In this prospective study, consistent with our hypothesis, serum levels of sRAGE had an inverse association with risk of pancreatic cancer. This association was independent of CML-AGE and glucose. In contrast to our expectation, higher CML-AGE levels were not associated with a higher risk of pancreatic cancer. However, the participants with a high CML-AGE/sRAGE ratio had a significantly higher risk of pancreatic cancer. The association between CML-AGE and pancreatic cancer risk differed by levels of sRAGE.
Several recent investigations indicate that RAGE plays a potentially important role in carcinogenesis (17
). The engagement of full-length RAGE by CML-AGE triggers rapid generation of intracellular reactive oxygen species and activates an array of key cell signaling pathways that have been implicated in oncogenesis. These cascades set the stage for sustained activation of innate immune response and proinflammatory reactions (32
). A role of AGEs/RAGE in pancreatic carcinogenesis has been suggested. One study conceived that chronic exposure to AGEs in prolonged hyperglycemic states could drive tumor growth. This study showed that AGEs-RAGE interaction stimulates the growth of human pancreatic cancer cells Mia PaCa-2 through the autocrine induction of platelet-derived growth factor-B (33
). High RAGE expression has been correlated with the metastatic potential of pancreatic carcinoma cell lines (34
). The role of AGEs/RAGE in pancreatic carcinogenesis is also indirectly supported by a few epidemiologic observations. The use of metformin has been shown to reduce pancreatic cancer risk among diabetics (35
). Metformin is a potent inhibitor of glycation (36
) and has been shown to reduce bovine endothelial cell protein expression of RAGE (37
). In two prospective studies, tooth loss and periodontal diseases have been positively associated with pancreatic cancer risk (38
). RAGE may play a role in the progression of periodontal diseases exacerbated by smoking (40
). Taken together, there are several lines of evidence that support the potential involvement of the AGEs/RAGE axis in pancreatic cancer development.
sRAGE binds RAGE ligands, such as CML-AGE, and blocks the engagement of RAGE and ligands. Therefore, sRAGE may be an endogenous protective factor against the effects mediated by RAGE (18
). With few exceptions (41
), many studies have shown an inverse association between circulating levels of sRAGE and type 2 diabetes (18
). Lower levels of serum sRAGE have been linked to poor glycemic control among patients with type 2 diabetes (43
). Although the functional role of sRAGE in the circulation remains to be elucidated, we speculated that the chronic inflammatory environment fostered by AGEs/RAGE interaction may be conductive to tumor growth, whereas sRAGE may be inhibitory.
The lack of a positive association between CML-AGE and risk of pancreatic cancer may be attributable to the detoxification or neutralization of CML-AGE by sRAGE or other receptors of CML-AGE (44
). The trend of an inverse association between CML-AGE and pancreatic cancer risk may be mediated through sRAGE as the association was attenuated and became non-significant after adjustment for sRAGE. We observed a borderline significant sub-multiplicative joint effect between CML-AGE and sRAGE on pancreatic cancer. This result suggested that lower sRAGE rather than higher CML-AGE was associated with pancreatic cancer. Low sRAGE was strongly associated with an increased risk of pancreatic cancer when CML-AGE was low. High CML-AGE was not associated with an increased risk. Nevertheless, we observed a positive association between the CML-AGE/sRAGE ratio and pancreatic cancer risk. Although speculative, it is possible that unbound CML-AGE is involved in pancreatic carcinogenesis. These aspects may be clarified with additional epidemiologic studies, as well as basic research.
Our study had several limitations. Firstly, as smokers have a higher burden of oxidative stress, our findings may not be generalizable to other populations that include non-smokers or women and need to be confirmed in other study populations. Nevertheless, the positive correlation between circulating levels of CML-AGE and sRAGE observed in the present study has also been reported in other study populations (45
). Secondly, we only had a single measurement of these biomarkers prior to diagnosis of pancreatic cancer. Repeated measurements within the same individual over time would provide a better picture for the risk assessment. Thirdly, although CML-AGE is a prominent type of AGEs compounds, it is unknown how well it reflects the total burden of AGEs exposure that was not quantified by the present study and may contribute to cancer development (47
). Fourthly, it is possible that the risk estimates were influenced by measurement imprecision due to the freeze-thaw cycle of serum or ELISA error; however, the risk estimates after exclusion of subjects whose serum have > 2 freeze-thaw cycles were similar to those in all study subjects. Lastly, the interpretations of the study findings are limited by the present incomplete understanding of the dynamic interaction of sRAGE with ligands of RAGE in cancer development. It is possible that sRAGE is associated with other ligands of RAGE or interacts with unmeasured molecules in a different pathway.
In summary, this prospective study supports the hypothesis that sRAGE is inversely associated with pancreatic cancer. Future studies should investigate the correlation between markers of insulin resistance, inflammation and oxidative stress and sRAGE and their interactions in relation to pancreatic cancer. Understanding the genetic and environmental factors (such as dietary intake and cigarette smoking) that regulate the RAGE/ligand axis may provide a clue into new etiology factors.