Pancreatic cancer (PaCa), the eighth most commonly diagnosed cancer in the developed world, has one of the worst prognoses of any malignancy with 98% succumbing to their disease within 5 years. Light is beginning to be shed on the underlying molecular events involved in development and progression of PaCa [1] but there is little information on the risk factors associated with disease.

Risk factors for PaCa include environmental exposure (such as cigarette smoking and excessive alcohol intake), type 2 diabetes (T2D) and genetic factors. Both smoking and T2D increase PaCa risk by about double [2-4]. Germline mutations in several genes: BRCA2, PALB2, CDKN2A, ATM, STK11, PRSS1, SPINK1, TP53, SMAD4, ARID1A, ROBO2, KDM6A, PREX2, and DNA mismatch repair have also been associated with an increased risk of disease [1,5]. In addition, two recently completed genome-wide association studies, PanScan1 and PanScan2, reported variants in ABO (rs505 922), 1q32.1 (rs3790844), 13q22.1 (rs9543325), and 5p15.3 (rs401681), which are associated with modestly increased risk of PaCa [6,7]. Familial associations of PaCa are rare and cannot account for the frequency of disease, although if three first-degree relatives are affected, disease risk can be increased over 30 times [8].

The important role of micronutrients in the pathogenesis of malignancy is not fully understood, but must include both selenium (Se) and copper (Cu). Both micronutrients are involved in many biochemical processes including cellular respiration, cellular utilization of oxygen, DNA and RNA production, maintenance of cell membrane integrity, and sequestration of free radicals [9]. In general, in relation to malignancy many studies suggest that Se supplementation can reduce not only the incidence of disease but also mortality [10]. Data from a meta-analysis of 49 prospective studies confirmed a reduction in cancer mortality, by 45% in persons with an optimized Se concentration [11].

The chemo-preventative benefit of Se may differ between individuals and the same dose may not be optimal for all. The preventative effect of Se supplementation strongly depends on the baseline levels of Se and is beneficial only for individuals with a low serum Se concentration. In terms of health benefit, the efficacy of Se is related to a “U” shaped curve [12]. Low levels of Se are associated with an increased risk of malignancy whereas too much (selenosis) is linked to an increased occurrence of common diseases, including T2D [13].

In cancer and inflammation, plasma Cu and ceruloplasmin concentrations rise and the rates of synthesis and secretion of ceruloplasmin by the liver are enhanced. The elevated ceruloplasmin concentrations in both of these conditions would provide additional Cu uptake by cells in normal tissues and as well as cancer cells. In addition, transcuprein (another Cu-binding protein) appears to be increased in malignancy. Ready uptake of Cu from non-ceruloplasmin fractions of plasma, which together account for the relatively high levels of Cu in tumor cells, has been demonstrated in neoplastic cells. Cu also plays a role in angiogenesis, a requirement for tumor growth, which may be mediated by Cu-dependent amine oxidases [14].

Higher Se levels were observed among healthy subjects both in regards to the patients with PaCa, and those with chronic pancreatitis. However, patients with chronic pancreatitis had higher serum Se levels compared with those observed in PaCa patients. Simultaneously an inverse observation was observed for serum Cu levels, where PaCa patients had the highest levels of serum Cu [15]. Taken together, this suggests that serum Se and Cu levels are required for the progression of pancreatic disease.

It has yet to be determined whether altered Se and Cu concentrations are the cause or effect of malignancy. Hence, the utility of serum Se and Cu evaluation for cancer prevention, detection, monitoring treATMent, and prognosis requires further investigation.

In the current study, we examined the levels of Se and Cu in PaCa patients and compared this to a healthy age-matched population from the same geographical region in Poland.

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Se and Cu were assayed in serum samples taken from patients and control subjects. All micronutrient concentrations are reported as μg/L. Among the control group the average Se level was 76 μg/L (range, 43 to 110 μg/L); Cu, 1,098 μg/L (range, 695 to 1,683 μg/L). The mean Se level among PaCa patients was 60 μg/L (range, 29 to 122 μg/L) and the mean Cu level was 1,432 μg/L (range, 764 to 2,901 μg/L). In the PaCa group, the mean serum Se level was 59 μg/L for women (range, 29 to 88 μg/L), 61 μg/L for men (range, 33 to 122 μg/L) and Cu level was 1,524 μg/L for women (range, 858 to 2,901 μg/L) and 1,369 μg/L for men (range, 764 to 2,449 μg/L). The average Se level among the group of healthy participants analyzed was 77 μg/L for women (range, 43 to 110 μg/L), 75 μg/L for men (range, 45 to 103 μg/L) and mean Cu level was 1,206 μg/L for women (range, 695 to 1,683 μg/L) and 1,039 μg/L for men (range, 740 to 1,421 μg/L). The average concentration of Se in the 480 individuals included in this study was 76 μg/L (range, 42 to 162 μg/L) and Cu level was 1,128 μg/L (range, 605 to 1,972 μg/L).

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The relationship between reactive oxygen species (ROS) and disease is well established and the role of Se is recognized as one of the more important micronutrients in the amelioration of ROS. Systematic studies aimed at understanding the protective effects of anti-oxidants in disease, including PaCa, have been conducted, as this is an attractive model in terms of pointing towards agents that can be administered safely to reduce disease development and/or progression.

Examination of Cu and particularly Cu:Se ratio in patients with PaCa revealed some surprising results. The data presented herein indicate that higher Cu levels are significantly more common in patients with PaCa compared to healthy age-matched control subjects. A recent genome-wide association study demonstrated an unequivocal association of SELENBP1 (selenium binding protein 1, a key protein involved in blood Cu metabolism), with Se metabolism, however it has not been associated with other trace elements [16]. The result of this study suggests that there is a relationship between Cu and Se, the precise nature of which remains to be described. For consideration of any potential relationship between Cu, Se, and PaCa, we examined the ratio of Cu:Se and found an even greater association between higher Cu to Se ratios and cancer than that observed for only higher Cu levels. This result suggests that there is an association between Cu and Se which may be mediated by the protein product of SELENBP1. Currently little is known about this protein and it awaits further characterization of its role beyond Se binding.

In general, little is known about the interaction between Se and Cu at the molecular level. Perhaps common ground in the relationship between the two trace elements is the interaction between the changes among the so-called oxidative stress genes, proteins encoded by them and trace elements such as Cu, Se, or Zn. Overproduction of reactive oxygen and nitrogen species and oxidative stress have been implicated in the pathogenesis of PaCa [17]. Reactive oxygen and nitrogen species are generated during endogenous oxidative stress that is linked to the pancreatic renin-angiotensin system [18] or exogenous oxidative stress caused by environmental or lifestyle-related xenobiotics, which is allied with the detoxification system [19].

The inverse association between Se concentration and PaCa incidence is well established [20] and suggests that Se plays a significant role in ameliorating the effects of ROS. The results of studies conducted in Spain on a patient group of similar size (n=118) showed an association of high concentrations of toenail Se with the occurrence of exocrine PaCa (OR, 0.05; 95% CI, 0.02 to 0.15; p(trend)=8×10(-11)) [20]. The association between PaCa and serum Se was also observed in an earlier small study (22 cases of PaCa, 44 matched controls) conducted in the United States. In this report, the association between incidence of PaCa and serum Se levels was significant when the data were analyzed as a whole, but its effect was observed principally in men (OR, 12.5; 95% CI, 1.78 to 84.0) and almost none among the women (OR, 1.2; CI, 0.56 to 2.53). Lower mean serum levels of Se were observed in cases (1.29±0.04 μmol/L) than in control subjects (1.42±0.03 μmol/L) and this difference was significant (0.01 < p < 0.025) [21]. A non-significant difference in serum Se level was observed in an Iranian study conducted among 80 PaCa patients (cases, 9.25 μg/dL; controls, 10.06 μg/dL) [22]. Our results are consistent with the observation that a low level of Se is a characteristic of patients with PaCa.

The role of Se in protecting against other diseases of the pancreas remains controversial with some studies suggesting a protective effect and others suggest at best no effect and possibly an increased risk of disease [13]. Of note, in many studies conducted outside of Poland there are relatively high base-line levels of Se, which may render any supplementation at best useless but more likely harmful.

Particularly intriguing is our finding that high Cu levels appear to be associated with PaCa. This finding, which is inversely related to Se levels, suggests that high Cu:Se ratios may result in higher levels of ROS that impact on the risk of developing and/or progression of PaCa. Cu is associated with ROS production [23] and Se, as a selenoprotein, acts to mitigate the effects of excessive ROS. Given that the Cu:Se was consistently greater in PaCa patients compared to age-matched control subjects suggests that the Cu:Se may be associated with high levels of ROS exposure that predispose susceptible patients to the development and/or progression of disease. This evidence ties in with recent studies examining the mutational landscape in PaCa, where there appears to be a breakdown in DNA repair making pancreatic cells exquisitely sensitive to DNA damaging agents, particularly ROS [1].

So far, a statistically significant increase in serum Cu level among patients suffering from PaCa was reported in a case-control study conducted among 50 PaCa patients with Greek origin. In this study, the average serum Cu level among 32 male PaCa patients was 171 g/100 mL and 137 g/100 mL among 34 healthy men. Among 18 women with PaCa the average serum Cu level was 165 g/100 mL and 137 g/100 mL among 29 healthy women [24]. In these studies, the authors probably rightly point to the potential diagnostic value of this observation. A non-significant difference in serum Cu levels (cases, 87.14 μg/dL; controls, 91.17 μg/dL) was observed in an Iranian study conducted among 80 PaCa individuals with PaCa and group of 100 healthy participants [22]. In light of our observations, the results suggest that determination of both the level of Se and Cu could be a good supplementary laboratory test for the current diagnosis of PaCa. This report also shows a high serum Cu level as a potential factor in development and/or progression of PaCa in the Polish population.

Thus far, one prospective study showed an association of high levels of Se, vitamins C and E with a reduced risk of PaCa (HR, 0.33; p < 0.05). This prospective study demonstrated that higher intakes of Se (and vitamin E), reduced the risk of PaCa by at least 40% [25].

Low levels of Se and high levels of Cu observed in our retrospective study of samples of PaCa patients cannot be treated as a marker for the risk of PaCa. When the serum Se level is examined in patients with newly diagnosed cancers the results can be influenced by the tumor itself. Therefore, retrospective case-control studies are not suitable to conclude that low Se levels are the cause of disease, although such studies can be valuable in determining whether Se levels may be used as a useful marker in the selection of patients for disease surveillance. The level of these micronutrients should rather be regarded as PaCa patients’ lab status not the causal explanation for cancer development. As we observed, a low level of Se/high Cu in patients with PaCa can be considered as a potential diagnostic marker indicative of the neoplastic process and not as a risk marker or a direct cause of cancer. However, it cannot exclude the possibility that micronutrients (Se, Cu) lab status of PaCa patients may affect the development of PaCa. In our study, we observed a longer survival (on the border of statistical significance) for patients with PaCa and a high level of Se compared to subjects with cancer of the pancreas and low level of Se (medium, 11 months vs. 6 months). Therefore, it cannot be excluded that the level of Se may be a prognostic marker in PaCa. The level of Se was far from optimal among the PaCa patients we examined, however, a longer survival time was observed even in patients whose levels of Se showed higher values. This observation must be verified in a larger series of PaCa cases, but if related to the results of prospective studies, it is not surprising. Data from meta-analysis of 49 prospective studies have also confirmed a reduction in cancer mortality by 45% in persons with an optimized Se concentration [11]. In our retrospective study, we observed that PaCa prolonged survival only in patients with higher levels of Se, but this observation is part of an overall favorable view of the importance of Se in the prevention of cancer in general. However, these data can suggest the potentially preferred meaning of chemoprevention of Se in populations with low levels of Se, which include the Polish population (mean level of Se in serum 70 μg/L).

There are several limitations to our study. Perhaps the most important limitation of our case-control study is that the Se and Cu and copper measurements for cases were made after the diagnosis of PaCa, although before therapy. It is possible that the low levels of Se and high levels of Cu detected could be a consequence of disease. If this is the case, then a low Se/high Cu level could potentially be a marker of progression rather than just a risk factor. The sample size in our study is relatively small but the associations for Se and Cu levels were strong and highly significant. The cases and controls were matched for smoking status and it is therefore unlikely that the association could be confounded by smoking, but it is possible that another confounding variable could introduce bias. Se levels could be affected by arsenic level, which is known to be present in cigarette smoke. However, since the cases have been matched with controls for smoking status (expressed in pack-years) and the arsenic content of the cigarettes is controlled by World Health Organization (WHO) guidelines, the effects have been mitigated as much as possible.

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This retrospective study suggests that low levels of Se and high levels of Cu may affect PaCa development. The results of our retrospective study support an inverse association of lower levels of Se and an increased probability of PaCa and indicate an association between higher serum Cu levels with disease. The determination of Se and Cu in the blood serum can complement conventional procedures used in diagnosis of PaCa as an additional laboratory marker. In addition, it appears that a higher level of Se is associated with longer survival in patients with PaCa. While our findings need to be replicated in other independent studies, they suggest a role of Se and Cu as markers in diagnosis of PaCa and possible development. Unquestionably, prospective cohort studies will be required to elucidate the use of Se and Cu measurements as markers of risk of PaCas. Currently it seems that determining the level of Se and Cu can be a marker for selection for control examinations in surveillance as a valuable complement to existing diagnostic procedures.

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