Polymorphisms of receptor for advanced glycation end products and risk of epithelial ovarian cancer in Chinese patients.
Impact Factor: 5.5
Level of Evidence: Level IV
Type of study: Case-control study
Sample size: 190 subjects and 210 controls
Introduction: This study was investigating if receptor for advanced glycation end products (RAGE) polymorphisms were associated with a risk of epithelial ovarian carcinoma (EOC). They looked at 4 different polymorphisms: 82G>S, -374T>A, -429C>T and 1704G>T. RAGE is a member of the immunoglobulin superfamily of cell surface molecules and its gene is found on chromosome 6p21.3 in the major histocompatibility locus class II/III junction and is composed of a 1.7 kb 5’ flanking region and 11 exons.
Statistical analysis: X2 tests were used in comparing the genotypes and demographic distributions between the subjects with EOC and the controls. They evaluated each polymorphism independently and took into consideration confounding variables; they also calculated the odds ratios and the 95% confidence intervals.
Results: They concluded that of the 4 polymorphisms that was evaluated that there was only a significant association for the (P<0.001) 82G>S polymorphism with a risk of EOC.
Discussion/Conclusion/Limitations: The subjects were matched with controls when considering age, body mass index, smoking status, tubal ligation, menopausal status and use of menopausal hormones. There was a higher rate of a family history of cancer and the use of oral contraceptives in the subjects with EOC (P<0.05). It was found that 82G>S was significantly higher in those with EOC when compared to controls; and there was no significant difference for the other 3 polymorphisms (P>0.05).
Zhang S, Hou X, Zi S, Wang Y, Chen L, Kong B. Polymorphisms of receptor for advanced glycation end products and risk of epithelial ovarian cancer in Chinese patients. Cell Physiol Biochem. 2013;31(4-5):525-31. doi: 10.1159/000350073. Epub 2013 Apr 2. PMID: 23571222.
Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer.
Impact Factor: 10.252
Level of Evidence: III
Type of Study: in vivo, in vitro, mouse study
Sample Size: 161 patients attending general gynecology clinics or postmenopausal bleeding (PMB) clinics within the Swansea Bay and Cwm Taf Morgannwg University Health Boards
Introduction: Existing therapies for endometrial cancer (EC) remain experimental, therefore demonstrating the need for effective treatments. Antibody-drug conjugates (ADCs) are a promising therapeutic option that can specifically target an overexpressed molecule within cancerous tissue. RAGE-targeting ADCs are toxic to RAGE expressing tumor cells in vitro, non-toxic to normal tissue in vivo, also reducing tumor growth in vivo.
Methods: Endometrial biopsies from 161 patients were evaluated for the expression of RAGE in endometrial tissues. Monoclonal antibodies against RAGE were produced. Additionally, the study incorporated in vitro methodologies within multiple cell lines to evaluate RAGE expression and antibody-drug conjugate efficacy. The RAGE-targeting ADCs developed by the investigators were tested for efficacy in a mouse xenograft model of disease. Further, the suitability of the therapy was determined using in vivo biodistribution and toxicity evaluation.
Statistical analysis: The data is presented as a mean with standard deviation. Parametric data was analyzed by ANOVA using Dunnett’s pairwise multiple comparison t-test. Non-parametric data was analyzed by Kruskal-Wallis, then by Mann Whitney U tests. Factorial Logistic Regression analyzed associations. Kaplan-Meier survival analysis in addition to the Log Rank (Mantel-Cox) test analyzed overall survival and disease-free period. Spearman’s Rank determined correlation within patient data. Pearson’s correlation coefficient and Manders co-localization coefficient determined co-localization within internalization experiments.
Results: An association between over-expression of the receptor for advanced glycation end products (RAGE) and endometrial cancer was determined. Increased RAGE expression was negatively correlated with patient survival. The investigators developed RAGE-targeting ADCs due to this correlation, and it was found that RAGE-targeting ADCs were up to 100-fold more efficacious in endometrial cancer cells compared to non-malignant cells and up to 200-fold more cytotoxic than drug treatments alone. RAGE-targeting ADCs were not toxic in an in vivo pre-clinical mouse model, and reduced tumor growth in a xenograft mouse model of disease.
Discussion/Conclusions/Limitations: RAGE-ADCs could be a novel therapeutic option of endometrial cancer patients
Healey GD, Pan-Castillo B, Garcia-Parra J, Davies J, Roberts S, Jones E, Dhar K, Nandanan S, Tofazzal N, Piggott L, Clarkson R, Seaton G, Frostell A, Fagge T, McKee C, Margarit L, Conlan RS, Gonzalez D. Antibody drug conjugates against the receptor for advanced glycation end products (RAGE), a novel therapeutic target in endometrial cancer. J Immunother Cancer. 2019 Oct 29;7(1):280. doi: 10.1186/s40425-019-0765-z. PMID: 31665084; PMCID: PMC6820928.
Perinatal exposure to high dietary advanced glycation end products affects the reproductive system in female offspring in mice.
Study Type: Rat Study/RTC
Impact Factor: 3.1
Level of Evidence: V
Summary: In this study, there was a recognition of the lack of understanding of what exactly stimulates the destruction of the beta cells that contributes to Type 1 Diabetes. This study was a rat study where there were mice crossed and then put on to a diet that was either saturated with AGEs or not saturated with AGEs. The female mice that were now pregnant, named NOD8.3+ mice were on an unsaturated and low in Advanced Glycation Product diet for about 28 days. The AGE levels in both the mother and her offspring were comparatively much lower than the start point. The unsaturated AGE diet group also had much higher levels of insulin and proinsulin which put them at less risk of developing Type 1 Diabetes. The Ins2 gene, which dictates the Pancreatic Islet Expression, was also higher in the group with the low AGE diet. This shows that the decrease in the amount of AGE that was there was a change in the genetics which may indicate the deviation away from developing Type 1 Diabetes may be more than temporary. There was also a very specific local decrease in the amount of immune cell attack on specifically beta cells whereas the immune cells in the lymph nodes and spleen remained constant. A low AGE diet may hold a therapeutic advantage when it comes to the control of Type 1 Diabetes.
Merhi Z, Du XQ, Charron MJ. Perinatal exposure to high dietary advanced glycation end products affects the reproductive system in female offspring in mice. Mol Hum Reprod. 2020 Aug 1;26(8):615-623. doi: 10.1093/molehr/gaaa046. PMID: 32609365.