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

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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.

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Acknowledgements

Supported by CA106610 (C.I.D.), a Career Development Award from the NIH SPORE (Specialized Programs of Research Excellence) in Gastrointestinal Cancer Grant CA62924 (C.I.D.), The George Rubis Family, The Jeff Zgonina Fund for Pancreatic Cancer Research, The Joseph C. Monastra Fund for Pancreatic Cancer Research, The Michael Rolfe Foundation and Sigma Beta Sorority.

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Authors and Affiliations

  1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Hospital, Baltimore, MD, USA

    Shiyama V. Mudali, Baojin Fu, Mingde Luo, Erlinda E. Embuscado & Christine A. Iacobuzio-Donahue

  2. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Hospital, Baltimore, MD, USA

    Christine A. Iacobuzio-Donahue

  3. Meyerhoff Scholar Program, University of Maryland, Baltimore, MD, USA

    Sindhu S. Lakkur

  4. Division of Gastrointestinal/Liver Pathology, The Johns Hopkins Hospital, 1550 Orleans Street, CRBII Rm 343, Baltimore, MD, 21231, USA

    Christine A. Iacobuzio-Donahue

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  1. Shiyama V. Mudali
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  2. Baojin Fu
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  3. Sindhu S. Lakkur
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  4. Mingde Luo
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  5. Erlinda E. Embuscado
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  6. Christine A. Iacobuzio-Donahue
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Correspondence to Christine A. Iacobuzio-Donahue.

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Shiyama V. Mudali and Baojin Fu contributed equally to this work.

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Mudali, S.V., Fu, B., Lakkur, S.S. et al. Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status. Clin Exp Metastasis 23, 357–365 (2006). https://doi.org/10.1007/s10585-006-9045-7

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  • DOI: https://doi.org/10.1007/s10585-006-9045-7

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