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Mezza T, Cefalo CMA, Cinti F, Quero G, Pontecorvi A, Alfieri S, Holst JJ, Giaccari A. Endocrine and Metabolic Insights from Pancreatic Surgery. Trends Endocrinol Metab 2020; 31:760-772. [PMID: 32830029 DOI: 10.1016/j.tem.2020.07.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/25/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023]
Abstract
Although it is well established that diabetes can also develop as a result of diseases or maneuvers on the exocrine pancreas, the complex relationship between glucose disorders and underlying pancreatic disease is still debated. There is evidence that several features linked to pancreatic diseases can modify endocrine and metabolic conditions before and after surgery. However, pancreatic surgery provides a rare opportunity to correlate in vivo endocrine and metabolic pathways with ex vivo pancreatic samples, to examine the endocrine and metabolic effects of acute islet removal, and finally to clarify the pathogenesis of diabetes. This approach could therefore represent a unique method to shed light on the molecular mechanisms, predicting factors, and metabolic consequences of insulin resistance, islet plasticity, β cell failure, and type 2 diabetes.
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Affiliation(s)
- Teresa Mezza
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Chiara M A Cefalo
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Cinti
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giuseppe Quero
- Chirurgia Digestiva, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alfredo Pontecorvi
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Sergio Alfieri
- Chirurgia Digestiva, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Jens J Holst
- Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Andrea Giaccari
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
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Gupta MK, Sarojamma V, Vadde R. Diabetes and Pancreatic Cancer: A Bidirectional Relationship Perspective. EXPLORING PANCREATIC METABOLISM AND MALIGNANCY 2019:35-51. [DOI: 10.1007/978-981-32-9393-9_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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Zhou PT, Li B, Liu FR, Zhang MC, Wang Q, Li YY, Xu C, Liu YH, Yao Y, Li D. Metformin is associated with survival benefit in pancreatic cancer patients with diabetes: a systematic review and meta-analysis. Oncotarget 2018; 8:25242-25250. [PMID: 28445955 PMCID: PMC5421925 DOI: 10.18632/oncotarget.15692] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 01/24/2017] [Indexed: 01/02/2023] Open
Abstract
Background Pancreatic cancer is a highly lethal disease with a poor prognosis while metformin has been associated with a decreased risk of pancreatic cancer. Although the benefit of metformin was observed for pancreatic cancer prevention, it is not clear whether it can also affect the survival of pancreatic cancer patients with type 2 diabetes mellitus. A systematic review and meta-analysis was conducted to assess the effect of metformin on the survival of pancreatic cancer patients with type 2 diabetes mellitus. Methods Two independent authors searched PubMed and Web of science up to 08/07/2016. We assessed studies for eligibility, extracted data, and examined their quality, with the primary outcome as overall survival. We used published hazard ratio (HR) available or estimated based on other survival data. We pooled the data and used a random-effect model to combine direct comparisons from included articles. We also investigated treatment effects by different countries, quality and the time of metformin initiation. RESULTS We found that there was a relative survival benefit associated with metformin treatment compared with non-metformin treatment in both overall survival (OS) ([HR] 0.84; 95% confidence interval [CI]: 0.73 – 0.96). These associations were also observed in subgroups of Asian countries and high quality articles. Conclusions Our results support the notion that metformin maybe the best anti-diabetic medicine of choice in patients with pancreatic cancer and concurrent type 2 diabetes mellitus. The perspectives of enhancing survival of pancreatic cancer patients with diabetes mellitus by the use of metformin deserve more attention in future research and clinical practice.
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Affiliation(s)
- Ping-Ting Zhou
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Bo Li
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Fu-Rao Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mei-Chao Zhang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qian Wang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yan-Yan Li
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ci Xu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuan-Hua Liu
- Department of Chemotherapy, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China
| | - Yuan Yao
- Department of Radiation Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Dong Li
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Szablewski L. Diabetes mellitus: influences on cancer risk. Diabetes Metab Res Rev 2014; 30:543-53. [PMID: 25044584 DOI: 10.1002/dmrr.2573] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 03/11/2013] [Accepted: 03/19/2013] [Indexed: 12/20/2022]
Abstract
Diabetes mellitus and cancer are common conditions, and their co-diagnosis in the same individual is not infrequent. The relative risks associated with type 2 diabetes are greater than twofold for hepatic, pancreatic, and endometrial cancers. The relative risk is somewhat lower, at 1.2-1.5-fold for colorectal, breast, and bladder cancers. In comparison, the relative risk of lung cancer is less than 1. The evidence for other malignancies (e.g. kidney, non-Hodgkin lymphoma) is inconclusive, whereas prostatic cancer occurs less frequently in male patients with diabetes. The potential biologic links between the two diseases are incompletely understood. Evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer. Whereas anti-diabetic drugs have a minor influence on cancer risk, drugs used to treat cancer may either cause diabetes or worsen pre-existing diabetes. If hyperinsulinemia acts as a critical link between the observed increased cancer risk and type 2 diabetes, one would predict that patients with type 1 diabetes would have a different cancer risk pattern than patients with type 2 diabetes because the former patients are exposed to lower levels of exogenous administered insulin. Obtained results showed that patients with type 1 diabetes had elevated risks of cancers of the stomach, cervix, and endometrium. Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes.
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Affiliation(s)
- Leszek Szablewski
- Chair of General Biology and Parasitology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
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Identifying patients with suspected pancreatic cancer in primary care: derivation and validation of an algorithm. Br J Gen Pract 2012; 62:e38-45. [PMID: 22520674 DOI: 10.3399/bjgp12x616355] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Pancreatic cancer has the worst survival for any cancer and is often diagnosed late when the cancer is advanced. Chances of survival are more likely if patients can be diagnosed earlier. AIM To derive and validate an algorithm to estimate absolute risk of having pancreatic cancer in patients with and without symptoms in primary care. DESIGN AND SETTING Cohort study using data from 375 UK QResearch® general practices for development and 189 for validation. METHOD Included patients were aged 30-84 years, free at baseline from a diagnosis of pancreatic cancer and had not had dysphagia, abdominal pain, abdominal distension, appetite loss, or weight loss recorded in the preceding 12 months. The primary outcome was incident diagnosis of pancreatic cancer recorded in the following 2 years. Risk factors examined included: age, body mass index, smoking status, alcohol, deprivation, diabetes, pancreatitis, previous diagnosis of cancer apart from pancreatic cancer, dysphagia, abdominal pain, abdominal distension, appetite loss, weight loss, diarrhoea, constipation, tiredness, itching, and anaemia. Cox proportional hazards models were used to develop separate risk equations in males and females. Measures of calibration and discrimination assessed performance in the validation cohort. RESULTS There were a total of 1415 incident cases of pancreatic cancer from 4.1 million person-years in the derivation cohort. Independent predictors in both males and females were age, smoking, type 2 diabetes, chronic pancreatitis, abdominal pain, appetite loss, and weight loss. Abdominal distension was a predictor for females only; dysphagia and constipation were predictors for males only. On validation, the algorithms explained 59% of the variation in females and 62% in males. The receiver operating characteristic statistics were 0.84 (females) and 0.87 (males). The D statistic was 2.44 (females) and 2.61 (males). The 10% of patients with the highest predicted risks contained 62% of all pancreatic cancers diagnosed over the following 2 years. CONCLUSION The algorithm has good discrimination and calibration and could potentially be used to help identify those at highest risk of pancreatic cancer to facilitate early referral and investigation.
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CA 19-9 level in patients with type 2 diabetes mellitus and its relation to the metabolic control and microvascular complications. Am J Med Sci 2011; 341:28-32. [PMID: 21139492 DOI: 10.1097/maj.0b013e3181f0e2a0] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION The aim of this study is to compare CA 19-9 levels in patients with type 2 diabetes mellitus (DM) and healthy control group. The relation of CA 19-9 levels to metabolic control and microvascular complications in patients with diabetes was also investigated. METHODS Three hundred forty patients with type 2 DM and age-, sex- and body mass index-matched 214 healthy controls group were included in the study. HbA₁(c), duration of DM and microvascular complications of DM were reviewed. CA 19-9 levels (normal range, 0-35 U/mL) were measured in all participants. RESULTS Median CA 19-9 level was significantly higher in patients with diabetes compared with control group [19.5 U/mL (0-214.8 U/mL) versus 7.4 U/mL (0.4-47.0 U/mL)] (P < 0.001). Prevalence of high CA 19-9 levels in patients with diabetes was 31.2%, and CA 19-9 level was positively correlated with age, duration of diabetes, HbA₁(c) and number of complications. Effects of duration of diabetes, HbA₁(c) and diabetic nephropathy were still continuing in multiple linear regression analysis. Using regression coefficients of all variables in multiple regression analysis, this study tried to determine a new cutoff value for CA 19-9 level in patients with diabetes. The cutoff value at 97th percentile was 57.14 U/mL. CONCLUSIONS High CA 19-9 value in patients with diabetes may indicate the need for a careful evaluation of blood glucose regulation and investigation of complications. Defining a new cutoff value in these patients would prevent unnecessary laboratory or imaging procedures.
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Katsumichi I, Pour PM. Diabetes mellitus in pancreatic cancer: is it a causal relationship? Am J Surg 2008; 194:S71-5. [PMID: 17903450 DOI: 10.1016/j.amjsurg.2007.05.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2007] [Revised: 05/21/2007] [Accepted: 05/21/2007] [Indexed: 11/30/2022]
Abstract
The relationship between type 2 diabetes mellitus and pancreatic cancer (PC) is not clear. It has been reported that the increased release of islet amyloid polypeptides (IAPPs) is responsible for the impaired glucose tolerance in PC patients. However, no information exists on the patterns of IAPP expression in PC tissue in comparison with tissue from the normal pancreas and that of a patient with type 2 diabetes. Therefore, we performed a morphometric study and compared the patterns of IAPP expression in 5 normal pancreases (as a control), 6 pancreases from patients with type 2 diabetes, and 11 surgical PC specimens, which were processed for immunohistochemistry using anti-insulin and an anti-IAPP antibody. From the cancer tissue, sections were taken from the tumor (T) and from adjacent tumor-free areas (TF). The size of islets and the number of immunostained cells in these islets were recorded. In diabetes and PC, the size of islets and the number of beta-cells was significantly lower than in the controls. Also, the number of IAPP-expressing cells was significantly lower in diabetes and in the T area but not in the TF region. In addition, no characteristic changes found in diabetic pancreases were observed in the TF area, indicating that PC patients had no prior diabetic diseases. The reduction in the number of IAPP in the T area seems to argue against the role of IAPP in glucose abnormality in PC patients. The primary endocrine alteration in the tumor area suggests that cancer cells produce diabetogenic substances, the nature of which awaits further research.
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Affiliation(s)
- Iki Katsumichi
- UNMC Eppley Cancer Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA
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Uygur-Bayramicli O, Dabak R, Orbay E, Dolapcioglu C, Sargin M, Kilicoglu G, Guleryuzlu Y, Mayadagli A. Type 2 dıabetes mellıtus and CA 19-9 levels. World J Gastroenterol 2007; 13:5357-9. [PMID: 17879406 PMCID: PMC4171326 DOI: 10.3748/wjg.v13.i40.5357] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To prospectively investigate serum CA 19-9 levels in type 2 diabetic patients in comparison with age- and gender-matched control subjects.
METHODS: We recorded duration of diabetes and examined fasting glucose levels, HbA1c levels and serum CA 19-9 levels in 76 type 2 diabetic patients and 76 controls. Abdominal CT was performed in order to eliminate abdominal malignancy in the diabetic and control groups.
RESULTS: The average CA 19-9 level was 46.0 ± 22.4 U/mL for diabetic patients whereas it was 9.97 ± 7.1 U/mL for the control group (P < 0.001 ). Regression analysis showed a positive correlation between diabetes and CA 19-9 independent from age, gender, glucose level and HbA1c level (t = 8.8, P < 001 ). Two of the diabetic patients were excluded from the study because of abdominal malignancy shown by CT at the initial evaluation. For all patients, abdominal CT showed no pancreatic abnormalities.
CONCLUSION: CA 19-9 is a tumor-associated antigen, which is elevated in pancreatic, upper gastrointestinal tract, ovarian hepatocellular, and colorectal cancers, as well as in inflammatory conditions of the hepatobiliary system, biliary obstruction and in thyroid diseases. Diabetes has been claimed to be a risk factor for pancreatic cancer, which is increasing its incidence and has one of the lowest survival rates of all cancers. CA 19-9 is used in the diagnosis of pancreatic cancer but is also a marker of pancreatic tissue damage that might be caused by diabetes. We propose that a higher cut-off value of CA 19-9 should be used in diabetics to differentiate benign and malignant pancreatic disease, and subtle elevations of CA 19-9 in diabetics should be considered as the indication of exocrine pancreatic dysfunction.
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Yun JE, Jo I, Park J, Kim MT, Ryu HG, Odongua N, Kim E, Jee SH. Cigarette smoking, elevated fasting serum glucose, and risk of pancreatic cancer in Korean men. Int J Cancer 2006; 119:208-12. [PMID: 16450398 DOI: 10.1002/ijc.21816] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Pancreatic cancer is one of the most fatal human cancers and continues to be a major unsolved health problem. The goal of this study was to estimate the independent effects and interactions between cigarette smoking and diabetes on the risk of pancreatic cancer in Korean male population. Cigarette smoking and the risk of incidence and death from pancreatic cancer were examined in a 10-year prospective cohort study of 446,407 Korean men aged 40 to 65 years who received health insurance from the National Health Insurance Corporation and who had a medical evaluation in 1992. Relative risks (RR) and 95% confidence intervals (CI) were calculated using a Cox proportional hazards model after adjusting for age, body mass index, exercise and alcohol use. Current smoking was associated with an increased risk of incidence (RR = 1.7, 95% CI = 1.6-1.9) and mortality (RR = 1.6, 95% CI = 1.4-1.7) from pancreatic cancer. The RR for pancreatic cancer increased with both duration and amount of smoking. Diabetes was also associated with an increased risk of both incidence (RR = 1.8, 95% CI = 1.5-2.2) and mortality (RR = 1.7, 95% CI = 1.4-2.1) from pancreatic cancer. There was no interaction between smoking and fasting serum glucose in terms of pancreatic cancer risk. Thus, our prospective study has demonstrated that cigarette smoking and elevated fasting serum glucose are independently associated with an increased risk of pancreatic cancer in a large cohort of Korean males.
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Affiliation(s)
- Ji Eun Yun
- Department of Public Health, Graduate School, Yonsei University, Seoul, Korea
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Inoue M, Tajima K, Takezaki T, Hamajima N, Hirose K, Ito H, Tominaga S. Epidemiology of pancreatic cancer in Japan: a nested case-control study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). Int J Epidemiol 2003; 32:257-62. [PMID: 12714546 DOI: 10.1093/ije/dyg062] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND To clarify lifestyle factors that affect the risk of pancreatic cancer among the Japanese population, a nested case-control study was conducted using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. METHODS The study subjects included 200 incident cases of pancreatic cancer and 2000 age-class frequency-matched cancer-free outpatients attending the baseline questionnaire of HERPACC in the period 1988-1999. Associations between lifestyles and the risk of pancreatic cancer were evaluated using odds ratios estimated by the unconditional logistic regression model, adjusting for potential confounding factors. RESULTS A positive family history of pancreatic cancer and a past or present history of diabetes significantly increased the risk of pancreatic cancer. In contrast, regular physical exercise, a regular bowel habit, and frequent consumption of raw vegetables appeared to be protective. Current alcohol drinkers showed decreased risk, but the opposite was the case for former drinkers. Current smoking did not affect the risk of pancreatic cancer, while former smokers showed a tendency for decreased risk. Compared with light smokers, heavy smokers showed a modest tendency for increase in risk, especially those who starting smoking at a younger age, but there were no clear tendencies for duration and pack-years of smoking. CONCLUSIONS From these results it appears that smoking habit, which has long been considered a sole important determinant, has only a modest role, if any, in pancreatic cancer in Japanese.
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Affiliation(s)
- Manami Inoue
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
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Abstract
Premalignant conditions of the pancreas include benign tumours of the pancreas, intraepithelial neoplasia arising within pancreatic ducts, and tumours of the neuroendocrine cells of the pancreas. In addition, there is a variety of rare genetic conditions that predispose to pancreatic exocrine malignancies such as Peutz-Jeghers syndrome, hereditary non-polyposis colorectal cancer syndrome, familial pancreatitis, germline BRCA2 mutations, and pancreatic endocrine malignancies such as type 1 neurofibromatosis (von Recklinghausen's disease) and multiple endocrine neoplasia type 1. More controversial is the concept of chronic pancreatitis and diabetes mellitus as conditions that increase the risk of pancreatic cancer. However, there is no doubt that smoking is a potentiating factor for pancreatic cancer, especially in people who have familial/genetic risk factors. This review will include the recently proposed new nomenclature and classification system for intraepithelial neoplasia in the pancreatic ducts, an overview of the various familial syndromes that are associated with an increased risk of pancreatic tumours, the surveillance programmes that have been introduced to monitor such families, and methods for early diagnosis.
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Affiliation(s)
- Pauline de la M Hall
- Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Observatory, South Africa,
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Pour PM, Schmied BM, Ulrich AB, Friess H, Andrén-Sandberg A, Büchler MW. Abnormal differentiation of islet cells in pancreatic cancer. Pancreatology 2002; 1:110-6. [PMID: 12120188 DOI: 10.1159/000055802] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pancreatic cancer in many patients is associated with altered glucose metabolism and abnormalities in pancreatic islet hormones at serum and tissue levels. Our previous studies have indicated a tendency of islet cells to differentiate toward ductal cell lineage, but the specificity of these findings for pancreatic cancer was not investigated. In the present study, we examined the immunoreactivity of pancreatic islets to antibodies against tumor-associated antigens DU-PAN-2, TAG-72 and CA19-9 in tissues from the normal pancreas, chronic pancreatitis and pancreatic cancer. Although no immunoreactive islet cells were found in the 12 normal pancreases and 20 chronic pancreatitis patients, 25 of 37 pancreatic cancer tissues showed the expression of these antigens, primarily CA19-9 and TAG-72, where the number of immunoreactive cells varied considerably from case to case. In 4 cases over 50% and in 2 of them more than 75% of the islets showed positive staining of 60-70% of islet cells within each islet. The presence of intrainsular ductular structures expressing the same antigen as the surrounding islet cells suggested transformation of antigen expressing islet cells to ductal cells. All but four islets were within or around the cancer favoring the notion that factors produced by cancer cells are responsible for the altered islet cell differentiation.
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Affiliation(s)
- P M Pour
- UNMC Eppley Cancer Center, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebr., USA.
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Hennig R, Ding XZ, Tong WG, Schneider MB, Standop J, Friess H, Büchler MW, Pour PM, Adrian TE. 5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. THE AMERICAN JOURNAL OF PATHOLOGY 2002; 161:421-8. [PMID: 12163367 PMCID: PMC1850753 DOI: 10.1016/s0002-9440(10)64198-3] [Citation(s) in RCA: 140] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The 5-lipoxygenase (5-LOX) pathway is critical for pancreatic cancer cell growth and escape from apoptosis. Inhibition of 5-LOX blocks proliferation and induces apoptosis in human pancreatic cancer cells. However, the expression of 5-LOX and its downstream signaling pathway have not been investigated in human pancreatic adenocarcinoma. Reverse transcriptase-polymerase chain reaction revealed expression of 5-LOX mRNA in all pancreatic cancer cell lines tested including, PANC-1, AsPC-1, and MiaPaCa2 cells, but not in normal pancreatic ductal cells. The expression of 5-LOX protein in pancreatic cancer cell lines was demonstrated by Western blotting. Finally, 5-LOX up-regulation in human pancreatic cancer tissues was verified by intense positive staining in cancer cells by immunohistochemistry. Staining for the 5-LOX protein was particularly evident in the ductal components of the more differentiated tumors but not in ductal cells in normal pancreatic tissues from cadaver donors. Immunohistochemistry also revealed strong staining of cancer tissues with an antibody to the receptor of the downstream 5-LOX metabolite, leukotriene B(4). The current study demonstrated marked expression of 5-LOX and the leukotriene B(4) receptor in human pancreatic cancer tissues. These findings provide further evidence of up-regulation of this pathway in pancreatic cancer and that LOX inhibitors are likely to be valuable in the treatment of this dreadful disease.
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Affiliation(s)
- René Hennig
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
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Bardeesy N, Sharpless NE, DePinho RA, Merlino G. The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model. Semin Cancer Biol 2001; 11:201-18. [PMID: 11407945 DOI: 10.1006/scbi.2000.0371] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Pancreatic cancer is among the leading causes of cancer death. Although a genetic profile for pancreatic cancer is emerging, many biological aspects of this disease are poorly understood. Indeed, fundamental questions regarding progenitor cell lineages, host stromal milieu, and the role of specific genetic alterations in tumor progression remain unresolved. A mouse model engineered with signature mutations would provide a powerful ally in the study of pancreatic cancer biology and may guide improved prognostic assessment and treatment for the human disease. In this review, we discuss the molecular basis for normal pancreatic development and the genetics of human pancreatic adenocarcinoma in the hope of charting a course for the development of a faithful mouse model for this lethal cancer.
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Affiliation(s)
- N Bardeesy
- Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA.
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Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE, Pour PM. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 2001; 120:1263-70. [PMID: 11266389 DOI: 10.1053/gast.2001.23258] [Citation(s) in RCA: 248] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND AND AIMS Our previous study suggested that the known promotional effect of a high fat diet, which in hamsters induces peripheral insulin resistance, is related to a compensatory proliferation of islet cells. The present study was to examine whether the prevention of islet cell proliferation can inhibit the promotional effect of a high-fat diet in pancreatic carcinogenesis. METHODS Two groups of high fat-fed hamsters were used. One group received Metformin in drinking water for life (HF+Met group), and the other group served as a control (HF group). At the time when the normalization of the plasma insulin level was expected, all hamsters were treated with the pancreatic carcinogen, N-nitrosobis-(2-oxopropyl)amine, and the experiment was terminated 42 weeks later. RESULTS Although 50% of the hamsters in the high-fat group developed malignant lesions, none was found in the HF+Met group (P < 0.05). Also, significantly more hyperplastic and premalignant lesions, most of which were found within the islets, were detected in the high-fat group (8.6 lesions/hamster) than in the HF+Met group (1.8 lesions/hamster). CONCLUSIONS The results lend further support on the significant role of islet cells in pancreatic carcinogenesis and may explain the association between pancreatic cancer and obesity, which is usually associated with peripheral insulin resistance.
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Affiliation(s)
- M B Schneider
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA
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