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Normal, Benign, Preneoplastic, and Malignant Prostate Cells Have Distinct Protein Expression Profiles Resolved by Surface Enhanced Laser Desorption/Ionization Mass Spectrometry¹

Departments of Microbiology and Molecular Cell Biology [L. H. C., B-L. A., M. D. W., O. J. S., G. L.W.], Pathology and Anatomy [S. N.], Urology [P. F. S., G. L. W.], and Virginia Prostate Center [L. H. C., B-L. A., M. D. W., S. N., P. F. S., O. J. S., G. L. W.], Eastern Virginia Medical School and Sentara Cancer Institute, Norfolk, Virginia 23501

Purpose: The objective of this study was to discover protein biomarkers thatdifferentiate malignant from nonmalignant cell populations, especially early protein alterations that signal the initiation of a developing cancer. We hypothesized that Surface Enhanced Laser Desorption/Ionization-time of flight-mass spectrometry-assisted protein profiling could detect these protein alterations.

Experimental Design: Epithelial cell populations [benign prostatic hyperplasia (BPH), prostate intraepithelial neoplasia (PIN), and prostate cancer (PCA)] were procured from nine prostatectomy specimens using laser capture microdissection. Surface Enhanced Laser Desorption/Ionization-time of flight-mass spectrometry analysis was performed on cell lysates, and the relative intensity levels of each protein or peptide in the mass spectra was calculated and compared for each cell type.

Results: Several small molecular mass peptides or proteins (3000–5000 Da) were found in greater abundance in PIN and PCA cell lysates. Another peak, with an average mass of 5666 Da, was observed to be up-regulated in 86% of the BPH cell lysates. Higher levels of this same peak were found in only 22% of the PIN lysates and none of the PCA lysates. Expression differences were also found for intracellular levels of prostate-specific antigen, which were reduced in PIN and PCA cells when compared with matched normals. Although no single protein alteration was observed in all PIN/PCA samples, combining two or more of the markers was effective in distinguishing the benign cell types (normal/BPH) from diseased cell types (PIN/PCA). Logistic regression analysis using seven differentially expressed proteins resulted in a predictive equation that correctly distinguished the diseased lysates with a sensitivity and specificity of 93.3 and 93.8%, respectively.

Conclusions: We have shown that the protein profiles from prostate cells with different disease states have discriminating differences. These differentially regulated proteins are potential markers for early detection and/or risk factors for development of prostate cancer. Studies are under way to identify these protein/peptides, with the goal of developing a diagnostic test for the early detection of prostate cancer.

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