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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)357-365
Number of pages9
JournalClinical and Experimental Metastasis
Volume23
Issue number7-8
DOIs
StatePublished - Dec 2006

Fingerprint

EphA2 Receptor
Pancreatic Neoplasms
Neoplasm Metastasis
Carcinoma
Neoplasm Proteins
Lymph Nodes
Receptor Protein-Tyrosine Kinases
Pancreatic Carcinoma
Heterografts
Paraffin
Protein-Tyrosine Kinases
Neoplasms
Cell Survival
Staining and Labeling
Cell Line
Lung
Mutation

Keywords

  • 1p36
  • Amplification
  • EphA2
  • Metastasis
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research

Cite this

Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status. / Mudali, Shiyama V.; Fu, Baojin; Lakkur, Sindhu S.; Luo, Mingde; Embuscado, Erlinda E.; Iacobuzio-Donahue, Christine A.

In: Clinical and Experimental Metastasis, Vol. 23, No. 7-8, 12.2006, p. 357-365.

Research output: Contribution to journalArticle

Mudali, Shiyama V. ; Fu, Baojin ; Lakkur, Sindhu S. ; Luo, Mingde ; Embuscado, Erlinda E. ; Iacobuzio-Donahue, Christine A. / Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status. In: Clinical and Experimental Metastasis. 2006 ; Vol. 23, No. 7-8. pp. 357-365.
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AU - Iacobuzio-Donahue, Christine A.

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AB - 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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