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Mao X, Huang L, Liu X, Lin X, Wu Q, Wang X, Ren Y, Ma J, Zhang M, Lin Y, Ralser DJ, Mustea A, Chen G, Sun P. High glucose levels promote glycolysis and cholesterol synthesis via ERRα and suppress the autophagy-lysosomal pathway in endometrial cancer. Cell Death Dis 2025; 16:182. [PMID: 40097416 PMCID: PMC11914573 DOI: 10.1038/s41419-025-07499-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 03/05/2025] [Indexed: 03/19/2025]
Abstract
Endometrial cancer (EC) patients with Diabetes Mellitus (DM) always have a poor prognosis. Estrogen-related receptor α (ERRα) is known as the metabolic-related prognostic factor for EC. However, the mechanism linking glycolipid metabolism dysfunction mediated by ERRα to poor prognosis of EC with DM is still unclear. In vitro, high-glucose (HG) levels showed enhancement of ERRα expression, cell proliferation, and inhibition of the autophagic lysosomes and apoptosis by flow cytometry analysis, transmission electron microscopy, and CCK-8 assays. Mechanistically, lose-and-gain function assay, DNA sequencing, and CO-IP revealed HG increased ERRα expression to promote the transcription of HK2 and HMGCS1, which were the key rate-limiting enzyme of glycolysis-cholesterol synthesis and their metabolites suppressed the autophagy-lysosomal pathway in an ERRα-dependent manner. Furthermore, CO-IP and molecular dynamics simulation uncovered the protein residues (ARG 769HK2 vs. ARG 313HMGCS1) of HK2 and HMGCS1 could bind to p62 to form stable protein complexes involved in the autophagy-lysosomal pathway. In EC tissue from patients with comorbid DM, ERRα was significantly higher expressed compared to EC tissue from patients without evidence for DM (p < 0.05). The 3D EC organoid model with HG stimulation showed that the cell viability of XCT790 + carboplatin treatment was similar to that of metformin+carboplatin treatment, while the obviously bigger volume of organoids was more visible in the metformin+carboplatin group, indicating the therapy of XCT790 + carboplatin had the better inhibition of EC organoids with the same carboplatin dose. Besides insights into the interaction of HG and the autophagy-lysosomal pathway via ERRα, our present study points out the potential benefit of targeting ERRα in patients with EC with dysregulation of glucose and cholesterol metabolism.
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Affiliation(s)
- Xiaodan Mao
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Lixiang Huang
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Xianhua Liu
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
- Pathology Department, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, China
| | - Xite Lin
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Qibin Wu
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Xinrui Wang
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China
- Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350013, China
| | - Yuan Ren
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Jincheng Ma
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Maotong Zhang
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Yao Lin
- Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350001, China
| | - Damian J Ralser
- Department of Gynecology and Gynecological Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Alexander Mustea
- Department of Gynecology and Gynecological Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Gang Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Pengming Sun
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China.
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China.
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China.
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Jiang S, Ye M, Wan J, Ye Q, Qiu S, Yang Y, Li X. Significance of Gelsolin Superfamily Genes in Diagnosis, Prognosis and Immune Microenvironment Regulation for Endometrial Cancer. Cancer Med 2025; 14:e70584. [PMID: 39964147 PMCID: PMC11834165 DOI: 10.1002/cam4.70584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 12/12/2024] [Accepted: 12/30/2024] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Previously, anti-CTLA4 and anti-PD-1/PD-L1 immunotherapies have shown limited efficacy in MSI-H/MMR-D endometrial cancer, leading to poor clinical outcomes. The gelsolin superfamily, which includes GSN, SCIN, VILL, VIL1, CAPG, AVIL, SVIL, and FLII, plays crucial roles in cell motility and gene regulation. AIMS The objective of this study is to explore the potential therapeutic and prognostic implications of the gelsolin superfamily in EC. MATERIALS & METHODS Data from TCGA, GEPIA, THPA, UALCAN, and Kaplan-Meier plotter databases were analyzed to investigate the expression and clinical relevance of gelsolin superfamily members. Co-expression networks of the gelsolin superfamily were assessed using LinkedOmics, GeneMANIA, and NetworkAnalyst. The relationship between gelsolin superfamily and immune cell infiltration was investigated using TIMER, ImmuCellAI, and GEPIA. RESULTS We found that high expressions of CAPG, AVIL, and SVIL were associated with poor prognosis, while high expressions of GSN and FLII were linked to better outcomes in EC. Functional enrichment analysis indicated the involvement of gelsolin superfamily members in pathways related to estrogen response, MYC targets, epithelial-mesenchymal transition, TGF beta signaling, MTORC1 signaling, oxidative phosphorylation, inflammatory response, and IL6-JAK-STAT3 signaling. Furthermore, gelsolin superfamily members demonstrated strong correlations with the levels of monocytes, natural killer T, naive CD4+ T, follicular helper T, and central memory T in EC. In vitro studies showed that silencing CAPG and FLII could inhibit proliferation and metastasis in endometrial cancer cell lines. CONCLUSION These findings indicate the significant association of gelsolin superfamily members with prognosis and immunological status in endometrial cancer.
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Affiliation(s)
- Senwei Jiang
- Department of GynecologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Minjuan Ye
- Department of GynecologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Jing Wan
- Department of GynecologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Qingjian Ye
- Department of GynecologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Suli Qiu
- Department of GynecologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Yuebo Yang
- Department of GynecologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
| | - Xiaomao Li
- Department of GynecologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouChina
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Pant A, Moar K, Maurya PK. Impact of estradiol in inducing endometrial cancer using RL95-2. Pathol Res Pract 2024; 263:155640. [PMID: 39383736 DOI: 10.1016/j.prp.2024.155640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 09/27/2024] [Accepted: 10/02/2024] [Indexed: 10/11/2024]
Abstract
BACKGROUND Endometrial cancer is the most common gynecological malignancy that originates from the inner lining of the uterus and predominantly affects postmenopausal women. Prolonged exposure to estrogen, family history of endometrial cancer, obesity, and hormonal imbalance are some of the risk factors associated with endometrial cancer. In our study, we investigated the effect of estradiol, a potent form of estrogen at various concentrations on endometrial cell line RL95-2. METHODS Endometrial cell RL95-2 were cultured in DMEM medium with optimal conditions required to maintain the cells. MTT assay and colony formation assay were further performed after treating the cells with different concentrations of estradiol (1, 10, and 100 nM) and TAM (100 nM). Moreover, the effect of genes regulated by estradiol was also examined using microarray and validated using real-time polymerase chain reaction (qRT-PCR). RESULTS Time-dependent MTT assay shows a significant change in the ability of the cells to survive relative to concentrations. Colony formation was found to be directly proportional to the concentration of the estradiol (p < 0.05). Among genes, MMP14 (p = 0.03), SPARCL1 (p = 0.005), and CLU (p = 0.06) showed a significant up-regulation in their expression after estradiol treatment while NRN1 (p < 0.001) showed significant downregulation in expression pattern compared to control. However, the TAM treatment was found to be significantly effective after 72 h (p < 0.001) compared to control and 100 nM E2 (p = 0.0206). CONCLUSION Our study suggests that estradiol significantly contributes to regulating the viability, colony formation, and expression of genes associated with endometrial cancer.
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Affiliation(s)
- Anuja Pant
- Department of Biochemistry, Central University of Haryana, Mahendergarh 123031, India
| | - Kareena Moar
- Department of Biochemistry, Central University of Haryana, Mahendergarh 123031, India
| | - Pawan Kumar Maurya
- Department of Biochemistry, Central University of Haryana, Mahendergarh 123031, India.
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Mao PCM, Chung MI, Hung YM, Chen HM, Chen CL. Acarbose might be associated with reduced risk of gastric cancer in patients with diabetes mellitus: A nationwide population-based cohort study. Pharmacoepidemiol Drug Saf 2024; 33:e5762. [PMID: 39290170 DOI: 10.1002/pds.5762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 11/10/2023] [Accepted: 01/18/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND Several epidemiologic studies have revealed a higher risk of cancer in patients with diabetes mellitus (DM) relative to the general population. To investigate whether the use of acarbose was associated with higher/lower risk of new-onset cancers. METHOD We conducted a retrospective cohort study, using a population-based National Health Insurance Research Database of Taiwan. Both inpatients and outpatients with newly onset DM diagnosed between 2000 and 2012 were collected. The Adapted Diabetes Complications Severity Index (aDCSI) was used to adjust the severity of DM. The Cox proportional hazards regression model was used to estimate the hazard ratio (HR) of disease. RESULTS A total of 22 502 patients with newly diagnosed DM were enrolled. The Cox proportional hazards regression model indicating acarbose was neutral for risk for gastroenterological malignancies, when compared to the acarbose non-acarbose users group. However, when gastric cancer was focused, acarbose-user group had significantly lowered HR than non-acarbose users group (p = 0.003). After adjusted for age, sex, cancer-related comorbidity, severity of DM, and co-administered drugs, the HR of gastric cancer risk was 0.43 (95% CI = 0.25-0.74) for acarbose-user patients. CONCLUSION This long-term population-based study demonstrated that acarbose might be associated with lowered risk of new-onset gastric cancer in diabetic patients after adjusting the severity of DM.
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Affiliation(s)
- Pili Chih-Min Mao
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Mei-Ing Chung
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yao-Min Hung
- Division of Nephrology, Taipei Veterans General Hospital Taitung Branch, Taitung, Taiwan
- Master Program in Biomedicine, National Taitung University, Taitung, Taiwan
- College of Health and Nursing, Meiho University, Neipu, Pingtung, Taiwan
| | - Hsiu-Min Chen
- Department of Business Administration, I-Shou University, Kaohsiung, Taiwan
- Department of Medical Education and Research and Research Center of Medical Informatics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chien-Liang Chen
- Department of Medical Education and Research and Research Center of Medical Informatics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
- Faculty of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
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Wang Y, Liu Q, Sun Y, Wu W, Cheng X, Chen X, Ren F. Association between metabolic disorders and clinicopathologic features in endometrial cancer. Front Endocrinol (Lausanne) 2024; 15:1351982. [PMID: 39257906 PMCID: PMC11385602 DOI: 10.3389/fendo.2024.1351982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 08/09/2024] [Indexed: 09/12/2024] Open
Abstract
Background In recent years, the incidence of Endometrial cancer (EC) has been on the rise due to high-fat, high-calorie diets and low-exercise lifestyles. However, the relationships between metabolic disorders and the progression of EC remain uncertain. The purpose of our study was to explore the potential association between obesity, hypertension, hyperglycemia and clinicopathologic characteristics in EC patients. Methods In categorical variables, Chi-square tests were used to calculate P values. Univariate logistic regression and multivariate logistic regression were used to identify the risk factors of myometrial invasion>1/2 and lymph node metastasis. Overall survival (OS) was estimated using the Kaplan-Meier method. Results The study included 406 individuals with EC, 62.6% had type I and 37.4% had type II. Hypertension was seen in 132 (32.5%), hyperglycemia in 75 (18.5%), and overweight or obesity in 217 (53.4%). Hypertension, hyperglycemia, and obesity are strongly associated with the clinicopathologic features of EC. Multivariate logistic regression revealed that hyperglycemia (OR=2.439,95% CI: 1.025-5.804, P = 0.044) was a risk factor for myometrial invasion depth >1/2 in patients with type I EC, and hypertension (OR=32.124,95% CI: 3.287-313.992, P = 0.003) was a risk factor for lymph node metastasis in patients with type I EC. Survival analysis found that hyperglycemia (P < 0.001) and hypertension (P = 0.002) were associated with OS in type I EC. Neither hyperglycemia, hypertension, nor obesity were associated with the prognosis in type II EC. Conclusion Hyperglycemia was a risk factor for myometrial invasion depth >1/2 in patients with type I EC and hypertension was a risk factor for lymph node metastasis in patients with type I EC. Hypertension and hyperglycemia were associated with poor prognosis in patients with type I EC.
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Affiliation(s)
- Yuanpei Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Hangzhou, China
| | - Qianwen Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Hangzhou, China
| | - Yi Sun
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Hangzhou, China
| | - Weijia Wu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Hangzhou, China
| | - Xiaoran Cheng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Hangzhou, China
| | - Xuerou Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Hangzhou, China
| | - Fang Ren
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Hangzhou, China
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Pliszka M, Szablewski L. Associations between Diabetes Mellitus and Selected Cancers. Int J Mol Sci 2024; 25:7476. [PMID: 39000583 PMCID: PMC11242587 DOI: 10.3390/ijms25137476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.
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Affiliation(s)
- Monika Pliszka
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
| | - Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
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Drevinskaite M, Kaceniene A, Linkeviciute-Ulinskiene D, Smailyte G. The impact of metformin on survival in diabetic endometrial cancer patients: a retrospective population-based analysis. J Diabetes Metab Disord 2024; 23:841-847. [PMID: 38932795 PMCID: PMC11196484 DOI: 10.1007/s40200-023-01358-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 11/20/2023] [Indexed: 06/28/2024]
Abstract
Purpose The aim of our study was to assess overall survival and cancer-specific survival in endometrial cancer patients with type 2 diabetes mellitus (T2DM) using metformin. Methods Patients with endometrial cancer and T2DM during 2000-2012 period were identified from the Lithuanian Cancer Registry and the National Health Insurance Fund database. Cancer-specific and overall survival were primary outcomes. Results In our study we included 6287 women with endometrial cancer out of whom 664 were diagnosed with T2DM (598 metformin users and 66 never users). During follow-up (mean follow-up time was 8.97 years), no differences in risk of endometrial cancer specific mortality was observed in diabetic patients treated with metformin (Hazard Ratio (HR) 0.87, 95% Confidence Interval (CI) 0.70-1.07). Overall mortality in the diabetic metformin ever users' group was significantly higher compared with the non-diabetic endometrial cancer women (HR 1.17, 95% CI 1.03-1.32) and in the group of metformin never users with T2DM (HR 1.42, 95% CI 1.07-1.87). Conclusion Our study results suggest no beneficial impact on overall and cancer-specific survival in endometrial cancer patients who were treated with metformin as part of their diabetes treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-023-01358-3.
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Affiliation(s)
- Mingaile Drevinskaite
- Laboratory of Cancer Epidemiology, National Cancer Institute, P. Baublio 3B, Vilnius Lithuania, LT-08406 Vilnius, Lithuania
| | - Auguste Kaceniene
- Laboratory of Cancer Epidemiology, National Cancer Institute, P. Baublio 3B, Vilnius Lithuania, LT-08406 Vilnius, Lithuania
| | | | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute, P. Baublio 3B, Vilnius Lithuania, LT-08406 Vilnius, Lithuania
- Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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Lin X, Zheng J, Cai X, Liu L, Jiang S, Liu Q, Sun Y. Glycometabolism and lipid metabolism related genes predict the prognosis of endometrial carcinoma and their effects on tumor cells. BMC Cancer 2024; 24:571. [PMID: 38720279 PMCID: PMC11080313 DOI: 10.1186/s12885-024-12327-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 05/01/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Glycometabolism and lipid metabolism are critical in cancer metabolic reprogramming. The primary aim of this study was to develop a prognostic model incorporating glycometabolism and lipid metabolism-related genes (GLRGs) for accurate prognosis assessment in patients with endometrial carcinoma (EC). METHODS Data on gene expression and clinical details were obtained from publicly accessible databases. GLRGs were obtained from the Genecards database. Through nonnegative matrix factorization (NMF) clustering, molecular groupings with various GLRG expression patterns were identified. LASSO Cox regression analysis was employed to create a prognostic model. Use rich algorithms such as GSEA, GSVA, xCELL ssGSEA, EPIC,CIBERSORT, MCPcounter, ESTIMATE, TIMER, TIDE, and Oncoppredict to analyze functional pathway characteristics of the forecast signal, immune status, anti-tumor therapy, etc. The expression was assessed using Western blot and quantitative real-time PCR techniques. A total of 113 algorithm combinations were combined to screen out the most significant GLRGs in the signature for in vitro experimental verification, such as colony formation, EdU cell proliferation, wound healing, apoptosis, and Transwell assays. RESULTS A total of 714 GLRGs were found, and 227 of them were identified as prognostic-related genes. And ten GLRGs (AUP1, ESR1, ERLIN2, ASS1, OGDH, BCKDHB, SLC16A1, HK2, LPCAT1 and PGR-AS1) were identified to construct the prognostic model of patients with EC. Based on GLRGs, the risk model's prognosis and independent prognostic value were established. The signature of GLRGs exhibited a robust correlation with the infiltration of immune cells and the sensitivity to drugs. In cytological experiments, we selected HK2 as candidate gene to verify its value in the occurrence and development of EC. Western blot and qRT-PCR revealed that HK2 was substantially expressed in EC cells. According to in vitro experiments, HK2 knockdown can increase EC cell apoptosis while suppressing EC cell migration, invasion, and proliferation. CONCLUSION The GLRGs signature constructed in this study demonstrated significant prognostic value for patients with endometrial carcinoma, thereby providing valuable guidance for treatment decisions.
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Affiliation(s)
- Xuefen Lin
- Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.420, Fuma Road, Jin'an District, Fuzhou City, Fujian Province, 350014, P. R. China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Jianfeng Zheng
- Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.420, Fuma Road, Jin'an District, Fuzhou City, Fujian Province, 350014, P. R. China
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Xintong Cai
- Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.420, Fuma Road, Jin'an District, Fuzhou City, Fujian Province, 350014, P. R. China
| | - Li Liu
- Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.420, Fuma Road, Jin'an District, Fuzhou City, Fujian Province, 350014, P. R. China
| | - Shan Jiang
- Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.420, Fuma Road, Jin'an District, Fuzhou City, Fujian Province, 350014, P. R. China
- Fujian University of Chinese Medicine, Fuzhou, 350014, China
| | - Qinying Liu
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Yang Sun
- Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No.420, Fuma Road, Jin'an District, Fuzhou City, Fujian Province, 350014, P. R. China.
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
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Burney IA, Al Ghafri S, Al Noumani J, Al Jabri A, Hasan AO, Bella S, Al-Sayegh H, Al Ajmi R, Al Kalbani M. Clinicopathological Features and Outcomes of Endometrial Cancer: A single institution experience. Sultan Qaboos Univ Med J 2024; 24:203-208. [PMID: 38828257 PMCID: PMC11139370 DOI: 10.18295/squmj.3.2024.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 11/25/2023] [Accepted: 12/26/2023] [Indexed: 06/05/2024] Open
Abstract
Objectives This study aimed to report the demographic features, clinical presentation, pathological types and long-term outcomes of patients diagnosed with endometrial cancer (EC) in Oman. EC is the sixth most common cancer in women worldwide and the fifth most common cancer in women in Oman. Survival outcomes of EC have not been reported previously from Oman. Methods This retrospective study was carried out on consecutive patients treated at the Sultan Qaboos University Hospital, Muscat, Oman, between 2008 and 2020. Survival was estimated using the Kaplan and Meier method. Results A total of 50 patients with EC were included. The median age was 61 years (range: 31-86 years), and 72% of the patients had type I histology. Most patients were diagnosed with stage IA and IB EC (49% and 20%, respectively), and the majority had grade 1 or 2 tumours (40% and 34%, respectively). Overall, the 5-year survival and 10-year survival rates were estimated to be 70% and 56%, respectively. Weight (>75 kg) and body mass index (>30 kg/m2) were significantly associated with better survival. Tumour histology (type I versus type II or carcinosarcoma), grade (1 versus 2 versus 3) and stage (IA or IB versus II-IV) were associated with better overall survival (P = 0.007, P <0.0001 and P <0.0003, respectively). Patients diagnosed with EC with co-morbidities, other than obesity, had inferior survival compared to those without co-morbidities. Conclusion Median age at presentation, histological sub-type, clinical stage and outcomes are comparable to the published literature. Almost two-thirds of the patients were obese. These data could be used as a benchmark for outcomes of EC in the region.
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Affiliation(s)
- Ikram A. Burney
- Women Health Program, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman
| | | | | | - Anisa Al Jabri
- Department of Radiation Oncology, The Royal Hospital, Muscat, Oman
| | - Anjum O. Hasan
- Women Health Program, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman
| | - Sarya Bella
- Women Health Program, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman
| | - Hasan Al-Sayegh
- Department of Research Laboratories, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman
| | - Radhiya Al Ajmi
- Pathology, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman
| | - Moza Al Kalbani
- Women Health Program, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman
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10
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Hardell KNL, Schonfeld SJ, Ramin C, Vo JB, Morton LM. Association between diabetes and subsequent malignancy risk among older breast cancer survivors. JNCI Cancer Spectr 2024; 8:pkae036. [PMID: 38718185 PMCID: PMC11135638 DOI: 10.1093/jncics/pkae036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/28/2024] [Accepted: 05/03/2024] [Indexed: 05/30/2024] Open
Abstract
Type II diabetes is associated with cancer risk in the general population but has not been well studied as a risk factor for subsequent malignancies among cancer survivors. We investigated the association between diabetes and subsequent cancer risk among older (66-84 years), 1-year breast cancer survivors within the linked Surveillance Epidemiology and End Results (SEER)-Medicare database using Cox regression analyses to quantify hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). Among 133 324 women, 29.3% were diagnosed with diabetes before or concurrent with their breast cancer diagnosis, and 10 452 women developed subsequent malignancies over a median follow-up of 4.3 years. Diabetes was statistically significantly associated with liver (HR = 2.35, 95% CI = 1.48 to 3.74), brain (HR = 1.94, 95% CI = 1.26 to 2.96), and thyroid cancer risks (HR = 1.38, 95% CI = 1.01 to 1.89). Future studies are needed to better understand the spectrum of subsequent cancers associated with diabetes and the role of diabetes medications in modifying subsequent cancer risk, alone or in combination with cancer treatments.
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Affiliation(s)
- Kaitlyn N Lewis Hardell
- Radiation Epidemiology Branch, Division of Cancer Epidemiology, National Cancer Institute, Bethesda, MD, USA
- Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Sara J Schonfeld
- Radiation Epidemiology Branch, Division of Cancer Epidemiology, National Cancer Institute, Bethesda, MD, USA
| | - Cody Ramin
- Cancer Research Center for Health Equity, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jacqueline B Vo
- Radiation Epidemiology Branch, Division of Cancer Epidemiology, National Cancer Institute, Bethesda, MD, USA
| | - Lindsay M Morton
- Radiation Epidemiology Branch, Division of Cancer Epidemiology, National Cancer Institute, Bethesda, MD, USA
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11
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Massouh N, Jaffa AA, Jaffa MA. Diabetes and the social, biologic, and behavioral determinants of endometrial cancer in the United States. BMC Cancer 2024; 24:540. [PMID: 38684955 PMCID: PMC11057164 DOI: 10.1186/s12885-024-12192-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 03/26/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Endometrial cancer is one of the most common types of cancer that affects women's reproductive system. The risk of endometrial cancer is associated with biologic, behavioral and social determinants of health (SDOH). The focus of the work is to investigate the cumulative effect of this cluster of covariates on the odds of endometrial cancer that heretofore have only been considered individually. METHODS We conducted a quantitative study using the Behavioral Risk Factor Surveillance System (BRFSS) national data collected in 2020. Data analysis using weighted Chi-square test and weighted logistic regression were carried out on 84,118 female study participants from the United States. RESULTS Women with diabetes mellitus were approximately twice as likely to have endometrial cancer compared to women without diabetes (OR 1.54; 95%CI: 1.01-2.34). Biologic factors that included obesity (OR 3.10; 95% CI: 1.96-4.90) and older age (with ORs ranging from 2.75 to 7.21) had a significant increase in the odds of endometrial cancer compared to women of normal weight and younger age group of 18 to 44. Among the SDOH, attending college (OR 1.83; 95% CI: 1.12-3.00) was associated with increased odds of endometrial cancer, while renting a home (OR 0.50; 95% CI: 0.28-0.88), having other arrangements (OR 0.05; 95% CI: 0.02-0.16), being divorced (OR 0.55; 95% CI: 0.30-0.99), and having higher incomes ranging from $35,000 to $50,000 (OR 0.35; 95% CI: 0.16-0.78), and above $50,000 (OR 0.29; 95% CI: 0.14-0.62), were all associated with decreased odds of endometrial cancer. As for race, Black women (OR 0.24; 95% CI: 0.07-0.84) and women of other races (OR 0.37; 95% CI: 0.15-0.88) were shown to have lower odds of endometrial cancer compared to White women. CONCLUSION Our results revealed the importance of adopting a comprehensive approach to the study of the associated factors of endometrial cancer by including social, biologic, and behavioral determinants of health. The observed social inequity in endometrial cancer among women needs to be addressed through effective policies and changes in social structures to advocate for a standardized healthcare system that ensures equitable access to preventive measures and quality of care.
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Affiliation(s)
- Nour Massouh
- Epidemiology and Population Health Department, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ayad A Jaffa
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
- Division of Endocrinology, Diabetes & Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
| | - Miran A Jaffa
- Epidemiology and Population Health Department, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon.
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12
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Szablewski L. Insulin Resistance: The Increased Risk of Cancers. Curr Oncol 2024; 31:998-1027. [PMID: 38392069 PMCID: PMC10888119 DOI: 10.3390/curroncol31020075] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/15/2024] [Accepted: 02/10/2024] [Indexed: 02/24/2024] Open
Abstract
Insulin resistance, also known as impaired insulin sensitivity, is the result of a decreased reaction of insulin signaling to blood glucose levels. This state is observed when muscle cells, adipose tissue, and liver cells, improperly respond to a particular concentration of insulin. Insulin resistance and related increased plasma insulin levels (hyperinsulinemia) may cause metabolic impairments, which are pathological states observed in obesity and type 2 diabetes mellitus. Observations of cancer patients confirm that hyperinsulinemia is a major factor influencing obesity, type 2 diabetes, and cancer. Obesity and diabetes have been reported as risks of the initiation, progression, and metastasis of several cancers. However, both of the aforementioned pathologies may independently and additionally increase the cancer risk. The state of metabolic disorders observed in cancer patients is associated with poor outcomes of cancer treatment. For example, patients suffering from metabolic disorders have higher cancer recurrence rates and their overall survival is reduced. In these associations between insulin resistance and cancer risk, an overview of the various pathogenic mechanisms that play a role in the development of cancer is discussed.
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Affiliation(s)
- Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego 5 Str., 02-004 Warsaw, Poland
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13
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Li H, Zhang Y, He Y, Huang J, Yao J, Zhuang X. Association between consumption of sweeteners and endometrial cancer risk: a systematic review and meta-analysis of observational studies. Br J Nutr 2024; 131:63-72. [PMID: 37424288 DOI: 10.1017/s0007114523001484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
The purpose of this study is to further investigate the relationship between sweetener exposure and the risk of endometrial cancer (EC). Up until December 2022, a literature search in an electronic database was carried out utilizing PubMed, Web of Science, Ovid, and Scopus. The odds ratio (OR) and 95 % confidence interval (CI) were used to evaluate the results. Sweeteners were divided into nutritional sweeteners (generally refers to sugar, such as sucrose and glucose) and non-nutritional sweeteners (generally refers to artificial sweeteners, such saccharin and aspartame). Ten cohort studies and two case-control studies were eventually included. The study found that in 12 studies, compared with the non-exposed group, the incidence rate of EC in the sweetener exposed group was higher (OR = 1·15, 95 % CI = [1·07, 1·24]). Subgroup analysis showed that in 11 studies, the incidence rate of EC in the nutritional sweetener exposed group was higher than that in the non-exposed group (OR = 1·25, 95 % CI = [1·14, 1·38]). In 4 studies, there was no difference in the incidence rate of EC between individuals exposed to non-nutritional sweeteners and those who were not exposed to non-nutritional sweeteners (OR = 0·90, 95 % CI = [0·81, 1·01]). This study reported that the consumption of nutritional sweeteners may increase the risk of EC, whereas there was no significant relationship between the exposure of non-nutritional sweeteners and the incidence of EC. Based on the results of this study, it is recommended to reduce the intake of nutritional sweeteners, but it is uncertain whether use of on-nutritional sweeteners instead of nutritional sweetener.
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Affiliation(s)
- Huiping Li
- Gynecology, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, People's Republic of China
| | - Yeyuan Zhang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Yujing He
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Jianing Huang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Jie Yao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Xieyan Zhuang
- Gynecology Department of Mingzhou Hospital, Ningbo, 315000Zhejiang, People's Republic of China
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14
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Emons G, Steiner E, Vordermark D, Uleer C, Paradies K, Tempfer C, Aretz S, Cremer W, Hanf V, Mallmann P, Ortmann O, Römer T, Schmutzler RK, Horn LC, Kommoss S, Lax S, Schmoeckel E, Mokry T, Grab D, Reinhardt M, Steinke-Lange V, Brucker SY, Kiesel L, Witteler R, Fleisch MC, Heinrich Prömpeler † 25, Friedrich M, Höcht S, Lichtenegger W, Mueller M, Runnebaum I, Feyer P, Hagen V, Juhasz-Böss I, Letsch A, Niehoff P, Zeimet AG, Battista MJ, Petru E, Widhalm S, van Oorschot B, Panke JE, Weis J, Dauelsberg T, Haase H, Beckmann MW, Jud S, Wight E, Prott FJ, Micke O, Bader W, Reents N, Henscher U, Reina Tholen † 52, Schallenberg M, Rahner N, Mayr D, Kreißl M, Lindel K, Mustea A, Strnad V, Goerling U, Bauerschmitz GJ, Langrehr J, Neulen J, Ulrich UA, Nothacker MJ, Blödt S, Follmann M, Langer T, Wenzel G, Weber S, Erdogan S. Endometrial Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry Number 032/034-OL, September 2022). Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer, Geriatric Assessment and Supply Structures. Geburtshilfe Frauenheilkd 2023; 83:919-962. [PMID: 37588260 PMCID: PMC10427205 DOI: 10.1055/a-2066-2051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/22/2023] [Indexed: 08/18/2023] Open
Abstract
Summary The S3-guideline on endometrial cancer, first published in April 2018, was reviewed in its entirety between April 2020 and January 2022 and updated. The review was carried out at the request of German Cancer Aid as part of the Oncology Guidelines Program and the lead coordinators were the German Society for Gynecology and Obstetrics (DGGG), the Gynecology Oncology Working Group (AGO) of the German Cancer Society (DKG) and the German Cancer Aid (DKH). The guideline update was based on a systematic search and assessment of the literature published between 2016 and 2020. All statements, recommendations and background texts were reviewed and either confirmed or amended. New statements and recommendations were included where necessary. Aim The use of evidence-based risk-adapted therapies to treat women with endometrial cancer of low risk prevents unnecessarily radical surgery and avoids non-beneficial adjuvant radiation therapy and/or chemotherapy. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimum level of radical surgery and indicates whether chemotherapy and/or adjuvant radiation therapy is necessary. This should improve the survival rates and quality of life of these patients. The S3-guideline on endometrial cancer and the quality indicators based on the guideline aim to provide the basis for the work of certified gynecological cancer centers. Methods The guideline was first compiled in 2018 in accordance with the requirements for S3-level guidelines and was updated in 2022. The update included an adaptation of the source guidelines identified using the German Instrument for Methodological Guideline Appraisal (DELBI). The update also used evidence reviews which were created based on selected literature obtained from systematic searches in selected literature databases using the PICO process. The Clinical Guidelines Service Group was tasked with carrying out a systematic search and assessment of the literature. Their results were used by interdisciplinary working groups as a basis for developing suggestions for recommendations and statements which were then modified during structured online consensus conferences and/or additionally amended online using the DELPHI process to achieve a consensus. Recommendations Part 1 of this short version of the guideline provides recommendations on epidemiology, screening, diagnosis, and hereditary factors. The epidemiology of endometrial cancer and the risk factors for developing endometrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer. The use of geriatric assessment is considered and existing structures of care are presented.
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Affiliation(s)
- Günter Emons
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Eric Steiner
- Frauenklinik GPR Klinikum Rüsselsheim am Main, Rüsselsheim, Germany
| | - Dirk Vordermark
- Universität Halle (Saale), Radiotherapie, Halle (Saale), Germany
| | - Christoph Uleer
- Facharzt für Frauenheilkunde und Geburtshilfe, Hildesheim, Germany
| | - Kerstin Paradies
- Konferenz onkologischer Kranken- und Kinderkrankenpfleger (KOK), Hamburg, Germany
| | - Clemens Tempfer
- Frauenklinik der Ruhr-Universität Bochum, Bochum/Herne, Germany
| | - Stefan Aretz
- Institut für Humangenetik, Universität Bonn, Zentrum für erbliche Tumorerkrankungen, Bonn, Germany
| | | | - Volker Hanf
- Frauenklinik Nathanstift – Klinikum Fürth, Fürth, Germany
| | | | - Olaf Ortmann
- Universität Regensburg, Fakultät für Medizin, Klinik für Frauenheilkunde und Geburtshilfe, Regensburg, Germany
| | - Thomas Römer
- Evangelisches Klinikum Köln Weyertal, Gynäkologie Köln, Köln, Germany
| | - Rita K. Schmutzler
- Universitätsklinikum Köln, Zentrum Familiärer Brust- und Eierstockkrebs, Köln, Germany
| | | | - Stefan Kommoss
- Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
| | - Sigurd Lax
- Institut für Pathologie, LKH Graz Süd-West, Graz, Austria
| | | | - Theresa Mokry
- Universitätsklinikum Heidelberg, Diagnostische und Interventionelle Radiologie, Heidelberg, Germany
| | - Dieter Grab
- Universitätsklinikum Ulm, Frauenheilkunde und Geburtshilfe, Ulm, Germany
| | - Michael Reinhardt
- Klinik für Nuklearmedizin, Pius Hospital Oldenburg, Oldenburg, Germany
| | - Verena Steinke-Lange
- MGZ – Medizinisch Genetisches Zentrum München, München, Germany
- Medizinische Klinik und Poliklinik IV, LMU München, München, Germany
| | - Sara Y. Brucker
- Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
| | - Ludwig Kiesel
- Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
| | - Ralf Witteler
- Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
| | - Markus C. Fleisch
- Helios, Universitätsklinikum Wuppertal, Landesfrauenklinik, Wuppertal, Germany
| | | | - Michael Friedrich
- Helios Klinikum Krefeld, Klinik für Frauenheilkunde und Geburtshilfe, Krefeld, Germany
| | - Stefan Höcht
- XCare, Praxis für Strahlentherapie Saarlouis, Saarlouis, Germany
| | - Werner Lichtenegger
- Universitätsmedizin Berlin, Frauenklinik Charité, Campus Virchow-Klinikum, Berlin, Germany
| | - Michael Mueller
- Universitätsklinik für Frauenheilkunde, Inselspital Bern, Bern, Switzerland
| | | | - Petra Feyer
- Vivantes Klinikum Neukölln, Klinik für Strahlentherapie und Radioonkologie, Berlin, Germany
| | - Volker Hagen
- Klinik für Innere Medizin II, St.-Johannes-Hospital Dortmund, Dortmund, Germany
| | | | - Anne Letsch
- Universitätsklinikum Schleswig Holstein, Campus Kiel, Innere Medizin, Kiel, Germany
| | - Peter Niehoff
- Strahlenklinik, Sana Klinikum Offenbach, Offenbach, Germany
| | - Alain Gustave Zeimet
- Medizinische Universität Innsbruck, Universitätsklinik für Gynäkologie und Geburtshilfe, Innsbruck, Austria
| | | | - Edgar Petru
- Med. Univ. Graz, Frauenheilkunde, Graz, Austria
| | | | - Birgitt van Oorschot
- Universitätsklinikum Würzburg, Interdisziplinäres Zentrum Palliativmedizin, Würzburg, Germany
| | - Joan Elisabeth Panke
- Medizinischer Dienst des Spitzenverbandes Bund der Krankenkassen e. V. Essen, Essen, Germany
| | - Joachim Weis
- Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät, Tumorzentrum Freiburg – CCCF, Freiburg, Germany
| | - Timm Dauelsberg
- Universitätsklinikum Freiburg, Klinik für Onkologische Rehabilitation, Freiburg, Germany
| | | | | | | | - Edward Wight
- Frauenklinik des Universitätsspitals Basel, Basel, Switzerland
| | - Franz-Josef Prott
- Facharzt für Radiologie und Strahlentherapie, Wiesbaden, Wiesbaden, Germany
| | - Oliver Micke
- Franziskus Hospital Bielefeld, Klinik für Strahlentherapie und Radioonkologie, Bielefeld, Germany
| | - Werner Bader
- Klinikum Bielefeld Mitte, Zentrum für Frauenheilkunde, Bielefeld, Germany
| | | | | | | | | | | | - Doris Mayr
- LMU München, Pathologisches Institut, München, Germany
| | - Michael Kreißl
- Universität Magdeburg, Medizinische Fakultät, Universitätsklinik für Radiologie und Nuklearmedizin, Germany
| | - Katja Lindel
- Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | - Alexander Mustea
- Universitätsklinikum Bonn, Zentrum Gynäkologie und gynäkologische Onkologie, Bonn, Germany
| | - Vratislav Strnad
- Universitätsklinikum Erlangen, Brustzentrum Franken, Erlangen, Germany
| | - Ute Goerling
- Universitätsmedizin Berlin, Campus Charité Mitte, Charité Comprehensive Cancer Center, Berlin, Germany
| | - Gerd J. Bauerschmitz
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Jan Langrehr
- Martin-Luther-Krankenhaus, Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Berlin, Germany
| | - Joseph Neulen
- Uniklinik RWTH Aachen, Klinik für Gynäkologische Endokrinologie und Reproduktionsmedizin, Aachen, Germany
| | - Uwe Andreas Ulrich
- Martin-Luther-Krankenhaus, Johannesstift Diakonie, Gynäkologie, Berlin, Germany
| | | | | | - Markus Follmann
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Thomas Langer
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Gregor Wenzel
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Sylvia Weber
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Saskia Erdogan
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
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LU YU, MIYAMOTO TSUTOMU, TAKEUCHI HODAKA, TSUNODA FUMI, TANAKA NAOKI, SHIOZAWA TANRI. PPARα activator irbesartan suppresses the proliferation of endometrial carcinoma cells via SREBP1 and ARID1A. Oncol Res 2023; 31:239-253. [PMID: 37305395 PMCID: PMC10229307 DOI: 10.32604/or.2023.026067] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 03/14/2023] [Indexed: 06/13/2023] Open
Abstract
Endometrial carcinoma (EMC) is associated with obesity; however, the underlying mechanisms have not yet been elucidated. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that is involved in lipid, glucose, and energy metabolism. PPARα reportedly functions as a tumor suppressor through its effects on lipid metabolism; however, the involvement of PPARα in the development of EMC remains unclear. The present study demonstrated that the immunohistochemical expression of nuclear PPARα was lower in EMC than in normal endometrial tissues, suggesting the tumor suppressive nature of PPARα. A treatment with the PPARα activator, irbesartan, inhibited the EMC cell lines, Ishikawa and HEC1A, by down-regulating sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) and up-regulating the tumor suppressor genes p21 and p27, antioxidant enzymes, and AT-rich interaction domain 1A (ARID1A). These results indicate the potential of the activation of PPARα as a novel therapeutic approach against EMC.
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Affiliation(s)
- YU LU
- Department of Obstetrics and Gynecology, School of Medicine, Shinshu University, Matsumoto, 390-8621, Japan
| | - TSUTOMU MIYAMOTO
- Department of Obstetrics and Gynecology, School of Medicine, Shinshu University, Matsumoto, 390-8621, Japan
| | - HODAKA TAKEUCHI
- Department of Obstetrics and Gynecology, School of Medicine, Shinshu University, Matsumoto, 390-8621, Japan
| | - FUMI TSUNODA
- Department of Obstetrics and Gynecology, School of Medicine, Shinshu University, Matsumoto, 390-8621, Japan
| | - NAOKI TANAKA
- Department of Global Medical Research Promotion, School of Medicine, Shinshu University Graduate, Matsumoto, Nagano, 390-8621, Japan
- International Relations Office, School of Medicine, Shinshu University, Matsumoto, Nagano, 390-8621, Japan
- Research Center for Social Systems, Shinshu University, Matsumoto, Nagano, 390-8621, Japan
| | - TANRI SHIOZAWA
- Department of Obstetrics and Gynecology, School of Medicine, Shinshu University, Matsumoto, 390-8621, Japan
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Semertzidou A, Grout-Smith H, Kalliala I, Garg A, Terzidou V, Marchesi J, MacIntyre D, Bennett P, Tsilidis K, Kyrgiou M. Diabetes and anti-diabetic interventions and the risk of gynaecological and obstetric morbidity: an umbrella review of the literature. BMC Med 2023; 21:152. [PMID: 37072764 PMCID: PMC10114404 DOI: 10.1186/s12916-023-02758-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/27/2023] [Indexed: 04/20/2023] Open
Abstract
BACKGROUND Diabetes has reached epidemic proportions in recent years with serious health ramifications. The aim of this study was to evaluate the strength and validity of associations between diabetes and anti-diabetic interventions and the risk of any type of gynaecological or obstetric conditions. METHODS Design: Umbrella review of systematic reviews and meta-analyses. DATA SOURCES PubMed, Medline, Embase, Cochrane Database of Systematic Reviews, manual screening of references. ELIGIBILITY CRITERIA Systematic reviews and meta-analyses of observational and interventional studies investigating the relationship between diabetes and anti-diabetic interventions with gynaecological or obstetric outcomes. Meta-analyses that did not include complete data from individual studies, such as relative risk, 95% confidence intervals, number of cases/controls, or total population were excluded. DATA ANALYSIS The evidence from meta-analyses of observational studies was graded as strong, highly suggestive, suggestive or weak according to criteria comprising the random effects estimate of meta-analyses and their largest study, the number of cases, 95% prediction intervals, I2 heterogeneity index between studies, excess significance bias, small study effect and sensitivity analysis using credibility ceilings. Interventional meta-analyses of randomised controlled trials were assessed separately based on the statistical significance of reported associations, the risk of bias and quality of evidence (GRADE) of included meta-analyses. RESULTS A total of 117 meta-analyses of observational cohort studies and 200 meta-analyses of randomised clinical trials that evaluated 317 outcomes were included. Strong or highly suggestive evidence only supported a positive association between gestational diabetes and caesarean section, large for gestational age babies, major congenital malformations and heart defects and an inverse relationship between metformin use and ovarian cancer incidence. Only a fifth of the randomised controlled trials investigating the effect of anti-diabetic interventions on women's health reached statistical significance and highlighted metformin as a more effective agent than insulin on risk reduction of adverse obstetric outcomes in both gestational and pre-gestational diabetes. CONCLUSIONS Gestational diabetes appears to be strongly associated with a high risk of caesarean section and large for gestational age babies. Weaker associations were demonstrated between diabetes and anti-diabetic interventions with other obstetric and gynaecological outcomes. TRIAL REGISTRATION Open Science Framework (OSF) (Registration https://doi.org/10.17605/OSF.IO/9G6AB ).
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Affiliation(s)
- Anita Semertzidou
- Department of Metabolism, Digestion and Reproduction - Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
| | - Harriet Grout-Smith
- Department of Metabolism, Digestion and Reproduction - Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
| | - Ilkka Kalliala
- Department of Metabolism, Digestion and Reproduction - Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
- Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Akanksha Garg
- Queen Charlotte's and Chelsea - Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Vasso Terzidou
- Department of Metabolism, Digestion and Reproduction - Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
- Queen Charlotte's and Chelsea - Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Julian Marchesi
- Department of Metabolism, Digestion and Reproduction - Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
- School of Biosciences, Cardiff University, Cardiff, UK
| | - David MacIntyre
- Department of Metabolism, Digestion and Reproduction - Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
| | - Phillip Bennett
- Department of Metabolism, Digestion and Reproduction - Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
- Queen Charlotte's and Chelsea - Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Konstantinos Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Maria Kyrgiou
- Department of Metabolism, Digestion and Reproduction - Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK.
- Queen Charlotte's and Chelsea - Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
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Huang P, Fan X, Yu H, Zhang K, Li H, Wang Y, Xue F. Glucose metabolic reprogramming and its therapeutic potential in obesity-associated endometrial cancer. J Transl Med 2023; 21:94. [PMID: 36750868 PMCID: PMC9906873 DOI: 10.1186/s12967-022-03851-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 12/24/2022] [Indexed: 02/09/2023] Open
Abstract
Endometrial cancer (EC) is a common gynecological cancer that endangers women health. Although substantial progresses of EC management have been achieved in recent years, the incidence of EC still remains high. Obesity has been a common phenomenon worldwide that increases the risk of EC. However, the mechanism associating obesity and EC has not been fully understood. Metabolic reprogramming as a remarkable characteristic of EC is currently emerging. As the primary factor of metabolic syndrome, obesity promotes insulin resistance, hyperinsulinemia and hyperglycaemia. This metabolic disorder remodels systemic status, which increases EC risk and is related with poor prognosis. Glucose metabolism in EC cells is complex and mediated by glycolysis and mitochondria to ensure energy requirement. Factors that affect glucose metabolism may have an impact on EC initiation and progression. In this study, we review the glucose metabolic reprogramming of EC not only systemic metabolism but also inherent tumor cell metabolism. In particular, the role of glucose metabolic regulation in malignant properties of EC will be focused. Understanding of metabolic profile and glucose metabolism-associated regulation mechanism in EC may provide novel perspective for treatment.
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Affiliation(s)
- Pengzhu Huang
- grid.412645.00000 0004 1757 9434Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052 China ,grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiangqin Fan
- grid.412645.00000 0004 1757 9434Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052 China ,grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongfei Yu
- grid.412645.00000 0004 1757 9434Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052 China ,grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Kaiwen Zhang
- grid.412645.00000 0004 1757 9434Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052 China ,grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Huanrong Li
- grid.412645.00000 0004 1757 9434Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052 China ,grid.412645.00000 0004 1757 9434Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Yingmei Wang
- Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China. .,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China.
| | - Fengxia Xue
- Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China. .,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China.
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18
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ELLENSON LH. ENDOMETRIAL CARCINOMA: THE INTERPLAY OF GENETICS AND HORMONES. TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION 2023; 133:274-282. [PMID: 37701602 PMCID: PMC10493730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 09/14/2023]
Abstract
Endometrial carcinoma is the most common malignancy of the genital tract in females in the United States, and it is one of the few human cancers increasing in incidence and mortality. Numerous studies have found an association of endometrial carcinoma with obesity, diabetes, and unopposed estrogen stimulation. Molecular studies, in our lab and others, have shown that endometrial carcinoma has a high frequency of alterations in the Phosphoinositide 3-kinase (PIK3) pathway, and notably, coexisting abnormalities in more than one member of the pathway are common. We have combined studies on primary human tumors and genetic mouse models to explore the role of the PIK3 pathway and estrogen, and their interactions, in the development and progression of endometrial carcinoma. Abnormalities in the PIK3 pathway do not simply play redundant roles in endometrial carcinoma and, although not required, the presence of estrogen can alter the course of the disease.
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19
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CRISPR-Cas9 Technology for the Creation of Biological Avatars Capable of Modeling and Treating Pathologies: From Discovery to the Latest Improvements. Cells 2022; 11:cells11223615. [PMID: 36429042 PMCID: PMC9688409 DOI: 10.3390/cells11223615] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/10/2022] [Accepted: 11/13/2022] [Indexed: 11/18/2022] Open
Abstract
This is a spectacular moment for genetics to evolve in genome editing, which encompasses the precise alteration of the cellular DNA sequences within various species. One of the most fascinating genome-editing technologies currently available is Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and its associated protein 9 (CRISPR-Cas9), which have integrated deeply into the research field within a short period due to its effectiveness. It became a standard tool utilized in a broad spectrum of biological and therapeutic applications. Furthermore, reliable disease models are required to improve the quality of healthcare. CRISPR-Cas9 has the potential to diversify our knowledge in genetics by generating cellular models, which can mimic various human diseases to better understand the disease consequences and develop new treatments. Precision in genome editing offered by CRISPR-Cas9 is now paving the way for gene therapy to expand in clinical trials to treat several genetic diseases in a wide range of species. This review article will discuss genome-editing tools: CRISPR-Cas9, Zinc Finger Nucleases (ZFNs), and Transcription Activator-Like Effector Nucleases (TALENs). It will also encompass the importance of CRISPR-Cas9 technology in generating cellular disease models for novel therapeutics, its applications in gene therapy, and challenges with novel strategies to enhance its specificity.
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20
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Liu HS, Chen CD, Lee CC, Chen YC, Cheng WF. Age Specific Risks of Uterine Cancer in Type 2 Diabetes and Associated Comorbidities in Taiwan. Cancers (Basel) 2022; 14:cancers14194912. [PMID: 36230836 PMCID: PMC9564306 DOI: 10.3390/cancers14194912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/27/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022] Open
Abstract
Introduction: The global incidence of uterine cancer has increased substantially in recent decades. We evaluated if the trend of increasing prevalence of diabetes mellitus (DM) and obesity are attributed to the development of uterine cancer. Methods: Using data derived from the National Health Insurance database and Taiwan Cancer Registry, multivariate Cox proportional hazards regression models were adapted to analyze the risk factors of uterine cancer with potential confounding variables. Results: There were a total of 5,104,242 women aged 30−70 years enrolled in the study and 147,772 of them were diagnosed with DM during 2005−2007. In a total of 11 years of follow-up, 14,398 subjects were diagnosed with uterine cancer. An elevated risk of uterine cancer was observed in women with DM of all ages (HR 1.66, 95% CI 1.53−1.81, p < 0.0001). The effect of DM was highest at age 30−39 years (RR 3.05, 95% CI 2.35−3.96, p < 0.0001). In the group of <50 years old, DM patients had at least a twofold higher risk of developing uterine cancer (HR 2.39, 95% CI 2.09−2.74, p < 0.0001). Subjects among all ages diagnosed with polycystic ovary syndrome (PCOS) (HR 2.91, 95% CI 2.47−3.42, p < 0.0001), obesity (HR 2.13, 95% CI 1.88−2.41, p < 0.0001), and those undergoing hormone replacement therapy (HRT) (HR 1.60, 95% CI 1.33−1.93, p < 0.0001) were also positively associated with uterine cancer. Positive associations of hyperlipidemia (HR 1.33, 95% CI 1.22−1.46, p < 0.0001) and statin use (HR 1.27, 95% CI 1.12−1.44, p = 0.0002) on uterine cancer were only observed in subjects <50 years. On the contrary, hyperlipidemia was negatively associated with uterine cancer in subjects ≥50 years (HR 0.91, 95% CI: 0.84−0.98, p = 0.0122). Conclusions: DM is in general the most important risk factor for uterine cancer, especially in premenopausal women. Obesity, PCOS, HPL, statin use, and HRT were also associated with uterine cancer in subjects younger than 50 years. Premenopausal women with DM and respective comorbidities should be aware of the development of uterine cancer.
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Affiliation(s)
- Hui-Shan Liu
- Department of Obstetrics and Gynecology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Chin-Der Chen
- Department of Obstetrics and Gynecology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Chung-Chen Lee
- Data Science Center, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Yong-Chen Chen
- Master’s Program of Big Data in Biomedicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- Correspondence: (Y.-C.C.); (W.-F.C.); Tel.: +886-2-23123456 (ext. 71964) (W.-F.C.); Fax: +886-2-23114965 (W.-F.C.)
| | - Wen-Fang Cheng
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, National Taiwan University, Taipei 100, Taiwan
- Correspondence: (Y.-C.C.); (W.-F.C.); Tel.: +886-2-23123456 (ext. 71964) (W.-F.C.); Fax: +886-2-23114965 (W.-F.C.)
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21
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Abstract
The traditional complications of diabetes mellitus are well known and continue to pose a considerable burden on millions of people living with diabetes mellitus. However, advances in the management of diabetes mellitus and, consequently, longer life expectancies, have resulted in the emergence of evidence of the existence of a different set of lesser-acknowledged diabetes mellitus complications. With declining mortality from vascular disease, which once accounted for more than 50% of deaths amongst people with diabetes mellitus, cancer and dementia now comprise the leading causes of death in people with diabetes mellitus in some countries or regions. Additionally, studies have demonstrated notable links between diabetes mellitus and a broad range of comorbidities, including cognitive decline, functional disability, affective disorders, obstructive sleep apnoea and liver disease, and have refined our understanding of the association between diabetes mellitus and infection. However, no published review currently synthesizes this evidence to provide an in-depth discussion of the burden and risks of these emerging complications. This Review summarizes information from systematic reviews and major cohort studies regarding emerging complications of type 1 and type 2 diabetes mellitus to identify and quantify associations, highlight gaps and discrepancies in the evidence, and consider implications for the future management of diabetes mellitus.
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Affiliation(s)
- Dunya Tomic
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Jonathan E Shaw
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Dianna J Magliano
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
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22
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Loukovaara M, Pasanen A, Bützow R. Molecular classification of endometrial carcinoma: a clinically oriented review. J Clin Pathol 2022; 75:jclinpath-2022-208345. [PMID: 35636924 DOI: 10.1136/jclinpath-2022-208345] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 05/16/2022] [Indexed: 12/24/2022]
Abstract
The Cancer Genome Atlas research network performed a genome-wide analysis of endometrial carcinomas in 2013 and classified tumours into four distinct subgroups: polymerase-ϵ ultramutated, microsatellite unstable hypermutated, copy-number low and copy-number high. These molecular alterations are mostly mutually exclusive as only about 3% of tumours exhibit more than one molecular signature. Apart from the polymerase-ϵ ultramutated subgroup, molecular classification can be reproduced by using surrogate markers. This has facilitated the implementation of molecular diagnostics into routine patient care. Molecular subgroups are associated with different prognoses; thus, improved risk assessment is their most obvious clinical application. However, based on their unique molecular architectures, molecular subgroups should not be regarded simply as risk groups but rather as distinct diseases. This has prompted us and others to examine the role of molecular subgroups in modifying the prognostic effect of traditional risk factors, including clinical factors, uterine factors and tissue biomarkers, and in predicting the response to adjuvant therapies. In the following review, we summarise the current knowledge of molecularly classified endometrial carcinoma and present, based on our own experience, a proposal for implementing molecular classification into daily practice in pathology laboratories.
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Affiliation(s)
- Mikko Loukovaara
- Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Annukka Pasanen
- Department of Pathology, Helsinki University Hospital and Research Program in Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Ralf Bützow
- Department of Pathology, Helsinki University Hospital and Research Program in Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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23
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Njoku K, Agnew HJ, Crosbie EJ. Impact of Type 2 Diabetes Mellitus on Endometrial Cancer Survival: A Prospective Database Analysis. Front Oncol 2022; 12:899262. [PMID: 35600348 PMCID: PMC9117616 DOI: 10.3389/fonc.2022.899262] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/14/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose Type 2 diabetes mellitus (T2DM) is an established risk factor for endometrial cancer but its impact on endometrial cancer survival outcomes is unclear. The aim of this study was to investigate whether pre-existing T2DM impacts survival outcomes in endometrial cancer. Patients and Methods Women diagnosed with endometrial cancer were recruited to a single centre prospective cohort study. Relevant sociodemographic and clinico-pathological data were recorded at baseline. T2DM status was based on clinical and biochemical assessment, verified by general practitioner records and analysed in relation to overall, cancer-specific and recurrence-free survival using Kaplan-Meier estimation and multivariable Cox-regression. Results In total, 533 women with median age and BMI of 66 years (Interquartile range (IQR), 56, 73) and 32kg/m2 (IQR 26, 39) respectively, were included in the analysis. The majority had low-grade (67.3%), early-stage (85.1% stage I/II), endometrial cancer of endometrioid histological phenotype (74.7%). A total of 107 (20.1%) had pre-existing T2DM. Women with T2DM had a two-fold increase in overall mortality (adjusted HR 2.07, 95%CI 1.21-3.55, p=0.008), cancer-specific mortality (adjusted HR 2.15, 95% CI 1.05-4.39, p=0.035) and recurrence rates (adjusted HR 2.22, 95% CI 1.08-4.56, p=0.030), compared to those without, in multivariable analyses. Conclusion T2DM confers an increased risk of death in endometrial cancer patients. Well-designed longitudinal studies with large sample sizes are now needed to confirm these findings.
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Affiliation(s)
- Kelechi Njoku
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, St Mary’s Hospital, University of Manchester, Manchester, United Kingdom
- Stoller Biomarker Discovery Centre, Institute of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Heather J. Agnew
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, St Mary’s Hospital, University of Manchester, Manchester, United Kingdom
| | - Emma J. Crosbie
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, St Mary’s Hospital, University of Manchester, Manchester, United Kingdom
- Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
- *Correspondence: Emma J. Crosbie,
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24
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Andrade Fernandes JP, da Camara AO, Frajacomo FT, Chaves CBP, Fernandes Pereira A, Chaves GV. Metabolic profile of patients with endometrial adenocarcinoma and association with tumor grade. Int J Gynecol Cancer 2022; 32:626-632. [PMID: 35173052 DOI: 10.1136/ijgc-2021-003245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE To describe the prevalence of metabolic syndrome and other metabolic indicators in patients with endometrial cancer and its association with tumor grade. METHODS This is a cross-sectional study of patients with endometrial cancer referred to the Brazilian National Cancer Institute. We collected data on sociodemographic variables, smoking, co-morbidities, physical activity level, menopausal status, and tumor characteristics (histological subtype, stage, and tumor grade). In addition, weight, height, and waist circumference were measured. Laboratory evaluation included lipid profile, fasting blood glucose and insulin, and C-reactive protein. Insulin resistance was estimated by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Characterization of metabolic syndrome and cardiovascular risk profile was performed. Binary logistic regression models were used to test the association between metabolic syndrome and its metabolic parameters, HOMA-IR, and C-reactive protein with tumor grade. RESULTS We included a total of 313 patients, 245 (78.3%) aged <65 years, 262 (83.7%) with endometrioid adenocarcinoma, 193 (61.7%) early stage, and 201 (64.2%) with lower tumor grade (G1 and G2). Metabolic syndrome, insulin resistance, and low levels of leisure-time physical activity were highly prevalent (90.7%). In binary logistic regression models, an association was observed between HOMA-IR and lower tumor grade (p<0.05), while high-grade tumors were associated with the highest C-reactive protein values (p<0.05). CONCLUSION The main finding of this study was the association between insulin resistance and low-grade tumors, and the association between high C-reactive protein levels and high-grade tumors.
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Affiliation(s)
| | - Alex Oliveira da Camara
- National School of Public Health, Fundação Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
- Nutrition Department, Cancer Hospital II, Brazilian National Cancer Institute, Rio de Janeiro, Brazil
| | | | - Claudia Bessa Pereira Chaves
- Gynecologic Oncology Department, Cancer Hospital II, Brazilian National Cancer Institute, Rio de Janeiro, Brazil
| | | | - Gabriela Villaça Chaves
- Nutrition Department, Cancer Hospital II, Brazilian National Cancer Institute, Rio de Janeiro, Brazil
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25
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Njoku K, Barr CE, Crosbie EJ. Current and Emerging Prognostic Biomarkers in Endometrial Cancer. Front Oncol 2022; 12:890908. [PMID: 35530346 PMCID: PMC9072738 DOI: 10.3389/fonc.2022.890908] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 03/28/2022] [Indexed: 12/19/2022] Open
Abstract
Endometrial cancer is the most common gynaecological malignancy in high income countries and its incidence is rising. Whilst most women with endometrial cancer are diagnosed with highly curable disease and have good outcomes, a significant minority present with adverse clinico-pathological characteristics that herald a poor prognosis. Prognostic biomarkers that reliably select those at greatest risk of disease recurrence and death can guide management strategies to ensure that patients receive appropriate evidence-based and personalised care. The Cancer Genome Atlas substantially advanced our understanding of the molecular diversity of endometrial cancer and informed the development of simplified, pragmatic and cost-effective classifiers with prognostic implications and potential for clinical translation. Several blood-based biomarkers including proteins, metabolites, circulating tumour cells, circulating tumour DNA and inflammatory parameters have also shown promise for endometrial cancer risk assessment. This review provides an update on the established and emerging prognostic biomarkers in endometrial cancer.
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Affiliation(s)
- Kelechi Njoku
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
- Stoller Biomarker Discovery Centre, University of Manchester, Manchester, United Kingdom
- Department of Obstetrics and Gynaecology, St Mary’s Hospital, Manchester, University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Chloe E. Barr
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
- Department of Obstetrics and Gynaecology, St Mary’s Hospital, Manchester, University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Emma J. Crosbie
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
- Department of Obstetrics and Gynaecology, St Mary’s Hospital, Manchester, University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
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26
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McVicker L, Cardwell CR, Edge L, McCluggage WG, Quinn D, Wylie J, McMenamin ÚC. Survival outcomes in endometrial cancer patients according to diabetes: a systematic review and meta-analysis. BMC Cancer 2022; 22:427. [PMID: 35439978 PMCID: PMC9019948 DOI: 10.1186/s12885-022-09510-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 04/04/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Diabetes is an established risk factor for endometrial cancer development but its impact on prognosis is unclear and epidemiological studies to date have produced inconsistent results. We aimed to conduct the first systematic review and meta-analysis to compare survival outcomes in endometrial cancer patients with and without pre-existing diabetes. METHODS We conducted a systematic search of MEDLINE, EMBASE and Web of Science databases up to February 2022 for observational studies that investigated the association between pre-existing diabetes and cancer-specific survival in endometrial cancer patients. Secondary outcomes included overall survival and progression or recurrence-free survival. Quality assessment of included studies was undertaken using the Newcastle-Ottawa Scale and a random-effects model was used to produce pooled hazard ratios (HRs) and 95% confidence intervals (CIs). (PROSPERO 2020 CRD42020196088). RESULTS In total, 31 studies were identified comprising 55,475 endometrial cancer patients. Pooled results suggested a worse cancer-specific survival in patients with compared to patients without diabetes (n = 17 studies, HR 1.15, 95% CI 1.00-1.32, I2 = 62%). Similar results were observed for progression or recurrence-free survival (n = 6 studies, HR 1.23, 95% CI 1.02-1.47, I2 = 0%) and for overall survival (n = 24 studies, HR 1.42, 95% CI 1.31-1.54, I2 = 46%). CONCLUSION In this systematic review and meta-analysis, we show that diabetes is associated with a worse cancer-specific and overall survival in endometrial cancer patients.
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Affiliation(s)
- Lauren McVicker
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK.
| | | | - Lauren Edge
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - W Glenn McCluggage
- Department of Pathology, Belfast Health and Social Care Trust, Grosvenor Road, Belfast, Northern Ireland, UK
| | - Declan Quinn
- Department of Obstetrics and Gynaecology, Antrim Area Hospital, Northern Health and Social Care Trust, Antrim, Northern Ireland, UK
| | - James Wylie
- Department of Obstetrics and Gynaecology, Antrim Area Hospital, Northern Health and Social Care Trust, Antrim, Northern Ireland, UK
| | - Úna C McMenamin
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK
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An Assessment of Serum Selenium Concentration in Women with Endometrial Cancer. Nutrients 2022; 14:nu14050958. [PMID: 35267933 PMCID: PMC8912795 DOI: 10.3390/nu14050958] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/22/2022] [Accepted: 02/22/2022] [Indexed: 12/04/2022] Open
Abstract
Background: Numerous studies have shown a relationship between low serum selenium levels and an increased risk of developing cancer. Methods: A total of 306 women participated in the study: 153 patients diagnosed with endometrial cancer and 153 healthy women who were matched, in terms of birth year (+/−3 years), to the patients from the study group. The quantitative measurement of selenium content in the collected blood samples was performed using a mass spectrometer with excitation in inductively coupled plasma. In order to determine the relationship between the risk factors and the incidence of endometrial cancer, analyses based on single- and multi-factor conditional logistic regression models were performed. Results: The mean concentration of selenium was lower in patients with endometrial cancer than in healthy controls (60.63 µg/L (0.77 µmol/L) vs. 78.74 µg/L (0.99 µmol/L), respectively). When compared in quartiles, a significant association of lower selenium concentration with the incidence of endometrial cancer was recorded. The highest OR was observed in the first and second quartiles (OR-22.0, p-value < 0.001; medium selenium level 46.95 µg/L (0.59 µmol/L), and OR-5.94; p-value < 0.001; medium selenium level 63.60 µg/L (0.80 µmol/L), respectively). Conclusion: A strong correlation between the level of selenium in the blood serum and the risk of endometrial cancer indicates that patients with low levels should be a candidate group requiring appropriate preventive examinations. Further research on a larger group of patients is required.
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Li S, Chen H, Zhang T, Li R, Yin X, Man J, He Q, Yang X, Lu M. Spatiotemporal trends in burden of uterine cancer and its attribution to body mass index in 204 countries and territories from 1990 to 2019. Cancer Med 2022; 11:2467-2481. [PMID: 35156336 PMCID: PMC9189473 DOI: 10.1002/cam4.4608] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 01/08/2022] [Accepted: 01/16/2022] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Uterine cancer is one of the most common female cancers worldwide, with huge heterogeneity in morbidity and mortality. Although a high body-mass index (BMI) has been linked to uterine cancer, systematic reports about the influence of high BMI and its temporal trends are scarce. METHODS The annual morbidity, mortality, and disability-adjusted life years (DALYs) of uterine cancer in 204 countries or territories were retrieved from the GBD 2019 study. To reflect trends in disease burden, we also calculated the estimated annual percentage change (EAPC) based on the age-standardized rates of uterine cancer from 1990 to 2019. RESULTS The global incident cases of uterine cancer increased 2.3 times from 187,190 in 1990 to 435,040 in 2019. Although the age-standardized incidence rate (ASIR) of uterine cancer increased worldwide from 8.67/100,000 in 1990 to 9.99/100,000 in 2019, the age-standardized death rate (ASDR) and DALY rate decreased during the same period. High socio-demographic index (SDI) countries tended to have a higher ASIR than developing regions, and their increasing trend in ASIR was also more pronounced. The disease was rare before 40 years old, but its risk rose sharply among women aged 50-70. A high BMI was linked to more than one-third of deaths from uterine cancer in 2019. CONCLUSIONS The incidence in developed areas was significantly higher than in developing areas and also increased much more rapidly. Elderly females, especially those with a high BMI, have a higher risk of uterine cancer. Therefore, more health resources may be needed to curb the rising burden in specific populations.
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Affiliation(s)
- Songbo Li
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Hui Chen
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Tongchao Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Rongrong Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xiaolin Yin
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jinyu Man
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Qiufeng He
- Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaorong Yang
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ming Lu
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China.,Clinical Research Center of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.,Department of Epidemiology and Health Statistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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Janowska M, Potocka N, Paszek S, Skrzypa M, Żulewicz K, Kluz M, Januszek S, Baszuk P, Gronwald J, Lubiński J, Zawlik I, Kluz T. An Assessment of GPX1 (rs1050450), DIO2 (rs225014) and SEPP1 (rs7579) Gene Polymorphisms in Women with Endometrial Cancer. Genes (Basel) 2022; 13:genes13020188. [PMID: 35205233 PMCID: PMC8871918 DOI: 10.3390/genes13020188] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 02/01/2023] Open
Abstract
Background: Numerous studies indicate a relationship between the presence of GPX1 (rs1050450), DIO2 (rs225014) and SEPP1 (rs7579) gene polymorphisms and the development of chronic or neoplastic diseases. However, there are no reports on the influence of these polymorphisms on the development of endometrial cancer. Methods: 543 women participated in the study. The study group consisted of 269 patients with diagnosed endometrial cancer. The control group consisted of 274 healthy women. Blood samples were drawn from all the participants. The PCR-RFLP method was used to determine polymorphisms in the DIO2 (rs225014) and GPX1 (rs1050450) genes. The analysis of polymorphisms in the SEPP1 (rs7579) gene was performed by means of TaqMan probes. Results: There was a 1.99-fold higher risk of developing endometrial cancer in CC homozygotes, DIO2 (rs225014) polymorphism (95% Cl 1.14–3.53, p = 0.017), compared to TT homozygotes. There was no correlation between the occurrence of GPX1 (rs1050450) and SEPP1 (rs7579) polymorphisms and endometrial cancer. Conclusion: Carriers of the DIO2 (rs225014) polymorphism may be predisposed to the development of endometrial cancer. Further research confirming this relationship is recommended.
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Affiliation(s)
- Magdalena Janowska
- Department of Gynecology and Obstetrics, Fryderyk Chopin University Hospital No. 1, 35-055 Rzeszow, Poland; (M.J.); (S.J.); (T.K.)
| | - Natalia Potocka
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, College of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland; (N.P.); (S.P.); (M.S.); (K.Ż.)
| | - Sylwia Paszek
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, College of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland; (N.P.); (S.P.); (M.S.); (K.Ż.)
| | - Marzena Skrzypa
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, College of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland; (N.P.); (S.P.); (M.S.); (K.Ż.)
| | - Kamila Żulewicz
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, College of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland; (N.P.); (S.P.); (M.S.); (K.Ż.)
| | - Marta Kluz
- Department of Pathology, Fryderyk Chopin University Hospital No. 1, 35-055 Rzeszow, Poland;
| | - Sławomir Januszek
- Department of Gynecology and Obstetrics, Fryderyk Chopin University Hospital No. 1, 35-055 Rzeszow, Poland; (M.J.); (S.J.); (T.K.)
| | - Piotr Baszuk
- Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland; (P.B.); (J.G.); (J.L.)
| | - Jacek Gronwald
- Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland; (P.B.); (J.G.); (J.L.)
| | - Jan Lubiński
- Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland; (P.B.); (J.G.); (J.L.)
| | - Izabela Zawlik
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, College of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland; (N.P.); (S.P.); (M.S.); (K.Ż.)
- Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland
- Correspondence:
| | - Tomasz Kluz
- Department of Gynecology and Obstetrics, Fryderyk Chopin University Hospital No. 1, 35-055 Rzeszow, Poland; (M.J.); (S.J.); (T.K.)
- Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-959 Rzeszow, Poland
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30
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Yoshihara M, Kitamura K, Tsuru S, Shimono R, Sakuda H, Mayama M, Tano S, Uno K, Ukai MO, Kishigami Y, Oguchi H, Hirota A. Factors associated with response to compression-based physical therapy for secondary lower limb lymphedema after gynecologic cancer treatment: a multicenter retrospective study. BMC Cancer 2022; 22:25. [PMID: 34980013 PMCID: PMC8722292 DOI: 10.1186/s12885-021-09163-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 11/30/2021] [Indexed: 11/30/2022] Open
Abstract
Background Lower limb lymphedema (LLL) is one of the most refractory and debilitating complications related to gynecological cancer treatment. We investigated factors associated with response to compression-based physical therapy (CPT) for secondary LLL after gynecologic cancer treatment. Methods We performed a multicenter retrospective study using the records of seven medical institutions from 2002 and 2014. Patients who developed LLL after gynecological cancer treatment were included. Limb volumes were calculated from the lengths of the limb circumferences at four points. All participants underwent compression-based physical therapy for LLL. Factors, including MLD, indicative of circumference reductions in LLL were determined. Results In total, 1,034 LLL met the required criteria of for the study. A multivariate linear regression analysis identified age; body mass index (BMI); endometrial cancer; radiotherapy; and initial limb circumference as significant independent prognostic factors related to improvement in LLL. In analysis of covariance for improvement in LLL adjusted by the initial limb circumference and stratified by BMI and radiotherapy, patients with BMI 28 kg/m2 or higher and receiving radiation rarely responded to CPT. Conclusions Improvements in the lower limb circumference correlated with clinical histories and physical characteristics, which may be used as independent prognostic factors for successful CPT for LLL after gynecological cancer treatment.
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Affiliation(s)
- Masato Yoshihara
- Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.,Obstetrics and Gynecology, TOYOTA Memorial Hospital, 1-1 Heiwa-cho, Toyota, Aichi, 471-8513, Japan
| | - Kaoru Kitamura
- Department of Breast Surgery, Kaizuka Hospital, 7-7-27 Hakozaki, Higashi-ku, Fukuoka, Fukuoka, 812-0053, Japan
| | - Satoko Tsuru
- School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
| | - Ryoko Shimono
- Organization for Interdisciplinary Research Project, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Hiromi Sakuda
- Graduate School of Nursing, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi-ku, Osaka-shi, 558-8585, Japan
| | - Michinori Mayama
- Obstetrics and Gynecology, TOYOTA Memorial Hospital, 1-1 Heiwa-cho, Toyota, Aichi, 471-8513, Japan.,Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita 8, Nishi 5, Kita-ku, Sapporo, Hokkaido, 060-0808, Japan
| | - Sho Tano
- Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.,Obstetrics and Gynecology, TOYOTA Memorial Hospital, 1-1 Heiwa-cho, Toyota, Aichi, 471-8513, Japan
| | - Kaname Uno
- Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.,Obstetrics and Gynecology, TOYOTA Memorial Hospital, 1-1 Heiwa-cho, Toyota, Aichi, 471-8513, Japan
| | - Mayu Ohno Ukai
- Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.,Obstetrics and Gynecology, TOYOTA Memorial Hospital, 1-1 Heiwa-cho, Toyota, Aichi, 471-8513, Japan
| | - Yasuyuki Kishigami
- Obstetrics and Gynecology, TOYOTA Memorial Hospital, 1-1 Heiwa-cho, Toyota, Aichi, 471-8513, Japan
| | - Hidenori Oguchi
- Obstetrics and Gynecology, TOYOTA Memorial Hospital, 1-1 Heiwa-cho, Toyota, Aichi, 471-8513, Japan
| | - Akio Hirota
- Hirota Internal Medicine Clinic, 5-19-10 Minami-karasuyama, Setagaya-ku, Tokyo, 157-0062, Japan
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31
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Wang Y, Yan J, Zhang P, Yang P, Zhang W, Lu M. Tai Chi Program to Improve Glucose Control and Quality of Life for the Elderly With Type 2 Diabetes: A Meta-analysis. INQUIRY : A JOURNAL OF MEDICAL CARE ORGANIZATION, PROVISION AND FINANCING 2022; 59:469580211067934. [PMID: 35282699 PMCID: PMC9111975 DOI: 10.1177/00469580211067934] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
OBJECTIVE To systematically evaluate the effects of Tai chi for improving elderly patients with type 2 diabetes. METHODS According to PRISMA checklist, we conducted this standard meta-analysis. The multiple databases like Pubmed, Embase, and Cochrane databases were used to search for the relevant studies, and full-text articles involved in the evaluation of Tai chi in improving elderly patients with type 2 diabetes. Review manager 5.2 was adopted to estimate the effects of the results among selected articles. Forest plots, sensitivity analysis and funnel plot for the articles included were also conducted. RESULTS Finally, 7 relevant studies were eventually satisfied the included criteria. We found that Tai chi group had lower glucose than control group (mean difference (MD)=-12.47, 95%CI [-21.20, -3.73], P=.005; I2 = 32%), Tai chi group had higher activities-specific balance confidence (ABC) scale than control group (MD =9.26 with 95%CI [6.68, 11.83], P < .001) and Tai chi group had higher single limb standing test score than control group (MD = 8.38, 95%CI [4.02, 12.74], P = .001). The study was robust and limited publication bias was observed in this study. CONCLUSION Since we found Tai chi had better performance than usual care in improving old diabetes patients' glucose and life quality, the study supports that Tai chi can help old diabetes patients from several aspects including disease indicators, independence and life quality.
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Affiliation(s)
- Yanmei Wang
- Nursing Department, Gongli Hospital, Shanghai, China
| | - Jianjun Yan
- Nursing Department, Gongli Hospital, Shanghai, China
| | - Peng Zhang
- School of Clinical Medicine, Shanghai University and Health
Sciences, Shanghai, China
| | - Pei Yang
- Department of Nursing, Ningxia Medical
University, Yinchuan, Ningxia
| | - Wenhui Zhang
- Department of Nursing, Ningxia Medical
University, Yinchuan, Ningxia
| | - Min Lu
- Nursing Department, Gongli Hospital, Shanghai, China
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32
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Hernández-Garduño E. The association between diabetes and cancer in Mexico: Analysis using death certificate databases, 2009-2017. J Cancer Res Ther 2021; 17:1397-1403. [PMID: 34916370 DOI: 10.4103/jcrt.jcrt_878_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Context Previous studies have shown that diabetes mellitus (DM) is a risk factor of some type-specific cancers. However, no data are available on the association between cancer and DM in Latin America. Aims The aim of this study is to determine which type-specific cancers are associated with DM using multiple cause of death data. Settings and Design Whole country of Mexico, cross-sectional design. Materials and Methods Analysis of all cancer deaths (2009-2017) using death certificate databases of Mexican adults aged ≥20 years. Statistical Analysis Used Multivariable logistic regression. Results There were 710,292 total cancer deaths. DM increased the risk of pancreatic (adjusted odds ratio [aOR] = 1.7), liver (aOR = 1.6), kidney (aOR = 1.4), gallbladder (aOR = 1.2) and endometrial (aOR = 1.1) cancers, all P < 0.05. Type 2 or unknown-type DM were associated with the same cancer types with little variation of estimates. Higher estimates were found in males than females (except for kidney cancer). Type 1 DM was associated with pancreatic cancer only (aOR = 1.9). Conclusions DM in Mexico is associated with gastrointestinal (pancreatic, liver, gallbladder), kidney and endometrial cancers. Dissemination of knowledge to both health-care workers and diabetics regarding potential cancer risks including adequate diet, regular exercise, weight reduction if obese/overweight, cessation of smoking, and good glucose control and medication compliance should be reinforced. Specific cancer preventative measures should be implemented for patients with DM.
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Affiliation(s)
- Eduardo Hernández-Garduño
- Administration and Personnel Development Department, Social Security Institute of the State of Mexico and Municipalities, Toluca de Lerdo, Estado de México, México
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Abstract
Although endometrial cancer management remains challenging, a deeper understanding of the genetic diversity as well as the drivers of the various pathogenic states of this disease has led to development of divergent management approaches in an effort to improve therapeutic precision in this complex malignancy. This comprehensive review provides an update on the epidemiology, pathophysiology, diagnosis and molecular classification, recent advancements in disease management, as well as important patient quality-of-life considerations and emerging developments in the rapidly evolving therapeutic landscape of endometrial cancers.
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Affiliation(s)
- Vicky Makker
- Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
| | - Helen MacKay
- University of Toronto, Division of Medical Oncology & Hematology, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
| | - Isabelle Ray-Coquard
- Department of Medical Oncology, Centre Leon Berard, Laboratoire Reshape University Claude Bernard Lyon, Lyon, France
| | - Douglas A Levine
- Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA
- Merck Research Labs, Rahway, NJ, USA
| | - Shannon N Westin
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Ana Oaknin
- Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
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Khatun M, Urpilainen E, Ahtikoski A, Arffman RK, Pasanen A, Puistola U, Tapanainen JS, Andersson LC, Butzow R, Loukovaara M, Piltonen TT. Low Expression of Stanniocalcin 1 (STC-1) Protein Is Associated With Poor Clinicopathologic Features of Endometrial Cancer. Pathol Oncol Res 2021; 27:1609936. [PMID: 34650342 PMCID: PMC8505533 DOI: 10.3389/pore.2021.1609936] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/13/2021] [Indexed: 12/14/2022]
Abstract
Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors (p = 0.030), deep myometrial invasion (p = 0.003), lymphovascular space invasion (p = 0.050), and large tumor size (p = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women (p = 0.014) and in women with diabetes mellitus type 2 (DMT2; p = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium (p = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment.
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Affiliation(s)
- Masuma Khatun
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Elina Urpilainen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Anne Ahtikoski
- Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland.,Department of Pathology, Turku University Hospital, Turku, Finland
| | - Riikka K Arffman
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Annukka Pasanen
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Ulla Puistola
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Juha S Tapanainen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.,Department of Obstetrics and Gynaecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Leif C Andersson
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Ralf Butzow
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - Mikko Loukovaara
- Department of Obstetrics and Gynaecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Terhi T Piltonen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
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Wang X, Ding S. The biological and pharmacological connections between diabetes and various types of cancer. Pathol Res Pract 2021; 227:153641. [PMID: 34619575 DOI: 10.1016/j.prp.2021.153641] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 12/18/2022]
Abstract
Diabetes and cancer incidence have risen tremendously over the years. Additionally, both cancer and diabetes share numerous risks, such as overweight, inactive lifestyles, older age, and smoking. Numerous methods have been suggested to connect obesity and diabetes to cancer advancements, such as increasing insulin/ Insulin-like growth factor I (IGF-1) signaling, lipid and glucose uptake and metabolism, shifts in the cytokine, chemokine, and adipokine profile also variations in the adipose tissue immediately adjacent to cancer spots. Diabetes has been found to have a complicated cancer-causing mechanism involving excessive reactive oxygen species (ROS) production, loss of critical macromolecules, chronic inflammation, and delayed repair, all of which contribute to carcinogenesis. Diabetes-associated epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition lead to the formation of cancer-associated fibroblasts in tumors by enabling tumor cells to extravasate via the endothelium and epithelium. This study aims to describe the correlation between diabetes and cancer, as well as summarize the molecular connections and shared pathways such as sex hormones, hyperglycemia, inflammation, insulin axis, metabolic symbiosis, and endoplasmic reticulum (ER) stress that exist between them.
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Affiliation(s)
- Xuechang Wang
- Department of Applied Sciences, University of the West of England, Bristol BS16 1QY, UK.
| | - Suming Ding
- Department of Ophthalmology, Jiujiang Maternal and Child Health Hospital, Jiujiang 332000, China
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Reed J, Bain S, Kanamarlapudi V. A Review of Current Trends with Type 2 Diabetes Epidemiology, Aetiology, Pathogenesis, Treatments and Future Perspectives. Diabetes Metab Syndr Obes 2021; 14:3567-3602. [PMID: 34413662 PMCID: PMC8369920 DOI: 10.2147/dmso.s319895] [Citation(s) in RCA: 178] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/09/2021] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes (T2D), which has currently become a global pandemic, is a metabolic disease largely characterised by impaired insulin secretion and action. Significant progress has been made in understanding T2D aetiology and pathogenesis, which is discussed in this review. Extrapancreatic pathology is also summarised, which demonstrates the highly multifactorial nature of T2D. Glucagon-like peptide (GLP)-1 is an incretin hormone responsible for augmenting insulin secretion from pancreatic beta-cells during the postprandial period. Given that native GLP-1 has a very short half-life, GLP-1 mimetics with a much longer half-life have been developed, which are currently an effective treatment option for T2D by enhancing insulin secretion in patients. Interestingly, there is continual emerging evidence that these therapies alleviate some of the post-diagnosis complications of T2D. Additionally, these therapies have been shown to induce weight loss in patients, suggesting they could be an alternative to bariatric surgery, a procedure associated with numerous complications. Current GLP-1-based therapies all act as orthosteric agonists for the GLP-1 receptor (GLP-1R). Interestingly, it has emerged that GLP-1R also has allosteric binding sites and agonists have been developed for these sites to test their therapeutic potential. Recent studies have also demonstrated the potential of bi- and tri-agonists, which target multiple hormonal receptors including GLP-1R, to more effectively treat T2D. Improved understanding of T2D aetiology/pathogenesis, coupled with the further elucidation of both GLP-1 activity/targets and GLP-1R mechanisms of activation via different agonists, will likely provide better insight into the therapeutic potential of GLP-1-based therapies to treat T2D.
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Affiliation(s)
- Josh Reed
- Institute of Life Science 1, Medical School, Swansea University, Swansea, SA2 8PP, UK
| | - Stephen Bain
- Institute of Life Science 1, Medical School, Swansea University, Swansea, SA2 8PP, UK
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Zabuliene L, Kaceniene A, Steponaviciene L, Linkeviciute-Ulinskiene D, Stukas R, Arlauskas R, Vanseviciute-Petkeviciene R, Smailyte G. Risk of Endometrial Cancer in Women with Diabetes: A Population-Based Retrospective Cohort Study. J Clin Med 2021; 10:3453. [PMID: 34441749 PMCID: PMC8397032 DOI: 10.3390/jcm10163453] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/26/2021] [Accepted: 08/02/2021] [Indexed: 12/21/2022] Open
Abstract
The aim of this study was to examine the association between type 2 diabetes (T2DM), use of glucose-lowering medications and endometrial cancer (EC) risk. METHODS The risk of EC incidence among women with T2DM in Lithuania was assessed using a retrospective cohort study design. Female patients who were registered with T2DM between 1 January 2000 and 31 December 2012 were identified in the National Health Insurance Fund database. EC cases (ICD-10 code C54) were identified from the Lithuanian Cancer Registry. Standardized incidence ratios (SIRs) were calculated by dividing the observed numbers of EC among patients with T2DM by the expected number of EC, calculated using national rates. RESULTS A total of 77,708 diabetic women were included in the analysis, and 995 cases of EC were identified. A significantly increased EC risk in diabetic women was found as compared to the general population (SIR = 1.69, 95% CI 1.59-1.80). The greatest EC risk was found among younger patients at T2DM diagnosis, and the risk declined gradually with increasing age but persisted in being significantly increased among all age groups. The risk for EC increased with increasing duration of diabetes, and the highest EC risk was observed more than 10 years after T2DM diagnosis. A significantly higher EC risk than expected from the general population was found in all patient groups by glucose-lowering medication combinations. The lowest EC risk was observed in diabetic women who were users of "oral only" (without metformin) (SIR = 1.42, 95% CI 1.10-1.83) and "metformin only" (SIR = 1.69, 95% CI 1.49-1.92) medications. A two times greater EC risk was observed among the remaining glucose-lowering medication categories. In contrast, use of insulin only was not related to a higher EC incidence risk (SIR = 0.45, 95% CI 0.23-0.86); however, the risk estimation was based on nine cases. CONCLUSIONS Our study shows a significantly increased EC risk in diabetic women as compared to the general population. In this study, a significantly higher EC risk was found in all patient groups by glucose-lowering medication combinations, except for insulin only users.
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Affiliation(s)
- Lina Zabuliene
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Ciurlionio g. 21, 03101 Vilnius, Lithuania;
| | - Augustė Kaceniene
- Laboratory of Cancer Epidemiology, National Cancer Institute, P. Baublio g. 3b, 08406 Vilnius, Lithuania;
| | - Laura Steponaviciene
- Consultative Polyclinic Department, National Cancer Institute, Santariskių Str. 1, 08660 Vilnius, Lithuania; (L.S.); (R.V.-P.)
| | - Donata Linkeviciute-Ulinskiene
- Institute of Biomedical Sciences, Department of Pathology, Forensic Medicine and Pharmacology, Faculty of Medicine, Vilnius University, Ciurlionio g. 21, 03101 Vilnius, Lithuania;
| | - Rimantas Stukas
- Institute of Health Sciences, Faculty of Medicine, Vilnius University, Ciurlionio g. 21, 03101 Vilnius, Lithuania; (R.S.); (R.A.)
| | - Rokas Arlauskas
- Institute of Health Sciences, Faculty of Medicine, Vilnius University, Ciurlionio g. 21, 03101 Vilnius, Lithuania; (R.S.); (R.A.)
| | - Rasa Vanseviciute-Petkeviciene
- Consultative Polyclinic Department, National Cancer Institute, Santariskių Str. 1, 08660 Vilnius, Lithuania; (L.S.); (R.V.-P.)
- Clinic of Obstetrics and Gynecology, Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, Ciurlionio g. 21, 03101 Vilnius, Lithuania
| | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute, P. Baublio g. 3b, 08406 Vilnius, Lithuania;
- Institute of Health Sciences, Faculty of Medicine, Vilnius University, Ciurlionio g. 21, 03101 Vilnius, Lithuania; (R.S.); (R.A.)
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Wang Y, Zhou R, Zhang X, Liu H, Shen D, Wang J. Significance of serum and pathological biomarkers in fertility-sparing treatment for endometrial cancer or atypical hyperplasia: a retrospective cohort study. BMC WOMENS HEALTH 2021; 21:252. [PMID: 34162378 PMCID: PMC8223344 DOI: 10.1186/s12905-021-01383-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/31/2021] [Indexed: 12/12/2022]
Abstract
Background This study analyzed the changes of serum and pathological biomarkers during fertility-sparing therapy of endometrial cancer (EC) or endometrial atypical hyperplasia (EAH), to investigate their implications for early prediction of treatment efficacy. Methods A retrospective analysis of EC or EAH patients who received fertility-sparing therapy between 2012 and 2016 was performed. Serum and endometrium sampling were obtained for each patient at three time points: at baseline, at 3–6 months' treatment and at the end of conservative treatment. Serum biomarkers including insulin resistance (HbA1c, HOMA-IR), sex hormones and thyroid hormones were measured. Meanwhile expression of endometrial pathological biomarkers including ER, PR, PRB and Ki-67 was also assessed by immunohistochemistry. Results For the 53 recruited patients, overall complete response, recurrence and pregnancy rates were 94%, 26% and 36.4%. During the treatment, the serum biomarkers of HOMA-IR remained stable, while pathological markers including PR, PRB and Ki67 diminished significantly. Patients who achieved remission faster had significant lower HOMA-IR level and higher PRB expression at baseline. We also found a more remarkable down-regulation of PRB related with faster remission. Further multivariate analysis confirmed that baseline HOMA-IR ≥ 2.5 negatively affected treatment time to remission (OR 0.206; p = 0.017). While marked reduction of PRB (≥ 30%) at 3–6 months' treatment correlated with faster remission (OR 5.788; p = 0.010). Conclusion For EC and EAH patients who received fertility-sparing therapy, baseline status of insulin resistance predicted poor response to progestin, while marked reduction of PRB following the initial 3–6 months' treatment predicted fast remission. Supplementary Information The online version contains supplementary material available at 10.1186/s12905-021-01383-5.
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Affiliation(s)
- Yiqin Wang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, 11th Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Rong Zhou
- Department of Obstetrics and Gynecology, Peking University People's Hospital, 11th Xizhimen South Street, Xicheng District, Beijing, 100044, China.
| | - Xiaobo Zhang
- Department of Pathology, Peking University People's Hospital, Beijing, China
| | - Huixin Liu
- Department of Clinical Epidemiology, Peking University People's Hospital, Beijing, China
| | - Danhua Shen
- Department of Pathology, Peking University People's Hospital, Beijing, China
| | - Jianliu Wang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, 11th Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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Pearson-Stuttard J, Papadimitriou N, Markozannes G, Cividini S, Kakourou A, Gill D, Rizos EC, Monori G, Ward HA, Kyrgiou M, Gunter MJ, Tsilidis KK. Type 2 Diabetes and Cancer: An Umbrella Review of Observational and Mendelian Randomization Studies. Cancer Epidemiol Biomarkers Prev 2021; 30:1218-1228. [PMID: 33737302 PMCID: PMC9398112 DOI: 10.1158/1055-9965.epi-20-1245] [Citation(s) in RCA: 149] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/22/2020] [Accepted: 02/25/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of developing several common cancers, but it is unclear whether this association is causal. We aimed to summarize the evidence on T2DM and cancer and evaluate the validity of associations from both observational and Mendelian randomization (MR) studies. METHODS We performed an umbrella review of the evidence across meta-analyses of observational studies that examined associations of T2DM with risk of developing or dying from site-specific cancers, and MR studies that explored the potential causal association of T2DM and associated biomarkers with cancer risk. RESULTS We identified eligible observational meta-analyses that assessed associations between T2DM and cancer incidence for 18 cancer sites, cancer mortality for seven sites, and cancer incidence or mortality for four sites. Positive associations between T2DM and six cancers reached strong or highly suggestive evidence. We found eight MR studies assessing the association of genetically predicted T2DM and seven and eight studies assessing the association of genetically predicted fasting insulin or fasting glucose concentrations, respectively, upon site-specific cancers. Positive associations were found between genetically predicted T2DM and fasting insulin and risk of six cancers. There was no association between genetically predicted fasting plasma glucose and cancer except for squamous cell lung carcinoma. CONCLUSIONS We found robust observational evidence for the association between T2DM and colorectal, hepatocellular, gallbladder, breast, endometrial, and pancreatic cancers. IMPACT Potential causal associations were identified for genetically predicted T2DM and fasting insulin concentrations and risk of endometrial, pancreas, kidney, breast, lung, and cervical cancers.
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Affiliation(s)
- Jonathan Pearson-Stuttard
- Department of Epidemiology and Biostatistics, MRC-PHE Center for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
| | - Nikos Papadimitriou
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Georgios Markozannes
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Sofia Cividini
- Department of Health Data Science, University of Liverpool, Liverpool, United Kingdom
| | - Artemisia Kakourou
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Evangelos C Rizos
- Department of Internal Medicine, University Hospital of Ioannina, Ioannina, Greece
- School of Medicine, European University of Cyprus, Nicosia, Cyprus
| | - Grace Monori
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Heather A Ward
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Maria Kyrgiou
- Department of Gut, Metabolism and Reproduction, and Surgery and Cancer, IRDB, Imperial College London, London, United Kingdom
- West London Gynecological Cancer Center, Imperial NHS Trust, London, United Kingdom
| | - Marc J Gunter
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
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Urpilainen E, Ahtikoski A, Arima R, Puistola U, Karihtala P. No Association Between Statin Use and the Prognosis of Endometrial Cancer in Women With Type 2 Diabetes. Front Pharmacol 2021; 12:621180. [PMID: 34054515 PMCID: PMC8155720 DOI: 10.3389/fphar.2021.621180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 04/26/2021] [Indexed: 11/13/2022] Open
Abstract
Preclinical studies have suggested statins have antiproliferative and anti-metastatic effects on endometrial cancer cells. Similarly, most previous epidemiological studies have reported a better prognosis of endometrial cancer in patients who used statins. In this study, we explored the role of statins in the prognosis of endometrial cancer in women with type 2 diabetes in a hospital-based cohort. This retrospective cohort consisted of 119 women with type 2 diabetes who were diagnosed and treated for endometrial cancer at Oulu University Hospital, Finland, between 2007 and 2014. The patients were classified as statin users (n = 58) and nonusers (n = 61) based on the type of medication they were using at the time of endometrial cancer diagnosis. Statin use showed no association with progression-free survival or overall survival in the whole cohort nor the subgroups with type I or type II histology, in lower or higher body mass index groups, or at an early or advanced stage. The results remained similar in the multivariate analysis after adjusting for the patient's age, cancer stage, and histology. Furthermore, statin use seemed not to have any association with most of the prognostic factors at the time of endometrial cancer diagnosis.
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Affiliation(s)
- Elina Urpilainen
- PEDEGO Research Unit, Medical Research Center Oulu, Department of Obstetrics and Gynecology, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Anne Ahtikoski
- Cancer and Translational Medicine Research Unit, Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Reetta Arima
- Department of Obstetrics and Gynecology, Central Finland Central Hospital, Jyväskylä, Finland
| | - Ulla Puistola
- PEDEGO Research Unit, Medical Research Center Oulu, Department of Obstetrics and Gynecology, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Peeter Karihtala
- Department of Oncology, University of Helsinki and Helsinki University Comprehensive Cancer Center, Helsinki, Finland
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Wang L, Zhong L, Xu B, Chen M, Huang H. Diabetes mellitus and the risk of ovarian cancer: a systematic review and meta-analysis of cohort and case-control studies. BMJ Open 2020; 10:e040137. [PMID: 33376163 PMCID: PMC7778773 DOI: 10.1136/bmjopen-2020-040137] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 10/05/2020] [Accepted: 11/18/2020] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Emerging evidence from observational studies (cohort and case-control studies) suggests that a history of diabetes mellitus (DM) has been linked to increased risk of ovarian cancer (OC), but the association between them remains inconclusive. The aim of this systematic review and meta-analysis of observational studies was to clarify this association. DESIGN Systematic review and meta-analysis. METHODS We searched PubMed, Embase and the Cochrane library databases published from the inception through 9 April 2020 without language restriction. Observational studies that evaluated the correlation between DM and the incidence of OC were included in our study. Relative risk (RR) with 95% CI was pooled by use of a random-effects model. RESULTS A total of 36 epidemiological articles, including 9 case-control and 27 cohort studies, were finally enrolled, consisting of 14 496 incident cases of OC. Synthesised RRs of developing OC by history of DM were 1.20 (95% CI=1.10 to 1.31) for all eligible studies, 1.08 (95% CI=0.77 to 1.53) for case-control studies and 1.22 (95% CI=1.11 to 1.33) for cohort studies. The above-mentioned positive association persisted across most of subgroup analyses, whereas it was not significant among studies from North American and European countries, level of unadjusted, and patients with low-quality and gestational DM group. The cumulative meta-analysis and sensitivity analysis showed pooled effect was stable and reliable, and no apparent publication bias was identified in this study. CONCLUSIONS Our study found weaker but still association between DM and OC risk. However, further well-designed prospective studies that control for potential confounders are warranted.
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Affiliation(s)
- Lihai Wang
- Obstetrics and Gynecology, Huzhou Central Hospital, Affiliated Central Hospital, HuZhou University, Huzhou, Zhejiang, China
| | - Lei Zhong
- Intensive Care Unit, Huzhou Central Hospital, Affiliated Central Hospital, HuZhou University, Huzhou, Zhejiang, China
| | - Bin Xu
- Obstetrics and Gynecology, Huzhou Central Hospital, Affiliated Central Hospital, HuZhou University, Huzhou, Zhejiang, China
| | - Min Chen
- Obstetrics and Gynecology, Huzhou Central Hospital, Affiliated Central Hospital, HuZhou University, Huzhou, Zhejiang, China
| | - Hongxiao Huang
- Obstetrics and Gynecology, Huzhou Central Hospital, Affiliated Central Hospital, HuZhou University, Huzhou, Zhejiang, China
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Medenwald D, Langer S, Gottschick C, Vordermark D. Effect of Radiotherapy in Addition to Surgery in Early Stage Endometrial Cancer: A Population-Based Study. Cancers (Basel) 2020; 12:E3814. [PMID: 33348738 PMCID: PMC7766752 DOI: 10.3390/cancers12123814] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/09/2020] [Accepted: 12/16/2020] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The role of radiotherapy in the management of early (FIGO I) endometrial cancer is controversial with limited availability of prospective data from randomized trials. METHODS German Epidemiologic Cancer Registries provided by the Robert Koch Institute. We considered FIGO I cases with recorded operative treatment (n = 12,718, 2000-2017). We computed hazard ratios (HR) from relative survival models in relation to the mortality of the general population with 95% confidence intervals (CI). Multivariate models were adjusted for age, stage (IA vs. IB), grading, and chemotherapy. Radiotherapy included external radiotherapy and brachytherapy. RESULTS Cases with a favorable risk profile (FIGO IA, G1/G2) had a slightly lower survival rate, relative to the general population (FIGO IA: 0.9, G1: 0.91). The proportion of FIGO IA cases was lower in the radiotherapy group (52.6%) vs. cases without radiotherapy (78.6%). Additional treatment with radiotherapy was beneficial in FIGO IB (HR = 0.74) and all histopathological grades, but not FIGO IA cases (HR = 0.93) cases. Compared to IA tumors, IB cases had a HR of 1.51 (95% CI: 1.34-1.7). CONCLUSIONS Radiotherapy in addition to surgery is beneficial for patients in a FIGO IB stage. Further studies need to address the impact of new techniques and risk assessment.
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Affiliation(s)
- Daniel Medenwald
- Department of Radiation Oncology, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany; (S.L.); (C.G.); (D.V.)
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Kolehmainen A, Pasanen A, Tuomi T, Koivisto-Korander R, Bützow R, Loukovaara M. Clinical factors as prognostic variables among molecular subgroups of endometrial cancer. PLoS One 2020; 15:e0242733. [PMID: 33232359 PMCID: PMC7685425 DOI: 10.1371/journal.pone.0242733] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/06/2020] [Indexed: 11/18/2022] Open
Abstract
Background Clinical factors may influence endometrial cancer survival outcomes. We examined the prognostic significance of age, body mass index (BMI), and type 2 diabetes among molecular subgroups of endometrial cancer. Methods This was a single institution retrospective study of patients who underwent surgery for endometrial carcinoma between January 2007 and December 2012. Tumors were classified into four molecular subgroups by immunohistochemistry of mismatch repair (MMR) proteins and p53, and sequencing of polymerase-ϵ (POLE). Overall, cancer-related, and non-cancer-related mortality were estimated using univariable and multivariable survival analyses. Results Age >65 years was associated with increased mortality rates in the whole cohort (n = 515) and in the “no specific molecular profile” (NSMP) (n = 218) and MMR deficient (MMR-D) (n = 191) subgroups during a median follow-up time of 81 months (range 1‒136). However, hazard ratios for cancer-related mortality were non-significant for NSMP and MMR-D. Diabetes was associated with increased overall and non-cancer-related mortality in the whole cohort and MMR-D subgroup. Overweight/obesity had no effect on outcomes in the whole cohort, but was associated with decreased overall and cancer-related mortality in the NSMP subgroup, and increased overall and non-cancer-related mortality in the MMR-D subgroup. Overweight/obesity effect on cancer-related mortality in the NSMP subgroup remained unchanged after controlling for confounders. High-risk uterine factors were more common, and estrogen and progesterone receptor expression less common in NSMP subtype cancers of normal-weight patients compared with overweight/obese patients. No clinical factors were associated with outcomes in p53 aberrant (n = 69) and POLE mutant (n = 37) subgroups. No cancer-related deaths occurred in the POLE mutant subgroup. Conclusions The prognostic effects of age, BMI, and type 2 diabetes do not appear to be uniform for the molecular subgroups of endometrial cancer. Our data support further evaluation of BMI combined with genomics-based risk-assessment.
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Affiliation(s)
- Anne Kolehmainen
- Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Annukka Pasanen
- Department of Pathology, Helsinki University Hospital and Research Program in Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Taru Tuomi
- Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Riitta Koivisto-Korander
- Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Ralf Bützow
- Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Department of Pathology, Helsinki University Hospital and Research Program in Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Mikko Loukovaara
- Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- * E-mail:
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Abstract
Background From a global viewpoint, endometrial cancer belongs to the most common female cancers. Despite the heavy burden of diseases and numerous unanswered questions, no detailed pictures of the global structure of endometrial cancer research are available so far. Therefore, this malignancy was reviewed using the New Quality and Quantity Indices in Science (NewQIS) protocol. Methods Using NewQIS, we identified endometrial carcinoma related research published in the Web of Science from 1900–2015 (P1) and from 2016–2020 (P2). Item analysis was performed with regard to research activity. Also, semi-qualitative aspects and socio-economic benchmarks were visualized using density equalizing mapping. Results In total, 9,141 from 1900–2015 and 4,593 from 2016–2020 endometrial cancer related studies were identified with the USA having the largest numbers of publications, citations, institutions, as well as the highest country-specific h-Index concerning endometrial cancer research in both periods. In contrast to other fields of cancer research, the two East Asian countries Japan and China followed concerning total research activities until 2015. From 2016 until 2020, China was found in short distance to the USA and was ranked second. In the socio-economic analysis, European countries were in prominent positions. Greece published 579.83 endometrial carcinoma-related articles per billion US-$ GDP, Finland (527.29), Sweden (494.65), Israel (493.75), and Norway (367.85) followed in the ranking. Density equalizing mapping visualized that large parts of Africa, Asia and South America with a high burden of disease played almost no visible role in the endometrial cancer research activities. Conclusions Endometrial cancer research activity is continuously increasing from a global viewpoint. However, the majority of original articles is published by authors based in high-income countries. Together with the finding that the research field of public health does only play a minimal role, our study points to the necessity that global health aspects should be introduced to endometrial cancer research.
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Francies FZ, Marima R, Hull R, Molefi T, Dlamini Z. Genomics and splicing events of type II endometrial cancers in the black population: racial disparity, socioeconomic and geographical differences. Am J Cancer Res 2020; 10:3061-3082. [PMID: 33163258 PMCID: PMC7642673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 09/27/2020] [Indexed: 06/11/2023] Open
Abstract
Endometrial cancer, also known as uterine cancer, is the most common gynaecological malignancy with burgeoning incidence and mortality rates globally. Racial disparity, socioeconomic and geographical differences are important determinants of endometrial cancer incidence and mortality. Endometrial cancer is mainly categorised as type I and type II. Although less prevalent, type II is the most aggressive form of the disease and typically diagnosed at a late stage, contributing to higher mortality. Black women are at higher risk of developing aggressive, type II disease. Type I tumours are related to higher levels of circulating estrogen with lower-grade tumours that have a good prognosis and frequently related to PTEN mutations. In comparison, type II tumours are estrogen-independent, typically have poor prognosis and associated with the p53, HER2, PPP2R1A, FBXW7 and PIK3R1 mutations. The risk of developing type II malignancy is higher in women with Lynch syndrome as a result of mutations in the MMR gene family. Genetic modifications contribute to aberrant alternative splicing events that are related to tumour development, progression and resistance to therapy. Alternative splicing events are rapidly emerging as potential biomarkers and therapeutic targets. Type II endometrial cancer lacks targeted therapy and biomarkers for novel therapeutic strategies. Recent advances have illustrated a number of molecular targets that are currently explored for the treatment of advanced, late-stage endometrial cancer. The aim of this review is to outline 1) the epidemiology of type II endometrial cancer in black women, 2) discuss the correlated risk factors that contribute to the development of type II endometrial cancer and 3) the associated molecular mechanisms and genetic factors underlying the disease, and 4) aberrant splicing events and biomarkers with therapeutic potential as novel drug targets.
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Affiliation(s)
- Flavia Zita Francies
- SAMRC/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Extramural Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Faculty of Health SciencesHatfield 0028, South Africa
| | - Rahaba Marima
- SAMRC/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Extramural Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Faculty of Health SciencesHatfield 0028, South Africa
| | - Rodney Hull
- SAMRC/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Extramural Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Faculty of Health SciencesHatfield 0028, South Africa
| | - Thulo Molefi
- Department of Medical Oncology, University of Pretoria, Faculty of Health SciencesHatfield 0028, South Africa
| | - Zodwa Dlamini
- SAMRC/UP Precision Prevention & Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Extramural Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Faculty of Health SciencesHatfield 0028, South Africa
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Yi ZH, Luther Y, Xiong GH, Ni YL, Yun F, Chen J, Yang Z, Zhang Q, Kuang YM, Zhu YC. Association between diabetes mellitus and lung cancer: Meta-analysis. Eur J Clin Invest 2020; 50:e13332. [PMID: 32589285 DOI: 10.1111/eci.13332] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 06/04/2020] [Accepted: 06/16/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND This study aimed to summarize the association between diabetes mellitus (DM) and the incidence of lung cancer using a meta-analysis of cohort studies. MATERIALS AND METHODS We systematically searched PubMed, Embase and the Cochrane Library to identify potential cohort studies. Relative risk (RR) was used to calculate the association between DM and the risk of lung cancer. Subgroup analysis, sensitivity analysis and test for publication bias were performed. Twenty cohort studies were selected. RESULTS The participants with DM showed little or no significant effect on the risk of lung cancer (RR: 1.10; 95% CI: 0.99-1.23; P = .087). DM was not associated with the risk of lung cancer in men (RR: 1.11; 95%CI: 0.92-1.35; P = .270), but a significant association was observed in women (RR: 1.18; 95%CI: 1.10-1.28; P < .001). Subgroup analysis suggested that smoker status was confounding variables that could bias the relationship between DM and the incidence of lung cancer. CONCLUSIONS This meta-analysis suggests that DM has no significant impact on the incidence of lung cancer in men but has a harmful effect on women.
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Affiliation(s)
- Zi-Han Yi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Yannick Luther
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Guo-Hang Xiong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Yue-Li Ni
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Fang Yun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Jing Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Zhe Yang
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Qiao Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
| | - Ying-Min Kuang
- Department of Organ Transplantation, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yue-Chun Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China
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Terlikowska KM, Dobrzycka B, Terlikowski R, Sienkiewicz A, Kinalski M, Terlikowski SJ. Clinical value of selected markers of angiogenesis, inflammation, insulin resistance and obesity in type 1 endometrial cancer. BMC Cancer 2020; 20:921. [PMID: 32977765 PMCID: PMC7519537 DOI: 10.1186/s12885-020-07415-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 09/15/2020] [Indexed: 12/24/2022] Open
Abstract
Background It is a well-known fact show that the risk of developing endometrial cancer (type 1 EC) is strongly associated with obesity. In this study, selected markers, such as obesity, insulin resistance, angiogenesis and inflammation markers related to EC type 1 progression and patients’ survival data were analyzed. Methods To measure levels of adiponectin, C-reactive protein (CRP), vascular endothelial growth factor-A (VEGF-A), angiopoietin-2 (Ang-2), insulin-like growth factor-1 (IGF-1), insulin and C-peptide in 176 preoperative serum samples, the immunoassay technique (EMIT) has been applied. Results Angiopoietin-2 levels increase with age (P = 0.005), FIGO stage (p = 0.042), myometrial invasion (P = 0.009) and LVSI (P < 0.001). The CRP levels increase with age (P = 0.01), as well as the advancement of the FIGO stage (P < 0.001), higher tumor grade (P = 0.012), and myometrial invasion (P < 0.001). A positive correlation between serum Ang-2 and CRP levels was demonstrated (r = 0.44; p < 0.001). Kaplan-Meier survival analysis showed that patients with high CRP levels in serum and Ang-2 presented a worse outcome (P = 0.03 and P = 0.015, respectively). Cox regression analysis of individual predictors revealed that high serum levels of Ang-2, CRP, advanced clinical FIGO stage (P < 0.001, respectively), old age (P = 0.013) were all significant overall survival predictors. By means of multivariate analysis, their predictive significance was confirmed. Conclusion Our study provides evidence that serum levels of Ang-2 and CRP may serve as predictors for assessment of the clinical stage of type 1 EC and are significantly associated with poor prognosis. It is likely that angiogenesis and inflammation associated with obesity have a significant impact on EC type 1 progression and survival rate of patients.
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Affiliation(s)
- Katarzyna M Terlikowska
- Department of Food Biotechnology, Medical University of Bialystok, Szpitalna 37 Street, 15-295, Bialystok, Poland
| | - Bozena Dobrzycka
- Department of Gynecology and Obstetrics, Medical University of Bialystok, M. Sklodowskiej-Curie 24A Street, 15-089, Bialystok, Poland
| | - Robert Terlikowski
- Department of Rehabilitation, Medical University of Bialystok, M. Sklodowskiej-Curie 24A Street, 15-089, Bialystok, Poland
| | - Anna Sienkiewicz
- Department of Gynecology and Obstetrics, Medical University of Bialystok, M. Sklodowskiej-Curie 24A Street, 15-089, Bialystok, Poland
| | - Maciej Kinalski
- Department of Gynecology and Obstetrics of the Independent Public Healthcare Facility Regional Complex Jan Sniadecki Hospital, M. Sklodowskiej-Curie 26 Street, 15-950, Bialystok, Poland
| | - Slawomir J Terlikowski
- Department of Obstetrics, Gynaecology and Maternity Care, Medical University of Bialystok, Szpitalna 37 Street, 15-295, Bialystok, Poland.
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Endometrial Cancer as a Metabolic Disease with Dysregulated PI3K Signaling: Shedding Light on Novel Therapeutic Strategies. Int J Mol Sci 2020; 21:ijms21176073. [PMID: 32842547 PMCID: PMC7504460 DOI: 10.3390/ijms21176073] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/21/2020] [Accepted: 08/21/2020] [Indexed: 12/15/2022] Open
Abstract
Endometrial cancer (EC) is one of the most common malignancies of the female reproductive organs. The most characteristic feature of EC is the frequent association with metabolic disorders. However, the components of these disorders that are involved in carcinogenesis remain unclear. Accumulating epidemiological studies have clearly revealed that hyperinsulinemia, which accompanies these disorders, plays central roles in the development of EC via the insulin-phosphoinositide 3 kinase (PI3K) signaling pathway as a metabolic driver. Recent comprehensive genomic analyses showed that over 90% of ECs have genomic alterations in this pathway, resulting in enhanced insulin signaling and production of optimal tumor microenvironments (TMEs). Targeting PI3K signaling is therefore an attractive treatment strategy. Several clinical trials for recurrent or advanced ECs have been attempted using PI3K-serine/threonine kinase (AKT) inhibitors. However, these agents exhibited far lower efficacy than expected, possibly due to activation of alternative pathways that compensate for the PIK3-AKT pathway and allow tumor growth, or due to adaptive mechanisms including the insulin feedback pathway that limits the efficacy of agents. Overcoming these responses with careful management of insulin levels is key to successful treatment. Further interest in specific TMEs via the insulin PI3K-pathway in obese women will provide insight into not only novel therapeutic strategies but also preventive strategies against EC.
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Abstract
Debate is ongoing regarding the relationship between type 2 diabetes and cancer, and the pathways linking the two are incompletely understood. Some posit that the relationship hinges on a common predisposing factor such as obesity, insulin resistance, or chronic inflammation that increases the risk of cancer independently. Others speculate that diabetes acts as an independent risk factor for cancer because of other molecular pathways and interactions. Additionally, antidiabetic medications have been associated with changes in cancer risk. This review presents a summary of the latest studies and data concerning the relationships among type 2 diabetes, antidiabetic medications, cancer risk, and cancer prognosis.
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Wang M, Yang Y, Liao Z. Diabetes and cancer: Epidemiological and biological links. World J Diabetes 2020; 11:227-238. [PMID: 32547697 PMCID: PMC7284016 DOI: 10.4239/wjd.v11.i6.227] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 04/24/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
The incidence of diabetes and cancer has increased significantly in recent years. Furthermore, there are many common risk factors for both diabetes and cancer, such as obesity, sedentary lifestyle, smoking, and ageing. A large body of epidemiological evidence has indicated that diabetes is considered as an independent risk factor for increased rates of heterogeneous types of cancer occurrence and death. The incidence and mortality of various types of cancer, such as pancreas, liver, colorectal, breast, endometrial, and bladder cancers, have a modest growth in diabetics. However, diabetes may work as a protective factor for prostate cancer. Although the underlying biological mechanisms have not been totally understood, studies have validated that insulin/insulin-like growth factor (IGF) axis (including insulin resistance, hyperinsulinemia, and IGF), hyperglycemia, inflammatory cytokines, and sex hormones provide good circumstances for cancer cell proliferation and metastasis. Insulin/IGF axis activates several metabolic and mitogenic signaling pathways; hyperglycemia provides energy for cancer cell growth; inflammatory cytokines influence cancer cell apoptosis. Thus, these three factors affect all types of cancer, while sex hormones only play important roles in breast cancer, endometrial cancer, and prostate cancer. This minireview consolidates and discusses the epidemiological and biological links between diabetes and various types of cancer.
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Affiliation(s)
- Mina Wang
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
- The Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing 100010, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yingying Yang
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna 17177, Sweden
- Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Zehuan Liao
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Solna 17177, Sweden
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