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Göktaş M, Karabulut D, Ünlü A, Achmet G, Tunçbilek N. MRI-based radiogenomics analysis for predicting prognosis and XRCC1 gene polymorphism in pancreatic ductal adenocarcinoma. Clin Transl Oncol 2025; 27:2517-2526. [PMID: 39487951 DOI: 10.1007/s12094-024-03763-3] [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: 06/02/2024] [Accepted: 10/10/2024] [Indexed: 11/04/2024]
Abstract
PURPOSE To evaluate the prognostic effects of apparent diffusion coefficient (ADC) values, qualitative MRI findings, and XRCC1 polymorphism in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS Between January 2019 and December 2021, 41 PDAC patients (23 males; 66.6 ± 8.9 years) diagnosed with MRI and treated with chemotherapy were included in this prospective, unicenter study. Quantitative b:0-800 ADC values were calculated at the workstation using a circular region of interest with a diameter of 2 cm2. Polymerase chain reaction restriction fragment length polymorphism was used to detect XRCC1 genotypes from blood samples. Demographic data, MRI findings, and survival times were recorded. Sensitivity, specificity of ADCmin values, and relationship between XRCC1 genes in predicting survival were calculated and compared. RESULTS The median overall survival time was calculated as 9.27 ± 1.4 months. The cut-off value of ADCmin was found to be 0.996 × 10-3 mm2/s for predicting a 4.6-month survival with 77.3% sensitivity and 84.2% specificity. The distribution of XRCC1 codon 399 polymorphism was determined as 26.8% (n = 11) GG, 65.9% (n = 27) AG, and 7.3% (n = 3) AA. There was no statistical correlation between ADCmin values and XRCC1 gene polymorphism (p > 0.05). ADCmin < 0.996 × 10-3 and the XRCC1 codon 399 AG/AA genotype was the subgroup with the worst prognosis (p = 0.035). The mean age at diagnosis was 71.0 ± 9.1 years in cases with GG genotype, while it was 64.6 ± 8.9 years in cases with AG/AA genotype, which was statistically significant (p = 0.038). CONCLUSIONS ADCmin values are useful for predicting prognosis in patients with PDAC. XRCC1 gene polymorphism may affect the age at diagnosis.
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Affiliation(s)
- Muhammet Göktaş
- Department of Radiology, Trakya University, Edirne, Turkey.
- Department of Radiology, Çerkezköy State Hospital, Tekirdağ, Turkey.
| | | | - Ayhan Ünlü
- Department of Biophysics, Trakya University, Edirne, Turkey
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Lu Y, Zhang J, Zhou Z, Zhang N, Ning W, Mao Y. Age-Period-Cohort Analysis on the Burden of Gastrointestinal Cancers in China: Trends, Risk Factors, and Predictions. Healthcare (Basel) 2025; 13:1096. [PMID: 40427934 PMCID: PMC12110969 DOI: 10.3390/healthcare13101096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 04/28/2025] [Accepted: 05/01/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Gastrointestinal cancer imposes a heavy public health burden worldwide. The six major subtypes of GI cancer cases accounted for over a quarter of the total cancer cases in China. We examined and predicted the amount and trend of the burden of gastrointestinal cancer in China. METHODS We collected the crude incidence rate (CIR), age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR), crude DALY rate, age-standardized DALY rate, crude death rate (CDR), and age-standardized death rate (ASDR) by gender, age, and risk factors from the Global Burden of Disease 2021 database, covering the period from 1990 to 2021. We used an age-period-cohort (APC) model to calculate the age, period, and cohort effects separately and a Bayesian APC model to predict the epidemiological trends and the age-specific incidence. RESULTS In 2021, 1,957,948 incidence cases of gastrointestinal cancers were estimated in China, with an incidence rate of 137.62 per 100,000. The burden was notably higher for males, with tobacco use accounting for 26.48% of male GI cancer DALYs versus dietary risks (13.22%) being predominant in females. Metabolic risk factors showed concerning growth trends, with high fasting plasma glucose increasing by 166.06% in males and 275.72% in females. The age-period-cohort analysis revealed peak incidence at advanced ages (>80 years) for most GI cancers. By 2050, China's gastrointestinal cancer burden is projected to increase substantially, with total cases reaching 2.92 (95% CI: 2.27, 3.77) million (49.06% increase) and crude incidence rate rising to 230.51 (95% CI: 178.98, 298.03) per 100,000 (a 67.49% increase), predominantly driven by colorectal cancer (41.74%) and stomach cancer (21.47%). While crude incidence rates show consistent increases across all GI cancers, particularly in males, age-standardized incidence rates are predicted to decrease for most cancer types except for male colorectal and biliary tract cancers. CONCLUSIONS The burden of gastrointestinal cancer in China is growing rapidly and will continue to increase. The performance of ASIR indicated that population aging is a potential driver of the increasing burden. Cancer control policies should focus on older people. It is critical to distinguish prevention strategies by gender and age according to the major risk factors.
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Affiliation(s)
- Yongbo Lu
- School of Public Policy and Administration, Xi’an Jiaotong University, Xi’an 710049, China
| | - Jingya Zhang
- School of Public Policy and Administration, Xi’an Jiaotong University, Xi’an 710049, China
| | - Zongyang Zhou
- School of Public Policy and Administration, Xi’an Jiaotong University, Xi’an 710049, China
| | - Ning Zhang
- Vanke School of Public Health, Tsinghua University, Beijing 100084, China
| | - Wei Ning
- School of Public Policy and Administration, Xi’an Jiaotong University, Xi’an 710049, China
| | - Ying Mao
- School of Public Policy and Administration, Xi’an Jiaotong University, Xi’an 710049, China
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Baghel K, Mehrotra S, Prajapati VK. Revolutionizing pancreatic cancer treatment with CAR-T therapy. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:331-353. [PMID: 39978971 DOI: 10.1016/bs.apcsb.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Pancreatic cancer remains one of the most lethal malignancies, with a five-year survival rate among the lowest of all cancers. This poor prognosis is largely due to the aggressive nature of the disease and its resistance to conventional treatments such as surgery, chemotherapy, and radiation therapy. Chimeric antigen receptor (CAR) T-cell therapy, a novel immunotherapeutic approach leverages the patient's own immune system to specifically target and eliminate cancer cells by genetically engineering T cells to express CARs that recognize tumor-specific antigens. While CAR-T therapy has demonstrated remarkable success in treating hematologic malignancies, its application to solid tumors like pancreatic cancer presents significant challenges. Recent advancements in CAR-T cell design, like the addition of co-stimulatory domains and dual-targeting CARs, have enhanced their efficacy against solid tumors. Additionally, strategies to modify the tumor microenvironment (TME), such as combining CAR-T therapy with immune checkpoint inhibitors and cytokine modulation, are being investigated to boost CAR-T cell activity against pancreatic cancer. Early-phase clinical trials targeting antigens such as carcinoembryonic antigen (CEA) and mesothelin (MSLN) in pancreatic cancer have yielded encouraging results, though obstacles like antigen escape and limited T-cell persistence remain significant challenges. This chapter outlines the current state of CAR-T therapy for pancreatic cancer, focusing on the emerging approaches to address these obstacles and underscore the potential of CAR-T therapy to transform the future of pancreatic cancer treatment.
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Affiliation(s)
- Kirti Baghel
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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Genc D, Ozbek O, Oral B, Yıldırım R, Ileri Ercan N. Phytochemicals in Pancreatic Cancer Treatment: A Machine Learning Study. ACS OMEGA 2024; 9:413-421. [PMID: 38222639 PMCID: PMC10785644 DOI: 10.1021/acsomega.3c05861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 11/17/2023] [Accepted: 11/28/2023] [Indexed: 01/16/2024]
Abstract
The discovery of new strategies and novel therapeutic agents is crucial to improving the current treatment methods and increasing the efficacy of cancer therapy. Phytochemicals, naturally occurring bioactive constituents derived from plants, have great potential in preventing and treating various diseases, including cancer. This study reviewed 74 literature studies published between 2006 and 2022 that conducted in vitro cytotoxicity and cell apoptosis analyses of the different concentrations of phytochemicals and their combinations with conventional drugs or supplementary phytochemicals on human pancreatic cell lines. From 34 plant-derived phytochemicals on 20 human pancreatic cancer cell lines, a total of 11 input and 2 output variables have been used to construct the data set that contained 2161 different instances. The machine learning approach has been implemented using random forest for regression, whereas association rule mining has been used to determine the effects of individual phytochemicals. The random forest models developed are generally good, indicating that the phytochemical type, its concentration, and the type of cell line are the most important descriptors for predicting the cell viability. However, for predicting cell apoptosis the primary phytochemical type is the most significant descriptor . Among the studied phytochemicals, catechin and indole-3-carbinol were found to be non-cytotoxic at all concentrations irrespective of the treatment time. On the other hand, berbamine and resveratrol were strongly cytotoxic with cell viabilities of less than 40% at a concentration range between 10 and 100 μM and above 100 μM, respectively, which brings them forward as potential therapeutic agents in the treatment of pancreatic cancer.
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Affiliation(s)
- Destina
Ekingen Genc
- Department
of Chemical Engineering, Bogazici University, Bebek, Istanbul 34342, Turkey
| | - Ozlem Ozbek
- Department
of Chemical Engineering, Bogazici University, Bebek, Istanbul 34342, Turkey
| | - Burcu Oral
- Department
of Chemical Engineering, Bogazici University, Bebek, Istanbul 34342, Turkey
| | - Ramazan Yıldırım
- Department
of Chemical Engineering, Bogazici University, Bebek, Istanbul 34342, Turkey
| | - Nazar Ileri Ercan
- Department
of Chemical Engineering, Middle East Technical
University, Çankaya, Ankara 06800, Turkey
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Saadh MJ, Baher H, Li Y, Chaitanya M, Arias-Gonzáles JL, Allela OQB, Mahdi MH, Carlos Cotrina-Aliaga J, Lakshmaiya N, Ahjel S, Amin AH, Gilmer Rosales Rojas G, Ameen F, Ahsan M, Akhavan-Sigari R. The bioengineered and multifunctional nanoparticles in pancreatic cancer therapy: Bioresponisive nanostructures, phototherapy and targeted drug delivery. ENVIRONMENTAL RESEARCH 2023; 233:116490. [PMID: 37354932 DOI: 10.1016/j.envres.2023.116490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/18/2023] [Accepted: 06/21/2023] [Indexed: 06/26/2023]
Abstract
The multidisciplinary approaches in treatment of cancer appear to be essential in term of bringing benefits of several disciplines and their coordination in tumor elimination. Because of the biological and malignant features of cancer cells, they have ability of developing resistance to conventional therapies such as chemo- and radio-therapy. Pancreatic cancer (PC) is a malignant disease of gastrointestinal tract in which chemotherapy and radiotherapy are main tools in its treatment, and recently, nanocarriers have been emerged as promising structures in its therapy. The bioresponsive nanocarriers are able to respond to pH and redox, among others, in targeted delivery of cargo for specific treatment of PC. The loading drugs on the nanoparticles that can be synthetic or natural compounds, can help in more reduction in progression of PC through enhancing their intracellular accumulation in cancer cells. The encapsulation of genes in the nanoparticles can protect against degradation and promotes intracellular accumulation in tumor suppression. A new kind of therapy for cancer is phototherapy in which nanoparticles can stimulate both photothermal therapy and photodynamic therapy through hyperthermia and ROS overgeneration to trigger cell death in PC. Therefore, synergistic therapy of phototherapy with chemotherapy is performed in accelerating tumor suppression. One of the important functions of nanotechnology is selective targeting of PC cells in reducing side effects on normal cells. The nanostructures are capable of being surface functionalized with aptamers, proteins and antibodies to specifically target PC cells in suppressing their progression. Therefore, a specific therapy for PC is provided and future implications for diagnosis of PC is suggested.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan; Applied Science Research Center. Applied Science Private University, Amman, Jordan
| | - Hala Baher
- Department of Radiology and Ultrasonography Techniques, College of Medical Techniques, Al-Farahidi University, Baghdad, Iraq
| | - Yuanji Li
- Institute of Electrical Engineering, Yanshan University, Qinhuangdao, 066004, China
| | - Mvnl Chaitanya
- Department of Pharmacognosy, School of Pharmacy, Lovely Professional University, Phagwara, Punjab, 144001, India
| | - José Luis Arias-Gonzáles
- Department of Social Sciences, Faculty of Social Studies, University of British Columbia, Vancouver, Canada
| | | | | | | | - Natrayan Lakshmaiya
- Department of Mechanical Engineering, Saveetha School of Engineering, SIMATS, Chennai, Tamil Nadu, India
| | - Salam Ahjel
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Ali H Amin
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt
| | | | - Fuad Ameen
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Muhammad Ahsan
- Department of Measurememts and Control Systems, Silesian University of Technology, Gliwice, 44-100, Poland.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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Oey O, Sunjaya AF, Khan Y, Redfern A. Stromal inflammation, fibrosis and cancer: An old intuition with promising potential. World J Clin Oncol 2023; 14:230-246. [PMID: 37583950 PMCID: PMC10424089 DOI: 10.5306/wjco.v14.i7.230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/07/2023] [Accepted: 06/21/2023] [Indexed: 07/19/2023] Open
Abstract
It is now well established that the biology of cancer is influenced by not only malignant cells but also other components of the tumour microenvironment. Chronic inflammation and fibrosis have long been postulated to be involved in carcinogenesis. Chronic inflammation can promote tumorigenesis via growth factor/cytokine-mediated cellular proliferation, apoptotic resistance, immunosuppression; and free-radical-induced oxidative deoxyribonucleic acid damage. Fibrosis could cause a perturbation in the dynamics of the tumour microenvironment, potentially damaging the genome surveillance machinery of normal epithelial cells. In this review, we will provide an in-depth discussion of various diseases characterised by inflammation and fibrosis that have been associated with an increased risk of malignancy. In particular, we will present a comprehensive overview of the impact of alterations in stromal composition on tumorigenesis, induced as a consequence of inflammation and/or fibrosis. Strategies including the application of various therapeutic agents with stromal manipulation potential and targeted cancer screening for certain inflammatory diseases which can reduce the risk of cancer will also be discussed.
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Affiliation(s)
- Oliver Oey
- Faculty of Medicine, University of Western Australia, Perth 6009, Crawley NA, Australia
- Department of Medical Oncology, Sir Charles Gardner Hospital, Nedlands 6009, Australia
| | - Angela Felicia Sunjaya
- Institute of Cardiovascular Science, University College London, London WC1E 6DD, United Kingdom
| | - Yasir Khan
- Department of Medical Oncology, St John of God Midland Public and Private Hospital, Midland 6056, WA, Australia
| | - Andrew Redfern
- Department of Medical Oncology, Fiona Stanley Hospital, Murdoch 6150, WA, Australia
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Weng H, Feng W, Li F, Huang D, Lin L, Wang Z. Transcription factor ETV1-induced lncRNA MAFG-AS1 promotes migration, invasion, and epithelial-mesenchymal transition of pancreatic cancer cells by recruiting IGF2BP2 to stabilize ETV1 expression. Growth Factors 2023:1-13. [PMID: 37428861 DOI: 10.1080/08977194.2023.2227272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/28/2023] [Indexed: 07/12/2023]
Abstract
We investigated the mechanism of ETS-translocation variant 1 (ETV1)/lncRNA-MAFG-AS1 in pancreatic cancer (PC). MAFG-AS1 and ETV1 levels in PC cell lines and HPNE cells were determined using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting (WB). After transfection with sh-MAFG-AS1, PC cell invasion, migration, proliferation, and epithelial-mesenchymal transition (EMT)-related proteins were measured by 5-ethynyl-2'-deoxyuridine (EdU), Transwell assay, and WB. The binding between ETV1 and MAFG-AS1 was studied using dual-luciferase assay and chromatin immunoprecipitation. The interactions between MAFG-AS1, IGF2BP2, and ETV1 were tested. Combined experiments were further performed using sh-MAFG-AS1 and pcDNA-ETV1 simultaneously. ETV1/MAFG-AS1 was highly expressed in PC cells. Blocking MAFG-AS1 inhibited the malignant behaviors of PC cells. ETV1 induced MAFG-AS1 transcription in PC cells. MAFG-AS1 stabilized ETV1 mRNA by recruiting IGF2BP2. ETV1 overexpression partially antagonized the suppression of silencing MAFG-AS1 on PC cells. ETV1-induced MAFG-AS1 stabilized the ETV1 expression by recruiting IGF2BP2 and promoted PC cell migration, invasion, proliferation, and EMT.
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Affiliation(s)
- Hanqin Weng
- Department of Hepatobiliary Surgery, Dongguan People's Hospital, Dongguan, China
| | - Weijian Feng
- Department of Hepatobiliary Surgery, Dongguan People's Hospital, Dongguan, China
| | - Fengling Li
- Department of Anesthesiology, Dongguan People's Hospital, Dongguan, China
| | - Dong Huang
- Department of Hepatobiliary Surgery, Dongguan People's Hospital, Dongguan, China
| | - Liangyi Lin
- Department of Hepatobiliary Surgery, Dongguan People's Hospital, Dongguan, China
| | - Zaiguo Wang
- Department of Hepatobiliary Surgery, Dongguan People's Hospital, Dongguan, China
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Dite GS, Spaeth E, Wong CK, Murphy NM, Allman R. Predicting 10-Year Risk of Pancreatic Cancer Using a Combined Genetic and Clinical Model. GASTRO HEP ADVANCES 2023; 2:979-989. [PMID: 39130772 PMCID: PMC11308393 DOI: 10.1016/j.gastha.2023.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 05/12/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Pancreatic cancer has the poorest 5-year survival rate of any major solid tumor, but when diagnosed at an early stage, survival rates improve. Population screening is impractical because pancreatic cancer is rare with a lifetime risk of 1.7%, but accurate risk stratification in the general population could enable health care providers to focus early detection strategies to at-risk individuals. Here, we validate a combined risk prediction model that integrates a polygenic risk score and a clinical risk model. Methods Using the UK Biobank, we conducted a prospective cohort study assessing 10-year pancreatic cancer risks based on a polygenic risk score, a clinical risk score, and a combined risk score. We assessed the association, discrimination, calibration, cumulative hazards, and standardized incidence ratios compared to population incidence rates for the risk scores. We also conducted net reclassification analyses. Results While all of the risk scores discriminated well between affected and unaffected participants, the combined risk score - with a Harrell's C-index of 0.714 (95% confidence interval [CI] = 0.698, 0.730) - discriminated better than both the polygenic risk score (P = .001) and the clinical risk score (P = .02). In terms of calibration, there was no problem with dispersion for the combined risk score (β = 0.952, 95% CI = 0.865-1.039, P = .3) and overall there was a small overestimation of risk (α = -0.089, 95% CI = -0.156 to -0.021, P = .009). Participants in the top decile of 10-year risk were at 1.413 (95% CI = 1.242-1.607) times population risk. Conclusion The combined risk score was able to identify individuals at substantially increased risk of pancreatic cancer and to whom targeted screening could be useful.
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Affiliation(s)
| | - Erika Spaeth
- Phenogen Sciences Inc, Charlotte, North Carolina
| | - Chi Kuen Wong
- Genetic Technologies Limited, Fitzroy, Victoria, Australia
| | | | - Richard Allman
- Genetic Technologies Limited, Fitzroy, Victoria, Australia
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Real World Data for Pancreatic Adenocarcinoma from a Population-Based Study in France. Cancers (Basel) 2023; 15:cancers15020525. [PMID: 36672474 PMCID: PMC9856436 DOI: 10.3390/cancers15020525] [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: 12/18/2022] [Revised: 01/08/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Pancreatic cancer is associated with high mortality rates, and most cases are diagnosed at advanced stages. This study aimed to evaluate the prognostic factors for survival in pancreatic adenocarcinoma. Data from the Finistere registry of digestive database were used in this analysis. This retrospective population-based study included 2117 patients with pancreatic adenocarcinoma diagnosed between 2005 and 2019. Cox regression was used to assess the impact of different prognostic factors. The overall median age was 74 (IQR 65.0−81.0). The majority of pancreatic adenocarcinoma 1120 (52.90%) occurred in the head of the pancreas. The type of surgical resection correlated with age (pancreaticoduodenectomy performed in 13.39% of patients aged under 65 years and only 1.49% of patients aged ≥ 80 years). For the entire cohort, 1-year mortality rate after diagnosis was 77.81%. Chemotherapy was associated with better survival for both operated (HR 0.17 95% CI 0.22; 0.64 p < 0.001) and unoperated patients (HR 0.41 95% CI 0.27; 0.61 p < 0.001). Palliative radiotherapy was associated with improved survival (HR 0.69 95% CI 0.56; 0.85 p < 0.001). Among operated patients, the presence of lung metastases (median 34.06; CI 20.06; 34.66) was associated with better survival compared with liver metastases (median 21.10; CI 18.10; 28.96), peritoneal carcinomatosis (median 11.00; CI 8.53; 14.63), or distant metastases (median 15.16; CI 12.66; 18.13) (p = 0.0001). Age, curative surgery, positive lymph nodes, chemotherapy, and palliative radiotherapy were corelated with overall survival. Surgical resection is the only potentially curative treatment, but less than a quarter of patients were eligible.
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Ajumeera R, Thipparapu G, Padya BS, Tirumala L, Challa S. Anti-cancer activity of pyridoxal phosphate and metformin combination in human pancreatic cancer cells. Nutr Health 2022:2601060221137624. [PMID: 36349362 DOI: 10.1177/02601060221137624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Background: Pancreatic cancer is the foremost cause of cancer-related deaths in many developed countries with a poor prognosis. With advanced disease conditions chemotherapy, surgery followed by radiation is the regimen to prolong the survival. But a complete cure is questionable. Metformin is the first-line drug used for the treatment of type 2 diabetes in the world. Aim: The study aims to assess the anti-cancer activity of metformin with the combination of micronutrient pyridoxal phosphate (PLP) in the human pancreatic cancer cell line (PANC-1). Methods: Panc1 cells were maintained in vitro cell culture conditions. The IC50 concentrations of metformin and PLP were estimated and selected by using MTT assay. Morphological changes upon treatments were observed under microscope. Distribution of cells pattern was observed with propidium iodide dye in cell cycle assay. Different phases of cell distribution were studied with apoptosis assay. Results: More morphological changes were observed with PLP followed metformin. MTT assay revelled the IC50 concentrations of metformin and PLP were 20.95 ± 0.98 mM and 5.70 ± 0.07 mM. The cell cycle assay revealed that the percentage of cells was arrested in different phases with the treatments. Apoptosis assay revelled metformin increased necrosis population to 9.9%, whereas PLP has enhanced to 14.2% apoptosis. Tumour suppressor protein p53 levels had increased to 24.8% with PLP and 3.5% with metformin. Conclusion: In conclusion, PLP has significantly induced cell cycle arrest, apoptosis and enhanced p53 protein expression but a combination of PLP with metformin drug has not synergised anti-cancer activity in human PANC1 cells.
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Affiliation(s)
- Rajanna Ajumeera
- Department of Cell Biology, ICMR-28603National Institute of Nutrition, Hyderabad, India
| | - Ganapathi Thipparapu
- Department of Cell Biology, ICMR-28603National Institute of Nutrition, Hyderabad, India
| | - Barath Singh Padya
- Department of Cell Biology, ICMR-28603National Institute of Nutrition, Hyderabad, India
| | - Lalitha Tirumala
- Department of Cell Biology, ICMR-28603National Institute of Nutrition, Hyderabad, India
| | - Suresh Challa
- Department of Cell Biology, ICMR-28603National Institute of Nutrition, Hyderabad, India
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Hoyt M, Song Y, Gao S, O'Palka J, Zhang J. Intake of Calcium, Magnesium, and Phosphorus and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. JOURNAL OF THE AMERICAN NUTRITION ASSOCIATION 2022; 41:747-757. [PMID: 34586963 DOI: 10.1080/07315724.2021.1970047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 08/09/2021] [Accepted: 08/14/2021] [Indexed: 10/20/2022]
Abstract
ObjectiveFew epidemiological studies have investigated the associations between calcium, magnesium, and phosphorus intake and pancreatic cancer. We examined these associations in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.MethodsDiet was assessed using the Dietary Questionnaire (DQX) at baseline in the intervention arm and the Dietary History Questionnaire (DHQ) in 1999 or around the third anniversary of randomization in both the intervention and control arms. During a median follow-up of 12.2 years, 279 cases of pancreatic cancer occurred from 58,477 participants who completed DQX; 380 cases arose from 101,622 participants who responded to DHQ over a median follow-up of 8.9 years. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI).ResultsTotal calcium intake was inversely associated with pancreatic cancer [HR (95% CI) for the fourth vs. the first quartiles in the DHQ cohort: 0.67 (0.47, 0.96); p-trend: 0.035]. An inverse association was also observed for total magnesium intake [HR (95% CI) for the fourth vs. the first quartiles in the DQX cohort: 0.61 (0.37, 1.00); p-trend: 0.023]. Reduced risk associated with total calcium intake was confined to subjects with a high fat intake (>73 g/day) in the DHQ cohort (p-interaction: 0.16).ConclusionsThere was not a significant association between dietary phosphorus intake and pancreatic cancer risk in both cohorts. Total intake of calcium and magnesium are associated with a lower pancreatic cancer risk. The effect of total calcium intake was modified by fat intake.
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Affiliation(s)
- Margaret Hoyt
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA
| | - Yiqing Song
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA
| | - Sujuan Gao
- Department of Biostatistics, Indiana University Richard M. Fairbanks School of Public Health and School of Medicine, Indianapolis, IN, USA
| | - Jacquelynn O'Palka
- Department of Nutrition and Dietetics, Indiana University School of Health and Human Sciences, Indianapolis, IN, USA
| | - Jianjun Zhang
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA
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Hoyt M, Song Y, Gao S, O'Palka J, Zhang J. Prediagnostic BMI trajectories in relation to pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Obesity (Silver Spring) 2022; 30:2275-2285. [PMID: 36156459 PMCID: PMC9826088 DOI: 10.1002/oby.23550] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/26/2022] [Accepted: 06/28/2022] [Indexed: 01/11/2023]
Abstract
OBJECTIVE It remains elusive whether prediagnostic BMI trajectory is associated with pancreatic cancer. METHODS This study investigated this question among 145,489 participants who gave rise to 696 incident cases of pancreatic cancer over a median follow-up of 12 years in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. At baseline, participants were asked to recall their weight at ages 20, 50, and 55 to 74 years (at enrollment), as well as their height. RESULTS At age 50 years, people with obesity had a significantly increased risk of pancreatic cancer compared with those with a normal weight after adjustment for confounders (hazard ratio [95% CI]: 1.27 [1.01-1.60]). Individuals who had overweight at age 20 years experienced a marginally significant elevated risk of pancreatic cancer (hazard ratio [95% CI]: 1.22 [0.99-1.50]). Compared with individuals who maintained a steady normal weight during follow-up, no significantly altered risk of pancreatic cancer was observed for those whose weight status changed from normal weight to overweight, from normal weight to obesity, and from overweight to obesity. CONCLUSIONS The present study revealed that prediagnostic adulthood BMI trajectory was not associated with pancreatic cancer risk, but overweight at young adulthood and obesity at middle adulthood may confer an elevated risk of this malignancy.
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Affiliation(s)
- Margaret Hoyt
- Department of EpidemiologyRichard M. Fairbanks School of Public Health, Indiana University–Purdue UniversityIndianapolisIndianaUSA
| | - Yiqing Song
- Department of EpidemiologyRichard M. Fairbanks School of Public Health, Indiana University–Purdue UniversityIndianapolisIndianaUSA
| | - Sujuan Gao
- Department of Biostatistics and Health Data ScienceRichard M. Fairbanks School of Public Health and School of Medicine, Indiana University–Purdue UniversityIndianapolisIndianaUSA
| | - Jacquelynn O'Palka
- Department of Nutrition and DieteticsSchool of Health and Human Sciences, Indiana University–Purdue UniversityIndianapolisIndianaUSA
| | - Jianjun Zhang
- Department of EpidemiologyRichard M. Fairbanks School of Public Health, Indiana University–Purdue UniversityIndianapolisIndianaUSA
- Melvin and Bren Simon Comprehensive Cancer CenterIndiana University–Purdue UniversityIndianapolisIndianaUSA
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Utility of 18F-FDG PET/CT in Management of Pancreatic and Periampullary Masses—Prospective Study from a Tertiary Care Center. Indian J Surg Oncol 2022; 13:288-298. [DOI: 10.1007/s13193-021-01434-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/05/2021] [Indexed: 12/24/2022] Open
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Prediction Model for Pancreatic Cancer-A Population-Based Study from NHIRD. Cancers (Basel) 2022; 14:cancers14040882. [PMID: 35205630 PMCID: PMC8870511 DOI: 10.3390/cancers14040882] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Pancreatic cancer has been ranked seventh in the top ten cancer mortality rates for the past three year in Taiwan. It is one of the more difficult cancers to detect early due to the lack of early diagnostic tools. This is a population-based study from NHIRD. A higher performance pancreatic cancer prediction model has been established. This predictive model can improve the awareness of the risk of pancreatic cancer and give patients with pancreatic cancer a simpler tool for early screening in the golden period when the disease can still be eradicated. Abstract (1) Background: Cancer has been the leading cause of death in Taiwan for 39 years, and among them, pancreatic cancer has been ranked seventh in the top ten cancer mortality rates for the past three years. While the incidence rate of pancreatic cancer is ranked at the bottom of the top 10 cancers, the survival rate is very low. Pancreatic cancer is one of the more difficult cancers to detect early due to the lack of early diagnostic tools. Early screening is important for the treatment of pancreatic cancer. Only a few studies have designed predictive models for pancreatic cancer. (2) Methods: The Taiwan Health Insurance Database was used in this study, covering over 99% of the population in Taiwan. The subset sample was not significantly different from the original NHIRD sample. A machine learning approach was used to develop a predictive model for pancreatic cancer disease. Four models, including logistic regression, deep neural networks, ensemble learning, and voting ensemble were used in this study. The ROC curve and a confusion matrix were used to evaluate the accuracy of the pancreatic cancer prediction models. (3) Results: The AUC of the LR model was higher than the other three models in the external testing set for all three of the factor combinations. Sensitivity was best measured by the stacking model for the first factor combinations, and specificity was best measured by the DNN model for the second factor combination. The result of the model that used only nine factors (third factor combinations) was equal to the other two factor combinations. The AUC of the previous models for the early assessment of pancreatic cancer ranged from approximately 0.57 to 0.71. The AUC of this study was higher than that of previous studies and ranged from 0.71 to 0.76, which provides higher accuracy. (4) Conclusions: This study compared the performances of LR, DNN, stacking, and voting models for pancreatic cancer prediction and constructed a pancreatic cancer prediction model with accuracy higher than that of previous studies. This predictive model will improve awareness of the risk of pancreatic cancer and give patients with pancreatic cancer a simpler tool for early screening in the golden period when the disease can still be eradicated.
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15
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Ariston Gabriel AN, Wang F, Jiao Q, Yvette U, Yang X, Al-Ameri SA, Du L, Wang YS, Wang C. The involvement of exosomes in the diagnosis and treatment of pancreatic cancer. Mol Cancer 2020; 19:132. [PMID: 32854710 PMCID: PMC7450552 DOI: 10.1186/s12943-020-01245-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 08/12/2020] [Indexed: 12/24/2022] Open
Abstract
At the moment, pancreatic cancer is among the deadliest gastrointestinal diseases, and pancreatic cancer growth is a complex biological process that is based on different kinds of genes. Exosomes are extracellular vesicles containing microRNAs (miRNAs), messenger RNA (mRNA), and proteins, they act as the most prominent mediator of intercellular communication, and they regulate, instruct, and re-educate their surrounding microenvironment and target specific organs. Due to accumulative evidence proved that exosomes are involved in metastasis, cell proliferation, EMT, angiogenesis, and TME of pancreatic cancer, exosomes are crucial potential candidates to detect pancreatic cancer early. This review aims to convey the current understanding of the main functions employed by exosomes in early diagnosis and treatment of pancreatic cancer.
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Affiliation(s)
- Abakundana Nsenga Ariston Gabriel
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People's Republic of China
- Department of Clinical Laboratory Diagnostics, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People's Republic of China
| | - Fang Wang
- Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People's Republic of China
| | - Qinlian Jiao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People's Republic of China
- Marine College, Shandong University, Weihai, 264209, People's Republic of China
| | - Umwali Yvette
- Department of Clinical Laboratory Diagnostics, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People's Republic of China
- Department of Clinical Laboratory, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People's Republic of China
| | - Xuemei Yang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People's Republic of China
| | - Samed Ahmed Al-Ameri
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People's Republic of China
- Department of Clinical Laboratory Diagnostics, School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People's Republic of China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People's Republic of China.
| | - Yun-Shan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People's Republic of China.
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, People's Republic of China.
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16
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Differences between KC and KPC pancreatic ductal adenocarcinoma mice models, in terms of their modeling biology and their clinical relevance. Pancreatology 2020; 20:79-88. [PMID: 31780287 DOI: 10.1016/j.pan.2019.11.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 11/15/2019] [Accepted: 11/18/2019] [Indexed: 12/24/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the dangerous human cancers, is the 10th highly prevalent cancer, and the fourth sole cause of cancer-related mortality in the United States of America. Notwithstanding the significant commitment, the forecast for people with this burden continues to have a five-year survival rate of just 4-6%. The most critical altered genes within PDAC consist of K-ras the proto-oncogene which is usually mutationally activated above 90% cases and tumor suppressors likeTrp53 are altered at 55%. To face the burden of pancreatic ductal adenocarcinoma, a variety of genetically engineered pancreatic cancer mice models have been created over the last past years. These models have distinctive features and are not all appropriate for preclinical studies. In this review, we focus on differences between two mice models K-rasLSL.G12D/+;Pdx-1-Cre(KC) and K-rasLSL.G12D/+; Trp53R172H/+; Pdx-1-Cre(KPC) in terms of their modeling biology and their clinical relevance.
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17
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James AD, Richardson DA, Oh IW, Sritangos P, Attard T, Barrett L, Bruce JIE. Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2). Br J Cancer 2020; 122:266-278. [PMID: 31819190 PMCID: PMC7052184 DOI: 10.1038/s41416-019-0675-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 11/13/2019] [Accepted: 11/15/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has poor survival and treatment options. PDAC cells shift their metabolism towards glycolysis, which fuels the plasma membrane calcium pump (PMCA), thereby preventing Ca2+-dependent cell death. The ATP-generating pyruvate kinase-M2 (PKM2) is oncogenic and overexpressed in PDAC. This study investigated the PKM2-derived ATP supply to the PMCA as a potential therapeutic locus. METHODS PDAC cell growth, migration and death were assessed by using sulforhodamine-B/tetrazolium-based assays, gap closure assay and poly-ADP ribose polymerase (PARP1) cleavage, respectively. Cellular ATP and metabolism were assessed using luciferase/fluorescent-based assays and the Seahorse XFe96 analyzer, respectively. Cell surface biotinylation identified membrane-associated proteins. Fura-2 imaging was used to assess cytosolic Ca2+ overload and in situ Ca2+ clearance. PKM2 knockdown was achieved using siRNA. RESULTS The PKM2 inhibitor (shikonin) reduced PDAC cell proliferation, cell migration and induced cell death. This was due to inhibition of glycolysis, ATP depletion, inhibition of PMCA and cytotoxic Ca2+ overload. PKM2 associates with plasma membrane proteins providing a privileged ATP supply to the PMCA. PKM2 knockdown reduced PMCA activity and reduced the sensitivity of shikonin-induced cell death. CONCLUSIONS Cutting off the PKM2-derived ATP supply to the PMCA represents a novel therapeutic strategy for the treatment of PDAC.
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Affiliation(s)
- Andrew D James
- Division of Cancer Sciences, Faculty of Biology, Medicine & Health Sciences, The University of Manchester, Michael Smith Building, Manchester, M13 9PT, UK
- Division of Cancer Sciences, Department of Biology, University of York, Heslington, York, YO10 5DD, UK
| | - Daniel A Richardson
- Division of Cancer Sciences, Faculty of Biology, Medicine & Health Sciences, The University of Manchester, Michael Smith Building, Manchester, M13 9PT, UK
| | - In-Whan Oh
- Division of Cancer Sciences, Faculty of Biology, Medicine & Health Sciences, The University of Manchester, Michael Smith Building, Manchester, M13 9PT, UK
| | - Pishyaporn Sritangos
- Division of Cancer Sciences, Faculty of Biology, Medicine & Health Sciences, The University of Manchester, Michael Smith Building, Manchester, M13 9PT, UK
| | - Thomas Attard
- Division of Cancer Sciences, Faculty of Biology, Medicine & Health Sciences, The University of Manchester, Michael Smith Building, Manchester, M13 9PT, UK
| | - Lisa Barrett
- Division of Cancer Sciences, Faculty of Biology, Medicine & Health Sciences, The University of Manchester, Michael Smith Building, Manchester, M13 9PT, UK
| | - Jason I E Bruce
- Division of Cancer Sciences, Faculty of Biology, Medicine & Health Sciences, The University of Manchester, Michael Smith Building, Manchester, M13 9PT, UK.
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18
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Gzil A, Zarębska I, Bursiewicz W, Antosik P, Grzanka D, Szylberg Ł. Markers of pancreatic cancer stem cells and their clinical and therapeutic implications. Mol Biol Rep 2019; 46:6629-6645. [PMID: 31486978 DOI: 10.1007/s11033-019-05058-1] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 08/31/2019] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer (PC) is the fourth most common cause of death among all cancers. Poor prognosis of PC may be caused by a prevalence of cancer stem cells (CSCs). CSCs are a population of cancer cells showing stem cell-like characteristics. CSCs have the ability to self-renew and may initiate tumorigenesis. PC CSCs express markers such as CD133, CD24, CD44, DCLK1, CXCR4, ESA, Oct4 and ABCB1. There is a wide complexity of interaction and relationships between CSC markers in PC. These markers are negative prognostic factors and are connected with tumor recurrence and clinical progression. Additionally, PC CSCs are resistant to treatment with gemcitabine. Thus, most current therapies for PC are ineffective. Numerous studies have shown, that targeting of these proteins may increase both disease-free and overall survival in PC.
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Affiliation(s)
- Arkadiusz Gzil
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.
| | - Izabela Zarębska
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
| | - Wiktor Bursiewicz
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
| | - Paulina Antosik
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
| | - Łukasz Szylberg
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
- Department of Pathomorphology, Military Clinical Hospital, Bydgoszcz, Poland
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19
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Morita Y, Sakaguchi T, Kitajima R, Furuhashi S, Kiuchi R, Takeda M, Hiraide T, Shibasaki Y, Kikuchi H, Konno H, Takeuchi H. Body weight loss after surgery affects the continuity of adjuvant chemotherapy for pancreatic cancer. BMC Cancer 2019; 19:416. [PMID: 31046709 PMCID: PMC6498638 DOI: 10.1186/s12885-019-5621-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 04/16/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Postoperative chemotherapy is beneficial for many pancreatic cancer patients. However, some patients require dose reduction or the discontinuation of adjuvant chemotherapy because of adverse treatment-related effects. In this study, we aimed to evaluate two main outcomes. First, we evaluated the clinicopathological factors affecting patient disease-free survival (DFS) and overall survival (OS) following upfront surgery. Second, we evaluated the factors that influence the continuity of adjuvant chemotherapy. METHODS Fifty-four patients with resected pancreatic cancer were enrolled. First, we evaluated the clinicopathological factors affecting postoperative survival using the Kaplan-Meier method and Cox regression method. Next, factors affecting the continuity of adjuvant chemotherapy were analyzed using multiple logistic regression analysis. RESULTS Univariate and multivariate analyses revealed that positive LN metastasis (HR (95% CI) 6.329 (2.381-16.95); p < 0.001) and relative dose intensity (RDI) < 80% for adjuvant chemotherapy (HR (95% CI) 5.154 (1.761-15.15); p = 0.003) were independent predictive factors for DFS. Regarding OS, extended dissection of the nerve plexus around the superior mesenteric artery (SMA) (HR (95% CI) 4.504 (1.721-11.76); p = 0.002), positive microscopic surgical margin (HR (95% CI) 5.565 (1.724-17.96); p = 0.004), and adjuvant chemotherapy of RDI < 80% (HR (95% CI) 3.534 (1.135-2.667); p = 0.029) were also independent predictive factors. Moreover, the level of RDI significantly correlated with DFS and OS. Multiple logistic regression analysis revealed that low RDI was significantly associated with postoperative body weight loss (BWL) ≥ 10%. CONCLUSIONS The following factors were significantly associated with poor survival: extended dissection of the nerve plexus around the SMA, lymph node metastasis, residual tumor, and RDI of the adjuvant chemotherapy. Patient's prognosis with adjuvant chemotherapy of RDI < 80% was worse. BWL ≥10% was the most important factor affecting the continuity of adjuvant chemotherapy. Perioperative nutritional intervention is necessary for patients who receive adjuvant chemotherapy for advanced pancreatic cancer.
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Affiliation(s)
- Yoshifumi Morita
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
| | - Takanori Sakaguchi
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Ryo Kitajima
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Satoru Furuhashi
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Ryota Kiuchi
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Makoto Takeda
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Takanori Hiraide
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | | | - Hirotoshi Kikuchi
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Hiroyuki Konno
- Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroya Takeuchi
- Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
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20
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Javed MA, Beyer G, Le N, Vinci A, Wong H, Palmer D, Morgan RD, Lamarca A, Hubner RA, Valle JW, Alam S, Chowdhury S, Ma YT, Archibugi L, Capurso G, Maisonneuve P, Neesse A, Sund M, Schober M, Krug S. Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine in Europe. Pancreatology 2019; 19:97-104. [PMID: 30529068 DOI: 10.1016/j.pan.2018.10.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/30/2018] [Accepted: 10/14/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma (MPA). Randomized clinical trials evaluating intensified chemotherapies including FOLFIRINOX and nab-paclitaxel plus gemcitabine (NAB+GEM) have shown improvement in survival. Here, we have evaluated the efficacy of intensified chemotherapy versus gemcitabine monotherapy in real-life settings across Europe. METHODS A retrospective multi-center study including 1056 MPA patients, between 2012 and 2015, from nine centers in UK, Germany, Italy, Hungary and the Swedish registry was performed. Follow-up was at least 12 months. Cox proportional Harzards regression was used for uni- and multivariable evaluation of prognostic factors. RESULTS Of 1056 MPA patients, 1030 (98.7%) were assessable for survival analysis. Gemcitabine monotherapy was the most commonly used regimen (41.3%), compared to FOLFIRINOX (n = 204, 19.3%), NAB+GEM (n = 81, 7.7%) and other gemcitabine- or 5-FU-based regimens (n = 335, 31.7%). The median overall survival (OS) was: FOLFIRINOX 9.9 months (95%CI 8.4-12.6), NAB+GEM 7.9 months (95%CI 6.2-10.0), other combinations 8.5 months (95%CI 7.7-9.3) and gemcitabine monotherapy 4.9 months (95%CI 4.4-5.6). Compared to gemcitabine monotherapy, any combination of chemotherapeutics improved the survival with no significant difference between the intensified regimens. Multivariable analysis showed an association between treatment center, male gender, inoperability at diagnosis and performance status (ECOG 1-3) with poor prognosis. CONCLUSION Gemcitabine monotherapy was predominantly used in 2012-2015. Intensified chemotherapy improved OS in comparison to gemcitabine monotherapy. In real-life settings, the OS rates of different treatment approaches are lower than shown in randomized phase III trials.
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Affiliation(s)
- Muhammad Ahsan Javed
- NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, Royal Liverpool University Hospital, United Kingdom
| | - Georg Beyer
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany; Medical Department II, University Hospital, LMU, Munich, Germany
| | - Nha Le
- Gastroenterology Division, Second Internal Medicine Department, Semmelweis University, Budapest, Hungary
| | - Alessio Vinci
- University of Pavia, Department of Surgery, S. Matteo University Hospital Foundation, Pavia, Italy
| | - Helen Wong
- Department of Quality and Information Intelligence, The Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, United Kingdom
| | - Daniel Palmer
- Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Robert D Morgan
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Salma Alam
- Department of Hepatobiliary Oncology, New Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Sumsur Chowdhury
- Department of Hepatobiliary Oncology, New Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Yuk Ting Ma
- Department of Hepatobiliary Oncology, New Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Livia Archibugi
- Digestive and Liver Disease Unit, S. Andrea Hospital, University Sapienza, Rome, Italy
| | - Gabriele Capurso
- Digestive and Liver Disease Unit, S. Andrea Hospital, University Sapienza, Rome, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
| | - Albrecht Neesse
- University Medical Centre Göttingen, Department of Gastroenterology and Gastrointestinal Oncology, Göttingen, Germany
| | - Malin Sund
- University of Umea, Department of Surgical and Perioperative Sciences, Umea, Sweden.
| | - Marvin Schober
- Department of Gastroenterology and Hepatology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Sebastian Krug
- Department of Gastroenterology and Hepatology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
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Zhang Z, Qin W, Sun Y. Contribution of biomarkers for pancreatic cancer-associated new-onset diabetes to pancreatic cancer screening. Pathol Res Pract 2018; 214:1923-1928. [PMID: 30477640 DOI: 10.1016/j.prp.2018.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/09/2018] [Accepted: 10/17/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Pancreatic cancer (PaC) is one of the deadliest types of tumor, and it is regarded as a fatal disease, with a 5-year survival rate less than 10%. Most clinical diagnoses for PaC are made at an advanced stage because of the insidious onset of the disease, which leads to an extremely poor prognosis. RECENT FINDINGS The relationship between diabetes mellitus (DM) and PaC has been established by several decades of research, and the prevalence of DM in patients with PaC has been reported to be 40%, with half of the patients having developed new-onset DM within 2 years or less. Increasing evidence suggests that new-onset DM is associated with a high prevalence of PaC, and PaC resection ameliorates DM. Therefore, screening for PaC may be needed in patients with newly developed DM. PURPOSE The objective of this review was to present our current understanding of biomarkers for PaC-associated new-onset DM (PCAND), to offer a perspective on the prospects and problems of using this strategy for early screening to differentiate PCAND from new-onset type 2 DM not associated with PaC and to suggest candidate biomarkers to use for PaC screening in patients with new-onset DM. Finding sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies.
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Affiliation(s)
- Zhenjun Zhang
- Institute of Hepatobiliary and Pancreatic Diseases, School of Medicine, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, China
| | - Wenjie Qin
- Institute of Hepatobiliary and Pancreatic Diseases, School of Medicine, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, China
| | - Yuling Sun
- Institute of Hepatobiliary and Pancreatic Diseases, School of Medicine, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, China.
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22
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Liu Y, Shao L, Chen K, Wang Z, Wang J, Jing W, Hu M. GDF11 restrains tumor growth by promoting apoptosis in pancreatic cancer. Onco Targets Ther 2018; 11:8371-8379. [PMID: 30568460 PMCID: PMC6267626 DOI: 10.2147/ott.s181792] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background Growth differentiation factor (GDF) acted as a factor that regulated proliferation, apoptosis and differentiation in several tumors. However, the effects of growth differentiation factor (GDF11) in pancreatic cancer remain unclear. Purpose To investigate the expression and significance of GDF11 in pancreatic cancer. Patients and methods Pancreatic cancer and corresponding paracancerous tissues (n=28) were collected from the Department of Hepatobiliary and Pancreatic Surgical Oncology of Chinese PLA General Hospital. Tissue microarray was obtained from Outdo Biotech Co., Ltd. (Shanghai, People’s Republic of China). GDF11 mRNA and protein expressions in pancreatic cancer samples and cell lines were detected using qRT-PCR, Western-Blot and immunohistochemistry. Overexpression and knockdown of GDF11 were performed with lentiviral transduction system and siRNA technique in PANC-1 cell line and CFPAC-1 cell line. Proliferation, migration and invasion of pancreatic cancer cell lines were examinated by MTS and transwell assay, respectively. Flow cytometry was used for cell apoptosis analysis. Results The results of this study indicated that GDF11 was significantly down-regulated in pancreatic cancer tissues compared with adjacent tissues of pancreatic cancer. GDF11 was also associated with low expression in pancreatic cancer cell lines when compared with normal pancreatic cell line. In a cohort of 63 pancreatic cancer patients, high GDF11 expression levels was associated with favorable perineural invasion, T classification, N classification and overall survival (OS). Cox proportional hazards model revealed that high GDF11 expression was an independent predictor of favorable prognosis (HR: 0.496; 95% CI: 0.255–0.967; P=0.040). Overexpression of GDF11 in PANC-1 cells repressed the proliferation, migration and invasion abilities in vitro. Inhibition of GDF11 in CFPAC-1 showed inverse results. Furthermore, enhanced GDF11 expression promoted apoptosis and down-regulated GDF11 expression inhibited apoptosis in pancreatic cancer cell lines. Conclusion These findings suggested that GDF11 acted as a tumor suppressor gene for pancreatic cancer.
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Affiliation(s)
- Yanzhe Liu
- Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China,
| | - Lijuan Shao
- Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, People's Republic of China
| | - Kuang Chen
- Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China,
| | - Zizheng Wang
- Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China,
| | - Jin Wang
- Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China,
| | - Wei Jing
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, People's Republic of China,
| | - Minggen Hu
- Department of Hepatobiliary and Pancreatic Surgical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China,
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Liang XH, Yan D, Zhao JX, Ding W, Xu XJ, Wang XY. Interaction of polymorphisms in xeroderma pigmentosum group C with cigarette smoking and pancreatic cancer risk. Oncol Lett 2018; 16:5631-5638. [PMID: 30344718 PMCID: PMC6176251 DOI: 10.3892/ol.2018.9350] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 06/08/2018] [Indexed: 12/18/2022] Open
Abstract
The aim of the present study was to evaluate the association between xeroderma pigmentosum group C (XPC) polymorphisms and pancreatic cancer (PC) risk. A total of 7 XPC tagging SNPs (tag-SNPs) were selected from the International HapMap Project Databases (rs2228001A/C, rs2470353G/C, rs2228000C/T, rs3731114C/G, rs3729587G/C, rs2607775C/G and rs3731055G/A) and were genotyped in 205 patients with PC and 230 non-cancer control subjects using a SNaPshot assay. The C allelic gene frequency of rs2470353 was higher in patients with PC compared with that in the control group (P=0.003). Compared with the GG gene type, PC risk was increased in subjects with GC and GC+CC gene types (P=0.012 and P=0.006, respectively). PC risk increased 3.505-fold for the subjects who were heavy smokers (tobacco, ≥25 packets/year) with the GC+CC gene type (P=0.008). The G allelic gene frequency of rs2607775 was higher in PC patients compared with that in the control group (P=0.003). Compared with the CC gene type, PC risk increased in subjects with CG and CG+GG gene types (P=0.013 and P=0.005, respectively). Furthermore, PC risk increased 3.950-fold in subjects who were heavy smokers (tobacco, ≥25 packets/year) with the CG+GG gene type (P=0.001). Haplotype analysis further revealed that the CCC haplotype of rs2228000, rs3731114 and rs3729587 increased PC risk (odds ratio, 1.610; 95% confidence interval, 1.035–2.481; P=0.034). The present study revealed that XPC gene polymorphisms could increase the risk of PC in the study population, particularly among heavy smokers.
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Affiliation(s)
- Xiao-Hui Liang
- Department of Hypertension, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Dong Yan
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Jia-Xing Zhao
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Wei Ding
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Xin-Jian Xu
- Department of Pancreatic Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Xi-Yan Wang
- Xinjiang Research Institute of Cancer Prevention and Control, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
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Using CRISPR/Cas9 to Knock out Amylase in Acinar Cells Decreases Pancreatitis-Induced Autophagy. BIOMED RESEARCH INTERNATIONAL 2018; 2018:8719397. [PMID: 29888283 PMCID: PMC5985122 DOI: 10.1155/2018/8719397] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 03/26/2018] [Accepted: 04/15/2018] [Indexed: 01/28/2023]
Abstract
Pancreatic cancer is a malignant neoplasm that originates from acinar cells. Acinar cells get reprogrammed to become duct cells, resulting in pancreatic cancer. Pancreatitis is an acinar cell inflammation, leading to "impaired autophagy flux". Pancreatitis promotes acinar-to-ductal transdifferentiation. Expression of amylase gets eliminated during the progression of pancreatic cancer. Amylase is considered as an acinar cell marker; however, its function in cells is not known. Thus, we investigated whether amylase affects the acinar cell autophagy and whether it plays any role in development of pancreatitis. Here, we knocked out ATG12 in a pancreatic cancer cells and acinar cells using CRISPR/Cas9. Autophagy inhibition led to an increase in the expression of duct cell markers and a simultaneous decrease in that of acinar cell markers. It also caused an increase in cell viability and changes in mitochondrial morphology. Next, we knocked out amylase in acinar cells. Amylase deficiency decreased autophagy induced by pancreatitis. Our results suggest that amylase controls pancreatitis-induced autophagy. We found that eliminating amylase expression contributes to pancreatic cancer etiology by decreasing autophagy. Furthermore, our results indicate that amylase plays a role in selective pancreatitis-induced autophagy of pancreatic enzyme vesicles.
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25
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Shang FM, Liu HL. Fusobacterium nucleatum and colorectal cancer: A review. World J Gastrointest Oncol 2018; 10:71-81. [PMID: 29564037 PMCID: PMC5852398 DOI: 10.4251/wjgo.v10.i3.71] [Citation(s) in RCA: 190] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 01/09/2018] [Accepted: 03/06/2018] [Indexed: 02/05/2023] Open
Abstract
Fusobacterium nucleatum (F. nucleatum) is a Gram-negative obligate anaerobe bacterium in the oral cavity and plays a role in several oral diseases, including periodontitis and gingivitis. Recently, several studies have reported that the level of F. nucleatum is significantly elevated in human colorectal adenomas and carcinomas compared to that in adjacent normal tissue. Several researchers have also demonstrated that F. nucleatum is obviously associated with colorectal cancer and promotes the development of colorectal neoplasms. In this review, we have summarized the recent reports on F. nucleatum and its role in colorectal cancer and have highlighted the methods of detecting F. nucleatum in colorectal cancer, the underlying mechanisms of pathogenesis, immunity status, and colorectal cancer prevention strategies that target F. nucleatum.
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Affiliation(s)
- Fu-Mei Shang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Hong-Li Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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26
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Naqvi AAT, Hasan GM, Hassan MI. Investigating the role of transcription factors of pancreas development in pancreatic cancer. Pancreatology 2018; 18:184-190. [PMID: 29289465 DOI: 10.1016/j.pan.2017.12.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 11/20/2017] [Accepted: 12/22/2017] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer (PC) is the seventh most common cause of cancer-related deaths worldwide that kills more than 300,000 people every year. Prognosis of PC is very poor with a five-year survival rate about 5%. The most common and highly observed type of PC is pancreatic ductal adenocarcinoma (PDAC). It is preceded by the progression of precursor lesions such as Pancreatic Intraepithelial Neoplasia (PanIN), Intraductal Papillary Neoplasm (IPMN) and Mucinous Cystic Neoplasm (MCN). PanIN is the most common among these premalignant lesions. Genes orchestrating the origin and differentiation of cells during organogenesis have the tendency to produce tumor cells in response to activating or inactivating mutations. Based on the following premise, we discuss the role of transcription factors (TFs) of pancreas development and cell fate differentiation in PC. Pancreas/duodenum homeobox protein 1 (PDX1), Pancreas transcription factor 1 subunit alpha (PTF1A), Nuclear receptor subfamily 5 group A member 2 (NR5A2), Hepatocyte nuclear factor 1-alpha (HNF1A) and Hepatocyte nuclear factor 1-beta (HNF1B) play vital role in the development and differentiation of pancreatic precursor cells. Mutated KRAS induces abnormalities in the regular function of these TFs which in turn cause abnormal cell growth and proliferation that leads to cancer. Thus, these TFs are highly susceptible for the origin of PC. Therefore, we propose that these TFs can be treated as therapeutic targets for the development of anticancer drugs.
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Affiliation(s)
- Ahmad Abu Turab Naqvi
- Center for Interdisciplinary Research in Basic Science, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Md Imtaiyaz Hassan
- Center for Interdisciplinary Research in Basic Science, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
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Pu W, Luo Y, Bai R, Guo A, Zhou K, Zhang Y, Miao L, Rüegg C, Hottiger MO, Gao X, Sun L. Baicalein inhibits acinar‐to‐ductal metaplasia of pancreatic acinal cell AR42J via improving the inflammatory microenvironment. J Cell Physiol 2018; 233:5747-5755. [DOI: 10.1002/jcp.26293] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 10/15/2017] [Accepted: 11/13/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Wei‐Ling Pu
- Institute of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Ying‐Ying Luo
- Institute of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Ru‐Yu Bai
- Institute of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Ao‐Wei Guo
- Institute of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Kun Zhou
- Institute of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin Key Laboratory of Chinese medicine PharmacologyTianjin University of Traditional Chinese MedicineTianjinChina
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of EducationTianjin University of Traditional Chinese MedicineTianjinChina
- Key Research Laboratory of Prescription Compatibility among ComponentsTianjin University of Traditional Chinese MedicineTianjinChina
| | - Yun‐Sha Zhang
- School of Integrative MedicineTianjin University of Traditional Chinese MedicineTianjinChina
- Pathology Unit, Faculty of Sciences, Department of MedicineUniversity of FribourgFribourgSwitzerland
| | - Lin Miao
- Institute of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin Key Laboratory of Chinese medicine PharmacologyTianjin University of Traditional Chinese MedicineTianjinChina
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of EducationTianjin University of Traditional Chinese MedicineTianjinChina
- Key Research Laboratory of Prescription Compatibility among ComponentsTianjin University of Traditional Chinese MedicineTianjinChina
- Department of Molecular Mechanisms of DiseaseUniversity of Zurich‐IrchelZurichSwitzerland
| | - Curzio Rüegg
- Pathology Unit, Faculty of Sciences, Department of MedicineUniversity of FribourgFribourgSwitzerland
| | - Micheal O. Hottiger
- Department of Molecular Mechanisms of DiseaseUniversity of Zurich‐IrchelZurichSwitzerland
| | - Xiu‐Mei Gao
- Institute of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin Key Laboratory of Chinese medicine PharmacologyTianjin University of Traditional Chinese MedicineTianjinChina
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of EducationTianjin University of Traditional Chinese MedicineTianjinChina
- Key Research Laboratory of Prescription Compatibility among ComponentsTianjin University of Traditional Chinese MedicineTianjinChina
| | - Li‐Kang Sun
- Institute of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
- Tianjin Key Laboratory of Chinese medicine PharmacologyTianjin University of Traditional Chinese MedicineTianjinChina
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of EducationTianjin University of Traditional Chinese MedicineTianjinChina
- Key Research Laboratory of Prescription Compatibility among ComponentsTianjin University of Traditional Chinese MedicineTianjinChina
- School of Integrative MedicineTianjin University of Traditional Chinese MedicineTianjinChina
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Du JP, Li L, Zheng J, Zhang D, Liu W, Zheng WH, Li XS, Yao RC, Wang F, Liu S, Tan X. Kallikrein-related peptidase 7 is a potential target for the treatment of pancreatic cancer. Oncotarget 2018; 9:12894-12906. [PMID: 29560118 PMCID: PMC5849182 DOI: 10.18632/oncotarget.24132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 12/01/2017] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is one of the deadliest cancers with very poor prognosis, and the five-year survival rate of the patients is less than 5% after diagnosis. Kallikrein-related peptidases (KLKs) belong to a serine protease family with 15 members that play important roles in cellular physiological behavior and diseases. The high expression level of KLK7 in pancreatic cancer tissues is considered to be a marker for the poor prognosis of this disease. In this work, we set out to investigate whether KLK7 could be a target for the treatment of pancreatic cancer. Short hairpin RNAs (shRNAs) were designed and constructed in lentivirus to knock down KLK7 in pancreatic cancer cell line PANC-1, and the real time cellular analysis (RTCA) was used to evaluate cell proliferation, migration and invasion abilities. Small molecules inhibiting KLK7 were discovered by computer-aided drug screening and used to inhibit PANC-1 cells. Our results confirmed that KLK7 is significantly up-regulated in pancreatic cancer tissue, and knocking down or inhibiting KLK7 efficiently inhibited the proliferation, migration and invasion of pancreatic cancer cells. This study suggested that KLK7 could be a potential chemotherapy target for treatment of pancreatic cancer, which would provide us a novel strategy for the treatment of this disease.
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Affiliation(s)
- Jian Ping Du
- Institute of Hepatopancreatobilary Surgery, China Three Gorges University, Yichang 443003, P.R. China
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, 443003, P.R. China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical School of China Three Gorges University, Yichang 443002, P.R. China
- Department of Vascular surgery, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437100, P.R. China
| | - Lin Li
- Institute of Hepatopancreatobilary Surgery, China Three Gorges University, Yichang 443003, P.R. China
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, 443003, P.R. China
| | - Jun Zheng
- Institute of Hepatopancreatobilary Surgery, China Three Gorges University, Yichang 443003, P.R. China
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, 443003, P.R. China
| | - Ding Zhang
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, 443003, P.R. China
| | - Wei Liu
- Institute of Hepatopancreatobilary Surgery, China Three Gorges University, Yichang 443003, P.R. China
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, 443003, P.R. China
| | - Wei Hong Zheng
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical School of China Three Gorges University, Yichang 443002, P.R. China
| | - Xiao Song Li
- Institute of Hepatopancreatobilary Surgery, China Three Gorges University, Yichang 443003, P.R. China
| | - Ru Cheng Yao
- Institute of Hepatopancreatobilary Surgery, China Three Gorges University, Yichang 443003, P.R. China
| | - Fangyu Wang
- College of Life Science and Environment, Hengyang Normal University, Hengyang, 421008, P.R. China
| | - Sen Liu
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical School of China Three Gorges University, Yichang 443002, P.R. China
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan 430068, P.R. China
| | - Xiao Tan
- Institute of Hepatopancreatobilary Surgery, China Three Gorges University, Yichang 443003, P.R. China
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, 443003, P.R. China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical School of China Three Gorges University, Yichang 443002, P.R. China
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Li X, Liu Z, Ye Z, Gou S, Wang C. Impact of age on survival of patients with pancreatic cancer after surgery: Analysis of SEER data. Pancreatology 2018; 18:133-138. [PMID: 29170052 DOI: 10.1016/j.pan.2017.11.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 11/04/2017] [Accepted: 11/17/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND To explore the impact of age on all-cause death and cancer-specific death in patients with pancreatic duct adenocarcinoma (PDAC) undergoing surgery. MATERIALS AND METHODS Individuals with PDAC undergoing surgery between 2004 and 2013 (N = 11,138) were retrospectively studied from the Surveillance, Epidemiology, and End Results (SEER) cancer registry database. The impact of age on all-cause death and cancer-specific death was assessed using Cox regression model and competing risk model respectively. RESULTS Multivariate Cox regression analysis indicated that the risks of all-cause death increased with age: hazard ratios (95% confidence interval, 95%CI) were 1.10 (1.04-1.17), 1.31 (1.23-1.38), 1.47 (1.35-1.61) for groups 61-70 years, 71-80 years, and >80 years, respectively, compared with ≤60 years. Multivariate competing risk analysis indicated that the risk of cancer-specific death was similar between patients ≤60 years and 61-70 years (subhazard ratio 0.93; 95% confidence interval 0.87-1.00), but decreased in patients 71-80 years (subhazard ratio 0.84; 95%CI 0.79-0.90) and >80 years (subhazard ratio 0.76; 95%CI 0.68-0.85). CONCLUSION Age at diagnosis appeared to be an independent predictor of prognosis, with reverse impacts on all-cause death and cancer-specific death.
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Affiliation(s)
- Xiaogang Li
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of General Surgery, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang 441021, China
| | - Zhiqiang Liu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zeng Ye
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shanmiao Gou
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Chunyou Wang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Chen J, Wang H, Li Z. Association between Polymorphisms of X-Ray Repair Cross Complementing Group 1 Gene and Pancreatic Cancer Risk: a Systematic Review with Meta-Analysis. Pathol Oncol Res 2017; 25:897-904. [PMID: 29285737 PMCID: PMC6614153 DOI: 10.1007/s12253-017-0364-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 11/08/2017] [Indexed: 01/15/2023]
Abstract
Emerging evidences have shown that common genetic polymorphisms in X-ray repair cross complementing group 1 (XRCC1) gene may be associated with the development of pancreatic cancer, but individually published studies and previous meta-analyses revealed inconclusive results. The aim of our study was to investigate the association between polymorphisms in XRCC1 gene and pancreatic cancer risk. We conducted a search of PubMed, Embase, the Cochrane Library and Web of Science databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined as measures of the strength of association between polymorphisms of XRCC1 and pancreatic cancer risk. Sensitivity analysis and publication bias were evaluated. All analyses were undertaken using the STATA 13.0. A total of 10 studies were included in this systematic review. Five common functional single-nucleotide polymorphisms (SNPs) in XRCC1 gene were found, including Arg399Gln G > A (rs25487), Arg194Trp C > T (rs1799782), Arg280His G > A (rs25489), c.1517G > C, c.1471G > A. Results from our stratified analysis based on Hardy-Weinberg equilibrium (HWE) showed that there was a robust significant association between Arg280His polymorphism and pancreatic cancer risk (allelic model, OR 0.743, 95% CI 0.576-0.958, P = 0.022; heterozygous model, OR 0.701, 95% CI 0.525-0.936, P = 0.016; dominant model, OR 0.710, 95% CI 0.537-0.939, P = 0.016). We also found a statistically significant association between c.1517G > C polymorphism and pancreatic cancer risk (Allelic model, OR 1.252, 95% CI 1.064-1.473, P = 0.007). No significant results were obtained for Arg399Gln, Arg194Trp and c.1471G > A polymorphisms. The present meta-analysis suggested that Arg280His and c.1517G > C polymorphisms in XRCC1 gene were associated with pancreatic cancer risk.
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Affiliation(s)
- Jun Chen
- Department of General Surgery, Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University, No. 116 the Yellow River Road, Urumqi, 830000, China.
| | - Hong Wang
- Department of General Surgery, Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University, No. 116 the Yellow River Road, Urumqi, 830000, China
| | - Zhiming Li
- Department of Surgery, Shihezi Hospital of traditional Chinese Medicine, Shihezi, China
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Lee SH, Hwang HK, Kang CM, Lee WJ. The Yonsei criteria as a clinically detectable parameter for excellent prognosis in resected left-sided pancreatic cancer: outcomes of a propensity score-matched analysis. Surg Endosc 2017; 31:4656-4664. [PMID: 28389802 DOI: 10.1007/s00464-017-5529-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Accepted: 03/15/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND This study aimed to identify that Yonsei criteria (YC) can be regarded as a preoperative clinical parameter to predict biological behavior of the left-sided pancreatic cancer. METHODS Between June 2007 and December 2014, 135 patients who underwent minimally invasive (MIS) or open distal pancreatectomy for left-sided pancreatic cancer were enrolled in this study consecutively. Perioperative short-term and long-term oncologic outcomes were analyzed according to the YC retrospectively. RESULTS Fifty-four and 81 patients did and did not meet the YC, respectively. Short-term oncologic outcomes were favorable among those meeting the YC even after propensity score matching. Patients within the YC also had better disease-free and disease-specific overall survival (p < 0.05). In analysis for receiver operating characteristic curve, area under curve of CA19-9 was satisfactory only within YC group. Multivariate analysis for disease-free survival identified the YC as a strong independent prognostic factor (p < 0.05). In preoperative clinical setting, patients' survival was clearly different based on following clinical groups, such as within YC, beyond YC, and unresectable. CONCLUSIONS Preoperative CT-based determined YC can predict excellent short-term and long-term oncologic outcomes. YC might have a potential role as a preoperative clinical staging for left-sided pancreatic cancer. External validations of YC based on multicenter cohorts are mandatory to confirm this oncologic significance of YC.
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Affiliation(s)
- Sung Hwan Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Ludlow Faculty Research Building #201, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Pancreatobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, Korea
| | - Ho Kyoung Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Ludlow Faculty Research Building #201, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Pancreatobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, Korea
| | - Chang Moo Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Ludlow Faculty Research Building #201, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea.
- Pancreatobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, Korea.
| | - Woo Jung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Ludlow Faculty Research Building #201, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Pancreatobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, Korea
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Kwon HM, Kang EJ, Kang K, Kim SD, Yang K, Yi JM. Combinatorial effects of an epigenetic inhibitor and ionizing radiation contribute to targeted elimination of pancreatic cancer stem cell. Oncotarget 2017; 8:89005-89020. [PMID: 29179494 PMCID: PMC5687664 DOI: 10.18632/oncotarget.21642] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 08/27/2017] [Indexed: 01/03/2023] Open
Abstract
Pancreatic cancer is associated with a high mortality rate, owing to de novo and acquired drug resistance, thereby leading to highly invasive and metastatic pancreatic cancer cells. Therefore, targeting pancreatic cancer stem cells (CSCs) may be a novel therapeutic strategy for the treatment of pancreatic cancer. Here, we combined a DNA methylation inhibitor (5-aza-2'-deoxycytidine; 5-aza-dC) and ionizing radiation (IR) to improve anti-cancer effects by inhibiting growth and proliferation and promoting apoptosis of pancreatic cancer cells in vitro and in vivo. Importantly, the combinatorial effect of 5-aza-dC with IR on sphere-forming pancreatic cancer cells was preferentially targeted toward CSCs through the downregulation of regulatory factors of self-renewal and CSC surface markers. We next performed the RNA sequencing to understand the underlying cellular mechanisms of the combined treatment with IR and 5-aza-dC in pancreatic cancer cells. Global transcriptome profiling indicated that the expression of the Oct4-centered transcriptional network of genes was significantly downregulated in cells with combination treatment. Our data suggested that combination treatment with DNA methylation inhibitor and IR may be a novel therapeutic strategy for pancreatic cancer. Overall, these findings support the use of epigenetic therapy in combination with radiotherapy to improve therapeutic efficacy by targeting and eradicating pancreatic CSCs.
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Affiliation(s)
- Hyun-Mi Kwon
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 46033, South Korea
| | - Eun-Jin Kang
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 46033, South Korea
| | - Keunsoo Kang
- Department of Microbiology, Dankook Universty, Cheonan 31116, South Korea
| | - Sung-Dae Kim
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 46033, South Korea
| | - Kwangmo Yang
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 46033, South Korea
| | - Joo Mi Yi
- Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan 46033, South Korea
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Female reproductive factors, exogenous hormone use, and pancreatic cancer risk: the Japan Public Health Center-based prospective study. Eur J Cancer Prev 2017; 26:378-384. [DOI: 10.1097/cej.0000000000000358] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Masko EM, Alfaqih MA, Solomon KR, Barry WT, Newgard CB, Muehlbauer MJ, Valilis NA, Phillips TE, Poulton SH, Freedland AR, Sun S, Dambal SK, Sanders SE, Macias E, Freeman MR, Dewhirst MW, Pizzo SV, Freedland SJ. Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model. Prostate 2017; 77:446-457. [PMID: 27900797 PMCID: PMC5822711 DOI: 10.1002/pros.23282] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 11/04/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Epidemiologic data suggest cholesterol-lowering drugs may prevent the progression of prostate cancer, but not the incidence of the disease. However, the association of combination therapy in cholesterol reduction on prostate or any cancer is unclear. In this study, we compared the effects of the cholesterol lowering drugs simvastatin and ezetimibe alone or in combination on the growth of LAPC-4 prostate cancer in vivo xenografts. METHODS Proliferation assays were conducted by MTS solution and assessed by Student's t-test. 90 male nude mice were placed on a high-cholesterol Western-diet for 7 days then injected subcutaneously with 1 × 105 LAPC-4 cells. Two weeks post-injection, mice were randomized to control, 11 mg/kg/day simvastatin, 30 mg/kg ezetimibe, or the combination and sacrificed 42 days post-randomization. We used a generalized linear model with the predictor variables of treatment, time, and treatment by time (i.e., interaction term) with tumor volume as the outcome variable. Total serum and tumor cholesterol were measured. Tumoral RNA was extracted and cDNA synthesized from 1 ug of total RNA for quantitative real-time PCR. RESULTS Simvastatin directly reduced in vitro prostate cell proliferation in a dose-dependent, cell line-specific manner, but ezetimibe had no effect. In vivo, low continuous dosing of ezetimibe, delivered by food, or simvastatin, delivered via an osmotic pump had no effect on tumor growth compared to control mice. In contrast, dual treatment of simvastatin and ezetimibe accelerated tumor growth. Ezetimibe significantly lowered serum cholesterol by 15%, while simvastatin had no effect. Ezetimibe treatment resulted in higher tumor cholesterol. A sixfold induction of low density lipoprotein receptor mRNA was observed in ezetimibe and the combination with simvastatin versus control tumors. CONCLUSIONS Systemic cholesterol lowering by ezetimibe did not slow tumor growth, nor did the cholesterol independent effects of simvastatin and the combined treatment increased tumor growth. Despite lower serum cholesterol, tumors from ezetimibe treated mice had higher levels of cholesterol. This study suggests that induction of low density lipoprotein receptor is a possible mechanism of resistance that prostate tumors use to counteract the therapeutic effects of lowering serum cholesterol. Prostate 77:446-457, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Elizabeth M. Masko
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Mahmoud A. Alfaqih
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Keith R. Solomon
- Department of Orthopedic Surgery, Harvard Medical School, Boston, Massachusetts
| | - William T. Barry
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
| | - Christopher B. Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina
| | - Michael J. Muehlbauer
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina
| | - Nikolaos A. Valilis
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Tameika E. Phillips
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Susan H. Poulton
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Alexis R. Freedland
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Stephanie Sun
- Department of Surgery, Durham Veterans Administration Hospital, Durham, North Carolina
| | - Shweta K. Dambal
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Sergio E. Sanders
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Everardo Macias
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Michael R. Freeman
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Mark W. Dewhirst
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Salvatore V. Pizzo
- Department of Pathology, Duke University Medical Center, Durham, North Carolina
| | - Stephen J. Freedland
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
- Department of Surgery, Durham Veterans Administration Hospital, Durham, North Carolina
- Correspondence to: Dr. Stephen Freedland, Division of Urology, Department of Surgery, Cedars Sinai Medical Center, 8635 West 3rd Street Suite 1070W, Los Angeles, CA 90048.
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Gholizadeh P, Eslami H, Kafil HS. Carcinogenesis mechanisms of Fusobacterium nucleatum. Biomed Pharmacother 2017; 89:918-925. [PMID: 28292019 DOI: 10.1016/j.biopha.2017.02.102] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 02/23/2017] [Accepted: 02/27/2017] [Indexed: 02/06/2023] Open
Abstract
Transformed cells of cancers may be related to stromal cells, immune cells, and some bacteria such as Fusobacterium nucleatum. This review aimed to evaluate carcinogenesis mechanisms of Fusobacterium spp. in the oral cavity, pancreatic and colorectal cancers. These cancers are the three of the ten most prevalence cancer in the worldwide. Recent findings demonstrated that F. nucleatum could be considered as the risk factor for these cancers. The most important carcinogenesis mechanisms of F. nucleatum are chronic infection, interaction of cell surface molecules of these bacteria with immune system and stromal cells, immune evasion and immune suppression. However, there are some uncertainty carcinogenesis mechanisms about these bacteria, but this review evaluates almost all the known mechanisms. Well-characterized virulence factors of F. nucleatum such as FadA, Fap2, LPS and cell wall extracts may act as effector molecules in the shift of normal epithelial cells to tumor cells. These molecules may provide new targets, drugs, and strategies for therapeutic intervention.
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Affiliation(s)
- Pourya Gholizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hosein Eslami
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Samadi Kafil
- Infectious and Tropical Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Zhou P, Li B, Liu F, Zhang M, Wang Q, Liu Y, Yao Y, Li D. The epithelial to mesenchymal transition (EMT) and cancer stem cells: implication for treatment resistance in pancreatic cancer. Mol Cancer 2017; 16:52. [PMID: 28245823 PMCID: PMC5331747 DOI: 10.1186/s12943-017-0624-9] [Citation(s) in RCA: 239] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 02/23/2017] [Indexed: 02/08/2023] Open
Abstract
The mechanical properties of epithelial to mesenchymal transition (EMT) and a pancreatic cancer subpopulation with stem cell properties have been increasingly recognized as potent modulators of the effective of therapy. In particular, pancreatic cancer stem cells (PCSCs) are functionally important during tumor relapse and therapy resistance. In this review we have surveyed recent advances in the role of EMT and PCSCs in tumor progression, metastasis and treatment resistance, and the mechanisms of integrated with biochemical signals and the underlying pathways involved in treatment resistance of pancreatic cancer. These findings highlight the importance of confirming stem-cells markers and complex molecular signaling pathways controlling EMT and cancer stem cells in pancreatic cancer during tumor formation, progression, and response to therapy.
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Affiliation(s)
- Pingting Zhou
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Bo Li
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Furao Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Meichao Zhang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qian Wang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuanhua Liu
- Department of Chemotherapy, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China
| | - Yuan Yao
- Department of Radiation Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Dong Li
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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Panje C, Andratschke N, Brunner TB, Niyazi M, Guckenberger M. Stereotactic body radiotherapy for renal cell cancer and pancreatic cancer : Literature review and practice recommendations of the DEGRO Working Group on Stereotactic Radiotherapy. Strahlenther Onkol 2016; 192:875-885. [PMID: 27778052 DOI: 10.1007/s00066-016-1053-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 09/19/2016] [Indexed: 01/05/2023]
Abstract
PURPOSE This report of the Working Group on Stereotactic Radiotherapy of the German Society of Radiation Oncology (DEGRO) aims to provide a literature review and practice recommendations for stereotactic body radiotherapy (SBRT) of primary renal cell cancer and primary pancreatic cancer. METHODS A literature search on SBRT for both renal cancer and pancreatic cancer was performed with focus on prospective trials and technical aspects for clinical implementation. RESULTS Data on renal and pancreatic SBRT are limited, but show promising rates of local control for both treatment sites. For pancreatic cancer, fractionated SBRT should be preferred to single-dose treatment to reduce the risk of gastrointestinal toxicity. Motion-compensation strategies and image guidance are paramount for safe SBRT delivery in both tumor entities. CONCLUSION SBRT for renal cancer and pancreatic cancer have been successfully evaluated in phase I and phase II trials. Pancreatic SBRT should be practiced carefully and only within prospective protocols due to the risk of severe gastrointestinal toxicity. SBRT for primary renal cell cancer appears a viable option for medically inoperable patients but future research needs to better define patient selection criteria and the detailed practice of SBRT.
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Affiliation(s)
- Cédric Panje
- Department of Radiation Oncology, Zurich University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland
| | - Nikolaus Andratschke
- Department of Radiation Oncology, Zurich University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland
| | - Thomas B Brunner
- Department of Radiation Oncology, Freiburg University Hospital, Freiburg, Germany
| | - Maximilian Niyazi
- Department of Radiation Oncology, University of Munich, Munich, Germany
| | - Matthias Guckenberger
- Department of Radiation Oncology, Zurich University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland.
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Affiliation(s)
- Anna L Means
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
| | - Craig D Logsdon
- Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas
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Wysocka O, Kulbacka J, Saczko J. Adjuvant, neoadjuvant, and experimental regimens in overcoming pancreatic ductal adenocarcinoma. PRZEGLAD GASTROENTEROLOGICZNY 2016; 11:155-162. [PMID: 27713776 PMCID: PMC5047971 DOI: 10.5114/pg.2016.61438] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 07/01/2016] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is one of the most aggressive and deadly malignancies. Despite better understanding of its biology and pathogenesis, contemporary treatment regimens are still insufficient. Along with the introduction of new treatment agents and combination therapy, the response rates are increasing, but these scores do not go with overall survival, and results are frequently conflicting. Therefore, contemporary medicine faces the challenge of expanding the knowledge base and practice on all grounds - pathology, factor risk, diagnosis, and finally surgical and palliative treatment of this disease. This paper provides a review of current adjuvant and neoadjuvant regimens and the role of experimental therapies in pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Olga Wysocka
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Julita Kulbacka
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | - Jolanta Saczko
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
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Jakubowska K, Pryczynicz A, Januszewska J, Sidorkiewicz I, Kemona A, Niewiński A, Lewczuk Ł, Kędra B, Guzińska-Ustymowicz K. Expressions of Matrix Metalloproteinases 2, 7, and 9 in Carcinogenesis of Pancreatic Ductal Adenocarcinoma. DISEASE MARKERS 2016; 2016:9895721. [PMID: 27429508 PMCID: PMC4939209 DOI: 10.1155/2016/9895721] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 05/13/2016] [Accepted: 05/31/2016] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease, usually diagnosed in an advanced stage which gives a slight chance of recovery. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that participate in tissue remodeling and stimulate neovascularization and inflammatory response. The aim of the study was to evaluate the expression of MMP-2, MMP-7, and MMP-9 in normal ducts, tumor pancreatic adenocarcinoma cells, and peritumoral stroma in correlation with clinicohistopathological parameters. The study material was obtained from 29 patients with pancreatic ductal adenocarcinoma. The expressions of MMP-2, MMP-7, and MMP-9 were performed by immunohistochemical technique. Microvessel density (MVD) was visualized by special immunostaining. The expressions of MMP-2, MMP-7, and MMP-9 were mainly observed in tumor cells and peritumoral stroma. MMP-2 expression in cancer cells was correlated with female gender, stronger inflammation, and histopathological type of cancer (R = 0.460, p = 0.013; R = 0.690, p = 0.0001; R = -0.440, p = 0.005, resp.). The expression of MMP-7 in tumor cells was found to positively correlate with the presence of necrosis and negatively correlate with MVD (R = 0.402, p = 0.031; R = -0.682, p = 0.000). We also showed that positive MMP-9 expression in tumor cells was associated with MVD (R = 0.368, p = 0.084); however, it was not statistically significant. Our results demonstrate that MMP-2, MMP-7, and MMP-9 expressions correlate with various morphological features of the PDAC tumor such as inflammation, necrosis, and formation of the new blood vessels.
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Affiliation(s)
- Katarzyna Jakubowska
- Department of Pathomorphology, Comprehensive Cancer Center, 15-027 Białystok, Poland
| | - Anna Pryczynicz
- Department of General Pathomorphology, Medical University of Białystok, 15-269 Białystok, Poland
| | - Joanna Januszewska
- Department of General Pathomorphology, Medical University of Białystok, 15-269 Białystok, Poland
| | - Iwona Sidorkiewicz
- Department of Reproduction and Gynecological Endocrinology, Medical University of Białystok, 15-276 Białystok, Poland
| | - Andrzej Kemona
- Department of General Pathomorphology, Medical University of Białystok, 15-269 Białystok, Poland
| | - Andrzej Niewiński
- Department of Rehabilitation, Medical University of Białystok, 15-276 Białystok, Poland
| | - Łukasz Lewczuk
- Department of General Pathomorphology, Medical University of Białystok, 15-269 Białystok, Poland
| | - Bogusław Kędra
- 2nd Department of General and Gastroenterological Surgery, Medical University of Białystok, 15-276 Białystok, Poland
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Freeman K, Connock M, Cummins E, Gurung T, Taylor-Phillips S, Court R, Saunders M, Clarke A, Sutcliffe P. Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion. Health Technol Assess 2016; 19:1-321, v-vi. [PMID: 26542268 DOI: 10.3310/hta19910] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND 5-Fluorouracil (5-FU) is a chemotherapy used in colorectal, head and neck (H&N) and other cancers. Dose adjustment is based on body surface area (BSA) but wide variations occur. Pharmacokinetic (PK) dosing is suggested to bring plasma levels into the therapeutic range to promote fewer side effects and better patient outcomes. We investigated the clinical effectiveness and cost-effectiveness of the My5-FU assay for PK dose adjustment to 5-FU therapy. OBJECTIVES To systematically review the evidence on the accuracy of the My5-FU assay compared with gold standard methods [high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS)]; the effectiveness of My5-FU PK dosing compared with BSA; the effectiveness of HPLC and/or LC-MS compared with BSA; the generalisability of published My5-FU and PK studies; costs of using My5-FU; to develop a cost-effectiveness model. DATA SOURCES We searched MEDLINE, EMBASE, Science Citation Index and other databases between January and April 2014. METHODS Two reviewers independently screened titles and abstracts with arbitration and consensus agreement. We undertook quality assessment. We reconstructed Kaplan-Meier plots for progression-free survival (PFS) and overall survival (OS) for comparison of BSA and PK dosing. We developed a Markov model to compare My5-FU with BSA dosing which modelled PFS, OS and adverse events, using a 2-week cycle over a 20 year time horizon with a 3.5% discount rate. Health impacts were evaluated from the patient perspective, while costs were evaluated from the NHS and Personal Social Services perspective. RESULTS A total of 8341 records were identified through electronic searches and 35 and 54 studies were included in the clinical effectiveness and cost-effectiveness reviews respectively. There was a high apparent correlation between My5-FU, HPLC and LC-MS/mass spectrometer but upper and lower limits of agreement were -18% to 30%. Median OS were estimated as 19.6 [95% confidence interval (CI) 17.0 to 21.0] months for PK versus 14.6 (95% CI 14.1 to 15.3) months for BSA for 5-FU+folinic acid (FA); and 27.4 (95% CI 23.2 to 38.8) months for PK versus 20.6 (95% CI 18.4 to 22.9) months for BSA for FOLFOX6 in metastatic colorectal cancer (mCRC). PK versus BSA studies were generalisable to the relevant populations. We developed cost-effectiveness models for mCRC and H&N cancer. The base case assumed a cost per My5-FU assay of £ 61.03. For mCRC for 12 cycles of a oxaliplatin in combination with 5-fluorouracil and FA (FOLFOX) regimen, there was a quality-adjusted life-year (QALY) gain of 0.599 with an incremental cost-effectiveness ratio of £ 4148 per QALY. Probabilistic and scenario analyses gave similar results. The cost-effectiveness acceptability curve showed My5-FU to be 100% cost-effective at a threshold of £ 20,000 per QALY. For H&N cancer, again, given caveats about the poor evidence base, we also estimated that My5-FU is likely to be cost-effective at a threshold of £ 20,000 per QALY. LIMITATIONS Quality and quantity of evidence were very weak for PK versus BSA dosing for all cancers with no randomised controlled trials (RCTs) using current regimens. For H&N cancer, two studies of regimens no longer in use were identified. CONCLUSIONS Using a linked evidence approach, My5-FU appears to be cost-effective at a willingness to pay of £ 20,000 per QALY for both mCRC and H&N cancer. Considerable uncertainties remain about evidence quality and practical implementation. RCTs are needed of PK versus BSA dosing in relevant cancers.
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Affiliation(s)
| | - Martin Connock
- Warwick Medical School, University of Warwick, Coventry, UK
| | | | - Tara Gurung
- Warwick Medical School, University of Warwick, Coventry, UK
| | | | - Rachel Court
- Warwick Medical School, University of Warwick, Coventry, UK
| | - Mark Saunders
- The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK
| | - Aileen Clarke
- Warwick Medical School, University of Warwick, Coventry, UK
| | - Paul Sutcliffe
- Warwick Medical School, University of Warwick, Coventry, UK
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Toste PA, Nguyen AH, Kadera BE, Duong M, Wu N, Gawlas I, Tran LM, Bikhchandani M, Li L, Patel SG, Dawson DW, Donahue TR. Chemotherapy-Induced Inflammatory Gene Signature and Protumorigenic Phenotype in Pancreatic CAFs via Stress-Associated MAPK. Mol Cancer Res 2016; 14:437-47. [PMID: 26979711 DOI: 10.1158/1541-7786.mcr-15-0348] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 03/01/2016] [Indexed: 12/18/2022]
Abstract
UNLABELLED Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer-associated fibroblasts (CAF). CAFs promote tumor growth, metastasis, and treatment resistance. This study aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAF) were generated by continuous incubation in gemcitabine. Gene expression differences between treatment-naïve CAFs (N-CAF) and R-CAFs were compared by array analysis. Functionally, tumor cells (TC) were exposed to N-CAF- or R-CAF-conditioned media and assayed for migration, invasion, and viability in vitro Furthermore, a coinjection (TC and CAF) model was used to compare tumor growth in vivo R-CAFs increased TC viability, migration, and invasion compared with N-CAFs. In vivo, TCs coinjected with R-CAFs grew larger than those accompanied by N-CAFs. Genomic analysis demonstrated that R-CAFs had increased expression of various inflammatory mediators, similar to the previously described senescence-associated secretory phenotype (SASP). In addition, SASP mediators were found to be upregulated in response to short duration treatment with gemcitabine in both immortalized and primary CAFs. Inhibition of stress-associated MAPK signaling (P38 MAPK or JNK) attenuated SASP induction as well as the tumor-supportive functions of chemotherapy-treated CAFs in vitro and in vivo These results identify a negative consequence of chemotherapy on the PDAC microenvironment that could be targeted to improve the efficacy of current therapeutic regimens. IMPLICATIONS Chemotherapy treatment of pancreatic cancer-associated fibroblasts results in a proinflammatory response driven by stress-associated MAPK signaling that enhances tumor cell growth and invasiveness. Mol Cancer Res; 14(5); 437-47. ©2016 AACR.
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Affiliation(s)
- Paul A Toste
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Andrew H Nguyen
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Brian E Kadera
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Mindy Duong
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Nanping Wu
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Irmina Gawlas
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Linh M Tran
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Mihir Bikhchandani
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Luyi Li
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Sanjeet G Patel
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - David W Dawson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California
| | - Timothy R Donahue
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, California.
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The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells. Stem Cells Int 2016; 2016:8352684. [PMID: 27006664 PMCID: PMC4783541 DOI: 10.1155/2016/8352684] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 12/24/2015] [Accepted: 01/27/2016] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.
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Bimonte S, Leongito M, Granata V, Barbieri A, Del Vecchio V, Falco M, Nasto A, Albino V, Piccirillo M, Palaia R, Amore A, Giacomo RD, Lastoria S, Setola SV, Fusco R, Petrillo A, Izzo F. Electrochemotherapy in pancreatic adenocarcinoma treatment: pre-clinical and clinical studies. Radiol Oncol 2016; 50:14-20. [PMID: 27069445 PMCID: PMC4825336 DOI: 10.1515/raon-2016-0003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 12/13/2015] [Indexed: 12/18/2022] Open
Abstract
Background Pancreatic adenocarcinoma is currently one of the deadliest cancers with high mortality rate. This disease leads to an aggressive local invasion and early metastases, and is poorly responsive to treatment with chemotherapy or chemo-radiotherapy. Radical resection is still the only curative treatment for pancreatic cancer, but it is generally accepted that a multimodality strategy is necessary for its management. Therefore, new alternative therapies have been considered for local treatment. Conclusions Chemotherapeutic resistance in pancreatic cancer is associated to a low penetration of drugs into tumour cells due to the presence of fibrotic stroma surrounding cells. In order to increase the uptake of chemotherapeutic drugs into tumour cells, electrochemotherapy can be used for treatment of pancreatic adenocarcinoma leading to an increased tumour response rate. This review will summarize the published papers reported in literature on the efficacy and safety of electrochemotherapy in pre-clinical and clinical studies on pancreatic cancer.
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Affiliation(s)
- Sabrina Bimonte
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Maddalena Leongito
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Vincenza Granata
- Division of Radiology, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Antonio Barbieri
- S.S.D Sperimentazione Animale, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Vitale Del Vecchio
- S.S.D Sperimentazione Animale, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Michela Falco
- S.S.D Sperimentazione Animale, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Aurelio Nasto
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Vittorio Albino
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Mauro Piccirillo
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Raffaele Palaia
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Alfonso Amore
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Raimondo di Giacomo
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Secondo Lastoria
- Division of Nuclear Medicine, Department of Diagnostic Imaging and Radiotherapy, Istituto Nazionale Tumori "Fondazione G.Pascale" IRCCS, Naples, Italy
| | - Sergio Venanzio Setola
- Division of Radiology, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Roberta Fusco
- Division of Radiology, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Antonella Petrillo
- Division of Radiology, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
| | - Francesco Izzo
- Division of Abdominal Surgical Oncology, Hepatobiliary Unit, Istituto Nazionale per lo studio e la cura dei Tumori "Fondazione G. Pascale", IRCCS, Naples, Italy
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Clemens DL, Schneider KJ, Arkfeld CK, Grode JR, Wells MA, Singh S. Alcoholic pancreatitis: New insights into the pathogenesis and treatment. World J Gastrointest Pathophysiol 2016; 7:48-58. [PMID: 26909228 PMCID: PMC4753189 DOI: 10.4291/wjgp.v7.i1.48] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/23/2015] [Accepted: 11/11/2015] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis is a necro-inflammatory disease of the exocrine pancreas that is characterized by inappropriate activation of zymogens, infiltration of the pancreas by inflammatory cells, and destruction of the pancreatic exocrine cells. Acute pancreatitis can progress to a severe life-threatening disease. Currently there is no pharmacotherapy to prevent or treat acute pancreatitis. One of the more common factors associated with acute pancreatitis is alcohol abuse. Although commonly associated with pancreatitis alcohol alone is unable to cause pancreatitis. Instead, it appears that alcohol and its metabolic by-products predispose the pancreas to damage from agents that normally do not cause pancreatitis, or to more severe disease from agents that normally cause mild pancreatic damage. Over the last 10 to 20 years, a tremendous amount of work has defined a number of alcohol-mediated biochemical changes in pancreatic cells. Among these changes are: Sustained levels of intracellular calcium, activation of the mitochondrial permeability transition pore, endoplasmic reticulum stress, impairment in autophagy, alteration in the activity of transcriptional activators, and colocalization of lysosomal and pancreatic digestive enzymes. Elucidation of these changes has led to a deeper understanding of the mechanisms by which ethanol predisposes acinar cells to damage. This greater understanding has revealed a number of promising targets for therapeutic intervention. It is hoped that further investigation of these targets will lead to the development of pharmacotherapy that is effective in treating and preventing the progression of acute pancreatitis.
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Abstract
OBJECTIVE The aim of this study is to explore how quercetin interacts with pancreatic cancer stem-like cells and the mechanism underlying the effective quercetin-mediated suppression. METHODS A model of pancreatic cancer stem-like cells was generated by using a sphere formation culture system. A comparative analysis was performed between the parent cells and pancreatic cancer stem-like cells with a related treatment strategy focusing on cancer stem cell (CSC) properties and drug-resistance-related mechanisms in vitro. RESULTS Our data show that pancreatic cancer stem-like cells have greater resistance to gemcitabine and stronger CSC properties compared with the parent cells. In contrast to the pancreatic cancer stem-like cells, overexpression of β-catenin was observed in the parent cells. Quercetin suppressed proliferation, invasion and self-renewal capacity, and CSC surface markers expression, with alterations of β-catenin in pancreatic cancer stem-like cells. The combination of quercetin and gemcitabine can reduce tumor growth and decrease drug resistance in pancreatic cancer. CONCLUSIONS β-Catenin plays an important role in maintenance and progression of pancreatic cancer. Targeting β-catenin using quercetin combined with gemcitabine may be a treatment strategy to improve prognosis in patients with pancreatic cancer.
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Grapsa D, Saif MW, Syrigos K. Targeted therapies for pancreatic adenocarcinoma: Where do we stand, how far can we go? World J Gastrointest Oncol 2015; 7:172-177. [PMID: 26483872 PMCID: PMC4606172 DOI: 10.4251/wjgo.v7.i10.172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/10/2015] [Accepted: 08/31/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic adenocarcinoma (usually referred to as pancreatic cancer) is a highly lethal and aggressive malignancy with a disease-related mortality almost equaling its incidence, and one of the most challenging cancers to treat. The notorious resistance of pancreatic cancer not only to conventional cytotoxic therapies but also to almost all targeted agents developed to date, continues to puzzle the oncological community and represents one of the biggest hurdles to reducing the death toll from this ominous disease. This editorial highlights the most important recent advances in preclinical and clinical research, with regards to targeted therapeutics for pancreatic cancer, outlines current challenges and provides an overview of potential future perspectives in this rapidly evolving field.
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Sahin IH, Geyer AI, Kelly DW, O'Reilly EM. Gemcitabine-Related Pneumonitis in Pancreas Adenocarcinoma--An Infrequent Event: Elucidation of Risk Factors and Management Implications. Clin Colorectal Cancer 2015; 15:24-31. [PMID: 26395520 DOI: 10.1016/j.clcc.2015.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 07/28/2015] [Accepted: 08/10/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Gemcitabine-related pneumonitis (GRP) has been reported relatively frequently for pancreas cancer in the literature; however, underlying risk factors and optimal management remain to be defined. We studied a cohort of patients with GRP and investigated potential predisposing factors in pancreatic cancer patients. PATIENTS AND METHODS A total 2440 patients at Memorial Sloan Kettering Cancer Center were identified between January 1, 2000, and December 31, 2012, and were screened for grade 2 or higher GRP in an institutional tumor registry and using an ICD billing code database. Demographic and clinical information was extracted by electronic chart review. RESULTS A total of 28 patients (1.1%) with GRP were identified. Incidence of grade 2, 3, and 4 reactions were 7 (25%), 18 (64%), and 3 (11%), respectively. No GRP-related mortality was observed. Twenty-one patients (75%) reported a history of cigarette smoking. Seventeen patients (61%) were alcohol users. Six patients (21%) were either regular or heavy drinkers. Most patients (93%) had either locally advanced or metastatic disease. Three patients (11%) underwent a diagnostic bronchoscopy, and in 1 patient a diagnosis of organizing pneumonia was established. Morbidity was significant; 3 patients (11%) required treatment in the intensive care unit. All hospitalized patients received steroid treatment. CONCLUSION GRP is relatively uncommon but incurs significant morbidity. Potential risk factors include advanced-stage disease, along with smoking and alcohol consumption and possibly underlying lung disease. We recommend a high level of clinical alertness regarding the diagnosis, early pulmonary referral, and cessation of gemcitabine on suspicion of GRP.
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Affiliation(s)
- Ibrahim Halil Sahin
- Mount Sinai Icahn School of Medicine, St Luke's Roosevelt Hospital Center, New York, NY
| | - Alexander I Geyer
- Memorial Sloan Kettering Cancer Center, Weill Medical College of Cornell University, New York, NY
| | - Daniel W Kelly
- Memorial Sloan Kettering Cancer Center, Weill Medical College of Cornell University, New York, NY
| | - Eileen Mary O'Reilly
- Memorial Sloan Kettering Cancer Center, Weill Medical College of Cornell University, New York, NY.
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Stark AP, Chang HH, Jung X, Moro A, Hertzer K, Xu M, Schmidt A, Hines OJ, Eibl G. E-cadherin expression in obesity-associated, Kras-initiated pancreatic ductal adenocarcinoma in mice. Surgery 2015; 158:1564-72. [PMID: 26297056 DOI: 10.1016/j.surg.2015.07.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 07/06/2015] [Accepted: 07/10/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND The epithelial-mesenchymal transition (EMT) is critical in the development of invasive epithelial malignancies. EMT is accelerated by inflammation and results in decreased E-cadherin expression. Diet-induced obesity is an inflammatory state that accelerates pancreatic carcinogenesis; its effect on EMT and E-cadherin expression in the development of pancreatic ductal adenocarcinoma is unclear. METHODS Conditional Kras(G12D) mice were fed a control diet or a high-fat, high-calorie diet for 3 or 9 months (n = 10 each). Immunohistochemistry with anti-E-cadherin antibody was performed. E-cadherin expression was characterized by staining intensity, location, and proportion of positive cells. In vitro expression of E-cadherin and Slug in primary pancreatic intraepithelial neoplasia (PanIN) and cancer cells was determined by Western blot. RESULTS The HFCD led to increased weight gain in both 3- (15.8 vs 5.6 g, P < .001) and 9-month (19.8 vs 12.9 g, P = .007) mice. No differences in E-cadherin expression among various stages of preinvasive PanIN lesions were found--regardless of age or diet. In invasive cancer, E-cadherin expression was aberrant, with loss of membranous staining and prominent cytoplasmic staining, associated with strong, cytoplasmic expression of β-catenin. In vitro expression of E-cadherin was greatest in primary PanIN cells, accompanied by absent Slug expression. Cancer cell lines demonstrated significantly decreased E-cadherin expression in the presence of upregulated Slug. CONCLUSION Despite increased pancreatic inflammation and accelerated carcinogenesis, the high-fat, high-calorie diet did not induce changes in E-cadherin expression in PanIN lesions of all stages. Invasive lesions demonstrated aberrant cytoplasmic E-cadherin staining. Loss of normal membranous localization may reflect a functional loss of E-cadherin.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/pathology
- Animals
- Cadherins/genetics
- Cadherins/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Cells, Cultured
- Diet, High-Fat/adverse effects
- Disease Models, Animal
- Energy Intake
- Epithelial-Mesenchymal Transition
- Gene Expression Regulation, Neoplastic/genetics
- Gene Expression Regulation, Neoplastic/physiology
- In Vitro Techniques
- Mice
- Mice, Mutant Strains
- Mutation/genetics
- Neoplasm Staging
- Obesity/complications
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Proto-Oncogene Proteins p21(ras)/genetics
- Proto-Oncogene Proteins p21(ras)/metabolism
- Snail Family Transcription Factors
- Transcription Factors/genetics
- Transcription Factors/metabolism
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Affiliation(s)
- Alexander P Stark
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Hui-Hua Chang
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Xiaoman Jung
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Aune Moro
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Kathleen Hertzer
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Mu Xu
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Andrea Schmidt
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - O Joe Hines
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
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Parikh U, Marcus C, Sarangi R, Taghipour M, Subramaniam RM. FDG PET/CT in Pancreatic and Hepatobiliary Carcinomas: Value to Patient Management and Patient Outcomes. PET Clin 2015; 10:327-43. [PMID: 26099670 DOI: 10.1016/j.cpet.2015.03.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Fludeoxyglucose F 18 ((18)F-FDG) PET/CT has not been shown to offer additional benefit in the initial diagnosis of pancreatic cancer, but studies show benefit of (18)F-FDG PET/CT in initial staging and patient prognosis. There is evidence for (18)F-FDG PET and (18)F-FDG PET/CT in staging and prognosis of cholangiocarcinoma and gallbladder cancer. (18)F-FDG PET/CT has shown promise in staging liver malignancies by detecting extrahepatic metastasis. There is evidence supporting the ability of PET/CT in predicting prognosis in patients with hepatocellular carcinoma. Evidence is evolving for the role of (18)F-FDGPET/CT in predicting prognosis and survival in patients with colorectal liver metastasis.
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Affiliation(s)
- Ujas Parikh
- Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, JHOC 3230, 601 North Caroline Street, Baltimore, MD 21287, USA
| | - Charles Marcus
- Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, JHOC 3230, 601 North Caroline Street, Baltimore, MD 21287, USA
| | - Rutuparna Sarangi
- Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, JHOC 3230, 601 North Caroline Street, Baltimore, MD 21287, USA
| | - Mehdi Taghipour
- Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, JHOC 3230, 601 North Caroline Street, Baltimore, MD 21287, USA
| | - Rathan M Subramaniam
- Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, JHOC 3230, 601 North Caroline Street, Baltimore, MD 21287, USA; Department of Oncology, Johns Hopkins School of Medicine, 401 North Broadway, Baltimore, MD 21231, USA; Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, 624 North Broadway, Baltimore, MD 21205, USA.
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