DISCUSSION
In the present study, we found an increased rate of RAGE expressions on the specimens of the localized and metastatic prostate cancer tissue samples to those of the patients with BPH. Additionally, we not only confirmed previous studies of RAGE expression in Prostate cancer samples but also compared the malignant prostate neoplasias (localized or metastatic) with benign prostate hyperplasia. A similar study has been previously reported on the overexpression of RAGE in patients with prostate neoplasias but not in a Turkish population29.
The association between diabetes mellitus and the development of prostate cancer has been studied in numerous studies, but this relationship has been still controversial6,7,30,31. Some of these studies32,33 documented that there was a decreased risk of prostate cancer in patients with type 2 diabetes mellitus whereas; others documented an elevated risk of prostate cancer in these patients11,34,35. Lower androgen levels have been suggested as an explanation for the inverse correlation between diabetes and prostate cancer36. Furthermore, it was reported that low PSA levels were related to diabetes mellitus, and lower PSA values could cause fewer biopsies and result in decreased diagnose of prostate cancer in patients with type 2 diabetes mellitus37,38. Contrary to these studies35,38,45, in this study, we did not find low PSA levels in diabetic patients than non-diabetic patients (p=0.06). But we know that the measurement of PSA levels seems to be influenced by number factors including demographic, lifestyle, and health characteristics46. Variation of the serum PSA measurements could be an alternative explanation for the inverse correlation between diabetes and prostate cancer. On the other hand, preliminary studies were reporting that obesity, hyperinsulinemia, inflammatory cytokines, dyslipidemia, and common factors associated with type 2 DM were revealed as risk factors for various cancer types, including prostate cancer39.
It is well known that AGE and interactions of their receptor (RAGE) are produced increasingly in diabetes mellitus, and they induce oxidative stress, inflammatory reaction, apoptosis, autophagy which resultant with cancer development40-42. The previous study claimed that RAGE/NF-κB signaling pathways facilitated the prostate cancer metastasis43. They studied the HMGB1 (high mobility group box 1) and RAGE expression on 36 prostate tissue specimens (12 BPH, 12 LPCa, 12 MetPCa) by immunohistochemically, and they showed the HMGB1 and RAGE expression were increased on tissues of LPCa and MetPCa and less detectable on muscles of BPH. In another study, they reported that RAGE expression was strongly correlated with progression and poor prognosis of prostate cancer44. They also found that RAGE’s positive expression was significantly higher in prostate cancer than BPH (p=0.002). They suggested that the RAGE expressions were positively correlated with tumor stage, lymph node metastasis, and distant metastasis. Inconsistent with this study, the other study29 demonstrated that RAGE expression rates were significantly high on tissues of untreated prostate cancer and hormone-refractory prostate cancer tissue.
In the present study, we focused on diabetic patients because diabetes mellitus is the most known causative underlying factor in the occurrence of glycated end products and RAGE expression on tissues. Consistent with these regards, RAGE expressions were found to be more intense on prostate cancer tissues (localized or metastatic) among patients with Diabetes Mellitus than hyperplasia. When we compared the diabetic LPCa patients with diabetic MetPCa patients, RAGE expression on specimens of the metastatic disease was higher than localized cancer. But this was not significant statistically related to sample size. Our finding is consistent with the study44 mentioned above that overexpression of RAGE was strongly correlated with the metastatic diseases44,47. We could not find any significant difference in cancer recurrence, cancer metastasis, and clinical survival in diabetic and non-diabetic.
When we screen the studies related to the RAGE expression and cancer progress, the relationship between RAGE expression and patient outcome has still been a controversial issue. In certain cohort studies, it has been reported that there was a weak connection between the RAGE expression and cancer course of other cancer types, including colorectal, esophageal carcinoma48,49. Further investigations with a large number of patients and more extended follow-up periods may support our hypothesis with more satisfactory results.
One of the major limitations of this study is the small sample size for all three (BPH-LPCa-MetPCa) subgroups. Besides, this is a retrospective study, so some parameters, including a history of medications, smoking, are missing. Another limitation of our study is that diabetic and non-diabetic patients with prostate cancer (localized or metastatic) cannot be compared in terms of prognosis and survival because the number of diabetic patients is insufficient for statistical analysis.
In conclusion, In the present study, we found a high rate of RAGE expression in malignant prostate neoplasias (localized or metastatic) to the benign prostate hyperplasia, furthermore (beside) those with type 2 diabetes mellitus as expected revealed higher scores than the non-diabetics. Disease progression and survival parameters were worse in the patients with high RAGE levels, but it was not statistically significant. We already do not know the exact mechanisms and clinical consequences or any reasonable diabetic metabolic control on the prostate cancer prognosis. Further studies are needed.