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Letters to the Editor |
2 Department of Urology, University Hospital Charité, Berlin, Germany
3 Berlin Institute for Urologic Research, Berlin, Germany
4 Republic Center of Urology, Bishkek, Kyrgyz Republic
aAddress correspondence to this author at: Department of Urology, Research Division, University Hospital Charité, Schumannstrasse 20/21, 10117 Berlin, Germany, Fax 49-30-450515904, E-mail klaus.jung{at}charite.de
To the Editor:
We read with great interest the article by Sarkissian et al. (1) reporting the identification of serum matrix metalloproteinase-7 (MMP-7)1 as a marker for renal cell carcinoma (RCC). For the purpose of identification, the authors used sera from healthy individuals and RCC patients and combined 2-dimensional electrophoresis of an RCC cell-line supernatant and an immunoblotting procedure. Subsequently the authors measured serum MMP-7 concentrations with a self-developed immunoassay. Higher concentrations were found in RCC patients than in healthy individuals (7.56 vs 2.13 µg/L), whereas serum MMP-7 concentrations in patients with localized RCC did not differ from concentrations in patients with metastatic RCC (7.26 vs 7.87 µg/L). These results suggest that MMP-7 could be a useful marker for detecting RCC during the early stages of the disease. These findings are of utmost importance because at present no blood marker is known for the early detection of RCC.
Continuing our studies on the diagnostic performance of MMPs, we investigated circulating MMP-7 in RCC patients, but our results (2) differed from those of Sarkissian et al. We measured MMP-7 in heparin-plasma samples using Fluorokine multianalyte profiling assays (R&D Systems). In our study MMP-7 concentrations (Fig. 1
) in healthy controls were not found to be different from those in RCC patients with localized cancer (N0M0 stage; TNM-1997 classification) (1.64 µg/L, n = 50 vs 1.85 µg/L, n = 39), but were markedly higher in patients with lymph-node involvement (N1M0 stage, n = 13; 3.82 µg/L) or distant metastases (M1 stage, n = 45; 3.34 µg/L). These data do not support the use of circulating MMP-7 as a marker for detecting early stages of RCC.
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The clinical importance of these data makes it worthwhile to consider possible reasons for the disparities between these 2 studies regarding the clinical validity of serum MMP-7 measurements. Preanalytical and analytical factors as well as aspects of study design should be considered. One reason may be differences in blood sampling, which is well known to be a significant preanalytical determinant of MMP measurements (3). Sarkissian et al.(1) used sera for their measurements, whereas we used plasma. Circulating MMP-7 values, however, are not greatly affected by the blood collection procedure(3); therefore blood sampling seems an unlikely explanation for the discrepant findings. Analytical variables seem more likely to be causes of the discrepant findings. The 2 studies used different antibodies in the MMP-7 assays. In consequence, different epitopes of MMP-7 may have been recognized, leading to differing detection of the various forms of MMP-7. MMP-7 exists in human serum as polymers or complexed with serum proteins(4). According to the information from the manufacturer, the assay that we used measures pro- and active forms of MMP-7 as well as MMP-7 complexed with tissue inhibitor of MMP 1. The assay used by Sarkissian et al.(1) detected only pro- and active MMP-7, but the detection of MMP-7 forms complexed with serum proteins cannot be excluded. Sarkissian et al. observed higher MMP-7 concentrations in their patients(1) than we did in ours, and more importantly, they found increased MMP-7 concentrations in both the patients with localized cancer and the patients with metastases. In contrast, the 95th percentile they observed in their control group (3.29 µg/L vs our 3.35 µg/L) suggested that these concentration differences did not exist in the healthy participants of the 2 studies. Because the same recombinant human MMP-7 was used as a calibrator in both assays, it can be assumed that MMP-7 forms possibly typical for RCC patients are more sensitively detected by the assay of Sarkissian et al.(1) than by the R&D MMP-7 assay we used. Different assay designs including the use of the mentioned specific antibodies could affect the assay sensitivity, but autoantibodies to pro–MMP-7 occurring in sera of RCC patients(1) could also interfere with measurement of MMP-7. The differences in study results may also be attributable to different approaches used for selection of study participants and the sizes of study groups. The study of Sarkissian et al.(1) was designed to identify proteins related to RCC rather than to validate the clinical utility of the analyte. In contrast, our study focused on the potential diagnostic and prognostic performance of MMP-7 in somewhat larger and well-classified RCC groups. Sarkissian et al.(1) may have been unable to demonstrate an association of MMP-7 with advanced RCC owing to the limited number of RCC patients in their study population. Finally, MMP-7, although predominantly expressed by tumor cells, may also be released from other cell types(2)(5). For this reason, various clinical conditions may influence the concentrations of circulating MMP-7 in study populations and contribute to such variation in data. Prospective studies will be required to clarify the clinical applicability of circulating MMP-7 as an early or metastatic marker in RCC patients.
Acknowledgments
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors’ Disclosures of Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: K. Jung, Sonnenfeld Foundation; A. Ramankulov, German Academic Exchange Service.
Expert Testimony: None declared.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
Acknowledgments: The authors thank Silke Klotzek for excellent technical assistance. We thank an unknown reviewer for his helpful comments to improve the manuscript.
Footnotes
1 Nonstandard abbreviations: MMP-7, matrix metalloproteinase-7; RCC, renal cell carcinoma. 
References
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