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Laeeq T, Ahmed M, Sattar H, Zeeshan MH, Ali MB. Role of SGLT2 Inhibitors, DPP-4 Inhibitors, and Metformin in Pancreatic Cancer Prevention. Cancers (Basel) 2024; 16:1325. [PMID: 38611003 PMCID: PMC11011099 DOI: 10.3390/cancers16071325] [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: 01/29/2024] [Revised: 03/08/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Pancreatic carcinoma is a highly aggressive tumor that usually presents when it has already metastasized. Therapeutic options for cure remain scarce and rely on combination chemotherapy with limited sustainability. Diabetes is considered an important risk factor for the development of pancreatic cancer due to the production of proinflammatory cytokines, which result in increased cell proliferation. More than half of patients diagnosed with pancreatic cancer eventually develop diabetes due to the destruction of insulin-producing cells. The interlinkage of both diseases might identify a possible preventative strategy for reducing the incidence of pancreatic carcinoma. This study reviewed the recent literature on the association between pancreatic cancer risk and SGLT2 inhibitors, GLP-1 RA, DPP-4 inhibitors, and biguanides. There are mixed data regarding the relationship between GLP-1 RA and DPP-4 inhibitors and pancreatic cancer, with some trials suggesting that they might increase the risk. In contrast, studies have mostly revealed that SGLT2 inhibitors have an antiproliferative effect on various tumors, such as liver, pancreatic, prostate, bowel, lung, and breast carcinoma, which might be due to their mechanism of blockage of reabsorption of glucose by cells, lowering the amount of available glucose for the growth of tumor cells. Metformin, the first-line agent for diabetes, has also been shown to be associated with decreasing pancreatic cancer risk and improving prognosis in those who already have the disease. Dedicated trials are needed to further delineate the association of antidiabetic drugs with the risk of pancreatic cancer in the general population, as previous studies have mostly focused on diabetic patients.
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Affiliation(s)
- Tooba Laeeq
- Internal Medicine, University of Nevada, 4505 S Maryland Pkwy, Las Vegas, NV 89154, USA
| | - Maheen Ahmed
- Internal Medicine, Dow University of Health Sciences, Mission Rd., New Labour Colony, Karachi 74200, Pakistan; (M.A.); (M.H.Z.)
| | - Hina Sattar
- Internal Medicine, Dow University of Health Sciences, Mission Rd., New Labour Colony, Karachi 74200, Pakistan; (M.A.); (M.H.Z.)
| | - Muhammad Hamayl Zeeshan
- Internal Medicine, Dow University of Health Sciences, Mission Rd., New Labour Colony, Karachi 74200, Pakistan; (M.A.); (M.H.Z.)
| | - Meher Binte Ali
- Internal Medicine, University of Maryland Medical Center, 827 Linden Ave., Baltimore, MD 21201, USA
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2
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Matsunaga A, Ando N, Yamagata Y, Shimura M, Gatanaga H, Oka S, Ishizaka Y. Identification of viral protein R of human immunodeficiency virus-1 (HIV) and interleukin-6 as risk factors for malignancies in HIV-infected individuals: A cohort study. PLoS One 2024; 19:e0296502. [PMID: 38166062 PMCID: PMC10760899 DOI: 10.1371/journal.pone.0296502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 12/14/2023] [Indexed: 01/04/2024] Open
Abstract
BACKGROUND Despite effective antiretroviral therapy, patients with human immunodeficiency virus type-1 (HIV) suffer from a high frequency of malignancies, but related risk factors remain elusive. Here, we focused on blood-circulating viral protein R (Vpr) of HIV, which induces proinflammatory cytokine production and genotoxicity by exogenous functions. METHODS AND FINDINGS A total 404 blood samples of HIV patients comprising of 126 patients with malignancies (tumor group) and 278 patients without malignancies (non-tumor group), each of 96 samples was first selected by one-to-one propensity score matching. By a detergent-free enzyme-linked immunosorbent assays (detection limit, 3.9 ng/mL), we detected Vpr at a higher frequency in the matched tumor group (56.3%) than in the matched non-tumor group (39.6%) (P = 0.030), although there was no different distribution of Vpr levels (P = 0.372). We also detected anti-Vpr immunoglobulin (IgG), less frequently in the tumor group compared with the tumor group (22.9% for tumor group vs. 44.8% for non-tumor group, P = 0.002), and the proportion of patients positive for Vpr but negative of anti-Vpr IgG was significantly higher in the tumor group than in the non-tumor group (38.6% vs. 15.6%, respectively, P < 0.001). Additionally, Interleukin-6 (IL-6), the levels of which were high in HIV-1 infected patients (P < 0.001) compared to non-HIV-infected individuals, was significantly higher in advanced cases of tumors (P < 0.001), and IL-6 level was correlated with Vpr in the non-tumor group (P = 0.010). Finally, multivariate logistic regression analysis suggested a positive link of Vpr with tumor occurrence in HIV patients (P = 0.002). CONCLUSION Vpr and IL-6 could be risk factors of HIV-1 associated malignancies, and it would be importance to monitor these molecules for well managing people living with HIV-1.
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Affiliation(s)
- Akihiro Matsunaga
- Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Toyama, Shinjuku, Tokyo, Japan
| | - Naokatsu Ando
- AIDS Clinical Center, Hospital, National Center for Global Health and Medicine, Toyama, Shinjuku, Tokyo, Japan
| | - Yuko Yamagata
- Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Toyama, Shinjuku, Tokyo, Japan
- RIKEN SPring-8 Center, Koto, Sayo, Hyogo, Japan
| | - Mari Shimura
- Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Toyama, Shinjuku, Tokyo, Japan
- RIKEN SPring-8 Center, Koto, Sayo, Hyogo, Japan
| | - Hiroyuki Gatanaga
- AIDS Clinical Center, Hospital, National Center for Global Health and Medicine, Toyama, Shinjuku, Tokyo, Japan
| | - Shinichi Oka
- AIDS Clinical Center, Hospital, National Center for Global Health and Medicine, Toyama, Shinjuku, Tokyo, Japan
| | - Yukihito Ishizaka
- Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Toyama, Shinjuku, Tokyo, Japan
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Miyashita Y, Hitsumoto T, Fukuda H, Kim J, Ito S, Kimoto N, Asakura K, Yata Y, Yabumoto M, Washio T, Kitakaze M. Metabolic syndrome is linked to the incidence of pancreatic cancer. EClinicalMedicine 2024; 67:102353. [PMID: 38169901 PMCID: PMC10758702 DOI: 10.1016/j.eclinm.2023.102353] [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: 08/16/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Although previous studies have showed that metabolic syndrome is one of the contributors of pancreatic cancer, there is no clear consensus that early stages of metabolic syndrome are linked to increased incidence of pancreatic cancer. Therefore, we confirmed the linkage between metabolic syndrome and pancreatic cancer, and shown that even early stage of metabolic syndrome is linked to pancreatic cancer in the retrospective observational study. METHODS We recruited approximately 4.6 million Japanese in 2005 and followed up these subjects for more than 10 years. At the time of the enrollment, after obtaining clinical data with prescribed drugs and examining the presence or absence of metabolic syndrome (MetS), we followed up on these subjects with and without MetS to examine the incidence of pancreatic cancer. The modified criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII) were used to define MetS. FINDINGS During the 40.7-month average follow-up period for 2,707,296 subjects with complete data for identifying MetS and important risk factors without pancreatic cancer before the enrollment, 87,857 suffered from pancreatic cancer. Pancreatic cancers occurred in 16,154 of 331,229 subjects (4.9%) in the MetS group and 71,703 of 2,376,067 patients (3.0%) in the non-MetS group (hazard ratio (HR), 1.37; 95% confidence interval [CI], 1.34-1.39; p < 0.0001 after the adjustment with age, smoking and sex). As the number of the constituent factors of MetS increased from one to five, the incidence of pancreatic cancer correspondingly increased (HR: 1.11, 1.23, 1.42, 1.66 and 2.03 using Cox proportional hazard models, p < 0.0001 each). When we defined MetS using the Japanese criteria, the results are in accord with the results using NCEP/ATPIII. Especially pre-metabolic syndrome (pre-MetS) in the Japanese criteria was tightly linked to the incidence of pancreatic cancers. INTERPRETATION MetS is confirmed to be linked to pancreatic cancer. Although we cannot conclude causality. We also demonstrated the link between pre-MetS and pancreatic cancer. FUNDING The sponsors of the study were Japanese Heart Foundation and Japan Cardiovascular Research Foundation. This is also partially supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and Grants-in-Aid from the Japan Agency for Medical Research and Development.
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Affiliation(s)
- Yohei Miyashita
- Department of Legal Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan
| | - Tatsuro Hitsumoto
- Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, Japan
| | - Hiroki Fukuda
- Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, Japan
| | - Jiyoong Kim
- Kim Cardiovascular Clinic, 3-6-8 Katsuyama, Tennoji-ku, Osaka, Japan
| | - Shin Ito
- Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, Japan
| | - Naoki Kimoto
- Non Profit Organization Think of Medicine in Science, 3-7-11 Minami-Sumiyoshi, Sumiyoshi-ku, Osaka, Japan
| | - Koko Asakura
- Department of Data Science, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, Japan
| | - Yutaka Yata
- Hanwa Memorial Hospital, 3-5-8 Minamisumiyoshi, Sumiyoshi-ku, Osaka, Japan
| | - Masami Yabumoto
- Hanwa Memorial Hospital, 3-5-8 Minamisumiyoshi, Sumiyoshi-ku, Osaka, Japan
| | - Takashi Washio
- The Institute of Scientific and Industrial Research, Osaka University, 1-1 Yamadaoka, Suita, Osaka, Japan
| | - Masafumi Kitakaze
- Non Profit Organization Think of Medicine in Science, 3-7-11 Minami-Sumiyoshi, Sumiyoshi-ku, Osaka, Japan
- Hanwa Memorial Hospital, 3-5-8 Minamisumiyoshi, Sumiyoshi-ku, Osaka, Japan
- The Osaka Medical Research Foundation for Intractable Diseases, 2-6-29 Abikohigashi, Sumiyoshi-ku, Osaka, Japan
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Yu W, Ma Y, Roy SK, Srivastava R, Shankar S, Srivastava RK. Ethanol exposure of human pancreatic normal ductal epithelial cells induces EMT phenotype and enhances pancreatic cancer development in KC (Pdx1-Cre and LSL-Kras G12D ) mice. J Cell Mol Med 2021; 26:399-409. [PMID: 34859959 PMCID: PMC8743655 DOI: 10.1111/jcmm.17092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 12/20/2022] Open
Abstract
Alcohol is a risk factor for pancreatic cancer. However, the molecular mechanism by which chronic alcohol consumption influences pancreatic cancer development is not well understood. We have recently demonstrated that chronic ethanol exposure of pancreatic normal ductal epithelial cells (HPNE) induces cellular transformation by generating cancer stem cells (CSCs). Here, we examined whether chronic ethanol treatment induces epithelial–mesenchymal transition in HPNE cells and promotes pancreatic cancer development in KC (Pdx1‐Cre, and LSL‐KrasG12D) mice. Our data demonstrate that chronic ethanol exposure of HPNE cells induces SATB2 gene and those cells became highly motile. Ethanol treatment of HPNE cells results in downregulation of E‐Cadherin and upregulation of N‐Cadherin, Snail, Slug, Zeb1, Nanog and BMI‐1. Suppression of SATB2 expression in ethanol‐transformed HPNE cells inhibits EMT phenotypes. KC mice fed with an ethanol‐containing diet show enhanced pancreatic cancer growth and development than those fed with a control diet. Pancreas isolated from KC mice fed with an ethanol‐containing diet show higher expression of stem cell markers (CD133, CD44, CD24), pluripotency‐maintaining factors (cMyc, KLF4, SOX‐2, and Oct‐4), N‐Cadherin, EMT‐transcription factors (Snail, Slug, and Zeb1), and lower expression of E‐cadherin than those isolated from mice fed with a control diet. Furthermore, pancreas isolated from KC mice fed with an ethanol‐containing diet show higher expression of inflammatory cytokines (TNF‐α, IL‐6, and IL‐8) and PTGS‐2 (COX‐2) gene than those isolated from mice fed with a control diet. These data suggest that chronic alcohol consumption may contribute to pancreatic cancer development by generating inflammatory signals and CSCs.
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Affiliation(s)
- Wei Yu
- Kansas City VA Medical Center, Kansas City, Missouri, USA
| | - Yuming Ma
- Kansas City VA Medical Center, Kansas City, Missouri, USA
| | - Sanjit K Roy
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA
| | - Rashmi Srivastava
- Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA
| | - Sharmila Shankar
- Kansas City VA Medical Center, Kansas City, Missouri, USA.,Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA.,Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA.,John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisina, USA.,Southeast Louisiana Veterans Health Care System, New Orleans, Louisina, USA
| | - Rakesh K Srivastava
- Kansas City VA Medical Center, Kansas City, Missouri, USA.,Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA.,Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA.,Southeast Louisiana Veterans Health Care System, New Orleans, Louisina, USA
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5
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Grossberg AJ, Chu LC, Deig CR, Fishman EK, Hwang WL, Maitra A, Marks DL, Mehta A, Nabavizadeh N, Simeone DM, Weekes CD, Thomas CR. Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. CA Cancer J Clin 2020; 70:375-403. [PMID: 32683683 PMCID: PMC7722002 DOI: 10.3322/caac.21626] [Citation(s) in RCA: 298] [Impact Index Per Article: 59.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/21/2020] [Accepted: 05/26/2020] [Indexed: 12/12/2022] Open
Abstract
Despite tremendous gains in the molecular understanding of exocrine pancreatic cancer, the prognosis for this disease remains very poor, largely because of delayed disease detection and limited effectiveness of systemic therapies. Both incidence rates and mortality rates for pancreatic cancer have increased during the past decade, in contrast to most other solid tumor types. Recent improvements in multimodality care have substantially improved overall survival, local control, and metastasis-free survival for patients who have localized tumors that are amenable to surgical resection. The widening gap in prognosis between patients with resectable and unresectable or metastatic disease reinforces the importance of detecting pancreatic cancer sooner to improve outcomes. Furthermore, the developing use of therapies that target tumor-specific molecular vulnerabilities may offer improved disease control for patients with advanced disease. Finally, the substantial morbidity associated with pancreatic cancer, including wasting, fatigue, and pain, remains an under-addressed component of this disease, which powerfully affects quality of life and limits tolerance to aggressive therapies. In this article, the authors review the current multidisciplinary standards of care in pancreatic cancer with a focus on emerging concepts in pancreatic cancer detection, precision therapy, and survivorship.
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Affiliation(s)
- Aaron J. Grossberg
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR
| | - Linda C. Chu
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Christopher R. Deig
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
| | - Eliot K. Fishman
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD
| | - William L. Hwang
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
- Broad Institute of Harvard and MIT, Cambridge, MA
| | - Anirban Maitra
- Departments of Pathology and Translational Molecular Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Daniel L. Marks
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR
- Department of Pediatrics and Pape Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR
| | - Arnav Mehta
- Broad Institute of Harvard and MIT, Cambridge, MA
- Dana Farber Cancer Institute, Boston, MA
| | - Nima Nabavizadeh
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
| | - Diane M. Simeone
- Departments of Surgery and Pathology, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Colin D. Weekes
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Charles R. Thomas
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
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6
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Li X, Xu H, Gao P. ABO Blood Group and Diabetes Mellitus Influence the Risk for Pancreatic Cancer in a Population from China. Med Sci Monit 2018; 24:9392-9398. [PMID: 30582832 PMCID: PMC6320638 DOI: 10.12659/msm.913769] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background The mechanism by which diabetes mellitus (DM) impacts the association between ABO blood types and pancreatic cancer is unclear. Material/Methods A retrospective case-control study of 264 patients with pancreatic cancer and 423 age- and sex-matched individuals with nonmalignant diseases was performed to assess whether ABO blood group and DM jointly contribute to pancreatic cancer risk. Results A multivariate analysis with adjustments for risk factors revealed that blood type, chronic pancreatitis, and DM were significantly associated with increased pancreatic cancer risk. The estimated adjusted odds ratios (AORs with 95% confidence intervals [CIs]) were 2.130 (1.409–3.220) for blood type A, 2.383 (1.313–4.325) for blood type AB, 1.518 (1.012–2.276) for DM, and 10.930 (1.202–99.405) for chronic pancreatitis. Blood type A significantly modified the risk for pancreatic cancer in individuals with DM (AOR, 3.506; 95% CI, 1.659–7.409). Conclusions The risk for pancreatic cancer was associated with ABO blood type, DM, and chronic pancreatitis in a Chinese population. The risk was greatest for individuals with blood type A and DM.
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Affiliation(s)
- Xu Li
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland)
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland).,Jilin Province Key Laboratory of Infectious Disease, Laboratory of Molecular Virology, Changchun, Jilin, China (mainland)
| | - Pujun Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China (mainland)
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7
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Yu W, Ma Y, Shankar S, Srivastava RK. Chronic ethanol exposure of human pancreatic normal ductal epithelial cells induces cancer stem cell phenotype through SATB2. J Cell Mol Med 2018; 22:3920-3928. [PMID: 29761897 PMCID: PMC6050497 DOI: 10.1111/jcmm.13666] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 03/31/2018] [Indexed: 12/13/2022] Open
Abstract
The incidence of pancreatic cancer is on the rise. Risk factors for pancreatic cancer include alcohol toxicity and metabolic conditions such as obesity, hypertension, dyslipidaemia, insulin resistance and type 2 diabetes. However, the molecular mechanism by which chronic alcohol consumption contributes to pancreatic cancer is not well understood. The purpose of the study was to demonstrate the effects of long-term chronic ethanol exposure on the transformation of human pancreatic normal ductal epithelial (HPNE) cells. Our data showed that ethanol-transformed HPNE cells were more progressively transformed exhibiting spheroids and colonies, and anchorage-independent growth. These transformed cells contained high levels of reactive oxygen species and induced SATB2 expression. Furthermore, during ethanol-induced cellular transformation, cells gained the phenotypes of cancer stem cells (CSCs) by expressing pluripotency maintaining factors (Oct4, Sox2, cMyc and KLF4) and stem cell markers (CD24, CD44 and CD133). Ethanol-induced SATB2 can bind to the promoters of KLF4, Oct4, cMyc, Sox2, Bcl-2 and XIAP genes. Suppression of SATB2 expression in ethanol-transformed HPNE cells inhibited cell proliferation, colony formation and markers of CSCs and pluripotency. These data suggest that chronic alcohol consumption may contribute toward the development of pancreatic cancer by converting HPNE cells to cancer stem-like cells.
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Affiliation(s)
- Wei Yu
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Yiming Ma
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Sharmila Shankar
- Kansas City VA Medical Center, Kansas City, MO, USA
- Department of Pathology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Rakesh K Srivastava
- Kansas City VA Medical Center, Kansas City, MO, USA
- Department of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO, USA
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8
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Peng W, Furuuchi N, Aslanukova L, Huang YH, Brown SZ, Jiang W, Addya S, Vishwakarma V, Peters E, Brody JR, Dixon DA, Sawicki JA. Elevated HuR in Pancreas Promotes a Pancreatitis-Like Inflammatory Microenvironment That Facilitates Tumor Development. Mol Cell Biol 2018; 38:e00427-17. [PMID: 29133460 PMCID: PMC5770537 DOI: 10.1128/mcb.00427-17] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 09/07/2017] [Accepted: 11/07/2017] [Indexed: 12/30/2022] Open
Abstract
Human antigen R (ELAVL1; HuR) is perhaps the best-characterized RNA-binding protein. Through its overexpression in various tumor types, HuR promotes posttranscriptional regulation of target genes in multiple core signaling pathways associated with tumor progression. The role of HuR overexpression in pancreatic tumorigenesis is unknown and led us to explore the consequences of HuR overexpression using a novel transgenic mouse model that has a >2-fold elevation of pancreatic HuR expression. Histologically, HuR-overexpressing pancreas displays a fibroinflammatory response and other pathological features characteristic of chronic pancreatitis. This pathology is reflected in changes in the pancreatic gene expression profile due, in part, to genes whose expression changes as a consequence of direct binding of their respective mRNAs to HuR. Older mice develop pancreatic steatosis and severe glucose intolerance. Elevated HuR cooperated with mutant K-rasG12D to result in a 3.4-fold increase in pancreatic ductal adenocarcinoma (PDAC) incidence compared to PDAC presence in K-rasG12D alone. These findings implicate HuR as a facilitator of pancreatic tumorigenesis, especially in the setting of inflammation, and a novel therapeutic target for pancreatitis treatment.
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Affiliation(s)
- Weidan Peng
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
| | - Narumi Furuuchi
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
| | | | - Yu-Hung Huang
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
| | - Samantha Z Brown
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Wei Jiang
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Sankar Addya
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | | | - Erika Peters
- University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Jonathan R Brody
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Dan A Dixon
- University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Janet A Sawicki
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
- Sidney Kimmel Cancer Center at the Jefferson Pancreatic, Biliary, and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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9
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Nomura A, Gupta VK, Dauer P, Sharma NS, Dudeja V, Merchant N, Saluja AK, Banerjee S. NFκB-Mediated Invasiveness in CD133 + Pancreatic TICs Is Regulated by Autocrine and Paracrine Activation of IL1 Signaling. Mol Cancer Res 2017; 16:162-172. [PMID: 28970361 DOI: 10.1158/1541-7786.mcr-17-0221] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 08/14/2017] [Accepted: 09/22/2017] [Indexed: 12/21/2022]
Abstract
Tumor-initiating cells (TIC) have been implicated in pancreatic tumor initiation, progression, and metastasis. Among different markers that define this cell population within the tumor, the CD133+ cancer stem cell (CSC) population has reliably been described in these processes. CD133 expression has also been shown to functionally promote metastasis through NF-κB activation in this population, but the mechanism is unclear. In the current study, overexpression of CD133 increased expression and secretion of IL1β (IL1B), which activates an autocrine signaling loop that upregulates NF-κB signaling, epithelial-mesenchymal transition (EMT), and cellular invasion. This signaling pathway also induces CXCR4 expression, which in turn is instrumental in imparting an invasive phenotype to these cells. In addition to the autocrine signaling of the CD133 secreted IL1β, the tumor-associated macrophages (TAM) also produced IL1β, which further activated this pathway in TICs. The functional significance of the TIC marker CD133 has remained elusive for a very long time; the current study takes us one step closer to understanding how the downstream signaling pathways in these cells regulate the functional properties of TICs.Implications: This study demonstrates the important role of tumor- and macrophage-derived IL1β stimulation in pancreatic cancer. IL1 signaling is increased in cells with CD133 expression, leading to increased NF-kB activity, EMT induction, and invasion. Increased invasiveness via IL1β stimulation is mediated by the upregulation of CXCR4 expression. The study highlights the importance of IL1-mediated signaling in TICs. Mol Cancer Res; 16(1); 162-72. ©2017 AACR.
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Affiliation(s)
- Alice Nomura
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.,II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Vineet K Gupta
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Patricia Dauer
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.,Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota
| | - Nikita S Sharma
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.,Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida
| | - Vikas Dudeja
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Nipun Merchant
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Ashok K Saluja
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Sulagna Banerjee
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
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10
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Abstract
Pancreatic diseases, chronic pancreatitis, pancreatic cancer and diabetes mellitus, taken together, occur in >10% of the world population. Pancreatic diseases, as with other diseases, benefit from early intervention and appropriate diagnosis. Although imaging technologies have given clinicians an unprecedented toolbox to aid in clinical decision-making, advances in these technologies and development of molecular-based diagnostic tools could enable physicians to identify diseases at an even earlier stage and, thereby, improve patient outcomes. In this Review, we discuss and identify gaps in the use of imaging techniques for the early detection and appropriate treatment stratification of various pancreatic diseases, including diabetes mellitus, acute and chronic pancreatitis and pancreatic cancer. Imaging techniques discussed are MRI, CT, PET and ultrasonography. Additionally, the identification of new molecular targets for imaging and the development of contrast agents that are able to give molecular information in noninvasive radionuclear imaging and ultrasonography are emerging areas of innovation that could lead to increased diagnostic accuracy and improved patient outcomes.
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Affiliation(s)
- Julien Dimastromatteo
- Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Building MR5, Charlottesville, Virginia 22903, USA
| | - Teresa Brentnall
- Division of Gastroenterology, Digestive Diseases Center, 1959 Northeast Pacific Street, Seattle, Washington 98195, USA
| | - Kimberly A Kelly
- Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Building MR5, Charlottesville, Virginia 22903, USA
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Franco-Barraza J, Francescone R, Luong T, Shah N, Madhani R, Cukierman G, Dulaimi E, Devarajan K, Egleston BL, Nicolas E, Katherine Alpaugh R, Malik R, Uzzo RG, Hoffman JP, Golemis EA, Cukierman E. Matrix-regulated integrin α vβ 5 maintains α 5β 1-dependent desmoplastic traits prognostic of neoplastic recurrence. eLife 2017; 6. [PMID: 28139197 PMCID: PMC5283834 DOI: 10.7554/elife.20600] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 01/05/2017] [Indexed: 12/18/2022] Open
Abstract
Desmoplasia, a fibrotic mass including cancer-associated fibroblasts (CAFs) and self-sustaining extracellular matrix (D-ECM), is a puzzling feature of pancreatic ductal adenocarcinoma (PDACs). Conflicting studies have identified tumor-restricting and tumor-promoting roles of PDAC-associated desmoplasia, suggesting that individual CAF/D-ECM protein constituents have distinguishable tumorigenic and tumor-repressive functions. Using 3D culture of normal pancreatic versus PDAC-associated human fibroblasts, we identified a CAF/D-ECM phenotype that correlates with improved patient outcomes, and that includes CAFs enriched in plasma membrane-localized, active α5β1-integrin. Mechanistically, we established that TGFβ is required for D-ECM production but dispensable for D-ECM-induced naïve fibroblast-to-CAF activation, which depends on αvβ5-integrin redistribution of pFAK-independent active α5β1-integrin to assorted endosomes. Importantly, the development of a simultaneous multi-channel immunofluorescence approach and new algorithms for computational batch-analysis and their application to a human PDAC panel, indicated that stromal localization and levels of active SMAD2/3 and α5β1-integrin distinguish patient-protective from patient-detrimental desmoplasia and foretell tumor recurrences, suggesting a useful new prognostic tool. DOI:http://dx.doi.org/10.7554/eLife.20600.001 Tumors are not entirely made out of cancerous cells. They contain many other components – referred to as tumor stroma – that may either encourage or hinder the tumor’s growth. Tumor stroma includes non-cancerous cells and a framework of fibrous sugary proteins, called the extracellular matrix, which surround and signal to cells while providing physical support. In the most common and aggressive form of pancreatic cancer, the stroma often makes up the majority of the tumor’s mass. Sometimes the stroma of these pancreatic tumors can protect the cancer cells from anti-cancer drugs. Researchers have therefore been interested in finding out exactly which aspects of the tumor stroma shield and support cancer cells, and which impede their growth and progression. Answering these questions could make it possible to develop new drugs that will change a tumor-supporting stroma into one that hinders the tumor’s growth and spread. The most abundant cells in the stroma of pancreatic tumors are called cancer-associated fibroblasts. Healthy specialized fibroblasts – known as pancreatic stellate cells – help to build and maintain the ‘normal’ extracellular matrix and so these cells normally restrict a tumor’s development. However, cancer cells can adapt healthy fibroblasts into cancer-associated fibroblasts, which produce an altered extracellular matrix that could allow the tumor to grow. Franco-Barraza et al. have now compared healthy and cancer-associated fibroblasts from patients’ pancreatic tumors. One of the main differences between these two cell types was the location of the activated form of a molecule called α5β1-integrin. Healthy fibroblasts, in a normal extracellular matrix, have active α5β1-integrin on the surface of the cell. However, a number of tumor-promoting signals, including some from the altered extracellular matrix, could force the active α5β1-integrins to relocate inside the fibroblasts instead. In further experiments, where the activated integrin was retained at the cell surface, the fibroblasts were able to resist the influence of the cancer-associated extracellular matrix. Then again, if the active α5β1-integrins were directed inside the cells, healthy cells turned into cancer-associated fibroblasts. With this information in hand, Franco-Barraza et al. examined tumor samples from over a hundred pancreatic cancer patients using a new microscopy-based technique that distinguishes cancer cells from stroma cells. The analysis confirmed the pattern observed in the laboratory: those patients who appeared to produce more normal extracellular matrix and have active α5β1-integrin localized mostly to the surface of the cells survived longer without the cancer returning than those patients who lacked these stroma traits. Samples from patients with kidney cancer also showed similar results and, as before, an altered extracellular matrix was linked to a worse outcome of the disease. Together these findings suggest that if future studies uncover ways to relocate or maintain active α5β1-integrin to the cell surface of fibroblasts they could lead to new treatments to restrict the growth of tumors in cancer patients. DOI:http://dx.doi.org/10.7554/eLife.20600.002
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Affiliation(s)
| | - Ralph Francescone
- Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
| | - Tiffany Luong
- Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
| | - Neelima Shah
- Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
| | - Raj Madhani
- Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
| | - Gil Cukierman
- Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
| | - Essel Dulaimi
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, United States
| | - Karthik Devarajan
- Department of Cancer Epigenetics, Fox Chase Cancer Center, Philadelphia, United States
| | - Brian L Egleston
- Department of Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, United States
| | - Emmanuelle Nicolas
- Programs in Genomics, Fox Chase Cancer Center, Philadelphia, United States
| | | | - Ruchi Malik
- Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
| | - Robert G Uzzo
- Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States.,Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, United States
| | - John P Hoffman
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, United States
| | - Erica A Golemis
- Department of Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, United States
| | - Edna Cukierman
- Department of Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
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Overbeek KA, Cahen DL, Canto MI, Bruno MJ. Surveillance for neoplasia in the pancreas. Best Pract Res Clin Gastroenterol 2016; 30:971-986. [PMID: 27938791 PMCID: PMC5552042 DOI: 10.1016/j.bpg.2016.10.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 10/25/2016] [Accepted: 10/31/2016] [Indexed: 01/31/2023]
Abstract
Despite its low incidence in the general population, pancreatic cancer is one of the leading causes of cancer-related mortality. Survival greatly depends on operability, but most patients present with unresectable disease. Therefore, there is great interest in the early detection of pancreatic cancer and its precursor lesions by surveillance. Worldwide, several programs have been initiated for individuals at high risk for pancreatic cancer. Their first results suggest that surveillance in high-risk individuals is feasible, but their effectiveness in decreasing mortality remains to be proven. This review will discuss which individuals are eligible for surveillance, which lesions are aimed to be detected, and which surveillance modalities are being used in current clinical practice. Furthermore, it addresses the management of abnormalities found during surveillance and topics for future research.
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Affiliation(s)
- Kasper A. Overbeek
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ‘s Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands,Corresponding author. Fax: +31 10 703 03 31
| | - Djuna L. Cahen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ‘s Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | - Marcia Irene Canto
- Division of Gastroenterology and Hepatology, The Johns Hopkins Medical Institutions, 1800 Orleans St., Blalock 407, Baltimore, MD, 21287, USA
| | - Marco J. Bruno
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, ‘s Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
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13
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Baines A, Martin P, Rorie C. Current and Emerging Targeting Strategies for Treatment of Pancreatic Cancer. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 144:277-320. [DOI: 10.1016/bs.pmbts.2016.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Abstract
OBJECTIVE We describe the first mouse model of pancreatic intraepithelial neoplasia (PanIN) lesions induced by alcohol in the presence and absence of chronic pancreatitis. METHODS Pdx1-Cre;LSL-K-ras mice were exposed to Lieber-DeCarli alcohol diet for 6 weeks with cerulein injections. The PanIN lesions and markers of fibrosis, inflammation, histone deacetylation, epithelial-to-mesenchymal transition (EMT), and cancer stemness were measured by immunohistochemistry and Western. RESULTS Exposure of Pdx1-Cre;LSL-K-ras mice to an alcohol diet significantly stimulated fibrosis and slightly but not significantly increased the level of PanIN lesions associated with an increase in tumor-promoting M2 macrophages. Importantly, the alcohol diet did not increase activation of stellate cells. Alcohol diet and cerulein injections resulted in synergistic and additive effects on PanIN lesion and M2 macrophage phenotype induction, respectively. Cerulein pancreatitis caused stellate cell activation, EMT, and cancer stemness in the pancreas. Pancreatitis caused histone deacetylation, which was promoted by the alcohol diet. Pancreatitis increased EMT and cancer stemness markers, which were not further affected by the alcohol diet. CONCLUSIONS The results suggest that alcohol has independent effects on promotion of PDAC associated with fibrosis formed through a stellate cell-independent mechanism and that it further promotes early PDAC and M2 macrophage induction in the context of chronic pancreatitis.
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Falzon M, Bhatia V. Role of Parathyroid Hormone-Related Protein Signaling in Chronic Pancreatitis. Cancers (Basel) 2015; 7:1091-108. [PMID: 26095761 PMCID: PMC4491701 DOI: 10.3390/cancers7020826] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 06/05/2015] [Accepted: 06/09/2015] [Indexed: 12/21/2022] Open
Abstract
Chronic pancreatitis (CP), a progressive inflammatory disease where acini are destroyed and replaced by fibrous tissue, increases the risk for pancreatic cancer. Risk factors include alcohol, smoking, and obesity. The effects of these risk factors are exacerbated in patients with mutations in genes that predispose to CP. The different environmental and genetic factors produce the same clinical phenotype; once CP develops, disease course is the same regardless of etiology. Critical questions still need to be answered to understand what modifies predisposition to develop CP in persons exposed to risk factors. We postulate that risk factors modulate endogenous pathways, with parathyroid hormone-related protein (PTHrP) signaling being one such pathway. In support, PTHrP levels are elevated in mice treated with alcohol, and in mouse models of cerulein- and pancreatic duct ligation-induced CP. Disrupting the Pthrp gene in acinar cells exerts protective effects (decreased edema, histological damage, amylase and cytokine release, and fibrosis) in these CP models. PTHrP levels are elevated in human CP. Currently, CP care lacks specific pharmacological interventions. Targeting PTHrP signaling may present a novel therapeutic strategy that inhibits pancreatic inflammation and fibrosis, especially since the risk of developing pancreatic cancer is strongly associated with duration of chronic inflammation.
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Affiliation(s)
- Miriam Falzon
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
| | - Vandanajay Bhatia
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
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16
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Abstract
Pancreatic cancer is one of the most lethal malignancies. Significant progresses have been made in understanding of pancreatic cancer pathogenesis, including appreciation of precursor lesions or premalignant pancreatic intraepithelial neoplasia (PanINs), description of sequential transformation from normal pancreatic tissue to invasive pancreatic cancer and identification of major genetic and epigenetic events and the biological impact of those events on malignant behavior. However, the currently used therapeutic strategies targeting tumor epithelial cells, which are potent in cell culture and animal models, have not been successful in the clinic. Presumably, therapeutic resistance of pancreatic cancer is at least in part due to its drastic desmoplasis, which is a defining hallmark for and circumstantially contributes to pancreatic cancer development and progression. Improved understanding of the dynamic interaction between cancer cells and the stroma is important to better understanding pancreatic cancer biology and to designing effective intervention strategies. This review focuses on the origination, evolution and disruption of stromal molecular and cellular components in pancreatic cancer, and their biological effects on pancreatic cancer pathogenesis.
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Affiliation(s)
- Dacheng Xie
- Department of Medical Oncology and Tumor Institute, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Keping Xie
- Department of Medical Oncology and Tumor Institute, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Orywal K, Jelski W, Werel T, Szmitkowski M. The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in renal cell carcinoma. Exp Mol Pathol 2015; 98:403-6. [PMID: 25779850 DOI: 10.1016/j.yexmp.2015.03.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 03/06/2015] [Accepted: 03/07/2015] [Indexed: 10/23/2022]
Abstract
OBJECTIVES Ethanol has been considered as a lifestyle risk factor for cancer in humans. While some studies have indicated that alcohol intake has a preventive effect for renal cell cancer, others have not. The metabolism of alcohol in cancer cells may be in many ways different than in healthy tissue and its disturbances could be associated with carcinogenesis. The aim of this study was to compare the metabolism of renal cell cancer cells and normal renal cells by measurement of ADH isoenzymes and ALDH activities in these tissues. MATERIAL AND METHODS The study material consisted of 43 cancerous renal tissues (14 patients in stage II, 19 in stage III and 10 in stage IV). Class III and IV ADH and total ADH activities were measured by the photometric method and class I and II ADH and ALDH activities by the fluorometric method with class-specific fluorogenic substrates. RESULTS The activity of the class I ADH isoenzyme and the total ADH was significantly higher in every stage of renal cell cancer as compared to healthy tissues. Analysis of ALDH activity did not show statistically significant differences between cancer and healthy cells. CONCLUSION The increased activity of total ADH in renal cell cancer, especially the class I isoenzyme and normal activity of ALDH, may be the factor intensifying carcinogenesis because of increasing the ability to highly carcinogenic acetaldehyde formation and causing disorders in metabolism of many biologically important substances.
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Affiliation(s)
- Karolina Orywal
- Department of Biochemical Diagnostics, Medical University, Bialystok, Poland.
| | - Wojciech Jelski
- Department of Biochemical Diagnostics, Medical University, Bialystok, Poland
| | - Tadeusz Werel
- Department of Urology, Medical University, Bialystok, Poland
| | - Maciej Szmitkowski
- Department of Biochemical Diagnostics, Medical University, Bialystok, Poland
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Kumaran S, Samantha K, Halagowder D. Does ß-Catenin Cross-Regulate NFκB Signalling in Pancreatic Cancer and Chronic Pancreatitis? Pathobiology 2015; 82:28-35. [DOI: 10.1159/000369887] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 11/13/2014] [Indexed: 11/19/2022] Open
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19
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Keenan BP, Saenger Y, Kafrouni MI, Leubner A, Lauer P, Maitra A, Rucki AA, Gunderson AJ, Coussens LM, Brockstedt DG, Dubensky TW, Hassan R, Armstrong TD, Jaffee EM. A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology 2014; 146:1784-94.e6. [PMID: 24607504 PMCID: PMC4035450 DOI: 10.1053/j.gastro.2014.02.055] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 02/09/2014] [Accepted: 02/26/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Premalignant lesions and early stage tumors contain immunosuppressive microenvironments that create barriers for cancer vaccines. Kras(G12D/+);Trp53(R172H/+);Pdx-1-Cre (KPC) mice, which express an activated form of Kras in pancreatic tissues, develop pancreatic intraepithelial neoplasms (PanIN) that progress to pancreatic ductal adenocarcinoma (PDA). We used these mice to study immune suppression in PDA. METHODS We immunized KPC and Kras(G12D/+);Pdx-1-Cre mice with attenuated intracellular Listeria monocytogenes (which induces CD4(+) and CD8(+) T-cell immunity) engineered to express Kras(G12D) (LM-Kras). The vaccine was given alone or in sequence with an anti-CD25 antibody (PC61) and cyclophosphamide to deplete T-regulatory (Treg) cells. Survival times were measured; pancreatic and spleen tissues were collected and analyzed by histologic, flow cytometry, and immunohistochemical analyses. RESULTS Interferon γ-mediated, CD8(+) T-cell responses were observed in KPC and Kras(G12D/+);Pdx-1-Cre mice given LM-Kras, but not in unvaccinated mice. Administration of LM-Kras to KPC mice 4-6 weeks old (with early stage PanINs), depleted of Treg cells, significantly prolonged survival and reduced PanIN progression (median survival, 265 days), compared with unvaccinated mice (median survival, 150 days; P = .002), mice given only LM-Kras (median survival, 150 days; P = .050), and unvaccinated mice depleted of Treg cells (median survival, 170 days; P = .048). In 8- to 12-week-old mice (with late-stage PanINs), LM-Kras, alone or in combination with Treg cell depletion, did not increase survival time or slow PanIN progression. The combination of LM-Kras and Treg cell depletion reduced numbers of Foxp3(+)CD4(+) T cells in pancreatic lymph nodes, increased numbers of CD4(+) T cells that secrete interleukin 17 and interferon γ, and caused CD11b(+)Gr1(+) cells in the pancreas to acquire an immunostimulatory phenotype. CONCLUSIONS Immunization of KPC mice with Listeria monocytogenes engineered to express Kras(G12D), along with depletion of Treg cells, reduces progression of early stage, but not late-stage, PanINs. This approach increases infiltration of the lesion with inflammatory cells. It might be possible to design immunotherapies against premalignant pancreatic lesions to slow or prevent progression to PDA.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- CD11b Antigen/metabolism
- Cancer Vaccines/immunology
- Cancer Vaccines/therapeutic use
- Carcinoma in Situ/drug therapy
- Carcinoma in Situ/genetics
- Carcinoma in Situ/immunology
- Carcinoma in Situ/metabolism
- Carcinoma in Situ/pathology
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/immunology
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cyclophosphamide/pharmacology
- Disease Models, Animal
- Disease Progression
- Forkhead Transcription Factors/metabolism
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Humans
- Inflammation Mediators/metabolism
- Integrases/genetics
- Integrases/metabolism
- Interferon-gamma/metabolism
- Interleukin-17/metabolism
- Listeria monocytogenes/genetics
- Listeria monocytogenes/immunology
- Listeria monocytogenes/metabolism
- Mice
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Transgenic
- Mutation
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/immunology
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Proto-Oncogene Proteins p21(ras)/genetics
- Proto-Oncogene Proteins p21(ras)/metabolism
- Receptors, Chemokine/metabolism
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Time Factors
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
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Affiliation(s)
- Bridget P Keenan
- The Sidney Kimmel Comprehensive Cancer Center, the Skip Viragh Center for Clinical Pancreatic Cancer Research, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, Maryland; Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yvonne Saenger
- Division of Hematology and Oncology, Tisch Cancer Institute and Department of Dermatology, Mount Sinai School of Medicine, New York, New York
| | - Michel I Kafrouni
- The Sidney Kimmel Comprehensive Cancer Center, the Skip Viragh Center for Clinical Pancreatic Cancer Research, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Ashley Leubner
- The Sidney Kimmel Comprehensive Cancer Center, the Skip Viragh Center for Clinical Pancreatic Cancer Research, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, Maryland
| | | | - Anirban Maitra
- Department of Pathology and Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Agnieszka A Rucki
- The Sidney Kimmel Comprehensive Cancer Center, the Skip Viragh Center for Clinical Pancreatic Cancer Research, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Andrew J Gunderson
- Department of Cell and Developmental Biology, Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon
| | - Lisa M Coussens
- Department of Cell and Developmental Biology, Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon
| | | | | | - Raffit Hassan
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Todd D Armstrong
- The Sidney Kimmel Comprehensive Cancer Center, the Skip Viragh Center for Clinical Pancreatic Cancer Research, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Elizabeth M Jaffee
- The Sidney Kimmel Comprehensive Cancer Center, the Skip Viragh Center for Clinical Pancreatic Cancer Research, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, Maryland.
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20
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Zhang Y, Yan W, Mathew E, Bednar F, Wan S, Collins MA, Evans RA, Welling TH, Vonderheide RH, di Magliano MP. CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice. Cancer Immunol Res 2014; 2:423-35. [PMID: 24795355 DOI: 10.1158/2326-6066.cir-14-0016-t] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer, one of the deadliest human malignancies, is associated with oncogenic Kras and is most commonly preceded by precursor lesions known as pancreatic intraepithelial neoplasias (PanIN). PanIN formation is accompanied by the establishment of an immunotolerant microenvironment. However, the immune contribution to the initiation of pancreatic cancer is currently poorly understood. Here, we genetically eliminate CD4+ T cells in the iKras* mouse model of pancreatic cancer, in the context of pancreatitis, to determine the functional role of CD4+ T cells during mutant Kras-driven pancreatic carcinogenesis. We show that oncogenic Kras-expressing epithelial cells drive the establishment of an immunosuppressive microenvironment through the recruitment and activity of CD4+ T cells. Furthermore, we show that CD4+ T cells functionally repress the activity of CD8+ T cells. Elimination of CD4+ T cells uncovers the antineoplastic function of CD8+ T cells and blocks the onset of pancreatic carcinogenesis. Thus, our studies uncover essential and opposing roles of immune cells during PanIN formation and provide a rationale to explore immunomodulatory approaches in pancreatic cancer.
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Affiliation(s)
- Yaqing Zhang
- Authors' Affiliations: Departments of Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Collins MA, Pasca di Magliano M. Kras as a key oncogene and therapeutic target in pancreatic cancer. Front Physiol 2014; 4:407. [PMID: 24478710 PMCID: PMC3896882 DOI: 10.3389/fphys.2013.00407] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 12/24/2013] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is one of the deadliest human malignancies and little progress has been achieved in its treatment over the past decades. Advances in our understanding of the biology of this disease provide new potential opportunities for treatment. Pancreatic cancer is preceded by precursor lesions, the most common of which are known as Pancreatic Intraepithelial Neoplasia (PanIN). PanIN lesions, which are the focus of this review, have a high incidence of Kras mutations, and Kras mutations are a hallmark of the late-stage disease. We now know from genetically engineered mouse models that oncogenic Kras is not only driving the formation of pancreatic cancer precursor lesions, but it is also required for their progression, and for the maintenance of invasive and metastatic disease. Thus, an enormous effort is being placed in generating Kras inhibitors for clinical use. Additionally, alternative approaches, including understanding the role of Kras effector pathways at different stages of the disease progression, are being devised to target Kras effector pathways therapeutically. In particular, efforts have focused on the MAPK pathway and the PI3K pathway, for which inhibitors are widely available. Finally, recent studies have highlighted the need for oncogenic Kras to establish feedback mechanisms that maintain its levels of activity; the latter might constitute alternative ways to target Kras in pancreatic cancer. Here, we will review recent basic research and discuss potential therapeutic applications.
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Affiliation(s)
- Meredith A Collins
- Program in Cellular and Molecular Biology, University of Michigan Ann Arbor, MI, USA
| | - Marina Pasca di Magliano
- Program in Cellular and Molecular Biology, University of Michigan Ann Arbor, MI, USA ; Department of Surgery, University of Michigan Ann Arbor, MI, USA ; Department of Cell and Developmental Biology, University of Michigan Ann Arbor, MI, USA
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22
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Stopczynski RE, Normolle DP, Hartman DJ, Ying H, DeBerry JJ, Bielefeldt K, Rhim AD, DePinho RA, Albers KM, Davis BM. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res 2014; 74:1718-27. [PMID: 24448244 DOI: 10.1158/0008-5472.can-13-2050] [Citation(s) in RCA: 147] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Perineural tumor invasion of intrapancreatic nerves, neurogenic inflammation, and tumor metastases along extrapancreatic nerves are key features of pancreatic malignancies. Animal studies show that chronic pancreatic inflammation produces hypertrophy and hypersensitivity of pancreatic afferents and that sensory fibers may themselves drive inflammation via neurogenic mechanisms. Although genetic mutations are required for cancer development, inflammation has been shown to be a precipitating event that can accelerate the transition of precancerous lesions to cancer. These observations led us to hypothesize that inflammation that accompanies early phases of pancreatic ductal adenocarcinoma (PDAC) would produce pathologic changes in pancreatic neurons and innervation. Using a lineage-labeled genetically engineered mouse model of PDAC, we found that pancreatic neurotrophic factor mRNA expression and sensory innervation increased dramatically when only pancreatic intraepithelial neoplasia were apparent. These changes correlated with pain-related decreases in exploratory behavior and increased expression of nociceptive genes in sensory ganglia. At later stages, cells of pancreatic origin could be found in the celiac and sensory ganglia along with metastases to the spinal cord. These results demonstrate that the nervous system participates in all stages of PDAC, including those that precede the appearance of cancer.
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Affiliation(s)
- Rachelle E Stopczynski
- Authors' Affiliations: Departments of Neurobiology, Biostatistics, Pathology, and Medicine, University of Pittsburgh School of Medicine; Departments of Genomic Medicine and Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
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Tang D, Wang D, Yuan Z, Xue X, Zhang Y, An Y, Chen J, Tu M, Lu Z, Wei J, Jiang K, Miao Y. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J Cancer 2013; 132:993-1003. [PMID: 22777597 DOI: 10.1002/ijc.27715] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Revised: 06/20/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors with poor prognosis due to extremely high malignancy, low rate of eligibility for surgical resection and chemoradiation resistance. Increasing evidence indicate that the interaction between activated pancreatic stellate cells (PSCs) and PDAC cells plays an important role in the development of PDAC. By producing high levels of cytokines, chemotactic factors, growth factors and excessive extracellular matrix (ECM), PSCs create desmoplasia and a hypoxic microenvironment that promote the initiation, development, evasion of immune surveillance, invasion, metastasis and resistance to chemoradiation of PDAC. Therefore, targeting the interaction between PSCs and PDAC cells may represent a novel therapeutic approach to advanced PDAC, especially therapies that target PSCs of the pancreatic tumor microenvironment.
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Affiliation(s)
- Dong Tang
- Department of Gastrointestinal Surgery, Subei People's Hospital of Jiangsu Province (Clinical Medical College of Yangzhou University), Yangzhou, People's Republic of China
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Herreros-Villanueva M, Hijona E, Bañales JM, Cosme A, Bujanda L. Alcohol consumption on pancreatic diseases. World J Gastroenterol 2013; 19:638-647. [PMID: 23429423 PMCID: PMC3574589 DOI: 10.3748/wjg.v19.i5.638] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Revised: 08/14/2012] [Accepted: 08/16/2012] [Indexed: 02/06/2023] Open
Abstract
Although the association between alcohol and pancreatic diseases has been recognized for a long time, the impact of alcohol consumption on pancreatitis and pancreatic cancer (PC) remains poorly defined. Nowadays there is not consensus about the epidemiology and the beverage type, dose and duration of alcohol consumption causing these diseases. The objective of this study was to review the epidemiology described in the literature for pancreatic diseases as a consequence of alcoholic behavior trying to understand the association between dose, type and frequency of alcohol consumption and risk of pancreatitis and PC. The majority of the studies conclude that high alcohol intake was associated with a higher risk of pancreatitis (around 2.5%-3% between heavy drinkers and 1.3% between non drinkers). About 70% of pancreatitis are due to chronic heavy alcohol consumption. Although this incidence rate differs between countries, it is clear that the risk of developing pancreatitis increases with increasing doses of alcohol and the average of alcohol consumption vary since 80 to 150 g/d for 10-15 years. With regard to PC, the role of alcohol consumption remains less clear, and low to moderate alcohol consumption do not appear to be associated with PC risk, and only chronic heavy drinking increase the risk compared with lightly drinkers. In a population of 10%-15% of heavy drinkers, 2%-5% of all PC cases could be attributed to alcohol consumption. However, as only a minority (less than 10% for pancreatitis and 5% for PC) of heavily drinkers develops these pancreatic diseases, there are other predisposing factors besides alcohol involved. Genetic variability and environmental exposures such as smoking and diet modify the risk and should be considered for further investigations.
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Kong X, Li L, Li Z, Xie K. Targeted destruction of the orchestration of the pancreatic stroma and tumor cells in pancreatic cancer cases: molecular basis for therapeutic implications. Cytokine Growth Factor Rev 2012; 23:343-56. [PMID: 22749856 PMCID: PMC3505269 DOI: 10.1016/j.cytogfr.2012.06.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 06/07/2012] [Indexed: 12/16/2022]
Abstract
Pancreatic cancer is one of the most lethal malignancies, with a prominent desmoplastic reaction as its defining hallmark. The past several decades have seen dramatic progress in understanding of pancreatic cancer pathogenesis, including identification of precursor lesions, sequential transformation from normal pancreatic tissue to invasive pancreatic cancer and corresponding signature genetic events, and the biological impact of these events on malignant behavior. However, the currently used therapeutic strategies for epithelial tumor cells, which have exhibited potent antitumor activity in cell culture and animal models, have failed to produce significant effects in the clinic. The desmoplastic stroma surrounding pancreatic cancer cells, which accounts for about 90% of a tumor's mass, clearly is not a passive scaffold for cancer cells but an active contributor to carcinogenesis. Improved understanding of the dynamic interaction between cancer cells and the stroma will be important to designing effective therapeutic strategies for pancreatic cancer. This review focuses on the origin of stromal molecular and cellular components in pancreatic tumors, their biological effects on pancreatic cancer cells, and the orchestration of these two components.
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Affiliation(s)
- Xiangyu Kong
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, The People’s Republic of China
| | - Lei Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, The People’s Republic of China
| | - Zhaoshen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, The People’s Republic of China
| | - Keping Xie
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Screening of R122H and N29I mutations in the PRSS1 gene and N34S mutation in the SPINK1 gene in Mexican pediatric patients with acute and recurrent pancreatitis. Pancreas 2012; 41:707-11. [PMID: 22699143 DOI: 10.1097/mpa.0b013e31823cd873] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVES The study's objective was to assess the association between the PRSS1 R122H and N29I and the SPINK1 N34S mutations and acute pancreatitis (AP) and recurrent pancreatitis in Mexican pediatric patients. METHODS The N34S and R122H mutations were detected using polymerase chain reaction-restriction fragment length polymorphism, and the N29I mutation was detected using allele-specific polymerase chain reaction in 92 pancreatitis patients (58 AP and 34 recurrent pancreatitis patients) and 144 controls. RESULTS We found 1 mutated allele in 4 (4.3%) of 92 pancreatitis patients and none in the controls. All 4 patients bearing mutations had AP, with a frequency of 6.8% (4/58). Three (5.2%) of 58 patients were heterozygous for the N34S mutation, and 1 (1.7%) of 58 patients was heterozygous for the N29I mutation. The comparison between the AP and control groups revealed both a significant number of patients carrying any mutations in the screened genes (P = 0.008) and bearing the N34S mutation (P = 0.023). Moreover, we found that the N34S G allele increased the risk of developing AP (odds ratio, 10.3; confidence interval, 1.1-248.8). CONCLUSIONS Patients bearing the N34S G allele exhibited a 10-fold increased risk of developing AP compared with controls, suggesting that the SPINK1 N34S mutation represents an etiologic risk factor for AP in our Mexican pediatric patients.
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Kirkegaard J. Incidence of pancreatic cancer in Greenland 2000-2010. Int J Circumpolar Health 2012; 71:18368. [PMID: 22663941 PMCID: PMC3417692 DOI: 10.3402/ijch.v71i0.18368] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Revised: 04/22/2012] [Accepted: 04/23/2012] [Indexed: 12/23/2022] Open
Abstract
Background Inuit people are known to be at an increased risk of cancers usually uncommon to the western world such as cancers of the nasopharynx and salivary glands. But what is the trend regarding pancreatic cancer? Objective To determine the incidence of pancreatic cancer (PC) in Greenland compared with Denmark in the period 2000–2010. Study design Retrospective register-based study. Cases were retrieved from The Danish Cancer Register and The Greenlandic Patient Register and stratified in 5-year age intervals for each year. Age-standardized incidence ratios (SIR) for each year for Greenland compared with Denmark were calculated using the number of cases and the number of inhabitants in each 5-year age interval and in each country. The average SIR for the entire period was calculated using a weighted average. Results The study revealed a SIR of 2.38 (95% CI: 1.97–2.86; p<0.0001) indicating a significantly increased incidence of PC in Greenland compared with Denmark. A linear regression analysis showed no significant change in the SIR over time (p for trend 0.25) as well as no significant change isolated in Greenland (p for trend 0.8). Furthermore, the Inuit were significantly younger at the time of diagnosis (mean 62.7 vs. 70.0; p<0.0001). Conclusions The age-standardized incidence of PC is 138% higher in Greenland than in Denmark. A part of this could be explained by a higher prevalence of smoking and DM-2. However, the impact of genetic factors cannot be disregarded and should be subjected to further investigation.
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Zhao G, Qin Q, Zhang J, Liu Y, Deng S, Liu L, Wang B, Tian K, Wang C. Hypermethylation of HIC1 promoter and aberrant expression of HIC1/SIRT1 might contribute to the carcinogenesis of pancreatic cancer. Ann Surg Oncol 2012; 20 Suppl 3:S301-11. [PMID: 22552606 DOI: 10.1245/s10434-012-2364-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Indexed: 11/18/2022]
Abstract
BACKGROUND DNA hypermethylation is proved to be involved in carcinogenesis. Because chronic pancreatitis (CP) is a consistent risk factor for pancreatic cancer, the possible alteration and tumor contribute effects of hypermethylated in cancer-1 (HIC1) promoter methylation in CP was investigated. METHODS Methylation of HIC1 promoter HIC1 and SIRT1 expression were detected in human normal pancreas (NP), CP and pancreatic adenocarcinoma tissues. Furthermore, HIC1/SIRT1 pathway was regulated by demethylating reagent and exogenous expression in PANC-1, BxPC-3 and AsPC-1 cell lines, cell biology behavior including proliferation, apoptosis, cell cycle and senescence were detected. RESULTS The methylation of HIC1 promoter was demonstrated in 70.3 % pancreatic carcinoma (45 of 64), 47.5 % CP (19 of 40) and 11.4 % NP tissues (4 of 35). Moreover, hypermethylation of HIC1 promoter and deregulation of HIC1 expression in pancreatic cancer were significantly related to high-stage tumor and older patient age. HIC1 promoter hypermethylation was also observed in pancreatic cancer cell lines including PANC-1, BxPC-3 and AsPC-1. Restoration of HIC1 function with 5-aza-dC treatment or pCDNA3FlagHIC1 plasmid transfection leaded to a reduction in cell proliferation, obvious cell senescence, cell cycle arrest and apoptosis, accompanied with acetylated p53 and p21(WAF1 of Cip1) upregulation. While after further transfected with pCDNA3FlagSIRT1 plasmid, the growth inhibition, senescence and cycle arrest without apoptosis were partially rescued with deregulated acetylated p53 and p21(WAF1 of Cip1). CONCLUSIONS Our results indicate that hypermethylation of HIC1 promoter in CP may contribute to the aberrant expression of HIC1/SIRT1 pathway and then involve in the pancreatic carcinogenesis.
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Affiliation(s)
- Gang Zhao
- Pancreatic Disease Institute, Union Hospital, Wuhan City, Hubei Province, China,
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Bhat K, Wang F, Ma Q, Li Q, Mallik S, Hsieh TC, Wu E. Advances in biomarker research for pancreatic cancer. Curr Pharm Des 2012; 18:2439-51. [PMID: 22372502 PMCID: PMC3408036 DOI: 10.2174/13816128112092439] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 01/18/2012] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer (PC) is a leading cause of cancer related deaths in United States. The lack of early symptoms results in latestage detection and a high mortality rate. Currently, the only potentially curative approach for PC is surgical resection, which is often unsuccessful because the invasive and metastatic nature of the tumor masses makes their complete removal difficult. Consequently, patients suffer relapses from remaining cancer stem cells or drug resistance that eventually lead to death. To improve the survival rate, the early detection of PC is critical. Current biomarker research in PC indicates that a serum carbohydrate antigen, CA 19-9, is the only available biomarker with approximately 90% specificity to PC. However, the efficacy of CA 19-9 for assessing prognosis and monitoring patients with PC remains contentious. Thus, advances in technology and the detection of new biomarkers with high specificity to PC are needed to reduce the mortality rate of pancreatic cancer.
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Affiliation(s)
- Kruttika Bhat
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Fengfei Wang
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Qinyu Li
- Department of Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China
| | - Sanku Mallik
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Tze-chen Hsieh
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
| | - Erxi Wu
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
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30
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Jelski W, Kutylowska E, Laniewska-Dunaj M, Orywal K, Laszewicz W, Szmitkowski M. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with acute and chronic pancreatitis. Exp Mol Pathol 2011; 91:631-5. [DOI: 10.1016/j.yexmp.2011.06.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 06/12/2011] [Accepted: 06/13/2011] [Indexed: 12/20/2022]
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Abstract
The clinical outcome of patients with pancreatic cancer remains dismal despite recent advances in diagnostic and therapeutic modalities. Several risk factors have been reported regarding the development of pancreatic cancer. These risk factors include family history, accompanying diseases, and lifestyle/personal habits. Family history includes that of pancreatic cancer and hereditary pancreatic cancer syndrome. Accompanying diseases that increase the risk include diabetes mellitus, obesity, chronic pancreatitis, hereditary pancreatic cancer syndrome and intraductal papillary mucinous neoplasms. Lifestyle-associated factors include smoking and diet. Detailed examination of patients with such risk factors is warranted, but the cost-benefit effect should be considered. Thus, patients with more than one risk factor should be carefully followed up, and periodic examination of such patients is necessary to ensure the detection of smaller and less-advanced pancreatic cancer lesions and thus to improve the clinical outcome of patients with pancreatic cancer.
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Affiliation(s)
- Koji Yamaguchi
- Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health Japan, Yahatanishiku, Kitakyusyu, Japan. yamaguch @ med.uoeh-u.ac.jp
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32
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Wang W, Liao Z, Li G, Li ZS, Chen J, Zhan XB, Wang LW, Liu F, Hu LH, Guo Y, Zou DW, Jin ZD. Incidence of pancreatic cancer in chinese patients with chronic pancreatitis. Pancreatology 2011; 11:16-23. [PMID: 21311209 DOI: 10.1159/000322982] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Accepted: 11/19/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM It is suggested that patients with chronic pancreatitis (CP) have a markedly increased risk of pancreatic cancer compared with the general population. This study was designed to determine the rate of pancreatic cancer in CP patients in China. METHODS This was a semiprospective, single-center study including 420 consecutive CP patients (285 males and 135 females, median age at onset 39.5 years), with the median follow-up time being 102.3 months (range 24-419 months). We calculated the standardized incidence ratio (SIR) based on the pancreatic cancer incidence in the general population of China. RESULTS Four cases of pancreatic cancer (0.9% of patients) were observed in 3,591 patient-years (expected number of cases 0.15; SIR 27.2, 95% CI 7.4-69.6). Similar results were seen in alcoholics and non-alcoholics, and in smokers and non-smokers. When patients lost to follow-up were considered to be followed up until the end point without having developed pancreatic cancer (4,280 patient-years), SIR was 22.8 (CI 6.2-58.4). Based on the Cox model, with inserting factors being sex, age at the time of CP clinical onset, type of pancreatitis, and presence or absence of diabetes, calcification, alcohol use and smoking status, only age was found to correlate positively with the occurrence of pancreatic cancer (>50 years, hazard ratio, 1.8 ± 0.5; p = 0.044). CONCLUSION The risk of pancreatic cancer is markedly increased in CP patients in China compared with the general population, especially in older patients. and IAP.
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Affiliation(s)
- Wei Wang
- Chronic Pancreatic Study Group, Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
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Chronic pancreatitis and pancreatic cancer: prediction and mechanism. Clin Gastroenterol Hepatol 2009; 7:S23-8. [PMID: 19896093 DOI: 10.1016/j.cgh.2009.07.042] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2009] [Revised: 07/06/2009] [Accepted: 07/08/2009] [Indexed: 02/07/2023]
Abstract
We investigated the SPINK 1 mutations in 156 sporadic pancreatic cancer (PCa), and 8 pancreatic cancer with chronic pancreatitis (CPPCa) patients, and in 527 healthy subjects. The results demonstrated that 3 of 8 patients with CPPCa (37.5%) had the SPINK 1 gene N34S mutation. In addition, 3 of 156 sporadic PCa patients (1.9%) and 1 of them (0.6%) had the N34S and IVS3+2T>C mutation, respectively. The combined frequency of 2.5% was significantly higher than that of healthy subjects (0.38%), suggesting that the SPINK 1 mutation is an important risk factor for the development of pancreatic cancer. To investigate the genetic difference between sporadic PCa and CPPCa, we investigated several factors involved in the pathogenesis of PCa in 6 CPPCa and 15 sporadic PCa patients. The factors examined were genes including K-ras, p53, smad 4, p-smad 1, CXCL 14, NF-kB subunit p65 and Wnt 5a. No significant difference was found in the comparative examination of these factors, suggesting that the molecular disorders appeared to occur similarly in CPPCa as well as sporadic PCa. To assess the role of fibrosis in pancreatic carcinogenesis, we investigated the effects of pancreatic stellate cells (PSCs), which are largely responsible for pancreatic fibrogenesis, on duct cells, in vitro and in vivo. Activated PSCs were found surrounding precancerous duct cells in the tissues of a dimethylbenzanthracene mouse model and those of human PCa. Consistently, human pancreatic epithelial duct cells cultured with PSC conditioned media showed increased cell proliferation and colony formation, suggesting that PSCs may promote pancreatic ductal tumorigenesis.
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Irisawa A, Sato A, Sato M, Ikeda T, Suzuki R, Ohira H. Early diagnosis of small pancreatic cancer: role of endoscopic ultrasonography. Dig Endosc 2009; 21 Suppl 1:S92-6. [PMID: 19691746 DOI: 10.1111/j.1443-1661.2009.00866.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Advanced pancreatic cancer is a major cause of cancer-related death. However, if surgery achieves clear margins and negative lymph nodes, the prognosis for survival can be prolonged. Therefore, early diagnosis - as early as possible - is important for improving overall survival and quality of life in patients with pancreatic cancer. Because of higher imaging resolution near the pancreas through the gastroduodenal wall, endoscopic ultrasonography enables detection of subtle pancreatic abnormalities. In fact, many investigators have reported the high ability of EUS not only for detection of small lesions but also recognition of chronic pancreatitis, which is the risky status of pancreatic cancer. As a tool for early diagnosis of pancreatic cancer, EUS is a highly anticipated modality.
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Affiliation(s)
- Atsushi Irisawa
- Department of Internal Medicine, Fukushima Medical University School of Medicine, Japan.
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35
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Wheatley-Price P, Asomaning K, Reid A, Zhai R, Su L, Zhou W, Zhu A, Ryan DP, Christiani DC, Liu G. Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of developing pancreatic adenocarcinoma. Cancer 2008; 112:1037-42. [PMID: 18205184 DOI: 10.1002/cncr.23267] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Pancreatic cancer risk has been linked to chronic pancreatitis and periodontitis, suggesting a role for inflammation in disease etiology. Myeloperoxidase (MPO) and superoxide dismutase (SOD2) are enzymes that regulate reactive oxygen species and contain recognized single nucleotide polymorphisms (SNPs) that confer altered enzyme activity. METHODS One hundred twenty-two patients with pancreatic cancer and 331 age- and sex-matched controls were analyzed for polymorphisms of the MPO - guanine 463 adenine (-G463A) and the SOD2 alanine (Ala)-to-valine (Val) polymorphism at codon 16 (Ala16Val) genes. Cases and controls were analyzed for associations between these polymorphisms, adjusting for sex, age, history of alcohol use and smoking history. RESULTS The variant A allele of MPO -G463A was associated with a lower risk of pancreatic cancer (adjusted odds ratio [OR] for pancreatic cancer, 0.57; 95% confidence interval [95% CI], 0.4-0.9; P = .02). The SOD2 homozygous variant genotype (Val/Val) was associated with a greater risk of pancreatic cancer (adjusted OR, 1.96; 95% CI, 1.0-3.8; P = .04). Compared with individuals who carried both low-risk alleles (A/- and Ala/-), significantly more cases than controls carried both high-risk genotypes (G/G and Val/Val; adjusted OR, 4.31; 95% CI, 1.8-10; P = .001), or 1 high-risk genotype (adjusted OR, 1.96; 95% CI, 1.1-3.4; P = .01). CONCLUSIONS Polymorphisms of the inflammatory pathway genes MPO -G463A and SOD2 Ala16Val are associated with elevated pancreatic cancer risk. Oxidative stress may play an important role in pancreatic cancer carcinogenesis.
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Affiliation(s)
- Paul Wheatley-Price
- Department of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital, Toronto, Ontario, Canada
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36
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Patterns and trends of pancreatic cancer mortality rates in Arkansas, 1969-2002: a comparison with the US population. Eur J Cancer Prev 2008; 17:18-27. [PMID: 18090906 DOI: 10.1097/cej.0b013e32809b4ccd] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Little is known about trends in pancreatic cancer mortality in individual states of the US and its whole population. This study aimed to describe the patterns and trends of pancreatic cancer mortality in Arkansas, 1969-2002, using the US national rates as a reference. Joinpoint regression analyses were performed to evaluate trends in age-standardized mortality rates of pancreatic cancer by age group, sex, and race, using data obtained from the National Center for Health Statistics. Throughout the period examined, mortality decreased in young and middle-aged people (<60 years) and men but increased in old people (>/=60 years) and women. A continuous fall in mortality occurred among whites except for a transient rise in the late 1970s. For blacks, mortality rates did not cease to increase until 1995. Unlike in Arkansas, a monotonic upward or downward trend in mortality by age group and sex was not observed in the US. A decline of mortality stopped in 1997 for US whites. Recent decreasing trends were more pronounced in Arkansas blacks than in US blacks. Changes of pancreatic cancer mortality in the last three decades in Arkansas remarkably differed by age, sex, and race and were different in patterns from those of the US population.
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37
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Blondet JJ, Carlson AM, Kobayashi T, Jie T, Bellin M, Hering BJ, Freeman ML, Beilman GJ, Sutherland DER. The role of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Surg Clin North Am 2008; 87:1477-501, x. [PMID: 18053843 DOI: 10.1016/j.suc.2007.08.014] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Total pancreatectomy and islet autotransplantation are done for chronic pancreatitis with intractable pain when other treatment measures have failed, allowing insulin secretory capacity to be preserved, minimizing or preventing diabetes, while at the same time removing the root cause of the pain. Since the first case in 1977, several series have been published. Pain relief is obtained in most patients, and insulin independence preserved long term in about a third, with another third having sufficient beta cell function so that the surgical diabetes is mild. Islet autotransplantation has been done with partial or total pancreatectomy for benign and premalignant conditions. Islet autotransplantation should be used more widely to preserve beta cell mass in major pancreatic resections.
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Affiliation(s)
- Juan J Blondet
- Division of Surgical Critical Care/Trauma, Department of Surgery, University of Minnesota, MMC 11, 420 Delaware Street Southeast, Minneapolis, MN 55455, USA
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López A, de la Cueva L, Martínez MJ, Gómez F, Ripollés T, Sopena R, Moreno-Osset E. Usefulness of technetium-99m hexamethylpropylene amine oxime-labeled leukocyte scintigraphy to detect pancreatic necrosis in patients with acute pancreatitis. Prospective comparison with Ranson, Glasgow and APACHE-II scores and serum C-reactive protein. Pancreatology 2007; 7:470-8. [PMID: 17912011 DOI: 10.1159/000108964] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2006] [Accepted: 04/04/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND In acute pancreatitis (AP), pancreatic necrosis (PN) is an important local complication that can be identified by means of contrast-enhanced computed tomography (CECT). Pancreatic leukocyte infiltration is a significant pathogenic event in the development of PN that can be detected by labeled leukocyte scintigraphy (LLS). The aim of this study was to evaluate the utility of LLS with technetium-99m hexamethylpropylene amine oxime ((99m)Tc-HMPAO) to detect the presence of PN in patients with AP. METHODS Prospective cohort study of 84 patients with AP. Patients underwent LLS and the activity of images was scored on a 0-3 scale. CETC was performed to assess PN. Ranson, Glasgow and APACHE-II scores were calculated. Serum C-reactive protein (CRP) was measured. Sensitivity (Sn), specificity (Sp), positive predictive values (PPV), negative predictive values (NPV), areas under receiver operating characteristic (ROC) curves, likelihood ratios, odds ratios, analysis of variances between groups and correlation coefficients between tests were calculated. RESULTS PN was present in 11 (13%) patients. Pancreatic labeled leukocyte uptake was present in 38 patients (45%). Sn, Sp, PPV and NPV of LLS grade 2-3 for PN diagnosis were the highest (91, 88, 53 and 98%, respectively) of all tests. Patients with LLS grade 2-3 were 71 times more likely to be at risk of PN compared to those with LLS grade 0-1. The area under ROC curve of the LLS was the largest. A significant correlation was obtained between LLS and CRP (p < 0.001). CONCLUSION In patients with AP, LLS with (99m)Tc-HMPAO detects PN with an acceptable level of confidence and therefore could be considered an alternative technique to CECT in detecting PN.
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Affiliation(s)
- Antonio López
- Department of Gastroenterology, Dr. Peset University Hospital, University of Valencia, Valencia, Spain.
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39
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Zhang L, Sanderson SO, Lloyd RV, Smyrk TC. Pancreatic intraepithelial neoplasia in heterotopic pancreas: evidence for the progression model of pancreatic ductal adenocarcinoma. Am J Surg Pathol 2007; 31:1191-5. [PMID: 17667542 DOI: 10.1097/pas.0b013e31806841e1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Morphologic, clinical, and genetic evidence suggests that pancreatic intraepithelial neoplasia (PanIN) is a precursor to ductal adenocarcinoma. But understanding precursor lesions in a pancreas with existing tumor is hampered by the fact that chronic pancreatitis often accompanies carcinoma, and the possible interactions between tumor, chronic pancreatitis, and PanIN are complex. Furthermore, cancerization of ducts can mimic high-grade PanIN. Heterotopic pancreas has a genetic make-up, physiologic function, and local environmental exposure similar to that of the pancreas. It offers an opportunity to study putative precursor lesions in a setting with fewer confounding factors. We identified 6 pancreatic cancer patients who had heterotopic pancreas removed at the time of surgery. All 6 cases were immunostained for p53, cyclin D1, and p16. Molecular analysis of K-ras mutation was also done. All 6 cancer-associated heterotopias had PanIN-1A or 1B; 5 had PanIN-2 and 1 had PanIN-3. Three of 6 cases harbored the same K-ras codon 12 mutation as the PanINs in orthotopic pancreas, and a similar pattern of p53, cyclin D1, and p16 expression was observed between heterotopic and orthotopic pancreas in all 6 cases. There was no chronic pancreatitis in the cancer-associated heterotopias, but chronic pancreatitis was seen adjacent to carcinoma in 5 of 6 cases. The presence of PanIN in heterotopic pancreas from patients with ductal adenocarcinoma supports the progression model.
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Affiliation(s)
- Lizhi Zhang
- Department of Pathology, Mayo Clinic, Rochester, MN 55905, USA
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Abstract
The genetic paradigm of cancer, focused largely on sequential molecular aberrations and associated biological impact in the neoplastic cell compartment of malignant tumors, has dominated our view of cancer pathogenesis. For the most part, this conceptualization has overlooked the dynamic and complex contributions of the surrounding microenvironment comprised of non-tumor cells (stroma) that may resist, react to, and/or foster tumor development. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease in which a prominent tumor stroma compartment is a defining characteristic. Indeed, the bulk of PDAC tumor volume consists of non-neoplastic fibroblastic, vascular, and inflammatory cells surrounded by immense quantities of extracellular matrix, far exceeding that found in most other tumor types. Remarkably, little is known about the composition and physiology of the PDAC tumor microenvironment, in particular, the role of stroma in tumor initiation and progression. This review attempts to define key challenges, opportunities and state-of-knowledge relating to the PDAC microenvironment research with an emphasis on how inflammatory processes and key cancer pathways may shape the ontogeny of the tumor stroma. Such knowledge may be used to understand the evolution and biology of this lethal cancer and may convert these insights into new points of therapeutic intervention.
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Affiliation(s)
- Gerald C Chu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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Algül H, Treiber M, Lesina M, Schmid RM. Mechanisms of Disease: chronic inflammation and cancer in the pancreas—a potential role for pancreatic stellate cells? ACTA ACUST UNITED AC 2007; 4:454-62. [PMID: 17667994 DOI: 10.1038/ncpgasthep0881] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2007] [Accepted: 06/07/2007] [Indexed: 02/07/2023]
Abstract
Late diagnosis and ineffective therapeutic options mean that pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer. The identification of genetic alterations facilitated the launch of the Pancreatic Intraepithelial Neoplasm nomenclature, a standardized classification system for pancreatic duct lesions, but the factors that contribute to the development of such lesions and their progression to high-grade neoplasia remain obscure. Age, smoking, obesity and diabetes confer increased risk of PDA, and the presence of chronic pancreatitis is a consistent risk factor for pancreatic cancer. It is hypothesized that chronic inflammation generates a microenvironment that contributes to malignant transformation in the pancreas, as is known to occur in other organs. Pancreatic stellate cells (PSCs) are the main mediator of fibrogenesis during chronic pancreatitis, but their contribution to the development of PDA has not been elucidated. Data now suggest that PSCs might assume a linking role in inflammation-associated carcinogenesis through their ability to communicate with inflammatory cells, acinar cells, and pancreatic cancer cells in a complicated network of interactions. In this Review, the role of PSCs in the process of inflammation-associated carcinogenesis is discussed and new potential treatment options evaluated.
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Affiliation(s)
- Hana Algül
- Department of Internal Medicine, Technical University of Munich, Munich, Germany
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Jelski W, Chrostek L, Szmitkowski M. The activity of class I, II, III, and IV of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in pancreatic cancer. Pancreas 2007; 35:142-6. [PMID: 17632320 DOI: 10.1097/mpa.0b013e318053eae2] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVES The pancreas can metabolize ethanol via oxidative pathway involving the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as well as the nonoxidative pathway. In this study, we compared the activity of ADH isoenzymes and ALDH in the pancreatic cancer with the activity in normal tissue. In addition, the differences between enzyme activities of drinkers and nondrinkers were compared. METHODS For the measurement of the activity of class I and II ADH isoenzymes and ALDH activity, we used the fluorometric methods. The total ADH activity and activity of class III and IV isoenzymes were measured by the photometric method. The samples were taken from 56 pancreatic cancer patients (22 drinkers and 34 nondrinkers) and 56 healthy subjects. RESULTS The activity of class III ADH was significantly higher in cancer than in healthy tissues. Total activities of ADH and ALDH were not significantly different in cancer and normal cells. The differences between enzymes of drinkers and nondrinkers in both cancer and healthy tissue were not significant. CONCLUSION Pancreatic cancer tissue exhibits higher activity of class III ADH isoenzyme than healthy tissue, and we consider that oxidative pathway of ethanol metabolism via ADH and ALDH does not play a role in pancreatic carcinogenesis.
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Affiliation(s)
- Wojciech Jelski
- Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok, Poland.
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Guerra C, Schuhmacher AJ, Cañamero M, Grippo PJ, Verdaguer L, Pérez-Gallego L, Dubus P, Sandgren EP, Barbacid M. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007; 11:291-302. [PMID: 17349585 DOI: 10.1016/j.ccr.2007.01.012] [Citation(s) in RCA: 951] [Impact Index Per Article: 52.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2006] [Revised: 11/28/2006] [Accepted: 01/11/2007] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA), one of the deadliest human cancers, often involves somatic activation of K-Ras oncogenes. We report that selective expression of an endogenous K-Ras(G12V) oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells. Surprisingly, adult mice become refractory to K-Ras(G12V)-induced PanINs and PDA. However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA. These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events.
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Affiliation(s)
- Carmen Guerra
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain.
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Vitone LJ, Greenhalf W, Howes NR, Raraty MGT, Neoptolemos JP. Trypsinogen mutations in pancreatic disorders. Endocrinol Metab Clin North Am 2006; 35:271-87, viii. [PMID: 16632092 DOI: 10.1016/j.ecl.2006.02.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
There are multiple PRSS1 mutations described in hereditary pancreatitis but only a minority of these are clinically relevant. The two most frequent point mutations are in exon 2 (N29I) and exon3 (R122H), found in diverse racial populations. Both mutations result in early onset pancreatitis but the mechanism underlying this phenotype is unclear. The frequency of these mutations in such diverse populations suggests they have spontaneously occurred many times. The origin of the major mutations may be explained by gene conversions, accounting for multiple founders. The implications are discussed in terms of mechanism of action of the mutations and clinical presentation.
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Affiliation(s)
- Louis J Vitone
- Division of Surgery and Oncology, The University of Liverpool, 5th Floor UCD Building, Daulby Street, Liverpool, L69 3GA, United Kingdom
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Vitone LJ, Greenhalf W, McFaul CD, Ghaneh P, Neoptolemos JP. The inherited genetics of pancreatic cancer and prospects for secondary screening. Best Pract Res Clin Gastroenterol 2006; 20:253-83. [PMID: 16549327 DOI: 10.1016/j.bpg.2005.10.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
It is estimated that pancreatic cancer has a familial component in approximately 5-10% of cases. Some of these cases are part of a defined cancer syndrome with a known gene mutation but in the remaining the causative gene remains unknown. In recent years, a better understanding of the molecular events that occur in the progression model of pancreatic cancer has lead to the development of secondary screening programmes with the aim of identifying early precursor lesions or pre-invasive cancer at a stage amenable to curative resection. High-risk groups who have an inherited predisposition for pancreatic cancer form the ideal group to study in developing a robust screening programme. Multimodality screening using computed tomography and endoluminal ultrasound in combination with molecular analysis of pancreatic juice are proving promising as diagnostics tools or at least serving as predictors of risk over a defined period.
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Affiliation(s)
- Louis J Vitone
- The University of Liverpool, Division of Surgery and Oncology, 5th Floor UCD, Daulby Street, Liverpool L69 3GA, UK
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Go VLW, Gukovskaya A, Pandol SJ. Alcohol and pancreatic cancer. Alcohol 2005; 35:205-11. [PMID: 16054982 DOI: 10.1016/j.alcohol.2005.03.010] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2005] [Revised: 03/18/2005] [Accepted: 03/25/2005] [Indexed: 12/13/2022]
Abstract
Findings obtained from numerous prospective cohort and case-control studies on alcohol consumption and pancreatic cancer risk have been inconsistent, with many confounding variables present in various investigations. However, heavy alcohol consumption has been known to be a major cause of chronic pancreatitis and a risk factor for type 2 diabetes mellitus, both of which are linked to pancreatic cancer. It has been established that an extensive normal interaction exists between the exocrine and endocrine pancreas, as well as in inflammatory processes and carcinogenesis. Alcohol and its metabolites (acetaldehyde and fatty acid ethyl esters) can alter metabolic pathways involved in the inflammatory response and carcinogenesis, and they are mediated by one or more of the following mechanisms: (1) premature activation of zymogens; (2) induction of the inflammatory response through activation of nuclear transcription factors, including nuclear factor-kappa and activation protein 1; (3) increased production of reactive oxygen species, resulting in oxidative DNA damage and altered effect of dietary antioxidants; (4) activation of pancreatic stellate cells, which leads to fibrosis; (5) gene mutation in enzymes related to cytochrome P450, glutathione S-transferase, aldehyde dehydrogenase, cationic trypsinogen, and pancreatic secretory trypsin inhibitor; (6) synergistic effects of ethanol and tobacco carcinogen on NNK [nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] metabolism; and (7) dysregulation of proliferation and apoptosis. These various metabolic effects of alcohol can lead to or interact with other risk factors (genetic, dietary, environmental, and lifestyle factors) that result in acute and chronic pancreatitis and diabetes mellitus and, ultimately, affect the multistep process of carcinogenesis toward the development of pancreatic cancer.
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Affiliation(s)
- Vay Liang W Go
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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Abstract
Pancreatic inflammation appears to increase the risk of pancreatic cancer. This observation is striking in the hereditary pancreatitis kindreds but also occurs in alcoholic, idiopathic, and tropical chronic pancreatitis and cystic fibrosis. However, the mutations associated with hereditary pancreatitis or cystic fibrosis are not found in sporadic pancreatic adenocarcinomas, suggesting that the effects are indirect by causing recurrent pancreatitis and chronic inflammation. The process of mutation accumulation and clonal expansion that is required for development of invasive pancreatic adenocarcinoma must therefore be accelerated in chronic pancreatitis to account for the high incidence of pancreatic cancer in these patients.
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Affiliation(s)
- David C Whitcomb
- UPMC Presbyterian, GI Div., Mezzanine 2, C Wing, 200 Lothrop St., Pittsburgh, PA 15213, USA.
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