To our knowledge, this is the first study to examine prostate tissue folate levels in either prostate cancer patients or cancer-free controls. Previous studies have compared prostate cancer incidence to serum or red blood cell folate, or, in many cases, dietary recall assessments of folate intake, in either a prospective or retrospective manner. However, there are great differences between tissues in regard to their sensitivity to changes in folate intake (19
). Fasting serum folate levels at time of radical prostatectomy were therefore measured to determine systemic folate status, and both cancer and histologically normal tissue folate concentrations were measured to determine folate status of the prostate.
Both cancer and normal prostate tissue from prostate cancer patients were positively correlated with the patient’s baseline serum folate, which contrasted with a lack of significant correlation among the control subjects. The potential for folate to serve as a growth factor for neoplastic cells is amplified by their tendency to up-regulate the membrane transporters that mediate their uptake of folate (20
): this upregulation might better enable tumor-bearing prostates to extract folate from the serum and to thereby maintain a closer concordance with circulating levels of the vitamin. Moreover, cancer folate was significantly higher than normal prostate tissue folate levels from cancer free controls. The mean serum folate level among the control group in our cohort (17.4 nM) approximates the mean folate level in the placebo group (22.7 nM) of the colon cancer chemoprevention study (4
). In addition, the mean level of serum folate observed among prostate cancer patients (62.6 nM) approaches the post-folate supplementation serum levels (72 nM) from that study (4
), suggesting that this cohort is representative of the U.S. population consuming folic acid supplements or large amounts of folic acid fortified food. Although folate is considered a water-soluble vitamin and therefore expected to be excreted when in excess, this may not be true in practice as a recent study indicated that 40% of older adults in the United States have unmetabolized serum folic acid that persists after fasting, the presence of which is not easily explained by folic acid intake alone (21
The wide range of prostate tissue folate concentrations observed is of interest. Prostate tissue folate concentrations varied by greater than 40-fold (range: 0.006 pg/ug to 0.223 pg/ug). Within the confines of either the cancer group or the cancer-free group, the range of tissue folate concentrations varied by 19 and 13-fold, respectively. Thus, considerable variability in prostate tissue folate concentrations exists within this population. If prostate tissue folate levels are related to the risk of prostate carcinogenesis or progression, such a large variation between individuals may contribute to the variable risk seen in the population.
A significantly greater mean Ki67 staining index in grade matched (Gleason score 7) prostate cancers from men with high versus low serum folate concentrations was observed. Ki67, a proliferation marker, is strongly associated with the biological behavior of prostate cancer (22
). Many studies have demonstrated the independent prognostic value of Ki67 staining both in clinically localized disease treated by radical prostatectomy (23
)or radiation (18
), and in patients with advanced disease (25
). Most recently, Gunia et al.
) reported that Ki67 SI >5% is an independent predictor of biochemical recurrence following radical prostatectomy. In a rat model of colorectal carcinogenesis, moderate folic acid supplementation positively correlated with tumor multiplicity and rectal epithelial cell proliferation (27
). Kim’s “dual effect” hypothesis (28
) proposes that prior to neoplastic transformation folate is protective, however once the tumor is initiated, folate drives cell division. Thus our results would support the second part of Kim’s hypothesis, implying that at least in prostate cancer patients, very high serum folate concentrations may potentiate tumor proliferation (29
). In the presence of limiting levels of folate in vitro
(≤50 nM), PSMA expression increases cell folate uptake and proliferation (30
). We therefore examined if expression of PSMA in tumors varied according to serum folate level; however our non-significant findings suggest PSMA expression is not regulated by folate levels and therefore it is unlikely that PSMA directly contributes in to the increased proliferation seen in the patients with high serum folate.
As suggested by a recent study (31
), the high serum folate levels observed in this cohort may indicate an underlying perturbation of one-carbon metabolism that supports prostate carcinogenesis in some individuals. The finding that 25% of the study cohort had more than 6-fold “adequate” serum folate levels (>81.72 nM) was unexpected. Such high levels are not likely to be achieved without long term folic acid supplementation, whether from consuming fortified foods or vitamin preparations. As half of the patients in this quartile reported that they do not take vitamin supplements, it is likely that their folate levels are due to sustained consumption of fortified food.
Although these observations are novel and may have important implications regarding folate supplementation in populations at risk for developing prostate cancer, the study has limitations. As a cross-sectional analysis, causality can only be implied, and not proven, by the correlations observed between folate concentrations and the presence and characteristics of prostate cancer. Unknown variables may be responsible for the observed differences in serum and prostate tissue folate concentrations rather than variances created by the effects of differences in the use of vitamin supplements or by tumor biology, as postulated. The number of subjects studied is limited, and it will be useful to confirm our observations in a larger cohort.
Given widespread dietary folate supplementation the relationship between folate intake and prostate cancer should be better defined.