinary bladder, ovarian, esophageal, pancreatic, and colorectal cancers [17][18][19][20][21][22][23][24]. Overexpression of EphA2 is associated with tumor progression or poor patient survival.…”

Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis: Role of the Eph receptors

“…EphA2 is overexpressed in a large number of tumor types including melanoma, prostate, breast, ovarian, pancreatic, and lung and is often linked with a poor clinical outcome (Duxbury et al, 2004a;Kinch et al, 2003;Mudali et al, 2006;Thaker et al, 2004;Walker-Daniels et al, 1999;Zelinski et al, 2001;Zeng et al, 2003). Given that EphA2 is often overexpressed in various tumor types combined with increasing amounts of evidence supporting a role for EphA2 in promoting angiogenesis, it is natural to hypothesize that overexpression of EphA2 by tumor cells may promote tumor neovascularization.…”

Structural and Functional Characterization of Monomeric EphrinA1 Binding Site to EphA2 Receptor

“…Similar to other receptor-tyrosine kinases, Ephs and ephrins have also been implicated in carcinogenesis, assuming critical roles in oncogenic transformation, metastasis, and angiogenesis (8 -10). Accordingly, Ephs and ephrins have been shown to be overexpressed in a variety of solid tumors (11)(12)(13), including breast (14,15), pancreas (16), gastric (17), colorectal (18), prostate (19), and brain (20,21).…”