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Clinical Cancer Research Vol. 11, 226-231, January 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Expression of EphA2 is Prognostic of Disease-Free Interval and Overall Survival in Surgically Treated Patients with Renal Cell Carcinoma

Christopher J. Herrem1, Tomohide Tatsumi4, Kathleen S. Olson2, Keisuke Shirai2, James H. Finke5, Ronald M. Bukowski6, Ming Zhou7, Amy L. Richmond5, Ithaar Derweesh6, Michael S. Kinch8 and Walter J. Storkus1,2,3

Departments of 1 Immunology and 2 Surgery, University of Pittsburgh School of Medicine and 3 University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; 4 Department of Molecular Therapeutics, Osaka University, Osaka, Japan; Departments of 5 Immunology, 6 Hematology & Oncology, and 7 Anatomic Pathology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio; and 8 MedImmune, Inc., Gaithersburg, Maryland

Requests for reprints: Walter J. Storkus, Department of Surgery, University of Pittsburgh School of Medicine, 1.32e The Hillman Cancer Center, 5117 Center Avenue, Pittsburgh, PA 15213-1863. Phone: 412-623-3240; Fax: 412-623-7709; E-mail:storkuswj{at}msx.upmc.edu.


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Whereas normally expressed at sites of cell-to-cell contact in adult epithelial tissues, recent studies have shown that the receptor tyrosine kinase EphA2 is overexpressed in numerous epithelial-type carcinomas, with the greatest level of EphA2 expression observed in metastatic lesions. In the current study, we have assessed EphA2 expression in archived renal cell carcinoma (RCC) tissues as it relates to patient disease course.

Using specific anti-EphA2 monoclonal antibody 208 and immunohistochemistry, we evaluated EphA2 protein expression levels in RCC specimens surgically resected from 34 patients (including 30 conventional clear-cell RCC, 3 papillary, and 1 chromophobic RCC cases) resulting in clinical cures.

Regardless of histopathologic subtype, RCC lesions expressing higher levels of EphA2 tended to be of a higher grade (P < 0.05) and larger (P = 0.093), more-highly-vascularized tumors (P = 0.005). Perhaps most notable, the degree of EphA2 overexpression (versus normal matched autologous kidney tissue) seemed predictive of short-term (<1 year) versus longer-term (≥1 year) disease-free interval (P < 0.001) and of overall survival (P < 0.001) among the RCC patients evaluated.

These data suggest that EphA2 expression level may serve as a useful prognostic tool in the clinical management of patients who have been successfully treated with surgery, but who are at greater risk for accelerated disease recurrence and who have a poorer prognosis.

Key Words: Renal Cell Carcinoma • EphA2 • Receptor Tyrosine Kinase • Disease-Free Interval • Immunohistochemistry


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The Eph family of molecules constitutes the largest known family of receptor tyrosine kinases, consisting of two classes of receptors, EphA and EphB, and two classes of corresponding ligands, ephrin-A and ephrin-B, respectively. Ephrin-A ligands are attached to the cell surface via glycosylphosphatidylinositol anchors and preferentially bind only EphA receptors. Ephrin-B ligands are transmembrane proteins and primarily bind EphB receptors. Largely known for their role(s) in neuronal development and tissue remodeling (1, 2), Eph receptors have also been shown to play a role(s) in oncogenesis (3–11).

EphA2 is of particular interest due to evidence suggesting its involvement in carcinogenesis. EphA2 is a 130-kDa protein normally localized to sites of cell-to-cell contact, where it plays a role in contact growth inhibition (3). However cellular overexpression of EphA2, either as a result of its constitutive dysregulation or ectopic gene insertion, results in the disruption of cell-to-cell contacts, and enhancement of cell-to-extracellular matrix attachments (3). Thus, tumor cells that overexpress EphA2 exhibit increased motility and invasive properties, consistent with a pro-metastatic phenotype (3). Overexpression of EphA2 has been observed in numerous cancer types (4), including melanoma (5, 6) and carcinomas of the breast (7–9), lung (10), pancreas (11), and prostate (12).

It has been recently suggested that the quantitative levels of EphA2 expressed by cancer cells might provide useful prognostic information with regard to the metastatic potential of human carcinomas in situ and the clinical course of cancer patients. Kinch et al. (13, 14) reported that high level EphA2 expression in primary lung cancers is predictive of brain metastases, whereas lower levels predict either extended disease-free status or locoregional (contralateral) lung metastasis. Likewise, Miyazaki et al. (15) reported a significant correlation between EphA2 overexpression in esophageal squamous cell carcinoma with lymph node metastasis, the number of lymph node metastasis, and less well differentiated phenotype. Five-year survival rates were also reported to be lower for patients with EphA2-positive tumors versus those patients with EphA2-negative tumors (15). In light of this evidence, and our previous report supporting the prevalent overexpression of EphA2 in renal cell carcinoma (RCC; ref. 16), we performed immunohistochemical analyses to determine whether the relative level of EphA2 expressed by resected RCC tumors was indicative of the disease-free survival of patients with RCC treated with surgery.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissues. RCC tumor and adjacent normal kidney specimens were analyzed from a total of 34 patients (23 males, 11 females; average age = 58.2 ± 10.4 years; range = 37–87 years old at the time of resection) with consent under Institutional Review Board–approved protocols. All patients were treated by radical or partial nephrectomy and rendered disease–free. Patient and tumor characteristics and time to recurrence are indicated in Table 1 Of the 34 RCC tumors evaluated, 30 were diagnosed as conventional clear cell RCC, 3 as papillary RCC, and 1 as chromophobe RCC. Among the 34 patients, a subset of six individuals remains clinically free of disease for more than 13 years postsurgery. For these patients, the time since surgery is reported as their "disease–free interval." All the resected tissues were fixed in paraformaldehyde (formalin; Sigma Chemical Co., St. Louis, MO) and embedded in paraffin.


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  		Table 1 RCC patient characteristics

 
Construction of RCC Tissue Microarray. Twelve RCC that recurred within 1 year of surgery, 13 RCC that recurred within 1 to 5 years after surgery, and 16 RCC that remained disease-free more than 5 years after surgery (totaling 41 RCC specimens) were selected for construction of the RCC tissue microarray. All cases were retrieved from the surgical pathology file at the Department of Anatomic Pathology of the Cleveland Clinic Foundation and were reviewed and the diagnoses confirmed. One representative paraffin block from each case was used to construct a tissue microarray. Briefly, areas of interest (tumor or normal adjacent tissue) were traced with a marker pen on an H&E–stained slide. The corresponding areas were then marked on the corresponding paraffin blocks. The tissue microarray was made on a manual tissue microarray arrayer (Beecher Instruments, Sun Praire, WI). Three 1.5–mm–thick tissue cores were taken from each block to build the tissue microarray. After construction, 4-µm sections were cut, mounted on Superfrost Plus glass slides, and stored for future use. An H&E staining was done on the initial slide to verify the histologic diagnosis (M.Z.), with a map of case number and tissue diagnosis maintained in a Microsoft Excel spreadsheet. In 34 of the 41 RCC cases (i.e., those patients characterized in (Table 1), patient-matched normal adjacent kidney tissue cores were also included in the tissue microarray, allowing for comparative analyses of tumor versus matched normal kidney to be evaluated by immunohistochemistry.

Immunohistochemistry. Tissue microarray slides were deparaffinized and stained with a murine anti-hEphA2 monoclonal antibody 208 (1:100 dilution; MedImmune, Inc., Gaithersburg, MD), rabbit anti–human Factor VIII monoclonal antibody (1:400 dilution; Dako Co., Carpinteria, CA), or normal mouse/rabbit IgG control Ab (1:200–1:1000 dilution; Sigma Chemical) in immunohistochemical analyses. Detection was determined by using Vectastain anti-IgG and NovaRed kits (Vector Labs, Burlingame, CA). The EphA2 expression index was defined as the weighed mean of the fraction of tumor or normal kidney cells displaying immunoreactivity with monoclonal antibody 208 (calculated by counting the number of EphA2–positive cells among at least 1,000 cells for each tissue section manually) multiplied by the degree of the staining intensity (0, 1-2, 3-4, 5-6 defined as no staining, weak staining, moderate staining, or strong staining, respectively). Normal kidney stroma served as an internal negative control. Almost all tumor cells showed some degree of staining. Three independent evaluators analyzed slides under 40x magnification and scored EphA2 expression, with three serial sections from each specimen were evaluated in order to reduce intraspecimen and interspecimen scoring variations. The mean (±SD) value of the nine aggregate determinations (3 readers x 3 sections per lesion) of EphA2 expression intensity for each tumor and matched normal adjacent kidney specimen were calculated for each patient. EphA2 staining results are reported as a ratio of EphA2 expression in tumor sections versus matched normal adjacent kidney.

Statistical Analyses. Statistics were done using SPSS software (SPSS, Inc., Chicago, IL). Regression analyses were assessed using 95% confidence intervals. Statistical differences between groups were evaluated using a two-tailed Student's t test. In these analyses, all RCC subtypes were included without distinction. P < 0.05 was considered significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
RCC Lesions Express Variable Levels of EphA2. RCC tumor specimens exhibited marked variability in their levels of EphA2 expression. For example, patient no. 19's tumor overexpressed EphA2 relative to their normal adjacent kidney tissue and EphA2 protein was located in the cytoplasm and on the cell membrane (Fig. 1A). In normal kidney, EphA2 expression was detected in the renal tubular epithelium (Fig. 1C). In marked contrast, RCC tumor resected from patient no. 16 exhibited a weaker EphA2 staining pattern (Fig. 1E), with the intensity of EphA2 expression by the tumor indistinguishable from that of the normal, matched kidney tissue (Fig. 1G).



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  		Fig. 1 Immunohistochemical analysis of EphA2 expression in RCC specimens. Resected tumor and adjacent normal kidney were obtained from RCC patients #19 (A-D) and #16 (E-H) and stained using anti-EphA2 (A, C, E, and G) or control IgG (B, D, F, and H) antibodies (original magnification x40).

 
RCC Expression of EphA2 Is Associated With the Grade but Not Stage of Disease. Given previous reports in which EphA2 expression was correlated with tumor aggressiveness as indexed by the patient's disease grade and/or stage in the setting of ovarian and prostate carcinoma (17, 18), we evaluated these correlations in our RCC specimens. For these studies, the relative expression level of EphA2 was first determined in tumor versus normal adjacent kidney tissue, with this value subsequently plotted versus patient disease stage and grade assignments (Table 1). As depicted in Fig. 2, the relative EphA2 overexpression in RCC tumors seemed most closely linked with tumor grade, with statistically significant increases observed for grade 3 versus grade 2 (P = 0.049) and grade 4 versus grade 2 (P = 0.002) disease. The observed difference between grade 4 and grade 3 disease approached but did not reach significance (P = 0.091). The only patient cohorts in the analysis of disease staging that approached significance for a correlation with EphA2 expression were the stage I versus stage II (P = 0.051) and stage I versus stage 4 (P = 0.094) comparisons.



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  		Fig. 2 Relative EphA2 expression by RCC is correlated with disease grade but not stage. Relative tumor expression of EphA2 was determined (as outlined in MATERIALS AND METHODS) and plotted against patient histopathologically determined stage and grade (Table 1). Individual patient evaluated with conventional clear-cell RCC ({bullet}), papillary RCC ({circ}), and chromophobic RCC ({blacktriangledown}). Horizontal line, mean values for each cohort. *, P < 0.05, comparisons reaching statistically significance.

 
Larger, More Vascularized Tumors Tend to Exhibit Higher Levels of EphA2 Expression. Recent reports in breast carcinoma and melanoma models suggest that EphA2 expression in situ may be associated with larger, better vascularized tumors (19, 20). Furthermore, EphA2 blockade limits murine breast tumor growth in vivo (21), suggesting that EphA2 plays a role in tumor progression. We therefore analyzed whether the relative EphA2 expression levels observed in RCC lesions was correlated with resected tumor volume and the degree of tumor vascularity. For these studies, the relative expression level of EphA2 was plotted against the volume of the resected tumor (from Table 1). As shown in Fig. 3A, we observed a trend between increased RCC tumor expression of EphA2 and tumor volume, although this correlation only provided an R2 value of 0.33 (P = 0.093) and would not be considered statistically significant. Similarly, an immunohistochemical stain for Factor VIII was used to delineate blood vessels. In this case, the trend between the degree of EphA2 expression levels and the number of blood vessels per tumor section was determined to be statistically significant R2 = 0.31, P = 0.005; (Fig. 3B).



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  		Fig. 3 Relative EphA2 expression is higher in larger, more vascularized RCC lesions. A, relative tumor expression of EphA2 determined (as outlined in MATERIALS AND METHODS) and plotted against the calculated volume of the resected RCC lesion (Table 1). Sequential tissue sections were also stained with anti-Factor VIII antibodies in order to assess the number of tumor blood vessels, with the relative level of vascularity then plotted against EphA2 expression level in B. Individual patient evaluated with conventional clear-cell RCC ({bullet}), papillary RCC ({circ}), and chromophobic RCC ({blacktriangledown}). Regression lines for all data with associated R2 and Ps.

 
High Levels of EphA2 Expression by RCC Tumors Seem Predictive of Acute Relapse and Overall Survival. Given previous reports supporting a prognostic potential for EphA2 expression in lung and esophageal cancer (13, 14), we next evaluated whether the relative level of EphA2 expressed by resected RCC tumors was predictive of the disease-free interval of a given patient treated by surgery. For these studies, patient materials were divided into three cohorts for prospective analyses: (a) patients who recurred within 1 year of surgery (n = 10), (b) patients who recurred between 1 and 5 years of surgery (n = 13), and (c) patients who recurred or who remain disease-free 5 or more years postsurgery (n = 11).

When data from all 34 patients was evaluated (Fig. 4), we observed that the disease-free interval was inversely correlated to the relative EphA2 levels expressed by the patient's resected RCC tumor (versus the matched normal kidney tissue). This difference was most striking (P = 0.0003) when comparing patients who recurred within 1 year (mean relative EphA2 expression = 3.47 ± 1.00 SD) versus patients who remain disease free for more than 5 years post-treatment (mean relative EphA2 expression = 1.03 ± 0.37). The difference was also significant between patients who recurred within 1 year of surgery and those patients who relapsed between 1 and 5 years postsurgery (relative EphA2 expression = 1.39 ± 0.62; P < 0.001). However, the relative expression of EphA2 was not statistically significant between patients recurring between 1 and 5 years and those who remain disease-free for >5 years (P = 0.086).



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  		Fig. 4 Relative EphA2 expression in resected RCC is prognostic of disease-free interval in surgically cured patients. The relative tumor expression of EphA2 was determined (as outlined in MATERIALS AND METHODS) for each patient and the data plotted based on the disease-free interval observed for that patient [i.e., <1 year (n = 10), between 1 and 5 years (n = 13), or >5 years (n = 11)] after curative surgery. Individual patient evaluated with conventional clear-cell RCC indicated ({bullet}), papillary RCC ({circ}), and chromophobic RCC ({blacktriangledown}). Horizontal line, mean values for each cohort. *, P < 0.001; NS, not significant.

 
Perhaps of greatest importance was the strong correlation (R2 = 0.57, P < 0.001) observed between the relative level of EphA2 antigen expressed by the resected tumor lesion at the time of diagnosis and the patient's overall survival (Fig. 5).



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  		Fig. 5 Relative EphA2 expression in resected RCC is prognostic of overall patient survival. The relative tumor expression of EphA2 was determined (as outlined in MATERIALS AND METHODS) for each patient and the data plotted based on the overall survival period of the patient since diagnosis. Individual patient evaluated with conventional clear-cell RCC ({bullet}), papillary RCC ({circ}), and chromophobic RCC ({blacktriangledown}). Regression lines for all data with associated R2 and Ps.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The key finding of this study is that the expression of EphA2 in resected RCC tumors may serve as a correlate for disease grade and a prognostic indicator of disease-free interval and overall survival in patients that were treated with surgery. Patients with RCC lesions exhibiting the highest expression levels of EphA2 protein seem more likely to experience disease recurrence within 1 year after surgery and to survive for shorter periods of time, whereas patients whose tumors expressed levels of EphA2 that were statistically indistinguishable from normal adjacent kidney tissue are more likely to remain disease-free and to survive for extended periods of time postsurgery. Since RCC represents a disease encompassing several histopathologic subtypes (22), it is important to note that our results seem applicable to patients diagnosed with the most prevalent form of RCC (i.e., clear-cell) as well as two more rare forms of the disease, papillary and chromophobe RCC. Given the small cohort sizes for these latter two RCC subtypes, however, formal statistics of their results versus those obtained from the clear cell cohort of patients could not be done. Such comparisons must be addressed in larger, appropriately powered studies.

When combined with recent studies in lung (14) and esophageal (16) carcinoma, our results support EphA2 expression as an important index of disease progression, metastatic spread, and durability of therapeutic efficacy in multiple tumor types. As EphA2 can be overexpressed in a broad range of cancer types (4–12), the prognostic utility of this marker may prove important in monitoring and clinical management of a large cohort of cancer patients.

Our results supporting a correlation between the level of EphA2 expressed by RCC and disease grade is consistent with two recent reports demonstrating similar associations in patients with prostate and ovarian carcinoma (17, 18). Whereas the study in ovarian cancer also determined a statistically significant correlation between EphA2 expression and tumor stage (17), this was not the case for either the study of prostate cancer (18) or for our current analysis, although we did observe a trend for statistical differences between stage I disease and more advanced disease. Thus, this comparison seems to warrant continued evaluation in a series of larger patient cohorts to support or refute its statistical significance in the setting of RCC.

Our finding that EphA2 expression levels tended to be directly associated with tumor volume (i.e., tumor burden) and more so with tumor microvascular density is consistent with a recent report by Kataoka et al. (23) in colorectal carcinoma and may be related to the involvement of EphA2 and its primary ligand Ephrin-A1 in the formation of neovessels in more aggressive tumor lesions (19). When the EphA2 signaling pathway is blocked, vascular endothelial growth factor–mediated angiogenesis is inhibited (20). In this context, we noted that many, but not all, Factor VIII+ vascular endothelial cells in RCC sections also expressed EphA2 (data not shown), similar to recent reports in human–severe combined immunodeficiency and murine breast cancer models (19, 20). Furthermore, recent studies have also shown that the expression of EphA2 is associated with increased tumor cell proliferation and increased tumor thickness in the melanoma setting (24). Overall, these data suggest that overexpression of EphA2 by tumor or endothelial cells within the tumor microenvironment provides a growth advantage to the neoplastic cells, favoring progressor lesions in situ.

The reason(s) why the EphA2 protein becomes overexpressed in aggressive cancers remains incompletely understood, but likely involves both transcriptional and post-transcripitonal mechanisms. cDNA array analyses provide strong support for elevation of EphA2 mRNA in the setting of melanoma (4, 20), and a similar finding would be anticipated for at least a subset of RCCs. Alternatively, or additionally, it has been recently suggested that the steady-state level of "accumulated" EphA2 in cancer cells may be regulated by (1) defective ligand-induced EphA2 activation and/or (2) the activity of the low molecular weight-protein tyrosine phosphatase which prevents the ubiquination and degradation of the phosphorylyated EphA2 receptor tyrosine kinase generated after receptor cross-linking (25, 26). Given these findings, clinical approaches invoking specific RNA interference, agonist antibodies (26) or PTP inhibitors may serve to reduce EphA2 expression within tumor cells, rendering tumors less aggressive, preventing tumor neoangiogenesis, augmenting specific T cell recognition and improving clinical outcomes.


   ACKNOWLEDGMENTS
 
We thank Amy Richmond for outstanding technical support and Drs. Amy Wesa, Jan Mueller-Berghaus and Hassane Zarour for their careful review and helpful comments provided in the generation of this article.


   FOOTNOTES
 
Grant support: NIH Immunology Training grant 5T32 CA82084 (C.J.H.), NIH R01 grants CA57840 (W.J. Storkus) and CA56937 (J.H. Finke), and Foundation for Advancement of International Science, Ibaraki, Japan (T. Tatsumi).

The cost of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 soley to indicate this fact.

Received 7/22/04; revised 8/30/04; accepted 9/14/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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T. Choueiri, B. Rini, J. Garcia, R. Baz, R. Abou-Jawde, S. Thakkar, P Elson, T. Mekhail, M Zhou, and R. Bukowski
Prognostic factors associated with long-term survival in previously untreated metastatic renal cell carcinoma
Ann. Onc., February 1, 2007; 18(2): 249 - 255.
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F. Liu, P. J. Park, W. Lai, E. Maher, A. Chakravarti, L. Durso, X. Jiang, Y. Yu, A. Brosius, M. Thomas, et al.
A Genome-Wide Screen Reveals Functional Gene Clusters in the Cancer Genome and Identifies EphA2 as a Mitogen in Glioblastoma
Cancer Res., November 15, 2006; 66(22): 10815 - 10823.
[Abstract] [Full Text] [PDF]

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