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1
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Zhang J, He J, Lu Y, Lan T. Global disease burden of breast cancer attributable to high fasting plasma glucose: a comprehensive analysis from the global burden of disease study. Front Endocrinol (Lausanne) 2025; 16:1498207. [PMID: 40017691 PMCID: PMC11864957 DOI: 10.3389/fendo.2025.1498207] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 01/24/2025] [Indexed: 03/01/2025] Open
Abstract
Background High fasting plasma glucose (HFPG) has been identified as one of the risk factors associated with the development of breast cancer. The worldwide distribution of breast cancer attributable to HFPG was not comprehensively investigated. Methods We utilized the data from the Global Burden of Disease Study 2021 to explore HFPG-related breast cancer deaths, disability adjusted life years (DALYs) and corresponding age-standardized rates (ASRs). The average annual percentage change (AAPC) and the estimated annual percentage change (EAPC) were employed to evaluate the temporal trend. Results The global effect of HFPG resulted in nearly 30,570 breast cancer deaths and 819,550 DALYs in 2021, representing an age-standardized deaths rate (ASMR) of 0.66 (95% UI -0.19-1.57) and an age-standardized DALYs rate (ASDR) of 18.05 (95% UI -5.31-42.71). In the regions with low, low-middle, and middle SDI, the ASRs of HFPG-related breast cancer increased significantly over time. The highest ASMR and ASDR were observed in several countries, such as Palau, American Samoa, Cook Islands, Marshall Islands, and United Arab Emirates. There was a positive correlation between ASRs and Socio-Demographic Index (SDI) in countries where SDI was below 0.75. The escalation in death and DALYs was primarily driven by epidemiological change and population growth in low, low-middle, middle SDI regions. Conclusions Substantial disparities exist across diverse regions in breast cancer burden attributed to HFPG. It is urgent to regulate glycemic levels, improve healthcare infrastructures, and provide cost-effective care in less developed and developing countries that endure a disproportionately heavier health burden.
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Affiliation(s)
- Jing Zhang
- Department of Cardiology, The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China
| | - Jiawei He
- Department of Breast Surgery, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Yunyan Lu
- Department of Cardiology, The First People’s Hospital of Xiaoshan District, Xiaoshan Affiliated Hospital of Wenzhou Medical University, Hangzhou, Zhejiang, China
| | - Tian Lan
- Department of Breast Surgery, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
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2
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Mortoglou M, Miralles F, Mould RR, Sengupta D, Uysal-Onganer P. Inhibiting CDK4/6 in pancreatic ductal adenocarcinoma via microRNA-21. Eur J Cell Biol 2023; 102:151318. [PMID: 37105116 DOI: 10.1016/j.ejcb.2023.151318] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/17/2023] [Accepted: 04/22/2023] [Indexed: 04/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a 5-year survival rate of 5-10 %. The high mortality rate is due to the asymptomatic progression of clinical features in metastatic stages of the disease, which renders standard therapeutic options futile. PDAC is characterised by alterations in several genes that drive carcinogenesis and limit therapeutic response. The two most common genetic aberrations in PDAC are the mutational activation of KRAS and loss of the tumour suppressor CDK inhibitor 2A (CDKN2A), which culminate the activation of the cyclin-dependent kinase 4 and 6 (CDK4/6), that promote G1 cell cycle progression. Therapeutic strategies focusing on the CDK4/6 inhibitors such as palbociclib (PD-0332991) may potentially improve outcomes in this malignancy. MicroRNAs (miRs/miRNAs) are small endogenous non-coding RNA molecules associated with cellular proliferation, invasion, apoptosis, and cell cycle. Primarily, miR-21 promotes cell proliferation and a higher proportion of PDAC cells in the S phase, while knockdown of miR-21 has been linked to cell cycle arrest at the G2/M phase and inhibition of cell proliferation. In this study, using a CRISPR/Cas9 loss-of-function screen, we individually silenced the expression of miR-21 in two PDAC cell lines and in combination with PD-0332991 treatment, we examined the synergetic mechanisms of CDK4/6 inhibitors and miR-21 knockouts (KOs) on cell survival and death. This combination reduced cell proliferation, cell viability, increased apoptosis and G1 arrest in vitro. We further analysed the mitochondrial respiration and glycolysis of PDAC cells; then assessed the protein content of these cells and revealed numerous Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with PD-0332991 treatment and miR-21 knocking out. Our results demonstrate that combined targeting of CDK4/6 and silencing of miR-21 represents a novel therapeutic strategy in PDAC.
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Affiliation(s)
- Maria Mortoglou
- Cancer Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, W1W 6UW London, UK
| | - Francesc Miralles
- Centre of Biomedical Education/Molecular and Clinical Sciences, Cell Biology Research Centre, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK
| | - Rhys Richard Mould
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, W1W 6UW London, UK
| | - Dipankar Sengupta
- Health Data Sciences Research Group, Research Centre for Optimal Health, School of Life Sciences, University of Westminster, W1W 6UW London, UK
| | - Pinar Uysal-Onganer
- Cancer Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, W1W 6UW London, UK.
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3
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Hsieh MC, Zhang L, Velasco-Gonzalez C, Yi Y, Pareti LA, Trapido EJ, Chen VW, Wu XC. Impact of diabetes and modifiable risk factors on pancreatic cancer survival in a population-based study after adjusting for clinical factors. Cancer Causes Control 2021; 33:37-48. [PMID: 34633573 DOI: 10.1007/s10552-021-01497-z] [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: 04/12/2021] [Accepted: 09/22/2021] [Indexed: 01/18/2023]
Abstract
PURPOSES Our study aimed to examine the impact of diabetes, smoking and BMI on pancreatic cancer survival in a population-based setting by adjusting both sociodemographic and clinical factors and measuring their attributable risk. METHODS Data on pancreatic adenocarcinoma patients diagnosed in 2011-2017 were acquired from the Louisiana Tumor Registry. Diabetes, smoking, height, and weight were abstracted from medical records and linked with Hospital Inpatient Discharge Data to enhance the completeness of the diabetes data. The Cox regression model was used to assess effect sizes of diabetes, smoking, and BMI on cancer-specific survival and survival rate. The partial population attributable risk was employed to measure the attributable risk of these risk factors. RESULTS Of the 3,200 eligible patients, 34.6% were diabetics, 23.9% were current smokers, and 52.3% had BMI ≥ 25 kg/m2. After adjusting for sociodemographic and clinical factors, diabetic patients had an increased cancer-specific death risk of 15% (95% CI, 1.06-1.25), 36% (95% CI, 1.19-1.44) for current smokers, and 24% (95% CI, 1.00-1.54) for patients with a BMI ≥ 40 when compared to their counterparts. Diabetic current smokers had significantly lower 2- and 3-year adjusted cancer-specific survival rates, 13.1% and 10.5%, respectively. By eliminating diabetes and modifiable risk factors, an estimated 16.6% (95% CI, 6.9%-25.9%) of the cancer-specific deaths could be avoided during a nine-year observational period between 2011 and 2019. CONCLUSIONS Diabetes and smoking contributed substantially to the reduction of pancreatic cancer survival even after controlling for sociodemographic and clinical factors; however, BMI ≥ 35 was observed to increase risk of mortality among stage III-IV patients only.
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Affiliation(s)
- Mei-Chin Hsieh
- Louisiana Tumor Registry, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3rd floor, New Orleans, LA, 70112, USA. .,Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
| | - Lu Zhang
- Department of Public Health Sciences, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC, 29634, USA
| | - Cruz Velasco-Gonzalez
- Center for Outcomes and Health Services Research, Ochsner Health System, Jefferson, LA, 70121, USA
| | - Yong Yi
- Louisiana Tumor Registry, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3rd floor, New Orleans, LA, 70112, USA
| | - Lisa A Pareti
- Louisiana Tumor Registry, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3rd floor, New Orleans, LA, 70112, USA
| | - Edward J Trapido
- Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Vivien W Chen
- Louisiana Tumor Registry, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3rd floor, New Orleans, LA, 70112, USA.,Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Xiao-Cheng Wu
- Louisiana Tumor Registry, School of Public Health, Louisiana State University Health Sciences Center, 2020 Gravier St., 3rd floor, New Orleans, LA, 70112, USA.,Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
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4
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Deo KB, Kulkarni AA, Kumar-M P, Krishnamurthy G, Shenvi S, Rana SS, Kapoor R, Gupta R. Impact of diabetes mellitus on morbidity and survival after pancreaticoduodenectomy for malignancy. Ann Hepatobiliary Pancreat Surg 2021; 25:230-241. [PMID: 34053926 PMCID: PMC8180397 DOI: 10.14701/ahbps.2021.25.2.230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/17/2021] [Accepted: 02/01/2021] [Indexed: 11/22/2022] Open
Abstract
Backgrounds/Aims Diabetes mellitus (DM) is a known risk factor for morbidity, length of hospital stay, or mortality after surgery, however, its impact on postoperative course and long-term survival after pancreaticoduodenectomy (PD) is not clear. Methods This is a retrospective analysis of prospectively maintained database of 141 patients with periampullary and pancreatic head adenocarcinoma operated between January 2001 and March 2019. Clinico-pathological records and follow-up data were retrieved and analyzed. Cumulative hazard was computed for comparing the survival between DM and non-DM. Results DM was present in 31/141 (21.9%) patients, while 16/31 (51.6%). were new-onset DM (NODM). Tumor size, lymphovascular & perineural invasion, type of surgery, lymph node positivity and R0 resection rate were comparable between diabetic and non-diabetic. There was no significant difference in postoperative pancreatic fistula, delayed gastric emptying, infectious complication, hospital stay and mortality between DM and nondiabetics. Patients with DM had worse survival at 3 years (OS: HR, 3.11 [1.43-6.76] p=0.004, DFS: HR, 2.61 [1.23-5.53] p=0.01) and 5 years (OS: HR, 3.32 [1.46-7.53] p=0.004, DFS: HR, 2.87 [1.29-6.41] p=0.009). On multivariate analysis, DM (3 year OS: HR, 2.61 [1.14-5.98] p=0.022, DFS: HR, 2.19; p=0.058) (5 year OS: HR, 2.55; p=0.04, DFS: HR, 2.25; p=0.068) and pylorus resecting surgery were significantly associated with worse survival at 3 and 5 years. Conclusions Preoperative DM has no significant effect on postoperative course but has negative impact on 3-year and 5-year OS and DFS after PD for pancreatic and periampullary adenocarcinoma.
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Affiliation(s)
- Kunal Bikram Deo
- Department of Surgical Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.,Department of Surgery, B.P. Koirala Institute of Health Sciences, Dharan, Nepal
| | - Aditya Atul Kulkarni
- Department of Surgical Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.,Department of Surgical Gastroenterology, D Y Patil Medical College, Pune, India
| | - Praveen Kumar-M
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Gautham Krishnamurthy
- Department of Surgical Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.,Department of Surgical Gastroenterology, SRM Institutes for Medical Science, Chennai, India
| | - Sunil Shenvi
- Department of Surgical Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.,Department of Liver Transplantation and Hepatobiliary Surgery, Gleneagles Global Hospital, Bangalore, India
| | - Surinder Singh Rana
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Rakesh Kapoor
- Department of Radiotherapy and Oncology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Rajesh Gupta
- Department of Surgical Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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AMPK Is the Crucial Target for the CDK4/6 Inhibitors Mediated Therapeutic Responses in PANC-1 and MIA PaCa-2 Pancreatic Cancer Cell Lines. STRESSES 2021. [DOI: 10.3390/stresses1010005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The survival rate of pancreatic ductal adenocarcinoma (PDAC) patients is short, and PDAC is a cancer type that ranks fourth in the statistics regarding death due to cancer. Mutation in the KRAS gene, which plays a role in pancreatic cancer development, activates the PI3K/AKT/mTOR signaling pathway. The activity of the AMPK as a cellular energy sensor is one of the fundamental mechanisms that can induce effective therapeutic responses against CDK4/6 inhibitors via adjusting the cellular and tumor microenvironment stress management. The phosphorylation of AMPKα at the different phosphorylation residues such as Thr172 and Ser 377 causes metabolic differentiation in the cells following CDK4/6 inhibitor treatment in accordance with an increased cell cycle arrest and senescence under the control of different cellular players. In this study, we examined the competencies of the CDK4/6 inhibitors LY2835219 and PD-0332991 on the mechanism of cell survival and death based on AMPK signaling. Both CDK4/6 inhibitors LY2835219 and PD-0332991 modulated different molecular players on the PI3K/AKT/mTOR and AMPK signaling axis in different ways to reduce cell survival in a cell type dependent manner. These drugs are potential inducers of apoptosis and senescence that can alter the therapeutic efficacy cells.
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Tao J, Yang G, Zhou W, Qiu J, Chen G, Luo W, Zhao F, You L, Zheng L, Zhang T, Zhao Y. Targeting hypoxic tumor microenvironment in pancreatic cancer. J Hematol Oncol 2021; 14:14. [PMID: 33436044 PMCID: PMC7805044 DOI: 10.1186/s13045-020-01030-w] [Citation(s) in RCA: 243] [Impact Index Per Article: 60.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/25/2020] [Indexed: 12/13/2022] Open
Abstract
Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.
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Affiliation(s)
- Jinxin Tao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Wenchuan Zhou
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, China
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Guangyu Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Wenhao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Fangyu Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China. .,Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China.
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7
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Liao W, Chen P, Huang C, Chang Y, Huang B, Chang C, Wu M, Chow L. Relationship between pancreatic cancer-associated diabetes and cachexia. J Cachexia Sarcopenia Muscle 2020; 11:899-908. [PMID: 32100478 PMCID: PMC7432579 DOI: 10.1002/jcsm.12553] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 01/22/2020] [Accepted: 02/03/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Pancreatic cancer-associated diabetes mellitus (PCDM) is a paraneoplastic phenomenon characterized by worsening hyperglycaemia and weight loss. Galectin-3 and S100A9, mediators of PCDM, have pro-inflammatory functions and might thereby induce systemic inflammation and cachexia. We aimed to examine whether PCDM directly mediates cachexia. METHODS Consecutive pancreatic cancer (PC) patients with and without PCDM (n = 88 each) with complete information were included. Cachexia was defined as weight loss >5% within 6 months or weight loss >2% and body mass index <20 kg/m2 or sarcopenia. Skeletal muscle mass was measured with lumbar skeletal muscle index (SMI) using computed tomography images. Cachexia-related parameters (prevalence of cachexia, weight loss, and SMI) were compared between patients with and without PCDM. Relations between cachexia-related parameters and fasting blood glucose or serum levels of galectin-3 and S100A9 were analysed by Spearman correlation and logistic regression analyses. RESULTS One hundred two (58.0%) patients had cachexia at diagnosis. No significant differences existed between patients with and without PCDM in prevalence of cachexia (64.8% vs. 51.1%, P = 0.093), percentage of weight loss (median 6.8 vs. 4.0, P = 0.085), and SMI (median 45.8 vs. 45.3 cm2 /m2 in men, P = 0.119; 34.9 vs. 36.3 cm2 /m2 in women, P = 0.418). In patients with cachexia, the percentage of weight loss and SMI were also similar between patients with and without PCDM. In patients with PCDM, fasting blood glucose was comparable between patients with and without cachexia (P = 0.458) and did not correlate with the percentage of weight loss (P = 0.085) or SMI (P = 0.797 in men and 0.679 in women). Serum S100A9 level correlated with fasting blood glucose (correlation coefficient 0.213, P = 0.047) but not with the percentage of weight loss (P = 0.977) or SMI (P = 0.247 in men and 0.458 in women). Serum galectin-3 level also did not correlate with the percentage of weight loss (P = 0.226) and SMI (P = 0.201 in men and 0.826 in women). Primary tumour size was associated with cachexia (adjusted odds ratio per 1 cm increase 1.28, 95% confidence interval 1.02-1.60, P = 0.034), whereas PCDM, fasting blood glucose, and levels of galectin-3 and S100A9 were not predictors of cachexia. CONCLUSIONS Neither fasting blood glucose nor levels of galectin-3 and S100A9 were associated with cachexia-related parameters. Mediators of PCDM and hyperglycaemia do not directly mediate PC-induced cachexia.
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Affiliation(s)
- Wei‐Chih Liao
- Division of Gastroenterology and Hepatology, Department of Internal MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
- Internal Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Peng‐Ruei Chen
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Cheng‐Chieh Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Yen‐Tzu Chang
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Bo‐Shih Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Chin‐Chen Chang
- Department of Medical ImagingNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
- Department and Graduate Institute of Forensic MedicineNational Taiwan University College of MedicineTaipeiTaiwan
| | - Ming‐Shiang Wu
- Division of Gastroenterology and Hepatology, Department of Internal MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
- Internal Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Lu‐Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
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8
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Ma Y, Li Y, Ling S, Li X, Kong B, Hu M, Huang P. Loss of heterozygosity for Kras G12D promotes REDD1-dependent, non-canonical glutamine metabolism in pancreatic ductal adenocarcinoma. Biochem Biophys Res Commun 2020; 526:880-888. [PMID: 32279996 DOI: 10.1016/j.bbrc.2020.03.137] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 03/24/2020] [Indexed: 12/22/2022]
Abstract
Pancreatic cancer is associated with high mortality, and pancreatic ductal adenocarcinoma (PDAC) is its most common subtype. The rapid growth of PDAC is dependent on the non-canonical pathway of glutamine (Gln) utilization, and loss of heterozygosity for KrasG12D (KrasG12D-LOH) frequently observed in PDAC is associated with an aggressive and invasive phenotype. However, it remains unclear whether KrasG12D-LOH contributes to non-canonical Gln metabolism in PDAC. Here, we showed that KrasG12D-LOH leads to a substantial increase in non-canonical Gln metabolism in PDAC cells. Importantly, we observed elevated expression of regulated in DNA damage and development 1 (REDD1), which is activated in response to hypoxia and nutrient deprivation, in KrasG12D-LOH PDAC, and that REDD1 knockdown efficiently repressed KrasG12D-LOH-regulated Gln metabolism and suppressed proliferation, migration, and invasion of KrasG12D-LOH PDAC cells. These data provide evidence that REDD1 is a downstream target of KrasG12D-LOH and is involved in promoting non-canonical Gln metabolism in PDAC.
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Affiliation(s)
- Yu Ma
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Yuan Li
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Sunkai Ling
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Xiaoxue Li
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Bo Kong
- Department of Surgery, Klinikumrechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, 81675, Germany
| | - Mingyue Hu
- School of Medicine, Southeast University, Nanjing, 210009, China; Department of Gastroenterology, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing, 210009, China.
| | - Peilin Huang
- School of Medicine, Southeast University, Nanjing, 210009, China.
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9
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Qin Y, Hu Q, Ji S, Xu J, Dai W, Liu W, Xu W, Sun Q, Zhang Z, Ni Q, Yu X, Zhang B, Xu X. Homeodomain-interacting protein kinase 2 suppresses proliferation and aerobic glycolysis via ERK/cMyc axis in pancreatic cancer. Cell Prolif 2019; 52:e12603. [PMID: 30932257 PMCID: PMC6536454 DOI: 10.1111/cpr.12603] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 02/16/2019] [Accepted: 02/22/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES To investigate the roles of the homeodomain-interacting protein kinase (HIPK) family of proteins in pancreatic cancer prognosis and the possible molecular mechanism. MATERIALS AND METHODS The expression of HIPK family genes and their roles in pancreatic cancer prognosis were analysed by using The Cancer Genome Atlas (TCGA). The roles of HIPK2 in pancreatic cancer proliferation and glycolysis were tested by overexpression of HIPK2 in pancreatic cancer cells, followed by cell proliferation assay, glucose uptake analysis and Seahorse extracellular flux analysis. The mechanism of action of HIPK2 in pancreatic cancer proliferation and glycolysis was explored by examining its effect on the ERK/cMyc axis. RESULTS Decreased HIPK2 expression indicated worse prognosis of pancreatic cancer. Overexpression of HIPK2 in pancreatic cancer cells decreased cell proliferation and attenuated aerobic glycolysis, which sustained proliferation of cancer cells. HIPK2 decreased cMyc protein levels and expression of cMyc-targeted glycolytic genes. cMyc was a mediator that regulated HIPK2-induced decrease in aerobic glycolysis. HIPK2 regulated cMyc protein stability via ERK activation, which phosphorylated and controlled cMyc protein stability. CONCLUSIONS HIPK2 suppressed proliferation of pancreatic cancer in part through inhibiting the ERK/cMyc axis and related aerobic glycolysis.
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Affiliation(s)
- Yi Qin
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Qiangsheng Hu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Shunrong Ji
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Jin Xu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Weixing Dai
- Cancer Research InstituteFudan University Shanghai Cancer CenterShanghaiChina
| | - Wensheng Liu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Wenyan Xu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Qiqing Sun
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Zheng Zhang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Quanxing Ni
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Xianjun Yu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Bo Zhang
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
| | - Xiaowu Xu
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Shanghai Pancreatic Cancer InstituteShanghaiChina
- Pancreatic Cancer InstituteFudan UniversityShanghaiChina
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Fasting but not casual blood glucose is associated with pancreatic cancer mortality in Japanese: EPOCH-JAPAN. Cancer Causes Control 2017; 28:625-633. [DOI: 10.1007/s10552-017-0884-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 03/11/2017] [Indexed: 12/20/2022]
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11
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Shi HJ, Jin C, Fu DL. Impact of postoperative glycemic control and nutritional status on clinical outcomes after total pancreatectomy. World J Gastroenterol 2017; 23:265-274. [PMID: 28127200 PMCID: PMC5236506 DOI: 10.3748/wjg.v23.i2.265] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 11/26/2016] [Accepted: 12/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the impact of glycemic control and nutritional status after total pancreatectomy (TP) on complications, tumor recurrence and overall survival. METHODS Retrospective records of 52 patients with pancreatic tumors who underwent TP were collected from 2007 to 2015. A series of clinical parameters collected before and after surgery, and during the follow-up were evaluated. The associations of glycemic control and nutritional status with complications, tumor recurrence and long-term survival were determined. Risk factors for postoperative glycemic control and nutritional status were identified. RESULTS High early postoperative fasting blood glucose (FBG) levels (OR = 4.074, 95%CI: 1.188-13.965, P = 0.025) and low early postoperative prealbumin levels (OR = 3.816, 95%CI: 1.110-13.122, P = 0.034) were significantly associated with complications after TP. Postoperative HbA1c levels over 7% (HR = 2.655, 95%CI: 1.299-5.425, P = 0.007) were identified as one of the independent risk factors for tumor recurrence. Patients with postoperative HbA1c levels over 7% had much poorer overall survival than those with HbA1c levels less than 7% (9.3 mo vs 27.6 mo, HR = 3.212, 95%CI: 1.147-8.999, P = 0.026). Patients with long-term diabetes mellitus (HR = 15.019, 95%CI: 1.278-176.211, P = 0.031) and alcohol history (B = 1.985, SE = 0.860, P = 0.025) tended to have poor glycemic control and lower body mass index levels after TP, respectively. CONCLUSION At least 3 mo are required after TP to adapt to diabetes and recover nutritional status. Glycemic control appears to have more influence over nutritional status on long-term outcomes after TP. Improvement in glycemic control and nutritional status after TP is important to prevent early complications and tumor recurrence, and improve survival.
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12
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Permuth JB, Choi JW, Chen DT, Jiang K, DeNicola G, Li JN, Coppola D, Centeno BA, Magliocco A, Balagurunathan Y, Merchant N, Trevino JG, Jeong D. A pilot study of radiologic measures of abdominal adiposity: weighty contributors to early pancreatic carcinogenesis worth evaluating? Cancer Biol Med 2017; 14:66-73. [PMID: 28443205 PMCID: PMC5365183 DOI: 10.20892/j.issn.2095-3941.2017.0006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Objective: Intra-abdominal fat is a risk factor for pancreatic cancer (PC), but little is known about its contribution to PC precursors known as intraductal papillary mucinous neoplasms (IPMNs). Our goal was to evaluate quantitative radiologic measures of abdominal/visceral obesity as possible diagnostic markers of IPMN severity/pathology. Methods: In a cohort of 34 surgically-resected, pathologically-confirmed IPMNs (17 benign; 17 malignant) with preoperative abdominal computed tomography (CT) images, we calculated body mass index (BMI) and four radiologic measures of obesity: total abdominal fat (TAF) area, visceral fat area (VFA), subcutaneous fat area (SFA), and visceral to subcutaneous fat ratio (V/S). Measures were compared between groups using Wilcoxon two-sample exact tests and other metrics. Results: Mean BMI for individuals with malignant IPMNs (28.9 kg/m2) was higher than mean BMI for those with benign IPMNs (25.8 kg/m2) (P=0.045). Mean VFA was higher for patients with malignant IPMNs (199.3 cm2) compared to benign IPMNs (120.4 cm2),P=0.092. V/S was significantly higher (P=0.013) for patients with malignant versus benign IPMNs (1.25vs. 0.69 cm2), especially among females. The accuracy, sensitivity, specificity, and positive and negative predictive value of V/S in predicting malignant IPMN pathology were 74%, 71%, 76%, 75%, and 72%, respectively.
Conclusions: Preliminary findings suggest measures of visceral fat from routine medical images may help predict IPMN pathology, acting as potential noninvasive diagnostic adjuncts for management and targets for intervention that may be more biologically-relevant than BMI. Further investigation of gender-specific associations in larger, prospective IPMN cohorts is warranted to validate and expand upon these observations.
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Affiliation(s)
| | - Jung W Choi
- Diagnostic Imaging and Interventional Radiology
| | | | | | - Gina DeNicola
- Cancer Imaging and Metabolism, Moffitt Cancer Center and Research Institute, Tampa 33612, FL, USA
| | | | | | | | | | - Yoganand Balagurunathan
- Cancer Imaging and Metabolism, Moffitt Cancer Center and Research Institute, Tampa 33612, FL, USA
| | - Nipun Merchant
- Department of Surgery, Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami 33136, FL, USA
| | - Jose G Trevino
- Department of Surgery, Division of General Surgery, University of Florida Health Sciences Center, Gainesville 32611, FL, USA
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13
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Crawley AS, O'Kennedy RJ. The need for effective pancreatic cancer detection and management: a biomarker-based strategy. Expert Rev Mol Diagn 2016; 15:1339-53. [PMID: 26394703 DOI: 10.1586/14737159.2015.1083862] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Pancreatic cancer (Pa) is generally a very aggressive disease, with few effective approaches available for early diagnosis or therapy. These factors, combined with the aggressiveness and chemoresistance of Pa, results in a bleak outcome post-diagnosis. Cancer-related biomarkers have established capabilities for diagnosis, prognosis and screening and can be exploited to aid in earlier less-invasive diagnosis and optimization of targeted therapies. Pa has only one US FDA-approved biomarker, CA19-9, which has significant limitations. Hence, it is vital that novel biomarkers are identified and validated to diagnose, treat, control and monitor Pa. This review focuses on existing and potential Pa-associated markers and discusses how they may be applied in cohort for improved management of Pa.
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Affiliation(s)
- Aoife S Crawley
- a 1 School of Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Richard J O'Kennedy
- a 1 School of Biotechnology, Dublin City University, Dublin 9, Ireland.,b 2 Biomedical Diagnostics Institute, National Centre for Sensor Research, Dublin City University, Dublin 9, Ireland
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Mao KS, Li MS, Zhou J. Update on the roles of liver kinase B1 in pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:3086-3093. [DOI: 10.11569/wcjd.v23.i19.3086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Germline mutations of the liver kinase B1 (STK11/LKB1) gene which encodes a serine/threonine kinase is responsible for Peutz-Jeghers syndrome. There are 14 AMP-activated protein kinase (AMPK)-related kinases in pathways downstream of LKB1, which are involved in many physiological and pathological processes such as regulation of energy metabolism, cell polarity and apoptosis in cells. LKB1 gene mutation has been investigated extensively in a variety of cancers, including pancreatic cancer. Pancreatic cancer is commonly recognized as a disease with extremely poor prognosis. Therefore, a full understanding of its molecular pathology is critical. This review aims to elucidate the structure, distribution, and function of LKB1, and the relationship with pancreatic cancer. In addition, we also point out that in some scenarios, LKB1 may play a role as a tumor protector.
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15
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Liao WC, Tu YK, Wu MS, Lin JT, Wang HP, Chien KL. Blood glucose concentration and risk of pancreatic cancer: systematic review and dose-response meta-analysis. BMJ 2015; 350:g7371. [PMID: 25556126 PMCID: PMC4282179 DOI: 10.1136/bmj.g7371] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/30/2014] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To evaluate potential linear and non-linear dose-response relations between blood glucose and risk of pancreatic cancer. DESIGN Systematic review and dose-response meta-analysis of prospective observational studies. DATA SOURCES Search of PubMed, Scopus, and related reviews before 30 November 2013 without language restriction. ELIGIBILITY CRITERIA Prospective studies evaluating the association between blood glucose concentration and pancreatic cancer. Retrospective and cross sectional studies excluded to avoid reverse causality. DATA EXTRACTION AND SYNTHESIS Two reviewers independently extracted relevant information and assessed study quality with the Newcastle-Ottawa scale. Random effects dose-response meta-analysis was conducted to assess potential linear and non-linear dose-response relations. RESULTS Nine studies were included for analysis, with a total of 2408 patients with pancreatic cancer. There was a strong linear dose-response association between fasting blood glucose concentration and the rate of pancreatic cancer across the range of prediabetes and diabetes. No non-linear association was detected. The pooled rate ratio of pancreatic cancer per 0.56 mmol/L (10 mg/dL) increase in fasting blood glucose was 1.14 (95% confidence interval 1.06 to 1.22; P<0.001) without significant heterogeneity. Sensitivity analysis excluding blood glucose categories in the range of diabetes showed similar results (pooled rate ratio per 0.56 mmol/L increase in fasting blood glucose was 1.15, 95% confidence interval 1.05 to 1.27; P=0.003), strengthening the association between prediabetes and pancreatic cancer. CONCLUSIONS Every 0.56 mmol/L increase in fasting blood glucose is associated with a 14% increase in the rate of pancreatic cancer. As prediabetes can be improved or even reversed through lifestyle changes, early detection of prediabetes coupled with lifestyle changes could represent a viable strategy to curb the increasing incidence of pancreatic cancer.
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Affiliation(s)
- Wei-Chih Liao
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 7 Chang Shan South Road, Taipei 100, Taiwan Institute of Epidemiology and Preventive Medicine, National Taiwan University, 17 Hsu Chow Road, Taipei 100, Taiwan
| | - Yu-Kang Tu
- Institute of Epidemiology and Preventive Medicine, National Taiwan University, 17 Hsu Chow Road, Taipei 100, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 7 Chang Shan South Road, Taipei 100, Taiwan
| | - Jaw-Town Lin
- School of Medicine, Fu Jen Catholic University, 510 Zhongzheng Road, New Taipei City 242, Taiwan
| | - Hsiu-Po Wang
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 7 Chang Shan South Road, Taipei 100, Taiwan
| | - Kuo-Liong Chien
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, 7 Chang Shan South Road, Taipei 100, Taiwan Institute of Epidemiology and Preventive Medicine, National Taiwan University, 17 Hsu Chow Road, Taipei 100, Taiwan
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16
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Cheng G, Zielonka J, McAllister D, Tsai S, Dwinell MB, Kalyanaraman B. Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation. Br J Cancer 2014; 111:85-93. [PMID: 24867695 PMCID: PMC4090735 DOI: 10.1038/bjc.2014.272] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/21/2014] [Accepted: 04/24/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Targeting both mitochondrial bioenergetics and glycolysis pathway is an effective way to inhibit proliferation of tumour cells, including those that are resistant to conventional chemotherapeutics. METHODS In this study, using the Seahorse 96-well Extracellular Flux Analyzer, we mapped the two intrinsic cellular bioenergetic parameters, oxygen consumption rate and proton production rate in six different pancreatic cancer cell lines and determined their differential sensitivity to mitochondrial and glycolytic inhibitors. RESULTS There exists a very close relationship among intracellular bioenergetic parameters, depletion of ATP and anti-proliferative effects (inhibition of colony-forming ability) in pancreatic cancer cells derived from different genetic backgrounds treated with the glycolytic inhibitor, 2-deoxyglucose (2-DG). The most glycolytic pancreatic cancer cell line was exquisitely sensitive to 2-DG, whereas the least glycolytic pancreatic cancer cell was resistant to 2-DG. However, when combined with metformin, inhibitor of mitochondrial respiration and activator of AMP-activated protein kinase, 2-DG synergistically enhanced ATP depletion and inhibited cell proliferation even in poorly glycolytic, 2-DG-resistant pancreatic cancer cell line. Furthermore, treatment with conventional chemotherapeutic drugs (e.g., gemcitabine and doxorubicin) or COX-2 inhibitor, celecoxib, sensitised the cells to 2-DG treatment. CONCLUSIONS Detailed profiling of cellular bioenergetics can provide new insight into the design of therapeutic strategies for inhibiting pancreatic cancer cell metabolism and proliferation.
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Affiliation(s)
- G Cheng
- Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - J Zielonka
- Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - D McAllister
- Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - S Tsai
- Department of Surgery/Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - M B Dwinell
- Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - B Kalyanaraman
- Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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17
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Diabetes and pancreatic cancer survival: a prospective cohort-based study. Br J Cancer 2014; 111:181-5. [PMID: 24786605 PMCID: PMC4090724 DOI: 10.1038/bjc.2014.224] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/01/2014] [Accepted: 04/04/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Diabetes is a risk factor for pancreatic cancer but its association with survival from pancreatic cancer is poorly understood. Our objective was to investigate the association of diabetes with survival among pancreatic cancer patients in a prospective cohort-based study where diabetes history was ascertained before pancreatic cancer diagnosis. METHODS We evaluated survival by baseline (1993-2001) self-reported diabetes history (n=62) among 504 participants that developed exocrine pancreatic cancer within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using Cox proportional hazards model, adjusted for age, sex, body mass index, race, smoking, and tumour stage (local, locally advanced, and metastatic). RESULTS The multivariable-adjusted HR for mortality comparing participants with diabetes to those without was 1.52 (95% CI=1.14-2.04, P-value <0.01). After excluding those diagnosed with pancreatic cancer within 3 years of study enrolment, HR for mortality among those with diabetes was 1.45 (95% CI=1.06-2.00, P-value=0.02). CONCLUSIONS Using prospectively collected data, our findings indicate that diabetes is associated with worse survival among patients with pancreatic cancer.
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18
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Søreide K, Sund M. Epidemiological-molecular evidence of metabolic reprogramming on proliferation, autophagy and cell signaling in pancreas cancer. Cancer Lett 2014; 356:281-8. [PMID: 24704294 DOI: 10.1016/j.canlet.2014.03.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 02/28/2014] [Accepted: 03/25/2014] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer remains one of the deadliest human cancers with little progress made in survival over the past decades, and 5-year survival usually below 5%. Despite this dismal scenario, progresses have been made in understanding of the underlying tumor biology through among other definition of precursor lesions, delineation of molecular pathways, and advances in genome-wide technology. Further, exploring the relationship between epidemiological risk factors involving metabolic features to that of an altered cancer metabolism may provide the foundation for new therapies. Here we explore how nutrients and caloric intake may influence the KRAS-driven ductal carcinogenesis through mediators of metabolic stress, including autophagy in presence of TP53, advanced glycation end products (AGE) and the receptors (RAGE) and ligands (HMGB1), as well as glutamine pathways, among others. Effective understanding the cancer metabolism mechanisms in pancreatic cancer may propose new ways of prevention and treatment.
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Affiliation(s)
- Kjetil Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
| | - Malin Sund
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
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19
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Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci 2014; 39:91-100. [PMID: 24388967 DOI: 10.1016/j.tibs.2013.12.004] [Citation(s) in RCA: 534] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 12/06/2013] [Accepted: 12/09/2013] [Indexed: 02/08/2023]
Abstract
Oncogenic KRAS mutation is the signature genetic event in the progression and growth of pancreatic ductal adenocarcinoma (PDAC), an almost universally fatal disease. Although it has been appreciated for some time that nearly 95% of PDAC harbor mutationally activated KRAS, to date no effective treatments that target this mutant protein have reached the clinic. A number of studies have shown that oncogenic KRAS plays a central role in controlling tumor metabolism by orchestrating multiple metabolic changes including stimulation of glucose uptake, differential channeling of glucose intermediates, reprogrammed glutamine metabolism, increased autophagy, and macropinocytosis. We review these recent findings and address how they may be applied to develop new PDAC treatments.
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Affiliation(s)
- Kirsten L Bryant
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Joseph D Mancias
- Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA
| | - Alec C Kimmelman
- Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA
| | - Channing J Der
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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Abstract
Up to 85% of patients with pancreatic cancer have diabetes or hyperglycaemia, which frequently manifests as early as 2-3 years before a diagnosis of pancreatic cancer. Conversely, patients with new-onset diabetes have a 5-8-fold increased risk of being diagnosed with pancreatic cancer within 1-3 years of developing diabetes. Emerging evidence now indicates that pancreatic cancer causes diabetes. As in type 2 diabetes, β-cell dysfunction and peripheral insulin resistance are seen in pancreatic cancer-induced diabetes. However, unlike in patients with type 2 diabetes, glucose control worsens in patients with pancreatic cancer in the face of ongoing, often profound, weight loss. Diabetes and weight loss, which precede cachexia onset by several months, are paraneoplastic phenomena induced by pancreatic cancer. Although the pathogenesis of these pancreatic cancer-induced metabolic alterations is only beginning to be understood, these are likely mechanisms to promote the survival and growth of pancreatic cancer in a hostile and highly desmoplastic microenvironment. Interestingly, these metabolic changes could enable early diagnosis of pancreatic cancer, if they can be distinguished from the ones that occur in patients with type 2 diabetes. One such possible biomarker is adrenomedullin, which is a potential mediator of β-cell dysfunction in pancreatic cancer-induced diabetes.
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21
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Wörmann SM, Algül H. Risk Factors and Therapeutic Targets in Pancreatic Cancer. Front Oncol 2013; 3:282. [PMID: 24303367 PMCID: PMC3831165 DOI: 10.3389/fonc.2013.00282] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 11/03/2013] [Indexed: 12/13/2022] Open
Affiliation(s)
- Sonja Maria Wörmann
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Hana Algül
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- *Correspondence: Hana Algül, II. Medizinische Klinik, Klinikum rechts der Isar, Universität München, Ismaninger Str. 22, Munich 81675, Germany e-mail:
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Tod J, Jenei V, Thomas G, Fine D. Tumor-stromal interactions in pancreatic cancer. Pancreatology 2012; 13:1-7. [PMID: 23395563 DOI: 10.1016/j.pan.2012.11.311] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Revised: 11/21/2012] [Accepted: 11/25/2012] [Indexed: 12/11/2022]
Abstract
Pancreatic adenocarcinoma has one of the worse prognoses of any cancer with a 5-year survival of only 3%. Pancreatic cancer displays one of the most prominent stromal reactions of all tumors and it is evident that this is a key contributing factor to disease outcome. The tumor microenvironment of pancreatic cancer harbors a wide spectrum of cell types and a complex network of mechanisms which all serve to promote tumor progression. It is clear that the symbiotic relationship between pancreatic cancer cells and stellate cells is the chief factor creating this unique tumor milieu. Pancreatic stellate cells play critical roles in evasion of cancer cell apoptosis, invasion and metastases, angiogenesis, and promotion of an immunosuppressive environment, all key hallmarks of malignancy. Existing treatments for pancreatic cancer focus on targeting the cancer cells rather than the whole tumor, of which cancer cells represent a small proportion. It is now increasingly evident that research targeted towards the interactions between these cell types, ideally at an early stage of tumor development, is imperative in order to propel the way forward to more effective treatments.
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Affiliation(s)
- Jo Tod
- Cancer Sciences Unit, Somers Building, University of Southampton School of Medicine, Tremona Rd., Southampton SO16 6YD, UK.
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