| Part I The Association between Overall Survival of Prostate Cancer Patients and Hyperglycemia, OverweightObjective:Metabolic disorders, such as hyperglycemia and overweight are considered to be associated with the development and progression of prostate cancer (PCa). This study is aimed at investigating the association between pre-existing hyperglycemia and overweight and the overall survival (OS) of PCa patients receiving surgical androgen deprivation.Methods and Materials:We retrospectively studied the clinical data of 323 patients of PCa receiving surgical androgen deprivation in Huashan Hospital from January 2003 to August 2012 aged 50-91 years old. All the patients had integrated clinical information, such as serum PSA level, Gleason score, imaging data of ultrasonography, computed tomography (CT) or magnetic resonance imaging (MRI), and bone scan with emission computed tomography (ECT). All subjects were ethnic Han Chinese. Each subject was informed about the aims and requirements of this study, and informed consent for participation was obtained. Subjects were grouped according to body-mass index (BMI) and fasting plasma glucose level. Hyperglycemia is defined as elevated fasting plasma glucose level (≥5.6 mmol/L) or pharmacological treatment for type 2 diabetes mellitus. And men with BMI≥25 kg/m2 are considered overweight, based on the definition established by the World Health Organization (WHO). Follow-up started on the day of surgical androgen deprivation and concluded on the date of death or the date of last follow-up for patients still alive.Patients were generally contact by phone every three months. All deaths were confirmed using both the Shanghai Medical Insurance System and information from Centers for Disease Control (CDC). The association between OS and hyperglycemia or overweight, both separately and combined, was analyzed via Kaplan-Meier method. The distributions of clinicopathological features among groups were evaluated using Fisher’s exact or chi-square test. Statistical analyses were processed using SPSS version 17.0 for Windows (SPSS Inc., Chicago, IL, USA);p<0.05 was considered statistically significant.Results:23 men (7.1%) were lost to follow-up during this study, and finally 300 patients were included.58 men (19.33%) were identified as overweight,50 men (16.67%) with hyperglycemia, and 26 men (8.67%) with both overweight and hyperglycemia. During a median follow-up for 43 months (range,3 to 119 months),122 deaths (40.7%) were confirmed from PCa, heart attack, stroke, and respiratory failure, and etc., including 62 men (37.35%) in control group,25 (43.10%) in overweight group, 22 (44%) in hyperglycemia group, and 13 (50%) in hyperglycemia and overweight group. The total one-year OS rate was estimated at 97% and the five-year OS rate was 65.33%. No statistically significant difference of one-year OS rate was observed among four groups. The five-year OS rate of men with both overweight and hyperglycemia (50%) was significantly lower than that of control group (70.48%, P=0.038). There was no significant difference among OS curves between control group, overweight group and hyperglycemia group. Men with both overweight and hyperglycemia had significantly shorter survival time than control group (P=0.044).Conclusions:Pre-existing hyperglycemia and overweight were associated with poor prognosis of PCa patients receiving surgical androgen deprivation. Men with both overweight and hyperglycemia had significantly lower five-year OS rate and shorter survival time. Metabolic disorders may contribute to the development and progression and PCa.Part Ⅱ IGF-1 Related Pathways and High-fat Diet Promotion of TRAMP Mouse Prostate Cancer ProgressionObjective:We aimed to examine the effect of high-fat diet on PCa development and progression by comparing tumor incidence and mortality among TRAMP mice fed with high-fat diet or not. Then we investigate the role of IGF-1 related pathway in high-fat diet promotion of TRAMP mouse PCa progression.Methods and Materials:TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mice were randomly divided into two groups:the experimental group-high-fat diet group (n=42), and the control group-normal diet group (n=42). High-fat diet group TRAMP mice were fed with high-fat forage to induce obesity and insulin resistance. TRAMP mice of both groups were sacrificed and sampled on the 20th,24th and 28th week respectively. TRAMP mice were required to fast overnight before sacrifice. Fasting blood glucose was measured when blood was taken. Serum levels of insulin, IGF-1 and IGF-2 were tested by ELISA. Prostate tissue of TRAMP mice was used for both HE staining and immunohistochemical staining of IGF-1 related pathway proteins, including IGF-IRα, IGF-1Rβ, IGFBP1, IGFBP2, IGFBP3, IGFBP5, IGFBP6 and Akt.Results:A total of 13 cases of death were observed in the study, including 3 TRAMP mice (7.14%) from the normal diet group, and 10 TRAMP mice (23.81%) from the high-fat diet group. The mortality rate of TRAMP mice from high-fat diet group was significantly higher than normal diet group (P=0.035). When TRAMP mice were sacrificed at 20th week, there were 11 TRAMP mice (78.57%) from high-fat diet group had typical PCa, while there were only 5 TRAMP mice (35.71%) from ordinary diet group had typical PCa. The tumor formation rate of high-fat diet TRAMP mice at 20th week was significantly higher than that of normal diet group (P=0.022). Blood glucose, serum insulin and IGF-2 levels were not significantly different among normal diet group and high-fat diet group at 20th,24th and 28th week. But serum IGF-1 level of high-fat diet TRAMP mice was significantly higher than that of normal diet TRAMP mice. The difference was even significant at 28th week with P value of 0.011. In addition, serum IGF-1 level tended to increase with high-fat diet TRAMP mice’s age. Immunohistochemical staining of TRAMP mice prostate showed that high-fat diet TRAMP mice had higher positive staining rate of IGF-1Rα, IGF-1Rβ, IGFBP3 and Akt than normal diet TRAMP mice. Though other IGF binding proteins (IGFBP1, IGFBP2, IGFBP5 and IGFBP6) were also expressed in TRAMP mice prostate, there was no significant difference of positive staining rate between the two groups.Conclusions:Tumor formation rate and mortality rate of high-fat diet TRAMP mice were significantly higher than those of normal diet TRAMP mice, indicating that high-fat diet can promote PCa development and progression. IGF-1 related pathway proteins, including IGF-1, IGF-1Rα, IGF-1Rβ, IGFBP3 and Akt, were found to have higher expression in high-fat diet TRAMP mice by ELISA and immunohistochemical staining study, suggesting that IGF-1 related pathway played an important role in high-fat diet promotion of TRAMP mouse PCa development and progression. |
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