Citrate in the diagnosis of prostate cancer

Abstract

Background: One of the major current problems involved in prostate cancer (PCa) is the unavailability of sensitive, accurate, and preferably noninvasive procedures for the diagnosis of PCa. Moreover, procedures are needed which will permit the early detection, staging, location, and estimation of the volume of malignancy, and preferably a mapping of the prostate for follow-up of progression and regression of the malignancy.

Methods: The unique citrate relationships of the prostate, coupled with recent developments and technological advancements in magnetic resonance spectroscopy (MRS) for the in situ determination of citrate levels, now provides an excellent diagnostic procedure which can achieve all these goals. There exist strong, compelling basic and clinical studies in support of the employment of 1H MRS measurements of citrate and other associated metabolites in the diagnosis of PCa.

Results: This review provides the background leading to the current status of MRS citrate analysis, summarizes the data from clinical trials, and describes the applications of the procedure for the diagnosis of PCa and follow-up of patients. The use of MRS studies in defining the functional, as well as pathological relationships of the prostate, is also discussed.

Conclusions: This review is intended to be informative to the prostate- and oncology-interested community, and, hopefully, to engender much-needed interest and support in future research regarding the prostate relationships described in this report.

Fig. 1

Representative in situ 1H MRS spectral analysis of the prostate of a subject with BPH and PCa. The analysis was achieved by 3-D MRS coupled with MRI (0.24 ccm resolution). Shaded area represents citrate signal. A: Region of the central zone which exhibited predominantly glandular BPH with some stromal BPH. B: Region of the central zone which exhibited predominantly stromal BPH with some glandular BPH. C: Region of the peripheral zone which exhibited prostate cancer. D: Region of the normal peripheral zone. Note the low citrate signal in the malignant peripheral zone compared to the normal peripheral zone, and the apparent differences in the citrate/choline + creatine ratios. Note that glandular BPH exhibits a high citrate level, whereas normal central zone typically exhibits very low citrate levels (not shown). As stroma replaces the glandular BPH, the citrate level decreases (Modified from Kurhanewicz et al. [23], with permission).

Fig. 2

Typical contiguous mapping of in situ 1H MRS spectra of citrate relationships in normal and malignant prostate. A: Normal zonal differences in citrate. Note that the peripheral zone is characterized by a distinctly high, sharp peak referenced against the choline/creatine peak, whereas the central zone and periurethral regions exhibit a lower, less defined citrate signal. B: Note that in BPH, the central zone exhibits a strong citrate signal comparable to the peripheral zone, whereas the periurethral region continues to exhibit a low citrate signal. This reveals that glandular BPH results from the invasion and proliferation of citrate-producing epithelial cells. C: Note that in PCa, the malignant regions of the peripheral zone exhibit a greatly decreased citrate signal which is much lower than the choline signal. The normal regions of the peripheral zone exhibit the typical high citrate signal (compiled from figures in Kurhanewicz et al. [23], with permission).

Fig. 3

In situ 1H MRS measurements of prostate citrate levels and the detection of malignancy in humans. A composite of three independent reports. The data present the range of values obtained and the mean of the values. The n for each set of measurements is presented at the end of each bar. PZ (N), normal peripheral zone of normal subject; PZ (P), normal peripheral zone of patients; CZ (N), normal central zone; BPH, central zone with glandular and stromal hyperplasia; Pca, cancer in the peripheral zone (figure compiled from Kurhanewicz et al. [23], Heerschap et al. [24], and Liney et al. [26], with permission; data from Kurhanewicz et al. [23], originally presented as choline + creatine/citrate ratios, have been inverted for comparative purposes to be consistent with the presentation of the other two studies).

Fig. 4

Proposed relationship of citrate in the development and progression of prostate malignancy as the basis for the diagnosis of PCa. A: Normal prostate glandular epithelial cells are citrate-producing cells in which high zinc accumulation inhibits citrate oxidation. These cells contain a zinc transport mechanism which is responsible for the intracellular accumulation of zinc. B: The neoplastic cell loses the ability to accumulate zinc, probably due to the lost activity of the zinc transporter. The inability to accumulate zinc causes a decline in intracellular zinc level, which results in removal of the zinc inhibition of citrate oxidation. C: Net citrate production no longer occurs, and the neoplastic cell is now a premalignant, citrate-oxidizing cell. D: Increased ATP production coupled to citrate oxidation occurs, and the premalignant cell is now able to perform its malignant activities and is histopathologically identifiable. This scheme accounts for the identification of early changes in zinc and citrate as a premalignant stage (C) prior to the appearance of detectable histopathological evidence of malignancy.