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Anastasia A, Formenti L, Ostano P, Minoli L, Resovi A, Morosi L, Fioravanti C, Micotti E, Matteo C, Scanziani E, Chiorino G, Giavazzi R, Ghilardi C, Belotti D. Stroma gene signature predicts responsiveness to chemotherapy in pancreatic ductal adenocarcinoma patient-derived xenograft models. Mol Oncol 2025. [PMID: 39902502 DOI: 10.1002/1878-0261.13816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 12/23/2024] [Accepted: 01/22/2025] [Indexed: 02/05/2025] Open
Abstract
Despite many efforts to understand the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) treatment resistance, there is still no reliable method for selecting patients who could benefit from standard pharmacological treatment. Here, four PDAC patient-derived xenografts (PDAC-PDXs) with different responses to gemcitabine plus nab-paclitaxel (nanoparticle albumin-bound paclitaxel) were studied to dissect the contribution of both tumor and host microenvironment to treatment response. PDAC-PDXs transplanted into the pancreas of immunodeficient mice retained the main genetic and histopathological characteristics of the original human tumors, including invasiveness and desmoplastic reaction. Response to chemotherapy was associated with a specific 294 stroma gene signature and was not due to the intrinsic responsiveness of tumor cells or differences in drug delivery. Human dataset analysis validated the expression of the 294 stroma gene signature in PDAC clinical samples, confirming PDAC-PDXs as a useful tool to study the biology of tumor-host interactions and to test drug efficacy. In summary, we identified a stroma gene signature that differentiates PDAC-PDXs that are responsive to gemcitabine plus Nab-paclitaxel treatment from those that are not, confirming the active role of the tumor microenvironment in the drug response.
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Affiliation(s)
- Alessia Anastasia
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
| | - Laura Formenti
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
| | - Paola Ostano
- Lab of Cancer Genomics, Fondazione "Edo ed Elvo Tempia", Biella, Italy
| | - Lucia Minoli
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan (Unimi), Lodi, Italy
| | - Andrea Resovi
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
| | - Lavinia Morosi
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
| | - Claudia Fioravanti
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
| | - Edoardo Micotti
- Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Cristina Matteo
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
| | - Eugenio Scanziani
- Mouse and Animal Pathology Laboratory (MAPLab), Fondazione Unimi, Milan, Italy
| | - Giovanna Chiorino
- Lab of Cancer Genomics, Fondazione "Edo ed Elvo Tempia", Biella, Italy
| | - Raffaella Giavazzi
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
| | - Carmen Ghilardi
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
| | - Dorina Belotti
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo and Milan, Italy
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Dominguez AA, Perz MT, Xu Y, Cedillo LG, Huang OD, McIntyre CA, Vudatha V, Trevino JG, Liu J, Wang P. Unveiling the Promise: Navigating Clinical Trials 1978-2024 for PDAC. Cancers (Basel) 2024; 16:3564. [PMID: 39518005 PMCID: PMC11544830 DOI: 10.3390/cancers16213564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/14/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Despite many decades of research, pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult cancers to diagnose and treat effectively. Although there have been improvements in the 5-year overall survival rate, it is still very low at 12.5%. The limited efficacy of current therapies, even when PDAC is detected early, underscores the aggressive nature of the disease and the urgent need for more effective treatments. Clinical management of PDAC still relies heavily on a limited repertoire of therapeutic interventions, highlighting a significant gap between research efforts and available treatments. Over 4300 clinical trials have been or are currently investigating different treatment modalities and diagnostic strategies for PDAC, including targeted therapies, immunotherapies, and precision medicine approaches. These trials aim to develop more effective treatments and improve early detection methods through advanced imaging techniques and blood-based biomarkers. This review seeks to categorize and analyze PDAC-related clinical trials across various dimensions to understand why so few chemotherapeutic options are available to patients despite the numerous trials being conducted. This review aims to provide a comprehensive and nuanced understanding of the landscape of PDAC-related clinical trials, with the overarching goal of identifying opportunities to accelerate progress in drug development and improve patient outcomes in the fight against this devastating disease.
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Affiliation(s)
- Angel A. Dominguez
- Department of Cell Systems & Anatomy; University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (A.A.D.); (M.T.P.); (Y.X.); (L.G.C.); (O.D.H.); (J.L.)
| | - Matthew T. Perz
- Department of Cell Systems & Anatomy; University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (A.A.D.); (M.T.P.); (Y.X.); (L.G.C.); (O.D.H.); (J.L.)
| | - Yi Xu
- Department of Cell Systems & Anatomy; University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (A.A.D.); (M.T.P.); (Y.X.); (L.G.C.); (O.D.H.); (J.L.)
| | - Leonor G. Cedillo
- Department of Cell Systems & Anatomy; University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (A.A.D.); (M.T.P.); (Y.X.); (L.G.C.); (O.D.H.); (J.L.)
| | - Orry D. Huang
- Department of Cell Systems & Anatomy; University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (A.A.D.); (M.T.P.); (Y.X.); (L.G.C.); (O.D.H.); (J.L.)
| | - Caitlin A. McIntyre
- Division of Surgical Oncology and Endocrine Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA;
| | - Vignesh Vudatha
- Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; (V.V.); (J.G.T.)
| | - Jose G. Trevino
- Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; (V.V.); (J.G.T.)
| | - Jun Liu
- Department of Cell Systems & Anatomy; University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (A.A.D.); (M.T.P.); (Y.X.); (L.G.C.); (O.D.H.); (J.L.)
| | - Pei Wang
- Department of Cell Systems & Anatomy; University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; (A.A.D.); (M.T.P.); (Y.X.); (L.G.C.); (O.D.H.); (J.L.)
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Sharma B, Twelker K, Nguyen C, Ellis S, Bhatia ND, Kuschner Z, Agriantonis A, Agriantonis G, Arnold M, Dave J, Mestre J, Shafaee Z, Arora S, Ghanta H, Whittington J. Bile Acids in Pancreatic Carcinogenesis. Metabolites 2024; 14:348. [PMID: 39057671 PMCID: PMC11278541 DOI: 10.3390/metabo14070348] [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: 05/08/2024] [Revised: 06/10/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Pancreatic cancer (PC) is a dangerous digestive tract tumor that is becoming increasingly common and fatal. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC). Bile acids (BAs) are closely linked to the growth and progression of PC. They can change the intestinal flora, increasing intestinal permeability and allowing gut microbes to enter the bloodstream, leading to chronic inflammation. High dietary lipids can increase BA secretion into the duodenum and fecal BA levels. BAs can cause genetic mutations, mitochondrial dysfunction, abnormal activation of intracellular trypsin, cytoskeletal damage, activation of NF-κB, acute pancreatitis, cell injury, and cell necrosis. They can act on different types of pancreatic cells and receptors, altering Ca2+ and iron levels, and related signals. Elevated levels of Ca2+ and iron are associated with cell necrosis and ferroptosis. Bile reflux into the pancreatic ducts can speed up the kinetics of epithelial cells, promoting the development of pancreatic intraductal papillary carcinoma. BAs can cause the enormous secretion of Glucagon-like peptide-1 (GLP-1), leading to the proliferation of pancreatic β-cells. Using Glucagon-like peptide-1 receptor agonist (GLP-1RA) increases the risk of pancreatitis and PC. Therefore, our objective was to explore various studies and thoroughly examine the role of BAs in PC.
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Affiliation(s)
- Bharti Sharma
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Kate Twelker
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Cecilia Nguyen
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Scott Ellis
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Navin D. Bhatia
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Zachary Kuschner
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Andrew Agriantonis
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - George Agriantonis
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Monique Arnold
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Jasmine Dave
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Juan Mestre
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Zahra Shafaee
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Shalini Arora
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Hima Ghanta
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Jennifer Whittington
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
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Kamata K, Takenaka M, Nishida N, Hara A, Otsuka Y, Tanaka H, Omoto S, Minaga K, Yamao K, Chiba Y, Sakai K, Nishio K, Watanabe T, Kudo M. Impact of Smad4 and p53 mutations on the prognosis of patients with pancreatic ductal adenocarcinoma undergoing chemotherapy. Int J Clin Oncol 2023; 28:1511-1519. [PMID: 37596505 DOI: 10.1007/s10147-023-02396-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 07/28/2023] [Indexed: 08/20/2023]
Abstract
BACKGROUND This prospective cohort study evaluated the feasibility of using endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) samples for comprehensive mutational analysis of cancer-related genes using microtissues. METHODS Fifty patients with suspected pancreatic cancer presenting consecutively at the Kindai University Hospital between January 2018 and January 2019 were enrolled. Cancerous tissues from EUS-FNB were obtained from each tumor and subjected to histological examination and mutational analysis. The primary endpoint was the collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing. Clinical history and genetic variations between the disease control and progressive disease groups of patients on chemotherapy were evaluated as secondary endpoints. RESULTS The collection rate of EUS-FNB specimens suitable for comprehensive cancer panels using deep sequencing was 93.6%. The cancer panel was sequenced for 25 patients with pancreatic cancer treated initially with systemic chemotherapy. Mutation in p53 and Smad4 were positively and negatively associated, respectively, with disease control at the initial evaluation. The median time to progression in 15 patients with p53 and without Smad4 mutations was 182.0 days; whereas, it was 92.5 days in other 10 patients; this difference was significant (p = 0.020). CONCLUSIONS Tissue samples from EUS-FNB were suitable for mutational analysis. Pancreatic cancers with p53 and without Smad4 mutations responded better to chemotherapy and had a better prognosis than those others.
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Affiliation(s)
- Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Mamoru Takenaka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
| | - Akane Hara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Yasuo Otsuka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Hidekazu Tanaka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Shunsuke Omoto
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Kentaro Yamao
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Yasutaka Chiba
- Clinical Research Center, Kindai University Hospital, Osaka-Sayama, Japan
| | - Kazuko Sakai
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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Potential role of Marine Bioactive Compounds targeting signaling pathways in cancer: A review. Eur J Pharmacol 2022; 936:175330. [DOI: 10.1016/j.ejphar.2022.175330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/23/2022]
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Islam F, Mitra S, Emran TB, Khan Z, Nath N, Das R, Sharma R, Awadh AAA, Park MN, Kim B. Natural Small Molecules in Gastrointestinal Tract and Associated Cancers: Molecular Insights and Targeted Therapies. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27175686. [PMID: 36080453 PMCID: PMC9457641 DOI: 10.3390/molecules27175686] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/24/2022] [Accepted: 08/29/2022] [Indexed: 12/22/2022]
Abstract
Gastric cancer is one of the most common cancers of the gastrointestinal tract. Although surgery is the primary treatment, serious maladies that dissipate to other parts of the body may require chemotherapy. As there is no effective procedure to treat stomach cancer, natural small molecules are a current focus of research interest for the development of better therapeutics. Chemotherapy is usually used as a last resort for people with advanced stomach cancer. Anti-colon cancer chemotherapy has become increasingly effective due to drug resistance and sensitivity across a wide spectrum of drugs. Naturally-occurring substances have been widely acknowledged as an important project for discovering innovative medications, and many therapeutic pharmaceuticals are made from natural small molecules. Although the beneficial effects of natural products are as yet unknown, emerging data suggest that several natural small molecules could suppress the progression of stomach cancer. Therefore, the underlying mechanism of natural small molecules for pathways that are directly involved in the pathogenesis of cancerous diseases is reviewed in this article. Chemotherapy and molecularly-targeted drugs can provide hope to colon cancer patients. New discoveries could help in the fight against cancer, and future stomach cancer therapies will probably include molecularly formulated drugs.
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Affiliation(s)
- Fahadul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
- Correspondence: (T.B.E.); (B.K.)
| | - Zidan Khan
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Nikhil Nath
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Rajib Das
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | - Ahmed Abdullah Al Awadh
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, P.O. Box 1988, Najran 61441, Saudi Arabia
| | - Moon Nyeo Park
- Department of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 05254, Korea
| | - Bonglee Kim
- Department of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 05254, Korea
- Correspondence: (T.B.E.); (B.K.)
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7
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Popov A, Mandys V. Senescence-Associated miRNAs and Their Role in Pancreatic Cancer. Pathol Oncol Res 2022; 28:1610156. [PMID: 35570840 PMCID: PMC9098800 DOI: 10.3389/pore.2022.1610156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 04/12/2022] [Indexed: 01/17/2023]
Abstract
Replicative senescence is irreversible cell proliferation arrest for somatic cells which can be circumvented in cancers. Cellular senescence is a process, which may play two opposite roles. On the one hand, this is a natural protection of somatic cells against unlimited proliferation and malignant transformation. On the other hand, cellular secretion caused by senescence can stimulate inflammation and proliferation of adjacent cells that may promote malignancy. The main genes controlling the senescence pathways are also well known as tumor suppressors. Almost 140 genes regulate both cellular senescence and cancer pathways. About two thirds of these genes (64%) are regulated by microRNAs. Senescence-associated miRNAs can stimulate cancer progression or act as tumor suppressors. Here we review the role playing by senescence-associated miRNAs in development, diagnostics and treatment of pancreatic cancer.
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Affiliation(s)
- Alexey Popov
- Department of Pathology, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czechia
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Cortesi M, Zanoni M, Pirini F, Tumedei MM, Ravaioli S, Rapposelli IG, Frassineti GL, Bravaccini S. Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight. Int J Mol Sci 2021; 23:ijms23010254. [PMID: 35008679 PMCID: PMC8745092 DOI: 10.3390/ijms23010254] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/21/2021] [Accepted: 12/24/2021] [Indexed: 01/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the most dismal prognoses of all cancers due to its late manifestation and resistance to current therapies. Accumulating evidence has suggested that the malignant behavior of this cancer is mainly influenced by the associated strongly immunosuppressive, desmoplastic microenvironment and by the relatively low mutational burden. PDAC develops and progresses through a multi-step process. Early in tumorigenesis, cancer cells must evade the effects of cellular senescence, which slows proliferation and promotes the immune-mediated elimination of pre-malignant cells. The role of senescence as a tumor suppressor has been well-established; however, recent evidence has revealed novel pro-tumorigenic paracrine functions of senescent cells towards their microenvironment. Understanding the interactions between tumors and their microenvironment is a growing research field, with evidence having been provided that non-tumoral cells composing the tumor microenvironment (TME) influence tumor proliferation, metabolism, cell death, and therapeutic resistance. Simultaneously, cancer cells shape a tumor-supportive and immunosuppressive environment, influencing both non-tumoral neighboring and distant cells. The overall intention of this review is to provide an overview of the interplay that occurs between senescent and non-senescent cell types and to describe how such interplay may have an impact on PDAC progression. Specifically, the effects and the molecular changes occurring in non-cancerous cells during senescence, and how these may contribute to a tumor-permissive microenvironment, will be discussed. Finally, senescence targeting strategies will be briefly introduced, highlighting their potential in the treatment of PDAC.
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Affiliation(s)
- Michela Cortesi
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
- Correspondence:
| | - Michele Zanoni
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
| | - Francesca Pirini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
| | - Maria Maddalena Tumedei
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
| | - Sara Ravaioli
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
| | - Ilario Giovanni Rapposelli
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (G.L.F.)
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (I.G.R.); (G.L.F.)
| | - Sara Bravaccini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (M.Z.); (F.P.); (M.M.T.); (S.R.); (S.B.)
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9
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Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models. Cancers (Basel) 2021; 14:cancers14010071. [PMID: 35008235 PMCID: PMC8750056 DOI: 10.3390/cancers14010071] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful tools to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. In this review, we summarize the main molecular alterations found in pancreatic neoplasms and GEMMs developed based on these alterations. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, and the seventh leading cause of cancer-related deaths worldwide. An improved understanding of tumor biology and novel therapeutic discoveries are needed to improve overall survival. Recent multi-gene analysis approaches such as next-generation sequencing have provided useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic cancer and precursor lesions are characterized by specific molecular alterations. Genetically engineered mouse models (GEMMs) of PDAC are useful to understand the roles of altered genes. Most GEMMs are driven by oncogenic Kras, and can recapitulate the histological and molecular hallmarks of human PDAC and comparable precursor lesions. Advanced GEMMs permit the temporally and spatially controlled manipulation of multiple target genes using a dual-recombinase system or CRISPR/Cas9 gene editing. GEMMs that express fluorescent proteins allow cell lineage tracing to follow tumor growth and metastasis to understand the contribution of different cell types in cancer progression. GEMMs are widely used for therapeutic optimization. In this review, we summarize the main molecular alterations found in pancreatic neoplasms, developed GEMMs, and the contribution of GEMMs to the current understanding of PDAC pathobiology. Furthermore, we attempted to modify the categorization of altered driver genes according to the most updated findings.
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10
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Yang HH, Liu JW, Lee JH, Harn HJ, Chiou TW. Pancreatic Adenocarcinoma Therapeutics Targeting RTK and TGF Beta Receptor. Int J Mol Sci 2021; 22:ijms22158125. [PMID: 34360896 PMCID: PMC8348294 DOI: 10.3390/ijms22158125] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/28/2021] [Accepted: 07/26/2021] [Indexed: 12/21/2022] Open
Abstract
Despite the improved overall survival rates in most cancers, pancreatic cancer remains one of the deadliest cancers in this decade. The rigid microenvironment, which majorly comprises cancer-associated fibroblasts (CAFs), plays an important role in the obstruction of pancreatic cancer therapy. To overcome this predicament, the signaling of receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFβR) in both pancreatic cancer cell and supporting CAF should be considered as the therapeutic target. The activation of receptors has been reported to be aberrant to cell cycle regulation, and signal transduction pathways, such as growth-factor induced proliferation, and can also influence the apoptotic sensitivity of tumor cells. In this article, the regulation of RTKs/TGFβR between pancreatic ductal adenocarcinoma (PDAC) and CAFs, as well as the RTKs/TGFβR inhibitor-based clinical trials on pancreatic cancer are reviewed.
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Affiliation(s)
- Hsin-Han Yang
- Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan;
| | - Jen-Wei Liu
- Everfront Biotech Inc., New Taipei City 221, Taiwan; (J.-W.L.); (J.-H.L.)
| | - Jui-Hao Lee
- Everfront Biotech Inc., New Taipei City 221, Taiwan; (J.-W.L.); (J.-H.L.)
| | - Horng-Jyh Harn
- Bioinnovation Center, Tzu Chi Foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien 970, Taiwan
- Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien 970, Taiwan
- Correspondence: (H.-J.H.); (T.-W.C.)
| | - Tzyy-Wen Chiou
- Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan;
- Correspondence: (H.-J.H.); (T.-W.C.)
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11
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Abstract
Pancreatic cancer is a genetic disease, and the recurrent genetic alterations characteristic of pancreatic cancer indicate the cellular processes that are targeted for malignant transformation. In addition to somatic alterations in the most common driver genes (KRAS, CDKN2A, TP53 and SMAD4), large-scale studies have revealed major roles for genetic alterations of the SWI/SNF and COMPASS complexes, copy number alterations in GATA6 and MYC that partially define phenotypes of pancreatic cancer, and the role(s) of polyploidy and chromothripsis as factors contributing to pancreatic cancer biology and progression. Germline variants that increase the risk of pancreatic cancer continue to be discovered along with a greater appreciation of the features of pancreatic cancers with mismatch repair deficiencies and homologous recombination deficiencies that confer sensitivity to therapeutic targeting. Wild-type KRAS pancreatic cancers, some of which are driven by alternative oncogenic events affecting NRG1 or NTRK1 - for which targeted therapies exist - further underscore that pancreatic cancer is formally entering the era of precision medicine. Given the vast developments within this field, here we review the wide-ranging and most current information related to pancreatic cancer genomics with the goal of integrating this information into a unifying description of the life history of pancreatic cancer.
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12
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Kenner B, Chari ST, Kelsen D, Klimstra DS, Pandol SJ, Rosenthal M, Rustgi AK, Taylor JA, Yala A, Abul-Husn N, Andersen DK, Bernstein D, Brunak S, Canto MI, Eldar YC, Fishman EK, Fleshman J, Go VLW, Holt JM, Field B, Goldberg A, Hoos W, Iacobuzio-Donahue C, Li D, Lidgard G, Maitra A, Matrisian LM, Poblete S, Rothschild L, Sander C, Schwartz LH, Shalit U, Srivastava S, Wolpin B. Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review. Pancreas 2021; 50:251-279. [PMID: 33835956 PMCID: PMC8041569 DOI: 10.1097/mpa.0000000000001762] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
ABSTRACT Despite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.
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Affiliation(s)
| | - Suresh T. Chari
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - David S. Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Stephen J. Pandol
- Basic and Translational Pancreas Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Anil K. Rustgi
- Division of Digestive and Liver Diseases, Department of Medicine, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY
| | | | - Adam Yala
- Department of Electrical Engineering and Computer Science
- Jameel Clinic, Massachusetts Institute of Technology, Cambridge, MA
| | - Noura Abul-Husn
- Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine, Mount Sinai, New York, NY
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | | | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Marcia Irene Canto
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Yonina C. Eldar
- Department of Math and Computer Science, Weizmann Institute of Science, Rehovot, Israel
| | - Elliot K. Fishman
- Department of Radiology and Radiological Science, Johns Hopkins Medicine, Baltimore, MD
| | | | - Vay Liang W. Go
- UCLA Center for Excellence in Pancreatic Diseases, University of California, Los Angeles, Los Angeles, CA
| | | | - Bruce Field
- From the Kenner Family Research Fund, New York, NY
| | - Ann Goldberg
- From the Kenner Family Research Fund, New York, NY
| | | | - Christine Iacobuzio-Donahue
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Debiao Li
- Biomedical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Anirban Maitra
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | | | | | - Lawrence H. Schwartz
- Department of Radiology, NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, NY
| | - Uri Shalit
- Faculty of Industrial Engineering and Management, Technion—Israel Institute of Technology, Haifa, Israel
| | - Sudhir Srivastava
- Division of Cancer Prevention, National Cancer Institute, Bethesda, MD
| | - Brian Wolpin
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA
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13
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Low Incidence of High-Grade Pancreatic Intraepithelial Neoplasia Lesions in a Crmp4 Gene-Deficient Mouse Model of Pancreatic Cancer. Transl Oncol 2020; 13:100746. [PMID: 32105991 PMCID: PMC7044544 DOI: 10.1016/j.tranon.2020.100746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 01/30/2020] [Accepted: 01/30/2020] [Indexed: 12/24/2022] Open
Abstract
Pancreatic intraepithelial neoplasia (PanIN), the most common premalignant lesion of the pancreas, is a histologically well-defined precursor to invasive pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms underlying the progression of PanINs have not been fully elucidated. Previously, we demonstrated that the expression of collapsin response mediator protein 4 (CRMP4) in PDAC was associated with poor prognosis. The expression of CRMP4 was also augmented in a pancreatitis mouse model. However, the role of CRMP4 in the progression of PanIN lesions remains uncertain. In the present study, we examined the relationship between CRMP4 expression and progression of PanIN lesions using genetically engineered mouse models. PanIN lesions were induced by peritoneal injection of the cholecystokinin analog caerulein in LSL-KRASG12D; Pdx1-Cre (KC-Crmp4 wild-type, WT) mice and LSL-KRASG12D; Pdx1-Cre; Crmp4−/− (KC-Crmp4 knockout, KO) mice. We analyzed pancreatic tissue sections from these mice and evaluated PanIN grade by hematoxylin and eosin staining. CRMP4 expression was examined and the cellular components assessed by immunohistochemistry using antibodies against CRMP4, CD3, and α-smooth muscle actin (SMA). The incidence of high-grade PanIN in KC-Crmp4 WT mice was higher than that in KC-Crmp4 KO animals. CRMP4 was expressed not only in epithelial cells but also in αSMA-positive cells in stromal areas of PanIN lesions. The CRMP4 expression in stromal areas correlated with PanIN grade in WT mice. These results suggested that the expression of CRMP4 in stromal cells may underlie the incidence or progression of PanIN.
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14
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Sun Z, Yan B. Multiple roles and regulatory mechanisms of the transcription factor GATA6 in human cancers. Clin Genet 2019; 97:64-72. [PMID: 31437305 DOI: 10.1111/cge.13630] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 08/13/2019] [Accepted: 08/20/2019] [Indexed: 12/24/2022]
Abstract
Cancer is a common type of non-communicable disease, and its morbidity and mortality are rapidly increasing. It is expected to become the largest obstacle to the promotion of global human health in the future. Some transcription factors that play important regulatory roles in embryogenesis and subsequent tissue maintenance can be selectively amplified during tumorigenesis. Due to its high expression in the embryonic endoderm and mesoderm, GATA6 plays a crucial role in the normal development of early human heart, lung, digestive system, adrenal glands, breasts, ovaries, retina, skin, and nervous system. Up to now, overexpression of the GATA6 gene has been shown to play an important role in several cancers, including lung cancer, digestive system tumors, breast cancer, and ovarian cancer. However, the human body is a complex organism, which causes the transcription factor GATA6 to have multiple roles in cancer. In this review, we summarize the multiple roles of transcription factor GATA6 in various cancers and its regulatory mechanisms. The aim is to better understand the relationship between GATA6 gene expression and cancer development and to provide new insights for exploring potential therapeutic targets.
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Affiliation(s)
- Zhaoqing Sun
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Bo Yan
- Shandong Provincial Key Laboratory of Cardiac Disease Diagnosis and Treatment, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China.,The Center for Molecular Genetics of Cardiovascular Diseases, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China.,Shandong Provincial Sino-US Cooperation Research Center for Translational Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China
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15
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Rozengurt E, Eibl G. Central role of Yes-associated protein and WW-domain-containing transcriptional co-activator with PDZ-binding motif in pancreatic cancer development. World J Gastroenterol 2019; 25:1797-1816. [PMID: 31057295 PMCID: PMC6478619 DOI: 10.3748/wjg.v25.i15.1797] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/20/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.
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Affiliation(s)
- Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
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16
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Zhou Q, Xia S, Guo F, Hu F, Wang Z, Ni Y, Wei T, Xiang H, Shang D. Transforming growth factor-β in pancreatic diseases: Mechanisms and therapeutic potential. Pharmacol Res 2019; 142:58-69. [PMID: 30682425 DOI: 10.1016/j.phrs.2019.01.038] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 12/27/2018] [Accepted: 01/18/2019] [Indexed: 12/16/2022]
Abstract
Pancreatic diseases, such as acute pancreatitis, chronic pancreatitis, and pancreatic cancer, are common gastrointestinal diseases resulting in the development of local and systemic complications with a high risk of death. Numerous studies have examined pancreatic diseases over the past few decades; however, the pathogenesis remains unclear, and there is a lack of effective treatment options. Recently, emerging evidence has suggested that transforming growth factor beta (TGF-β) exerts controversial functions in apoptosis, inflammatory responses, and carcinogenesis, indicating its complex role in the pathogenesis of pancreas-associated disease. Therefore, a further understanding of relevant TGF-β signalling will provide new ideas and potential therapeutic targets for preventing disease progression. This is the first systematic review of recent data from animal and human clinical studies focusing on TGF-β signalling in pancreas damage and diseases. This information may aid in the development of therapeutic agents for regulating TGF-β in this pathology to prevent or treat pancreatic diseases.
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Affiliation(s)
- Qi Zhou
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China; Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shilin Xia
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fangyue Guo
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Fenglin Hu
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Zhizhou Wang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yujia Ni
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Tianfu Wei
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Hong Xiang
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Dong Shang
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China; Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
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17
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Gotoh Y, Ohtsuka T, Nakamura S, Shindo K, Ohuchida K, Miyasaka Y, Mori Y, Mochidome N, Oda Y, Nakamura M. Genetic assessment of recurrent pancreatic high-risk lesions in the remnant pancreas: Metachronous multifocal lesion or local recurrence? Surgery 2018; 165:767-774. [PMID: 30497813 DOI: 10.1016/j.surg.2018.10.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 10/11/2018] [Accepted: 10/16/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND It is difficult to determine whether a second high-risk lesion, including pancreatic ductal adenocarcinoma or high-grade pancreatic intraepithelial neoplasm, is a metachronous multifocal lesion or represents local recurrence after resection of the first high-risk lesion. This study attempts to clarify the characteristics of second high-risk lesions in the remnant pancreas using genetic analyses. METHODS Clinicopathologic data were collected from 12 patients who underwent pancreatectomy for a second high-risk lesion in the remnant pancreas. We performed mutational and immunohistochemical analyses of 4 major genes-KRAS, TP53, CDKN2A, and SMAD4-associated with pancreatic ductal adenocarcinoma progression, as well as targeted next-generation sequencing. RESULTS Mutations in the four genes in the second high-risk lesion were consistent with the first lesion in four patients but were inconsistent in the remaining eight patients, and thus we considered that the latter eight patients likely had metachronous multifocal high-risk lesions and the other four patients had local recurrence. The estimated cumulative recurrence rate after resection of the second high-risk lesion was greater in the local recurrence group compared with the metachronous multifocal group, and the estimated cumulative disease-specific survival rate was greater in the metachronous multifocal group. Targeted next-generation sequencing demonstrated that the second lesions in the metachronous multifocal high-risk lesion group showed differences in founder mutations compared with the first lesion. In the local recurrence group, the founder mutations in the second lesion were common with those in the first lesion. CONCLUSION Genetic assessment might help discriminate metachronous multifocal high-risk lesions from local recurrence.
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Affiliation(s)
- Yoshitaka Gotoh
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takao Ohtsuka
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - So Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Shindo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Miyasaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuhisa Mori
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoki Mochidome
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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18
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Overexpression of the Long Noncoding RNA HomeoboxA Transcript at the Distal Tip Predicts Poor Prognosis in a KRAS-Independent Manner in Periampullary Region Tumors. Pancreas 2018; 47:213-220. [PMID: 29329159 DOI: 10.1097/mpa.0000000000000984] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Periampullary region tumors (PRTs) are the fifth highest cause of cancer-related deaths worldwide. Although recent studies have highlighted the prognostic value of the long noncoding RNA HomeoboxA transcript at the distal tip (HOTTIP) in patients with pancreatic ductal adenocarcinoma, the relationship between HOTTIP and clinical outcome of all PRTs remains obscure. The aim of this study was to clarify the prognostic significance of HOTTIP in patients with all PRTs related to KRAS mutational status. METHODS HomeoboxA transcript at the distal tip expression was detected in 100 PRT samples using quantitative real-time polymerase chain reaction. The associations between HOTTIP levels, clinicopathological factors, and patient prognosis were also analyzed. RESULTS The expression of HOTTIP was found to be significantly upregulated by 32-fold (P = 0.031) in tumor tissues compared with normal tissues. The over expression of HOTTIP was related with presence of invasion and metastasis (P = 0.0467, P = 0.0256). In addition, increased HOTTIP expression was associated with poor prognosis independent of KRAS mutation (P < 0.001; n = 72). Moreover, multivariate analysis showed that high HOTTIP expression was an unfavorable prognostic factor for overall survival. CONCLUSIONS Our findings indicate that high levels of HOTTIP expression have the potential to be an independent, unfavorable prognostic factor for patients with PRT.
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19
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Grover P, Nath S, Nye MD, Zhou R, Ahmad M, Mukherjee P. SMAD4-independent activation of TGF-β signaling by MUC1 in a human pancreatic cancer cell line. Oncotarget 2018; 9:6897-6910. [PMID: 29467938 PMCID: PMC5805524 DOI: 10.18632/oncotarget.23966] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 12/18/2017] [Indexed: 12/18/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDA) has a mortality rate that nearly matches its incidence rate. Transforming Growth Factor Beta (TGF-β) is a cytokine with a dual role in tumor development switching from a tumor suppressor to a tumor promoter. There is limited knowledge of how TGF-β function switches during tumorigenesis. Mucin 1 (MUC1) is an aberrantly glycosylated, membrane-bound, glycoprotein that is overexpressed in >80% of PDA cases and is associated with poor prognosis. In PDA, MUC1 promotes tumor progression and metastasis via signaling through its cytoplasmic tail (MUC1-CT) and interacting with other oncogenic signaling molecules. We hypothesize that high levels of MUC1 in PDA may be partly responsible for the TGF-β functional switch during oncogenesis. We report that overexpression of MUC1 in BxPC3 human PDA cells (BxPC3.MUC1) enhances the induction of epithelial to mesenchymal transition leading to increased invasiveness in response to exogenous TGF-β1. Simultaneously, these cells resist TGF-β induced apoptosis by downregulating levels of cleaved caspases. We show that mutating the tyrosines in MUC1-CT to phenylalanine reverses the TGF-β induced invasiveness. This suggests that the tyrosine residues in MUC1-CT are required for TGF-β induced invasion. Some of these tyrosines are phosphorylated by the tyrosine kinase c-Src. Thus, treatment of BxPC3.MUC1 cells with a c-Src inhibitor (PP2) significantly reduces TGF-β induced invasiveness. Similar observations were confirmed in the Chinese hamster ovarian (CHO) cell line. Data strongly suggests that MUC1 may regulate TGF-β function in PDA cells and thus have potential clinical relevance in the use of TGF-β inhibitors in clinical trials.
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Affiliation(s)
- Priyanka Grover
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina 28223-0001, USA
| | - Sritama Nath
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina 28223-0001, USA
| | - Monica D. Nye
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina 28223-0001, USA
| | - Ru Zhou
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina 28223-0001, USA
| | - Mohammad Ahmad
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina 28223-0001, USA
| | - Pinku Mukherjee
- Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, North Carolina 28223-0001, USA
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20
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Eibl G, Rozengurt E. KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops. Semin Cancer Biol 2017; 54:50-62. [PMID: 29079305 DOI: 10.1016/j.semcancer.2017.10.007] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 10/22/2017] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) continues to be a lethal disease with no efficacious treatment modalities. The incidence of PDAC is expected to increase, at least partially because of the obesity epidemic. Increased efforts to prevent or intercept this disease are clearly needed. Mutations in KRAS are initiating events in pancreatic carcinogenesis supported by genetically engineered mouse models of the disease. However, oncogenic KRAS is not entirely sufficient for the development of fully invasive PDAC. Additional genetic mutations and/or environmental, nutritional, and metabolic stressors, e.g. inflammation and obesity, are required for efficient PDAC formation with activation of KRAS downstream effectors. Multiple factors "upstream" of KRAS associated with obesity, including insulin resistance, inflammation, changes in gut microbiota and GI peptides, can enhance/modulate downstream signals. Multiple signaling networks and feedback loops "downstream" of KRAS have been described that respond to obesogenic diets. We propose that KRAS mutations potentiate a signaling network that is promoted by environmental factors. Specifically, we envisage that KRAS mutations increase the intensity and duration of the growth-promoting signaling network. As the transcriptional activator YAP plays a critical role in the network, we conclude that the rationale for targeting the network (at different points), e.g. with FDA approved drugs such as statins and metformin, is therefore compelling.
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Affiliation(s)
- Guido Eibl
- Departments of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, CA, United States.
| | - Enrique Rozengurt
- Departments of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; CURE: Digestive Diseases Research Center, University of California at Los Angeles, Los Angeles, CA, United States
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Drosos Y, Escobar D, Chiang MY, Roys K, Valentine V, Valentine MB, Rehg JE, Sahai V, Begley LA, Ye J, Paul L, McKinnon PJ, Sosa-Pineda B. ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer. Sci Rep 2017; 7:11144. [PMID: 28894253 PMCID: PMC5593966 DOI: 10.1038/s41598-017-11661-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 08/29/2017] [Indexed: 12/11/2022] Open
Abstract
Germline mutations in ATM (encoding the DNA-damage signaling kinase, ataxia-telangiectasia-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and ATM somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (KrasG12D). We show that partial or total ATM deficiency cooperates with KrasG12D to promote highly metastatic pancreatic cancer. We also reveal that ATM is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that ATM deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and liver metastases we show that ATM loss accelerates Kras-induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16Ink4a and p19Arf. However, ATM deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and liver metastases. More importantly, ATM deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that ATM activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability.
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Affiliation(s)
- Yiannis Drosos
- Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - David Escobar
- Department of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Ming-Yi Chiang
- Department of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Kathryn Roys
- Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Virginia Valentine
- Department of Cytogenetics, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Marc B Valentine
- Department of Cytogenetics, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Jerold E Rehg
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Vaibhav Sahai
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Lesa A Begley
- Department of General Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Jianming Ye
- Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Leena Paul
- Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Peter J McKinnon
- Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Beatriz Sosa-Pineda
- Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, United States.
- Department of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
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TGF-β in pancreatic cancer initiation and progression: two sides of the same coin. Cell Biosci 2017; 7:39. [PMID: 28794854 PMCID: PMC5545849 DOI: 10.1186/s13578-017-0168-0] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 08/03/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is highly lethal malignant tumor with characterised rapid progression, invasiveness and resistance to radiochemotherapy. Transforming growth factor-β (TGF-β) signaling plays a dual role in both pro-tumorigenic and tumor suppressive of pancreatic cancer, depending on tumor stage and microenvironment. TGF-β signaling components alteration are common in pancreatic cancer, and its leading role in tumor formation and metastases has received increased attention. Many therapies have investigated to target TGF-β signaling in the preclinical and clinical setting. In this review, we highlight the dual roles of TGF-β and touch upon the perspectives on therapeutic target of TGF-β signaling in pancreatic cancer.
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Azarnezhad A, Mehdipour P. Cancer Genetics at a Glance: The Comprehensive Insights. CANCER GENETICS AND PSYCHOTHERAPY 2017:79-389. [DOI: 10.1007/978-3-319-64550-6_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Egeli U, Ak S, Cecener G, Tunca B, Tezcan G, Sevinc ED, Kaya E, Dundar HZ, Sarkut P, Ozen Y, Balcin O, Evrensel T, Yerci O, Ugras N. Impact of 3'UTR variation patterns of the KRAS gene on the aggressiveness of pancreatobiliary tumors with the KRAS G13D mutation in a Turkish population. Pancreatology 2016; 16:677-86. [PMID: 27256640 DOI: 10.1016/j.pan.2016.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 04/26/2016] [Accepted: 05/20/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Several studies have demonstrated the importance of mutations in codons 12, 13 and 61 and variations in the 3' untranslated region (3'UTR) of the KRAS gene, frequently observed genetic events in the progression of pancreatobiliary tumors (PBT). However, limited data exist on the clinical effect of these alterations. The aim of the current study was to clarify the frequency of relevant alterations of the 3'UTR regions of the KRAS gene and the effect of KRAS 3'UTR polymorphisms on the prognosis of patients with codon 12, 13 and 61 mutations in a Turkish population with PBT. METHODS Codons 12, 13, and 61 and 3'UTRs of the KRAS gene were screened by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing in 43 patients and 10 controls. Chi-squared and independent sample T tests were used to evaluate the results of the mutation analysis and clinical features of the patients. RESULTS We defined the c.38G > A (rs112445441, p.G13D) (39.54%) mutation and two 3'UTR variations, c.*4066delA (rs560890523) (23.26%) and c.*4065_*4066delAA (rs57698689) (6.98%), in the KRAS gene of Turkish patients. There was a statistically significant relationship between the c.*4066delA (rs560890523) and c.*4065_*4066delAA (rs57698689) variations and invasion and lymph node metastasis status of the patients (p < 0.001). Compared to patients with c.38G > A (rs112445441, p.G13D), patients with c.*4066delA (rs560890523) and c.38G > A (rs112445441, p.G13D) presented more aggressive tumors with highly invasive features. The present study contributes findings regarding the clinical effects of KRAS alterations in PBT. Based on our study, further investigations are required.
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Affiliation(s)
- Unal Egeli
- Department of Medical Biology, Medical Faculty, Uludag University, Bursa, Turkey.
| | - Secil Ak
- Department of Medical Biology, Medical Faculty, Uludag University, Bursa, Turkey
| | - Gulsah Cecener
- Department of Medical Biology, Medical Faculty, Uludag University, Bursa, Turkey
| | - Berrin Tunca
- Department of Medical Biology, Medical Faculty, Uludag University, Bursa, Turkey
| | - Gulcin Tezcan
- Department of Medical Biology, Medical Faculty, Uludag University, Bursa, Turkey
| | | | - Ekrem Kaya
- Department of General Surgery, Medical Faculty, Uludag University, Bursa, Turkey
| | - Halit Ziya Dundar
- Department of General Surgery, Medical Faculty, Uludag University, Bursa, Turkey
| | - Pinar Sarkut
- Department of General Surgery, Medical Faculty, Uludag University, Bursa, Turkey
| | - Yilmaz Ozen
- Department of General Surgery, Medical Faculty, Uludag University, Bursa, Turkey
| | - Ozkan Balcin
- Department of General Surgery, Medical Faculty, Uludag University, Bursa, Turkey
| | - Turkkan Evrensel
- Department of Medical Oncology, Medical Faculty, Uludag University, Bursa, Turkey
| | - Omer Yerci
- Department of Pathology, Medical Faculty, Uludag University, Bursa, Turkey
| | - Nesrin Ugras
- Department of Pathology, Medical Faculty, Uludag University, Bursa, Turkey
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Seldon CS, Colbert LE, Hall WA, Fisher SB, Yu DS, Landry JC. Chromodomain-helicase-DNA binding protein 5, 7 and pronecrotic mixed lineage kinase domain-like protein serve as potential prognostic biomarkers in patients with resected pancreatic adenocarcinomas. World J Gastrointest Oncol 2016; 8:358-365. [PMID: 27096031 PMCID: PMC4824714 DOI: 10.4251/wjgo.v8.i4.358] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 12/05/2015] [Accepted: 01/11/2016] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose and provide prognostic information for pancreatic cancer. These markers can be used clinically to optimize and personalize therapy for individual patients. In this review, we focused on 3 biomarkers involved in the DNA damage response pathway and the necroptosis pathway: Chromodomain-helicase-DNA binding protein 5, chromodomain-helicase-DNA binding protein 7, and mixed lineage kinase domain-like protein. The aim of this article is to review present literature provided for these biomarkers and current studies in which their effectiveness as prognostic biomarkers are analyzed in order to determine their future use as biomarkers in clinical medicine. Based on the data presented, these biomarkers warrant further investigation, and should be validated in future studies.
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Bittoni A, Piva F, Santoni M, Andrikou K, Conti A, Loretelli C, Mandolesi A, Lanese A, Pellei C, Scarpelli M, Principato G, Cascinu S. KRAS mutation status is associated with specific pattern of genes expression in pancreatic adenocarcinoma. Future Oncol 2016; 11:1905-17. [PMID: 26161927 DOI: 10.2217/fon.15.98] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIMS To evaluate potential differences at a molecular level between KRAS mutant tumors (MT) and KRAS wild-type (WT) pancreatic tumors and the biological and prognostic significance of different KRAS mutations. MATERIALS & METHODS Expression of a panel of 29 genes was analyzed in KRAS WT and MT tumors. Effects of KRAS mutation and gene expression levels were assessed on patients' survival. RESULTS MUC6 (p = 0.009), HGF (p = 0.011), VEGFR-2 (p = 0.020) and VEGFB (p = 0.026) were significantly more expressed and SMAD4 was less suppressed (p = 0.003) in WT KRAS. Contrariwise, SHH (p = 0.012) and IHH (p = 0.031) were more expressed in MT KRAS patients. No OS difference was found between WT and MT KRAS tumors. CONCLUSION KRAS mutation status seems to identify two different subtypes of pancreatic ductal adenocarcinoma with similar outcome but distinct molecular features and probably different therapeutic targets.
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Affiliation(s)
- Alessandro Bittoni
- Department of Medical Oncology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - Francesco Piva
- Department of Specialistic Clinical & Odontostomatological Sciences, Polytechnic University of Marche, Ancona 60131, Italy
| | - Matteo Santoni
- Department of Medical Oncology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - Kalliopi Andrikou
- Department of Medical Oncology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - Alessandro Conti
- Department of Medical Oncology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - Cristian Loretelli
- Department of Medical Oncology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - Alessandra Mandolesi
- Department of Pathology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - Andrea Lanese
- Department of Medical Oncology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - Chiara Pellei
- Department of Medical Oncology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - Marina Scarpelli
- Department of Pathology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
| | - Giovanni Principato
- Department of Specialistic Clinical & Odontostomatological Sciences, Polytechnic University of Marche, Ancona 60131, Italy
| | - Stefano Cascinu
- Department of Medical Oncology, AOU Ospedali Riuniti, Università Politecnica delle Marche, via Conca 71, 60126 Ancona, Italy
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28
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Katz LH, Likhter M, Jogunoori W, Belkin M, Ohshiro K, Mishra L. TGF-β signaling in liver and gastrointestinal cancers. Cancer Lett 2016; 379:166-72. [PMID: 27039259 DOI: 10.1016/j.canlet.2016.03.033] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Revised: 03/16/2016] [Accepted: 03/18/2016] [Indexed: 02/07/2023]
Abstract
Transforming Growth Factor-β (TGF-β) plays crucial and complex roles in liver and gastrointestinal cancers. These include a multitude of distinct functions, such as maintaining stem cell homeostasis, promoting fibrosis, immune modulating, as a tumor suppressor and paradoxically, as a tumor progressor. However, key mechanisms for the switches responsible for these distinct actions are poorly understood, and remain a challenge. The Cancer Genome Atlas (TCGA) analyses and genetically engineered mouse models now provide an integrated approach to dissect these multifaceted and context-dependent driving roles of the TGF-β pathway. In this review, we will discuss the molecular mechanisms of TGF-β signaling, focusing on colorectal, gastric, pancreatic, and liver cancers. Novel drugs targeting the TGF-β pathway have been developed over the last decade, and some have been proven effective in clinical trials. A better understanding of the TGF-β pathway may improve our ability to target it, thus providing more tools to the armamentarium against these deadly cancers.
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Affiliation(s)
- L H Katz
- Department of Gastroenterology, Sheba Medical Center, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Israel
| | - M Likhter
- Department of Gastroenterology, Sheba Medical Center, Israel
| | - W Jogunoori
- Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA
| | - M Belkin
- Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA
| | - K Ohshiro
- Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA
| | - L Mishra
- Department of Surgery and GWU Cancer Center, George Washington University and DVAMC, Washington, DC, USA.
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Rossi MK, Gnanamony M, Gondi CS. The 'SPARC' of life: Analysis of the role of osteonectin/SPARC in pancreatic cancer (Review). Int J Oncol 2016; 48:1765-71. [PMID: 26983777 DOI: 10.3892/ijo.2016.3417] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 01/27/2016] [Indexed: 12/24/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most clinically challenging cancers to manage. An estimated 48,960 people will be diagnosed with pancreatic cancer in 2015, of that population, 94% are projected to perish within 5 years. These dismal survival rates can be attributed, in part, to an advanced diagnosis occurring in 80% of cases. The heterogeneous and dynamic microenvironment of pancreatic cancer, and the lack of both specific risk factors and efficacious screening tools contribute to the challenge of diagnosing pancreatic cancer in its early stages. These clinical challenges have directed research into the unique characteristics that define PDAC. Recently, there has been an increased focus on the interaction of tumor cells with their microenvironment in the hope of identifying new therapeutic targets. One of the most promising avenues in this new vein of research is targeting protein communication between the cancer cells and the extracellular matrix. The secreted protein acidic and rich in cysteine (SPARC) is one such extracellular matrix protein that has shown potential as a therapeutic target due to its influence on PDAC invasion and metastasis. In this review, we discuss the complex interaction of SPARC with PDAC cells and its potential to guide treatment and eventually improve the survival of patients diagnosed with this devastating disease.
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Affiliation(s)
- Monica K Rossi
- Department of Internal Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
| | - Manu Gnanamony
- Department of Internal Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
| | - Christopher S Gondi
- Department of Internal Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA
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Constitutively active Akt1 cooperates with KRas(G12D) to accelerate in vivo pancreatic tumor onset and progression. Neoplasia 2015; 17:175-82. [PMID: 25748236 PMCID: PMC4351297 DOI: 10.1016/j.neo.2014.12.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 12/13/2014] [Accepted: 12/17/2014] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND AND AIMS: Pancreatic adenocarcinoma is a deadly disease characterized by metastatic progression and resistance to conventional therapeutics. Mutation of KRAS is the most frequent early event in pancreatic tumor progression. AKT isoforms are frequently activated in pancreatic cancer, and reports have implicated hyperactivation of AKT1, as well as AKT2, in pancreatic tumor formation. The objective here is to delineate the role of AKT in facilitating in vivo pancreatic tumor progression in the context of KRAS mutation and predisposition to pancreatic cancer. METHODS: Mice with Akt1 and KRas mutant alleles expressed using the pancreas Pdx promoter were mated to characterize the incidence and frequency of histologic and genetic alterations known to occur commonly in human pancreatic ductal adenocarcinoma. RESULTS: Active Akt1 (Akt1Myr, containing a myristoylation sequence) cooperated with active mutant KRasG12D to accelerate pancreatic carcinoma onset and progression and increase phosphorylation of downstream effectors in the Akt pathway. Mucin and smooth muscle actin expression was found in and around pancreatic intraepithelial neoplasms (PanINs), and accelerated time to metastasis was found in Akt1Myr/KRasG12D mice. CONCLUSIONS: In contrast to prior reports of pancreatic KRas mutant mice mated with mice deficient for various tumor suppressor genes, which resulted in aggressive disease within a few months of age, Akt1Myr/KRasG12D mice enabled the study of PanINs and spontaneous pancreatic transformation more characteristic of human pancreatic progression in elderly individuals. The Akt1Myr/KRasG12D model holds promise for delineating the tumor biology and biomarkers critical for understanding their cooperation in cancer oncogenesis and future targeting in therapeutic strategies.
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Moir JAG, Mann J, White SA. The role of pancreatic stellate cells in pancreatic cancer. Surg Oncol 2015; 24:232-8. [PMID: 26080604 DOI: 10.1016/j.suronc.2015.05.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 05/11/2015] [Indexed: 01/05/2023]
Abstract
BACKGROUND The prognosis of pancreatic cancer remains desperately poor, with little progress made over the past 30 years despite the development of new combination chemotherapy regimens. Stromal activity is especially prominent in the tissue surrounding pancreatic tumours, and has a profound influence in dictating tumour development and dissemination. Pancreatic stellate cells (PaSCs) have a key role in this tumour microenvironment, and have been the subject of much research in the past decade. This review examines the relationship between PaSCs and cancer cells. METHODS A comprehensive literature search was performed of multiple databases up to March 2014, including Medline, Pubmed and Google Scholar. RESULTS A complex bidirectional interplay exists between PaSCs and cancer cells, resulting in a perpetuating loop of increased activity and an overriding pro-tumorigenic effect. This involves a number of signalling pathways that also impacts on other stromal components and vasculature, contributing to chemoresistance. The Reverse Warburg Effect is also introduced as a novel concept in tumour stroma. CONCLUSION This review highlights the pancreatic tumour microenvironment, and in particular PaSCs, as an ideal target for therapeutics. There are a number of cellular processes involving PaSCs which could hold the key to more effectively treating pancreatic cancer. The feasibility of targeting these pathways warrant further in depth investigation, with the aim of reducing the aggressiveness of pancreatic cancer and improving chemodelivery.
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Affiliation(s)
- John A G Moir
- Freeman Hospital, Department of HPB and Transplant Surgery, Newcastle upon Tyne, United Kingdom; Institute of Cellular Medicine, Fibrosis Lab, Newcastle upon Tyne, United Kingdom.
| | - Jelena Mann
- Institute of Cellular Medicine, Fibrosis Lab, Newcastle upon Tyne, United Kingdom
| | - Steve A White
- Freeman Hospital, Department of HPB and Transplant Surgery, Newcastle upon Tyne, United Kingdom
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Mizuuchi Y, Aishima S, Ohuchida K, Shindo K, Fujino M, Hattori M, Miyazaki T, Mizumoto K, Tanaka M, Oda Y. Anterior gradient 2 downregulation in a subset of pancreatic ductal adenocarcinoma is a prognostic factor indicative of epithelial-mesenchymal transition. J Transl Med 2015; 95:193-206. [PMID: 25418581 DOI: 10.1038/labinvest.2014.138] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Revised: 08/28/2014] [Accepted: 09/22/2014] [Indexed: 12/24/2022] Open
Abstract
Anterior gradient 2 (AGR2), a member of the protein disulfide isomerase family, has been implicated in various cancers including pancreatic ductal adenocarcinoma (PDAC) and is known to promote cancer progression. However, the prognostic value of AGR2 expression and the interaction with epithelial-mesenchymal transition (EMT) remain unclear. We investigated the clinical significance of AGR2 and EMT markers in PDAC patients by immunohistochemical analyses. Although AGR2 expression was not observed in normal pancreas, all pancreatic precursor neoplastic lesions were positive for AGR2, even at the earliest stages, including pancreatic intraepithelial neoplasia-1A, AGR2 expression was reduced in 27.7% (54/195 cases) of PDAC patients. AGR2 downregulation correlated with EMT markers (vimentin overexpression and reduced membranous E-cadherin expression), high Union for International Cancer Control stage (P<0.0001), high histological cellular grade (P<0.0001), and adverse outcome (P<0.0001). In vitro, targeted silencing of AGR2 in cancer cells using siRNA reduced cell proliferation, colony formation, cell invasiveness, and migration, but did not alter EMT markers. To confer a more aggressive phenotype and induce EMT in PDAC cells, we co-cultured PDAC cell lines with primary-cultured pancreatic stellate cells (PSCs) and found that AGR2 was downregulated in co-cultured PDAC cells compared with PDAC monocultures. Treatment with transforming growth factor beta-1 (TGF-β), secreted from PSCs, decreased AGR2 expression, whereas inhibition of TGF-β signaling using recombinant soluble human TGF-β receptor type II and TGF-β-neutralizing antibodies restored AGR2 expression. We conclude that AGR2 downregulation is a useful prognostic marker, induced by EMT, and that secreted TGF-β from PSCs may partially contribute to AGR2 downregulation in PDAC patients. AGR2 downregulation does not induce EMT or a more aggressive phenotype, but is a secondary effect of these processes in advanced PDAC.
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Affiliation(s)
- Yusuke Mizuuchi
- 1] Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan [2] Reserch Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Shinichi Aishima
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Shindo
- 1] Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan [2] Reserch Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Minoru Fujino
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masami Hattori
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tetsuyuki Miyazaki
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Masao Tanaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Moir JAG, White SA, Mann J. Arrested development and the great escape--the role of cellular senescence in pancreatic cancer. Int J Biochem Cell Biol 2014; 57:142-8. [PMID: 25461770 DOI: 10.1016/j.biocel.2014.10.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 10/14/2014] [Accepted: 10/15/2014] [Indexed: 12/26/2022]
Abstract
The outcomes of pancreatic cancer remain dismal due to late clinical presentation and the aggressive nature of the disease. A heterogeneous combination of genetic mutations, including KRAS, INK4a/CDKN2A and p53, underpin the propensity of pancreatic cancer to rapidly invade and disseminate. These oncogenes and tumour suppressors are strongly associated with cellular senescence, therefore suggesting this process as having a key role in malignant transformation. In the context of cancer, oncogenic stimuli trigger the senescent phenotype resulting in cell cycle growth arrest and prevention of progression of premalignant lesions such as PanINs. However mutations of the aforementioned oncogenes or tumour suppressors result in cells escaping senescence and thus allowing tumours to progress. This review presents current evidence regarding both senescence induction and escape with respect to pancreatic cancer, highlighting the key roles of p19ARF, p53, Rb and P16INK4a. The epigenetic regulatory component is also discussed, with relevance to DNA methylation and HDACs. Lastly the role of the tumour microenvironment, and in particular pancreatic stellate cells, is discussed with regards to the induction of a senescence associated secretory phenotype (SASP), with SASP-associated secretory factors contributing to the pro-tumorigenic effects of the surrounding activated stroma. Further work is required in this field to elucidate the most important pathways relating to cellular senescence that contribute to the belligerent nature of this disease, with the aim of discovering therapeutic targets to improve patient outcomes.
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Affiliation(s)
- John A G Moir
- Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, 4th Floor, William Leech Building, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Steven A White
- Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, 4th Floor, William Leech Building, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Jelena Mann
- Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, 4th Floor, William Leech Building, Newcastle upon Tyne NE2 4HH, United Kingdom.
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Association between CLPTM1L-TERT rs401681 polymorphism and risk of pancreatic cancer: a meta-analysis. Clin Exp Med 2014; 15:477-82. [PMID: 25284078 DOI: 10.1007/s10238-014-0316-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Accepted: 09/15/2014] [Indexed: 12/19/2022]
Abstract
Telomere biology plays a critical and complex role in the initiation and progression of cancer. Several recent studies have provided evidence that rs401681 polymorphisms in intronic region of cleft lip and palate trans-membrane 1-like (CLPTM1L) gene sequence are associated with pancreatic cancer (PC) development, but a comprehensive synopsis is not available. We performed a meta-analysis of 6 case-control studies that included 8,253 pancreatic cancer cases and 37,646 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95 % confidence intervals (CIs). Overall, this meta-analysis showed that rs401681 allele T was associated with a significantly increased PC risk (OR = 1.17, 95 % CI = 1.12-1.22, P heterpgeneity = 0.596 and I (2) = 0). Similarly, in the subgroup analysis by ethnicity, a significantly increased risk was found among Asians (OR = 1.15, 95 % CI = 1.07-1.24, P heterpgeneity = 0.297 and I (2) = 8.0 %) and among Caucasian (OR = 1.13, 95 % CI = 1.02-1.26, P heterpgeneity = 0.385 and I (2) = 0). No publication bias was found in the present study. This meta-analysis suggests that T allele of CLPTM1L-telomerase reverse transcriptase rs401681 polymorphism is associated with an increased PC risk, especially among Chinese. Further large and well-designed studies are needed to confirm this association.
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Rossi ML, Rehman AA, Gondi CS. Therapeutic options for the management of pancreatic cancer. World J Gastroenterol 2014; 20:11142-11159. [PMID: 25170201 PMCID: PMC4145755 DOI: 10.3748/wjg.v20.i32.11142] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/11/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Since its initial characterization, pancreatic ductal adenocarcinoma has remained one of the most devastating and difficult cancers to treat. Pancreatic cancer is the fourth leading cause of death in the United States, resulting in an estimated 38460 deaths annually. With few screening tools available to detect this disease at an early stage, 94% of patients will die within five years of diagnosis. Despite decades of research that have led to a better understanding of the molecular and cellular signaling pathways in pancreatic cancer cells, few effective therapies have been developed to target these pathways. Other treatment options have included more sophisticated pancreatic cancer surgeries and combination therapies. While outcomes have improved modestly for these patients, more effective treatments are desperately needed. One of the greatest challenges in the future of treating this malignancy will be to develop therapies that target the tumor microenvironment and surrounding pancreatic cancer stem cells in addition to pancreatic cancer cells. Recent advances in targeting pancreatic stellate cells and the stroma have encouraged researchers to shift their focus to the role of desmoplasia in pancreatic cancer pathobiology in the hopes of developing newer-generation therapies. By combining novel agents with current cytotoxic chemotherapies and radiation therapy and personalizing them to each patient based on specific biomarkers, the goal of prolonging a patient’s life could be achieved. Here we review the most effective therapies that have been used for the treatment of pancreatic cancer and discuss the future potential of therapeutic options.
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Liu C, Huang H, Wang C, Kong Y, Zhang H, Zhang H. Association between OGG1 gene single nucleotide polymorphisms and risk of pancreatic cancer in Chinese. Med Oncol 2014; 31:40. [PMID: 24935623 DOI: 10.1007/s12032-014-0040-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 05/16/2014] [Indexed: 11/24/2022]
Abstract
Previous studies have suggested that the 8-oxoguanine DNA glycosylase gene (OGG1) has potentially influenced the risk of pancreatic cancer. The objective of this study was to assess the association between single nucleotide polymorphisms (SNPs) of OGG1 gene and risk of pancreatic cancer. A case-control study has been conducted in 370 pancreatic cancer patients and 395 healthy controls. Genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. The association analysis was evaluated by the unconditional logistic regression test. Our data suggested that the distributions of alleles and genotypes were statistically different between pancreatic cancer patients and healthy controls. The c.307G>C SNP was associated with the decreased risk of pancreatic cancer (C vs. G: OR 0.73, 95 % CI 0.59-0.91, P = 0.006). As for c.828A>G SNP, the significantly decreased risk of pancreatic cancer was detected (G vs. A: OR 0.74, 95 % CI 0.59-0.92, P = 0.006). The allele C of c.307G>C and allele G of c.828A>G SNPs might be associated with a protection from pancreatic cancer. Findings from this study indicate that OGG1 SNPs are associated with pancreatic cancer risk in Chinese Han population and could be useful molecular biomarkers for assessing the risk of pancreatic cancer.
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Affiliation(s)
- Chengli Liu
- Department of Hepatobiliary Surgery, The Air Force General Hospital of People's Liberation Army, No. 30 Fucheng Road, Haidian District, Beijing, 100142, People's Republic of China,
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Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, Pasche B, Lee C, Grippo PJ. TGF-β: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst 2014; 106:djt369. [PMID: 24511106 DOI: 10.1093/jnci/djt369] [Citation(s) in RCA: 407] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Several mechanisms underlying tumor progression have remained elusive, particularly in relation to transforming growth factor beta (TGF-β). Although TGF-β initially inhibits epithelial growth, it appears to promote the progression of advanced tumors. Defects in normal TGF-β pathways partially explain this paradox, which can lead to a cascade of downstream events that drive multiple oncogenic pathways, manifesting as several key features of tumorigenesis (uncontrolled proliferation, loss of apoptosis, epithelial-to-mesenchymal transition, sustained angiogenesis, evasion of immune surveillance, and metastasis). Understanding the mechanisms of TGF-β dysregulation will likely reveal novel points of convergence between TGF-β and other pathways that can be specifically targeted for therapy.
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Affiliation(s)
- Daniel R Principe
- Affiliations of authors: Department of Medicine, Division of Gastroenterology (DRP, JB, BJ) and Division of Hematology/Oncology (HGM), Department of Surgery, Division of GI Surgical Oncology (DRP, PJG), and Department of Urology (CL), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Biomedical Engineering. McCormick School of Engineering, Northwestern University, Evanston, IL (DRP); Department of Biomedical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI (JAD); UMR INSERM U1052, CNRS 5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France (LB); Division of Hematology/Oncology, Department of Medicine, University of Alabama-Birmingham, Birmingham, AL (BP); Department of Pathology and Laboratory Medicine, University of California-Irvine, Irvine, CA (CL)
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He G, Chen G, Chen W, Zhang W, Cao J, Ye Q. Lack of association of XRCC1 rs1799782 genetic polymorphism with risk of pancreatic cancer: a meta-analysis. Tumour Biol 2014; 35:4545-50. [PMID: 24435745 DOI: 10.1007/s13277-013-1598-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Accepted: 12/23/2013] [Indexed: 02/07/2023] Open
Abstract
UNLABELLED Emerging evidence suggests that genetic polymorphisms in X-ray repair cross-complementation group 1 (XRCC1) gene could be associated with pancreatic cancer risk. However, previous published studies on the association between XRCC1 rs1799782 genetic polymorphism and pancreatic cancer risk reported inconsistent results. For better understanding of the effects of XRCC1 rs1799782 genetic polymorphism on pancreatic cancer risk, we conducted a meta-analysis of previous published studies by calculating the pooled odds ratio (OR) with a 95% confidence interval (95% CI). A total of five eligible studies with 1,144 pancreatic cancer cases and 2,925 controls were eventually enrolled. Overall, we found that the XRCC1 rs1799782 genetic polymorphism was not associated with pancreatic cancer risk in total population under all genetic models (TT vs. CC: OR = 1.11, 95% CI 0.76-1.63, P = 0.583; CT vs. CC: OR = 1.39, 95% CI 0.92-2.10, P = 0.118; TT/CT vs. CC: OR = 1.39, 95% CI 0.92-2.10, P = 0.121; TT vs. CT/CC OR = 1.07, 95% CI 0.73-1.55, P = 0.743; T vs. C: OR = 1.31, 95% CI 0.93-1.86, P = 0.125). In the subgroup analysis based on ethnicity, there was no statistically significant association between XRCC1 rs1799782 genetic polymorphism and pancreatic cancer risk in Asians/Caucasians under all genetic models (all P values > 0.05). No publication bias was detected in this study. Our meta-analysis suggests that the XRCC1 rs1799782 genetic polymorphism is not significantly associated with pancreatic cancer risk. Considering the limited sample size and ethnicity enrolled in this meta-analysis, further larger scaled studies are needed to provide a more precise estimation on the association.
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Affiliation(s)
- Gengsheng He
- Center of Transplant Surgery, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan, People's Republic of China
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Voorneveld PW, Stache V, Jacobs RJ, Smolders E, Sitters AI, Liesker A, Korkmaz KS, Lam SM, De Miranda NFCC, Morreau H, Kodach LL, Hardwick JCH. Reduced expression of bone morphogenetic protein receptor IA in pancreatic cancer is associated with a poor prognosis. Br J Cancer 2013; 109:1805-12. [PMID: 23969729 PMCID: PMC3790157 DOI: 10.1038/bjc.2013.486] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 07/15/2013] [Accepted: 07/26/2013] [Indexed: 02/07/2023] Open
Abstract
Background: The expression of SMAD4, the central component of the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathways, is lost in 50% of pancreatic cancers and is associated with a poor survival. Although the TGF-β pathway has been extensively studied and characterised in pancreatic cancer, there is very limited data on BMP signalling, a well-known tumour-suppressor pathway. BMP signalling can be lost not only at the level of SMAD4 but also at the level of BMP receptors (BMPRs), as has been described in colorectal cancer. Methods: We performed immunohistochemical analysis of the expression levels of BMP signalling components in pancreatic cancer and correlated these with survival. We also manipulated the activity of BMP signalling in vitro. Results: Reduced expression of BMPRIA is associated with a significantly worse survival, primarily in a subset of SMAD4-positive cancers. In vitro inactivation of SMAD4-dependent BMP signalling increases proliferation and invasion of pancreatic cancer cells, whereas inactivation of BMP signalling in SMAD4-negative cells does not change the proliferation and invasion or leads to an opposite effect. Conclusion: Our data suggest that BMPRIA expression is a good prognostic marker and that the BMP pathway is a potential target for future therapeutic interventions in pancreatic cancer.
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Affiliation(s)
- P W Voorneveld
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
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Abstract
No common malignancy is as rapidly and inevitably fatal as pancreatic ductal adenocarcinoma (PDA). This grim fact has driven substantial research efforts into this disease in recent decades. Unfortunately, the investment has yet to result in a meaningful increase in 5-year survival. This has prompted many pancreatic cancer researchers and advocates to redouble their efforts, but also requires one to step back and ask why the previous efforts were lacking and to consider why pancreatic cancer is so difficult to treat. The difficulties are legion. PDA is characterized by an insidious clinical syndrome, but is rarely diagnosed at a time when surgical resection is feasible. We lack markers of early detection and screening programs remain unproven even in high risk populations. The location of the tumor in the retroperitoneum, the advanced age of patients, and the systemic effects of disease limit the options for local therapy. Chemotherapy may provide a small benefit, but most efforts to improve on the current regimens consistently and stubbornly fail in advanced clinical trials. The molecular and cellular features of ductal pancreatic tumors are aggressive and underlay multiple levels of therapeutic resistance. Non-cell-autonomous features including stromal proliferation, reduced vascular density and immune suppression also contribute to therapeutic resistance. Growing awareness of these the fundamental features of PDA has begun to guide ongoing research efforts. Clinical trials are now specifically targeting these tumor properties and actively focusing on the therapeutic implications of tumor stroma. As reviewed here, reflecting on the fundamental question of why pancreatic cancer is so difficult to treat is a necessary and informative exercise that will aid our efforts to improve patient outcomes. These efforts will lead to improvements in clinical trial design, expand our focus to include the molecular and histologic implications of novel treatment paradigms, and ultimately change the lives of our patients.
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Affiliation(s)
- Paul E. Oberstein
- Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center, New York, NY, USA
| | - Kenneth P. Olive
- Department of Medicine, Division of Digestive and Liver Diseases, Department of Pathology & Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 Saint Nicholas Ave, ICRC 217A, New York, NY 10032, USA
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Association between X-ray repair cross-complementation group 1 rs25487 polymorphism and pancreatic cancer risk. Tumour Biol 2013; 34:3417-21. [PMID: 23807675 DOI: 10.1007/s13277-013-0914-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 06/03/2013] [Indexed: 10/26/2022] Open
Abstract
Previous published studies suggested that genetic polymorphisms in DNA repair genes could modify the DNA repair capacity and could be associated with pancreatic cancer risk. However, previous studies on the association between X-ray repair cross-complementation group 1 (XRCC1) rs25487 (Arg399Gln) polymorphism and pancreatic cancer risk reported inconsistent results. To obtain a more precise estimation of the association between XRCC1 rs25487 polymorphism and pancreatic cancer risk, we performed a meta-analysis of previous published studies by calculating the pooled odds ratio (OR) with a 95% confidence interval (95% CI). Eight individual studies with 5,542 subjects from six publications were finally included into this meta-analysis. The meta-analysis of total eight studies showed that there was no association between XRCC1 rs25487 polymorphism and pancreatic cancer risk in total population under all four genetic models (Gln versus Arg: OR = 1.10, 95% CI 0.95-1.28, P = 0.199; GlnGln versus ArgArg: OR = 1.15, 95% CI 0.93-1.41, P = 0.191; GlnGln/ArgGln versus ArgArg: OR = 1.10, 95% CI 0.97-1.25, P = 0.127; GlnGln versus ArgArg/ArgGln: OR = 1.12, 95% CI 0.92-1.36, P = 0.253). Subgroup analysis showed that there was no association between XRCC1 rs25487 polymorphism and pancreatic cancer risk in Caucasians, but XRCC1 rs25487 polymorphism was associated with pancreatic cancer risk in Asians (GlnGln/ArgGln versus ArgArg: OR = 1.24, 95% CI 1.01-1.53, P = 0.040). Therefore, the meta-analysis suggests that XRCC1 rs25487 polymorphism is associated with pancreatic cancer risk in Asians. Further studies with more participants are needed to provide a more precise estimation on the association above.
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Heparin-binding epidermal growth factor-like growth factor eliminates constraints on activated Kras to promote rapid onset of pancreatic neoplasia. Oncogene 2013; 33:823-31. [PMID: 23376846 PMCID: PMC3929321 DOI: 10.1038/onc.2013.3] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Revised: 12/20/2012] [Accepted: 12/21/2012] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer remains as one of the most deadly cancers with few treatment options at late stages and little information about how it develops through earlier stages. Activating mutation of the Kras gene has been implicated in, but is not sufficient for, tumorigenesis. In mouse models of pancreatic cancer, loss of tumor suppressor genes in conjunction with Kras mutation leads to gradual stochastic acquisition of neoplastic precursors and carcinomas, whereas many cells remain phenotypically unaltered in younger mice. Here, we demonstrate that two oncogenic events, mutation of Kras and production of the growth factor heparin-binding epidermal growth factor-like growth factor (HB-EGF), are sufficient for rapid and complete neoplastic transformation of the exocrine pancreas. We found that macrophages are the major source of HB-EGF production in pancreatic cancer tissue samples, and that macrophages are present in high density and in close association with human pancreatic cancer lesions. In a mouse model, high macrophage density was observed at the earliest stages of neoplastic transformation. The consequence of elevated HB-EGF signaling was investigated without the confounding effects of other macrophage-produced factors via transgenic overexpression of the active form of HB-EGF. In this model, HB-EGF was sufficient to promote Kras-initiated tumorigenesis, inducing rapid and complete neoplastic transformation of the entire exocrine pancreas shortly after birth. HB-EGF overexpression and Kras(G12D) together, but neither alone, increased proliferation with increased cyclinD1 and decreased Cdkn2a/2d (p16/p19(Ink4A/Arf)). These findings establish the importance of oncogenic synergy in cancer initiation and promotion, and establish a molecular link between inflammation and the earliest stages of tumor induction.
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Woo SM, Joo J, Lee WJ, Park SJ, Han SS, Kim TH, Koh YH, Kim HB, Hong EK. Risk of pancreatic cancer in relation to ABO blood group and hepatitis C virus infection in Korea: a case-control study. J Korean Med Sci 2013; 28:247-51. [PMID: 23400555 PMCID: PMC3565136 DOI: 10.3346/jkms.2013.28.2.247] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 12/26/2012] [Indexed: 12/14/2022] Open
Abstract
Several studies have reported that ABO blood group, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection contribute to the development of pancreatic cancer. The aim of this study was to evaluate the association between these factors and pancreatic cancer in the Korean population. We retrospectively recruited 753 patients with pancreatic cancer and 3,012 healthy controls, matched 4 to 1 with cancer patients for age and sex, between 2001 and 2011, at the National Cancer Center, Korea. A multivariate logistic regression analysis was employed to estimate adjusted odds ratios (AORs). The AOR for pancreatic cancer in subjects with non-O blood types (A, AB, and B), compared to blood type O, was 1.29 (95% CI, 1.05-1.58; P = 0.01). Seropositivity for hepatitis B virus surface antigen was not significantly related to pancreatic cancer, either in univariate (odds ratio 1.03; 95% CI, 0.69-1.53; P = 0.91) or multivariate analysis (AOR, 1.02; 95% CI, 0.67-1.56; P = 0.93). The AOR for pancreatic cancer in subjects displaying seropositivity for anti-HCV was 2.30 (95% CI, 1.30-4.08; P < 0.01). Our results suggest that the non-O blood types and anti-HCV seropositivity, but not HBV infection, may increase the risk of developing pancreatic cancer in Korea, where HBV is endemic.
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Affiliation(s)
- Sang Myung Woo
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Jungnam Joo
- Biometric Research Branch, National Cancer Center, Goyang, Korea
| | - Woo Jin Lee
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Sang-Jae Park
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Sung-Sik Han
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Tae Hyun Kim
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Young Hwan Koh
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Hyun Bum Kim
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Eun Kyung Hong
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
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Palagani V, El Khatib M, Kossatz U, Bozko P, Müller MR, Manns MP, Krech T, Malek NP, Plentz RR. Epithelial mesenchymal transition and pancreatic tumor initiating CD44+/EpCAM+ cells are inhibited by γ-secretase inhibitor IX. PLoS One 2012; 7:e46514. [PMID: 23094026 PMCID: PMC3477166 DOI: 10.1371/journal.pone.0046514] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Accepted: 09/04/2012] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that the Notch signalling pathway is important in PDAC initiation and maintenance, although the specific cell biological roles of the pathway remain to be established. Here we sought to examine this question in established pancreatic cancer cell lines using the γ-secretase inhibitor IX (GSI IX) to inactivate Notch. Based on the known roles of Notch in development and stem cell biology, we focused on effects on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. Notably, apoptosis was induced after GSI IX treatment and EMT markers were selectively targeted. Furthermore, under GSI IX treatment, decline in the growth of pancreatic tumor initiating CD44+/EpCAM+ cells was observed in vitro and in a xenograft mouse model. This study demonstrates a central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit selectively EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.
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Affiliation(s)
- Vindhya Palagani
- Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany
| | - Mona El Khatib
- Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany
| | - Uta Kossatz
- Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany
| | - Przemyslaw Bozko
- Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany
| | - Martin R. Müller
- Department of Internal Medicine II, Medical University Hospital, Tuebingen, Germany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Till Krech
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Nisar P. Malek
- Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany
| | - Ruben R. Plentz
- Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany
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Eyol E, Murtaga A, Zhivkova-Galunska M, Georges R, Zepp M, Djandji D, Kleeff J, Berger MR, Adwan H. Few genes are associated with the capability of pancreatic ductal adenocarcinoma cells to grow in the liver of nude rats. Oncol Rep 2012; 28:2177-87. [PMID: 23007550 DOI: 10.3892/or.2012.2049] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Accepted: 08/17/2012] [Indexed: 11/05/2022] Open
Abstract
Owing to aggressiveness and chemoresistance, pancreatic ductal adenocarcinoma (PDAC) is characterised by a poor prognosis. To address this disease-spe-cific dilemma we aimed to establish animal models, which can be used for identifying new specific tumor markers, as well as serving as tools for potential therapeutic approaches. From a panel of sixteen pancreatic cancer cell lines, two human (Suit2-007 and Suit2-013) and a rat (ASML) cell line were selected for their properties to grow in the liver of male RNU rats and mimic liver metastasis of PDAC. For better monitoring of metastatic tumor growth in vivo, all three pancreatic cancer cell lines were stably transfected with eGFP and luciferase marker genes. In addition, the mRNA expression profile of 13 human PDAC cell lines was analyzed by BeadChip array analysis. Only 33 genes and 5 signaling pathways were identified as significantly associated with the ability of the cell lines to grow initially and/or consistently in rat liver. Only a minority of these genes (osteopontin, matrix metalloproteinase-1 and insulin-like growth factor 1) has been intensively studied and shown to be closely related to cancer progression. The function of the remaining 30 genes ranges from moderate to poorly investigated, and their function in cancer progression is still unclear. The ensuing three pancreatic cancer liver metastasis models vary in their aggressiveness and macroscopic growth. They will be used for preclinical evaluation of new therapeutic approaches aiming at the genes identified.
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Affiliation(s)
- Ergül Eyol
- Toxicology and Chemotherapy Unit, German Cancer Research Center, G401, Heidelberg, Germany
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Norris AM, Gore A, Balboni A, Young A, Longnecker DS, Korc M. AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. Oncogene 2012; 32:3867-76. [PMID: 22945649 PMCID: PMC3515713 DOI: 10.1038/onc.2012.394] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 07/11/2012] [Accepted: 07/16/2012] [Indexed: 12/14/2022]
Abstract
The mechanisms controlling expression of the putative oncogene AGR2 in pancreatic ductal adenocarcinoma (PDAC) are not well understood. We now show that AGR2 is a TGF-β-responsive gene in human pancreatic cancer cells, whose down-regulation is SMAD4-dependent. We also provide evidence supporting a role for AGR2 as an ER-chaperone for the cancer-associated mucin, MUC1. AGR2 is both sufficient and required for MUC1 expression in pancreatic cancer cells. Furthermore, AGR2 is co-expressed with MUC1 in mouse pancreatic intraepithelial neoplasia (mPanIN)-like lesions and in the cancer cells of four distinct genetically engineered mouse models of PDAC. We also show that Pdx1-Cre/LSL-KrasG12D/Smad4lox/lox mice heterozygous for Agr2 exhibit a delay in mPanIN initiation and progression to PDAC. It is proposed that loss of Smad4 may convert TGF-β from a tumor suppressor to a tumor promoter by causing the up-regulation of AGR2, which then leads to increased MUC1 expression, at which point both AGR2 and MUC1 facilitate mPanIN initiation and progression to PDAC.
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Affiliation(s)
- A M Norris
- Department of Medicine, Dartmouth Medical School, Hanover, NH, USA
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Changes in connexin43 expression and localization during pancreatic cancer progression. J Membr Biol 2012; 245:255-62. [PMID: 22729649 DOI: 10.1007/s00232-012-9446-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 06/01/2012] [Indexed: 12/11/2022]
Abstract
Gap junctions and gap junction communication have long been recognized to play roles in tissue organization and remodeling through both cell autonomous and intercellular means. We hypothesized that these processes become dysregulated during pancreas cancer progression. Molecular and histological characterization of the gap junction protein, connexin43, during progression of pancreatic ductal adenocarcinoma could yield insight into how these events may contribute to or be modulated during carcinogenesis. In a mouse model of pancreatic ductal adenocarcinoma generated through targeted endogenous expression of Kras(G12D) in the murine pancreas, we examined the evolving expression and localization of connexin43. Overall, connexin43 expression increased over time, and its localization became more widespread. At early stages, connexin43 is found almost exclusively in association with the basolateral membrane of duct cells found in invasive lesions. Connexin43 became increasingly associated with the surrounding stroma over time. Connexin43 phosphorylation was also altered during tumorigenesis, as assessed by migrational changes of the protein in immunoblots. These data suggest a potential role for gap junctions and connexin43 in mediating interactions between and amongst the stromal and epithelial cells in pancreatic ductal adenocarcinoma.
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Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc Natl Acad Sci U S A 2012; 109:5934-41. [PMID: 22421440 DOI: 10.1073/pnas.1202490109] [Citation(s) in RCA: 177] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty (SB) in mice to identify new candidate cancer genes in pancreatic cancer. By combining SB with an oncogenic Kras allele, we observed highly metastatic pancreatic adenocarcinomas. Using two independent statistical methods to identify loci commonly mutated by SB in these tumors, we identified 681 loci that comprise 543 candidate cancer genes (CCGs); 75 of these CCGs, including Mll3 and Ptk2, have known mutations in human pancreatic cancer. We identified point mutations in human pancreatic patient samples for another 11 CCGs, including Acvr2a and Map2k4. Importantly, 10% of the CCGs are involved in chromatin remodeling, including Arid4b, Kdm6a, and Nsd3, and all SB tumors have at least one mutated gene involved in this process; 20 CCGs, including Ctnnd1, Fbxo11, and Vgll4, are also significantly associated with poor patient survival. SB mutagenesis provides a rich resource of mutations in potential cancer drivers for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma.
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49
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Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression. Biochem J 2012; 441:541-52. [PMID: 22187935 DOI: 10.1042/bj20111240] [Citation(s) in RCA: 160] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PDAC (pancreatic ductal adenocarcinoma) is among the most deadly of human malignances. A hallmark of the disease is a pronounced collagen-rich fibrotic extracellular matrix known as the desmoplastic reaction. Intriguingly, it is precisely these areas of fibrosis in which human PDAC tumours demonstrate increased expression of a key collagenase, MT1-MMP [membrane-type 1 MMP (matrix metalloproteinase); also known as MMP-14]. Furthermore, a cytokine known to mediate fibrosis in vivo, TGF-β1 (transforming growth factor-β1), is up-regulated in human PDAC tumours and can promote MT1-MMP expression. In the present review, we examine the regulation of PDAC progression through the interplay between type I collagen (the most common extracellular matrix present in human PDAC tumours), MT1-MMP and TGF-β1. Specifically, we examine the way in which signalling events through these pathways mediates invasion, regulates microRNAs and contributes to chemoresistance.
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50
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Güllü G, Karabulut S, Akkiprik M. Functional roles and clinical values of insulin-like growth factor-binding protein-5 in different types of cancers. CHINESE JOURNAL OF CANCER 2012; 31:266-80. [PMID: 22313597 PMCID: PMC3777492 DOI: 10.5732/cjc.011.10405] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Insulin-like growth factor-binding proteins (IGFBPs) are critical regulators of the mitogenic activity of insulin-like growth factors (IGFs). IGFBP5, one of these IGFBPs, has special structural features, including a nuclear transport domain, heparin-binding motif, and IGF/extracellular matrix/acid-labile subunit-binding sites. Furthermore, IGFBP5 has several functional effects on carcinogenesis and even normal cell processes, such as cell growth, death, motility, and tissue remodeling. These biological effects are sometimes related with IGF (IGF-dependent effects) and sometimes not (IGF-independent effects). The functional role of IGFBP5 is most likely determined in a cell-type and tissue-type specific manner but also depends on cell context, especially in terms of the diversity of interacting proteins and the potential for nuclear localization. Clinical findings show that IGFBP5 has the potential to be a useful clinical biomarker for predicting response to therapy and clinical outcome of cancer patients. In this review, we summarize the functional diversity and clinical importance of IGFBP5 in different types of cancers.
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Affiliation(s)
- Gökçe Güllü
- Department of Medical Biology, School of Medicine, DMarmara University, Istanbul 34468, Turkey
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