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.