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Wen B, Huang Y, Deng G, Yan Q, Jia L. Gut microbiota analysis and LC-MS-based metabolomics to investigate AMPK/NF-κB regulated by Clostridium butyricum in the treatment of acute pancreatitis. J Transl Med 2024; 22:1072. [PMID: 39604956 PMCID: PMC11600808 DOI: 10.1186/s12967-024-05764-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 10/14/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is an inflammatory condition with potentially life-threatening complications. This study investigates the therapeutic potential of Clostridium butyricum for modulating the inflammatory cascade through the AMPK/NF-κB signaling pathway, focusing on inflammation induced by AP. LC-MS analysis of serum samples from AP patients highlighted the regulation of lipid metabolism and inflammation, and found that metabolites involved in the inhibition of NF-κB phosphorylation and the AMPK activation pathway were downregulated. We hypothesized that pre-administration of Clostridium butyricum and its culture supernatant could mitigate AP-induced damage by modulating the AMPK/NF-κB pathway. METHODS Lipopolysaccharide (LPS)-induced cell inflammation models. LPS combined with CAE induced acute pancreatitis in mice. We divided mice into four groups: Con, AP, AP + C.Buty (AP with Clostridium butyricum treatment), and AP + CFS (AP with culture supernatant treatment). Analyses were performed using WB, RT-qPCR, Elisa, flow cytometry, IHC, and HE, respectively. RESULTS Our study shows that CFS can reduce the apoptosis of LPS-induced cellular inflammation and reduce the release of LPS-induced cytoinflammatory factors through the AMPK/NF-κB pathway in vitro. In vivo, Clostridium butyricum and its supernatant significantly reduced inflammatory markers, and corrected histopathological alterations in AP mice. Gut microbiota analysis further supported these results, showing that Clostridium butyricum and its supernatant could restore the balance of intestinal flora disrupted by AP. CONCLUSIONS Mechanistically, our results indicated that the therapeutic effects of Clostridium butyricum are mediated through the activation of AMPK, leading to the inhibition of the NF-κB pathway, thereby reducing the production of pro-inflammatory cytokines. Clostridium butyricum and its culture supernatant exert a protective effect against AP-induced damage by modulating the AMPK/NF-κB signaling pathway. Future studies will further elucidate the molecular mechanisms underlying the beneficial effects of Clostridium butyricum in AP and explore its clinical applicability in human subjects.
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Affiliation(s)
- Biyan Wen
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510013, China
- Department of Gastroenterology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China
| | - Yaoxing Huang
- Department of Gastroenterology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China
| | - Guiqing Deng
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510013, China
| | - Qingqing Yan
- Department of Gastroenterology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China
| | - Lin Jia
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510013, China.
- Department of Gastroenterology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510180, China.
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Jeong SH, Hurh K, Park EC, Leigh JH, Kim SH, Jang SI. Risk of Pancreatic Cancer After Acute Pancreatitis: A Retrospective Analysis of the Korean National Sample Cohort. J Korean Med Sci 2024; 39:e21. [PMID: 38288535 PMCID: PMC10825454 DOI: 10.3346/jkms.2024.39.e21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 11/22/2023] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Acute pancreatitis may increase the risk of pancreatic cancer, although this association remains unclear. Therefore, we aimed to investigate this association. METHODS We retrospectively analyzed the 2002-2019 Korean National Health Insurance Service-National Sample Cohort using 1:3 propensity score matching for sex and age (acute pancreatitis, n = 4,494; matched controls, n = 13,482). We calculated the hazard ratio (HR) for pancreatic cancer risk in patients with acute pancreatitis using Cox proportional hazards regression. RESULTS Acute pancreatitis was significantly associated with an increased risk of pancreatic cancer throughout the study period (adjusted HR, 7.56 [95% confidence interval, 5.00-11.41]), which persisted for 2, 2-5, and > 5 years post-diagnosis (19.11 [9.60-38.05], 3.46 [1.35-8.33], and 2.73 [1.21-6.15], respectively). This pancreatitis-related pancreatic cancer risk became insignificant beyond 10 years of follow-up (1.24 [0.24-6.49]). Furthermore, this risk notably increased as the number of recurrent acute pancreatitis episodes increased (1 episode: 5.25 [3.31-8.33], 2 episodes: 11.35 [6.38-20.19], ≥ 3 episodes: 24.58 [13.66-44.26]). CONCLUSION Following an acute pancreatitis diagnosis, the risk of pancreatic cancer increases significantly in the initial years, with a rapid increase further accentuated with recurrent acute pancreatitis episodes. Additional study is needed to evaluate whether this increased risk of carcinogenesis is attributed to accumulated inflammation.
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Affiliation(s)
- Sung Hoon Jeong
- Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, Korea
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Rehabilitation Medicine, National Traffic Injury Rehabilitation Hospital, Yangpyeong, Korea
| | - Kyungduk Hurh
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Eun-Cheol Park
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ja-Ho Leigh
- Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Rehabilitation Medicine, National Traffic Injury Rehabilitation Hospital, Yangpyeong, Korea
| | - Seung Hoon Kim
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Preventive Medicine, Eulji University School of Medicine, Daejeon, Korea.
| | - Sung-In Jang
- Institute of Health Services Research, Yonsei University, Seoul, Korea
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea.
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Alshammary AF, Alshammari AM, Alsobaie SF, Alageel AA, Ali Khan I. Evidence from genetic studies among rs2107538 variant in the CCL5 gene and Saudi patients diagnosed with type 2 diabetes mellitus. Saudi J Biol Sci 2023; 30:103658. [PMID: 37181637 PMCID: PMC10172835 DOI: 10.1016/j.sjbs.2023.103658] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 03/23/2023] [Accepted: 04/16/2023] [Indexed: 05/16/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic and metabolic disorder that affects the adult population. Chemokines are proinflammatory cytokines that play a role in the development of chronic diseases such as obesity, gestational diabetes, and T2DM. The C-C Motif Chemokine Ligand 5 (CCL5) gene plays a role in antiviral immunity, tumor development, obesity, impaired glucose tolerance, and T2DM. This study aimed to investigate the genetic role of the rs2107538 variant in the CCL5 gene in Saudi patients with T2DM. Sixty subjects with T2DM patients and 60 healthy controls participated in this prospective case-control study. Prior to Sanger sequencing, genomic DNA was extracted and amplified with Polymerase chain reaction (PCR), after which the PCR products were purified. The collected data were used to conduct various statistical analyses to determine the relationship between T2DM and control subjects. The findings of the current study revealed a positive association for most parameters between T2DM and control subjects (p < 0.05). The frequency of genotypes (p = 0.002, AA vs.GG: p = 0.008, GA + AA vs. GG: p = 0.0002) and alleles (A vs. G: p = 0.0007) revealed a strong risk association. Multiple logistic regression with individual effects revealed a link between SBP and HDLc levels (p = 0.03). In patients with T2DM, waist (p = 0.001), TG (p = 0.0007), and LDLc (p = 0.0004) levels were all associated with the ANOVA. Finally, the rs2107538 variant was linked to an increased risk of T2DM in the Saudi Population. The GA and AA genotypes were strongly connected to the T2DM subjects. In order to rule out disease-causing variants in the global population, future research should use a large sample size.
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Affiliation(s)
- Amal F. Alshammary
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
- Corresponding author.
| | - Abdulrahman M. Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sarah F. Alsobaie
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Arwa A. Alageel
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Imran Ali Khan
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
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Popek-Marciniec S, Styk W, Wojcierowska-Litwin M, Szudy-Szczyrek A, Dudek P, Swiderska-Kolacz G, Czerwik-Marcinkowska J, Zmorzynski S. The Relationship of CCL5 and CCR1 Variants with Response Rate and Survival Taking into Account Thalidomide/Bortezomib Treatment in Patients with Multiple Myeloma. J Clin Med 2023; 12:jcm12062384. [PMID: 36983384 PMCID: PMC10056693 DOI: 10.3390/jcm12062384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/16/2023] [Accepted: 03/17/2023] [Indexed: 03/22/2023] Open
Abstract
(1) Background: Chemokines and chemokine receptors play an important role in tumor development. The aim of this study was to check the significance of CCL5 and CCR1 variants with response rate, survival, and the level of regulated on activation, normal T cells expressed and secreted (RANTES/CCL5) in multiple myeloma (MM) patients; (2) Methods: Genomic DNA from 101 newly diagnosed MM patients and 100 healthy blood donors were analyzed by Real-time PCR method (for CCL5 and CCR1 genotyping). In a subgroup of 70 MM patients, serum samples were collected to determine the level of RANTES; (3) Results: multivariate Cox regression showed increased risk of disease relapse or progression (HR = 4.77; p = 0.01) in MM patients with CG + CC genotypes of CCL5 rs2280788. In contrast, CT + TT genotypes of CCL5 rs2107538 were associated withdecreased risk of death (HR = 0.18; p = 0.028) and disease relapse or progression (HR = 0.26; p = 0.01). In MM patients with major genotypes of rs2280789, rs2280788, and rs2107538, higher survival rates were observed in response to treatment with thalidomide and bortezomib. Statistically significant lower RANTES levels were seen in minor genotypes and heterozygotes of CCL5 and CCR1 variants; (4) Conclusions: Major genotypes of CCL5 variants may be independent positive prognostic factors in MM.
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Affiliation(s)
- Sylwia Popek-Marciniec
- Department of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, 20-059 Lublin, Poland
| | - Wojciech Styk
- Department of Psychology, Medical University of Lublin, 20-059 Lublin, Poland
| | | | - Aneta Szudy-Szczyrek
- Chair and Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-059 Lublin, Poland
| | - Paul Dudek
- Department of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, 20-059 Lublin, Poland
| | | | | | - Szymon Zmorzynski
- Department of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, 20-059 Lublin, Poland
- Correspondence:
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Farr KP, Moses D, Haghighi KS, Phillips PA, Hillenbrand CM, Chua BH. Imaging Modalities for Early Detection of Pancreatic Cancer: Current State and Future Research Opportunities. Cancers (Basel) 2022; 14:cancers14102539. [PMID: 35626142 PMCID: PMC9139708 DOI: 10.3390/cancers14102539] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary While survival rates for many cancers have improved dramatically over the last 20 years, patients with pancreatic cancer have persistently poor outcomes. The majority of patients with pancreatic cancer are not suitable for potentially curative surgery due to locally advanced or metastatic disease stage at diagnosis. Therefore, early detection would potentially improve survival of pancreatic cancer patients through earlier intervention. Here, we present clinical challenges in the early detection of pancreatic cancer, characterise high risk groups for pancreatic cancer and current screening programs in high-risk individuals. The aim of this scoping review is to investigate the role of both established and novel imaging modalities for early detection of pancreatic cancer. Furthermore, we investigate innovative imaging techniques for early detection of pancreatic cancer, but its widespread application requires further investigation and potentially a combination with other non-invasive biomarkers. Abstract Pancreatic cancer, one of the most lethal malignancies, is increasing in incidence. While survival rates for many cancers have improved dramatically over the last 20 years, people with pancreatic cancer have persistently poor outcomes. Potential cure for pancreatic cancer involves surgical resection and adjuvant therapy. However, approximately 85% of patients diagnosed with pancreatic cancer are not suitable for potentially curative therapy due to locally advanced or metastatic disease stage. Because of this stark survival contrast, any improvement in early detection would likely significantly improve survival of patients with pancreatic cancer through earlier intervention. This comprehensive scoping review describes the current evidence on groups at high risk for developing pancreatic cancer, including individuals with inherited predisposition, pancreatic cystic lesions, diabetes, and pancreatitis. We review the current roles of imaging modalities focusing on early detection of pancreatic cancer. Additionally, we propose the use of advanced imaging modalities to identify early, potentially curable pancreatic cancer in high-risk cohorts. We discuss innovative imaging techniques for early detection of pancreatic cancer, but its widespread application requires further investigation and potentially a combination with other non-invasive biomarkers.
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Affiliation(s)
- Katherina P. Farr
- School of Clinical Medicine, Faculty of Medicine & Health, UNSW, Sydney, NSW 2052, Australia; (K.S.H.); (B.H.C.)
- Correspondence:
| | - Daniel Moses
- Graduate School of Biomedical Engineering, UNSW, Sydney, NSW 2052, Australia;
| | - Koroush S. Haghighi
- School of Clinical Medicine, Faculty of Medicine & Health, UNSW, Sydney, NSW 2052, Australia; (K.S.H.); (B.H.C.)
- Department of General Surgery, Prince of Wales Hospital, Sydney, NSW 2052, Australia
| | - Phoebe A. Phillips
- Pancreatic Cancer Translational Research Group, School of Clinical Medicine, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia;
| | - Claudia M. Hillenbrand
- Research Imaging NSW, Division of Research & Enterprise, UNSW, Sydney, NSW 2052, Australia;
| | - Boon H. Chua
- School of Clinical Medicine, Faculty of Medicine & Health, UNSW, Sydney, NSW 2052, Australia; (K.S.H.); (B.H.C.)
- Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Sydney, NSW 2052, Australia
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Munigala S, Subramaniam DS, Subramaniam DP, Burroughs TE, Conwell DL, Sheth SG. Incidence and Risk of Pancreatic Cancer in Patients with a New Diagnosis of Chronic Pancreatitis. Dig Dis Sci 2022; 67:708-715. [PMID: 33630214 DOI: 10.1007/s10620-021-06886-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 02/01/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Chronic pancreatitis (CP) is a risk factor for pancreatic ductal adenocarcinoma (PDAC); nevertheless, the true incidence of PDAC in CP patients in the United States remains unclear. AIMS We evaluated the risk of developing PDAC two or more years after a new diagnosis of CP. METHODS Retrospective study of veterans from September 1999 to October 2015. A three-year washout period was applied to exclude patients with preexisting CP and PDAC. PDAC risk was evaluated in patients with new-diagnosis CP and compared with controls without CP using Cox-proportional hazards model. CP, PDAC, and other covariates were extracted using ICD-9 codes. RESULTS After exclusions, we identified 7,883,893 patients [new-diagnosis CP - 21,765 (0.28%)]. PDAC was diagnosed in 226 (1.04%) patients in the CP group and 15,858 (0.20%) patients in the control group (p < 0.001). CP patients had a significantly higher PDAC risk compared to controls > 2 years [adjusted hazard ratio (HR) 4.28, 95% confidence interval (CI) 3.74-4.89, p < 0.001], 5 years (adjusted HR 3.32, 95% CI 2.75-4.00, p < 0.001) and 10 years of follow-up (adjusted HR 3.14, 95% CI 1.99-4.93, p < 0.001), respectively. By multivariable analysis, age (odds ratio 1.02, 95% CI 1.00-1.03, p = 0.03), current smoker (odds ratio 1.67, 95% CI 1.02-2.74, p = 0.042), current smoker + alcoholic (odds ratio 2.29, 95% CI 1.41-3.52, p < 0.001), and diabetes (odds ratio 1.51, 95% CI 1.14-1.99, p = 0.004) were the independent risk factors for PDAC. CONCLUSION Our data show that after controlling for etiology of CP and other cofactors, the risk of PDAC increased in CP patients after two years of follow-up, and risk was consistent and sustained beyond 5 years and 10 years of follow-up.
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Affiliation(s)
- Satish Munigala
- Saint Louis University Center for Outcomes Research (SLUCOR), 3545 Lafayette Ave, Salus Center 4th Floor, SLUCOR Office, St. Louis, MO, 63104, USA.
| | - Divya S Subramaniam
- Saint Louis University Center for Outcomes Research (SLUCOR), 3545 Lafayette Ave, Salus Center 4th Floor, SLUCOR Office, St. Louis, MO, 63104, USA
| | - Dipti P Subramaniam
- School of Nursing and Health Studies, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Thomas E Burroughs
- Saint Louis University Center for Outcomes Research (SLUCOR), 3545 Lafayette Ave, Salus Center 4th Floor, SLUCOR Office, St. Louis, MO, 63104, USA
| | - Darwin L Conwell
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Sunil G Sheth
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Bozic T, Sersa G, Kranjc Brezar S, Cemazar M, Markelc B. Gene electrotransfer of proinflammatory chemokines CCL5 and CCL17 as a novel approach of modifying cytokine expression profile in the tumor microenvironment. Bioelectrochemistry 2021; 140:107795. [PMID: 33789177 DOI: 10.1016/j.bioelechem.2021.107795] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 11/19/2022]
Abstract
The effectiveness of immunotherapy highly correlates with the degree and the type of infiltrated immune cells in the tumor tissue. Treatments based on modifying the immune cell infiltrate of the tumor microenvironment are thus gaining momentum. Therefore, the aim of our study was to investigate the effects of gene therapy with two proinflammatory chemokines CCL5 and CCL17 on inflammatory cytokine expression profile and immune cell infiltrate in two murine breast tumor models, 4T1 and E0771, and two murine colon tumor models, CT26 and MC38. In vitro, lipofection of plasmid DNA encoding CCL5 or CCL17 resulted in changes in the cytokine expression profile similar to control plasmid DNA, implying that the main driver of these changes was the entry of foreign DNA into the cell's cytosol. In vivo, gene electrotransfer resulted in high expression levels of both Ccl5 and Ccl17 transgenes in the 4T1 and CT26 tumor models. Besides a minor increase in the survival of the treated mice, the therapy also resulted in increased expression of Cxcl9 and Ifnγ, potent activators of the immune system, in CT26 tumors. However, this was not recapitulated in changes of TME, implying that a further refinement of the dosing schedule is needed.
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Affiliation(s)
- T Bozic
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia
| | - G Sersa
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia
| | - S Kranjc Brezar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia
| | - M Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenia.
| | - B Markelc
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia; Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia.
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Wang N, Wang S, Wang X, Zheng Y, Yang B, Zhang J, Pan B, Gao J, Wang Z. Research trends in pharmacological modulation of tumor-associated macrophages. Clin Transl Med 2021; 11:e288. [PMID: 33463063 PMCID: PMC7805405 DOI: 10.1002/ctm2.288] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/27/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023] Open
Abstract
As one of the most abundant immune cell populations in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play important roles in multiple solid malignancies, including breast cancer, prostate cancer, liver cancer, lung cancer, ovarian cancer, gastric cancer, pancreatic cancer, and colorectal cancer. TAMs could contribute to carcinogenesis, neoangiogenesis, immune-suppressive TME remodeling, cancer chemoresistance, recurrence, and metastasis. Therefore, reprogramming of the immune-suppressive TAMs by pharmacological approaches has attracted considerable research attention in recent years. In this review, the promising pharmaceutical targets, as well as the existing modulatory strategies of TAMs were summarized. The chemokine-chemokine receptor signaling, tyrosine kinase receptor signaling, metabolic signaling, and exosomal signaling have been highlighted in determining the biological functions of TAMs. Besides, both preclinical research and clinical trials have suggested the chemokine-chemokine receptor blockers, tyrosine kinase inhibitors, bisphosphonates, as well as the exosomal or nanoparticle-based targeting delivery systems as the promising pharmacological approaches for TAMs deletion or reprogramming. Lastly, the combined therapies of TAMs-targeting strategies with traditional treatments or immunotherapies as well as the exosome-like nanovesicles for cancer therapy are prospected.
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Affiliation(s)
- Neng Wang
- The Research Center for Integrative MedicineSchool of Basic Medical SciencesGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
| | - Shengqi Wang
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Xuan Wang
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Yifeng Zheng
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Bowen Yang
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Juping Zhang
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Bo Pan
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
| | - Jianli Gao
- Academy of Traditional Chinese MedicineZhejiang Chinese Medical UniversityHangzhouZhejiangChina
| | - Zhiyu Wang
- The Research Center for Integrative MedicineSchool of Basic Medical SciencesGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- The Research Center of Integrative Cancer MedicineDiscipline of Integrated Chinese and Western MedicineThe Second Clinical College of Guangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong‐Hong Kong‐Macau Joint Lab on Chinese Medicine and Immune Disease ResearchGuangzhou University of Chinese MedicineGuangzhouGuangdongChina
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine SyndromeGuangdong Provincial Hospital of Chinese MedicineGuangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongChina
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Waseem M, Husain H, Ahmad I. Role of Gene Polymorphism in Obesity and Cancer. OBESITY AND CANCER 2021:129-142. [DOI: 10.1007/978-981-16-1846-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Zhao HB, Jia L, Yan QQ, Deng Q, Wei B. Effect of Clostridium butyricum and Butyrate on Intestinal Barrier Functions: Study of a Rat Model of Severe Acute Pancreatitis With Intra-Abdominal Hypertension. Front Physiol 2020; 11:561061. [PMID: 33192557 PMCID: PMC7658654 DOI: 10.3389/fphys.2020.561061] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 09/29/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIMS Severe acute pancreatitis (SAP) is associated with intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS), but treatment of these conditions is difficult. We studied a rat model of SAP + IAH to determine the effect of oral administration of Clostridium butyricum and butyrate (its major metabolite) on intestinal barrier functions. METHODS A total of 48 rats were assigned to four groups, with 12 rats per group: Sham, SAP+IAH, SAP+IAH+C. butyricum, and SAP + IAH + butyrate. SAP was induced by sodium taurocholate infusion into the biliopancreatic duct, intra-abdominal pressure (IAP), mortality was measured 24 h later, and then rats were euthanized. The plasma levels of several markers [amylase, diamine oxidase (DAO), fluorescein isothiocyanate (FITC)-dextran, tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, IL-12, lipopolysaccharide (LPS)] and fecal butyric acid level were determined. The pancreas and intestine were examined using histology, and RT-PCR and Western blotting of intestinal tissues were used to measure the expression of six markers {tight junction proteins [zonula occludens protein-1 (ZO-1), claudin-1, claudin-2, occluding], matrix metalloproteinase 9 [MMP9], and TNF-α}. The gut flora of the rats was examined by 16S rRNA sequencing. RESULTS Induction of SAP + IAH altered several functions of the intestinal barrier, and enhanced intestinal permeability, decreased the levels of ZO-1, claudin-1, occludin, the richness and diversity of the microflora community, the relative abundance (RA) of Firmicutes, and the number of probiotic organisms. However, induction of SAP+IAH increased the expression of claudin-2, MMP9, and TNF-α, and the RA of Proteobacteria and pathogens in the feces. Rats that received oral C. butyricum or butyrate had reduced intestinal injury and plasma levels of DAO, LPS, and inflammatory cytokines. CONCLUSION This study of rats with SAP+IAH indicated that oral dosing of C. butyricum or butyrate reduced intestinal injury, possibly by altering the functions of the intestinal mucosal barrier.
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Affiliation(s)
- Han-bing Zhao
- Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Lin Jia
- Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
- Department of Gastroenterology, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, China
| | - Qing-qing Yan
- Department of Gastroenterology, Guangzhou First People’s Hospital, South China University of Technology, Guangzhou, China
| | - Qi Deng
- Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Bo Wei
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
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11
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Liu J, Wang Y, Yu Y. Meta-analysis reveals an association between acute pancreatitis and the risk of pancreatic cancer. World J Clin Cases 2020; 8:4416-4430. [PMID: 33083401 PMCID: PMC7559689 DOI: 10.12998/wjcc.v8.i19.4416] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/26/2020] [Accepted: 08/26/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Chronic pancreatitis is associated with pancreatic cancer (PC), although the relationship between acute pancreatitis (AP) and the risk of PC remains unclear due to inconsistent and contradictory results. AIM To conduct a meta-analysis of retrospective and prospective studies to explore the association between AP and PC risk. METHODS We first searched original articles on the association of AP with PC using PubMed, Web of Science, Cochrane, and EMBASE databases. Then we calculated the combined overall effect estimates (EEs) between AP and PC risk at a 95% confidence interval (CI) deploying a random-effects model, and assessed heterogeneity using the I 2 test. The combined relative risk with 95%CI was performed to examine the relationship between AP and PC. Publication bias and subgroup analyses were also conducted. Furthermore, we performed sensitivity analysis to explain this heterogeneity. RESULTS Eleven studies were eligible for inclusion standards in this meta-analysis, resulting in pooled EEs of 2.07 (95%CI: 1.36-2.78) for AP and PC risk. Additionally, five prospective cohort studies reported 103961 patients in the AP group, relative to 1442158 subjects in the control group, with a pooled relative risk of 7.81 (95%CI: 5.00-12.19). We also performed subgroup analyses using different follow-up times and type of research methods (case-control or cohort). Results from analyses of different follow-up times revealed the following pooled effect values: 1-year lag period (EEs = 23.47, 95%CI: 3.26-43.68), 2-year lag period (EEs = 9.82, 95%CI: 3.01-16.64), 5-year lag period (EEs = 2.47, 95%CI: 1.93-3.02), 10-year lag period (EEs = 1.69, 95%CI: 1.26-2.11), and > 10-year lag period (EEs = 1.17, 95%CI: 0.78-1.57). With regards to the methods, the case-control studies recorded EEs = 3.03 (95%CI: -1.02 to 7.08), whereas cohort studies had EEs = 2.09 (95%CI: 1.22-2.97) pooled effect values. CONCLUSION Overall, our findings indicated an association between AP and PC risk. Based on subgroup analyses, AP is unlikely to be a causal factor for PC.
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Affiliation(s)
- Jie Liu
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei 230001, Anhui Province, China
| | - Ying Wang
- Endoscopy Center Department, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, Anhui Province, China
| | - Yue Yu
- Department of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei 230001, Anhui Province, China
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12
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Shan YS, Chen LT, Wu JS, Chang YF, Lee CT, Wu CH, Chiang NJ, Huang HE, Yen CJ, Chao YJ, Tsai HJ, Chen CY, Kang JW, Kuo CF, Tsai CR, Weng YL, Yang HC, Liu HC, Chang JS. Validation of genome-wide association study-identified single nucleotide polymorphisms in a case-control study of pancreatic cancer from Taiwan. J Biomed Sci 2020; 27:69. [PMID: 32456644 PMCID: PMC7251895 DOI: 10.1186/s12929-020-00664-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 05/22/2020] [Indexed: 02/07/2023] Open
Abstract
Background Due to differences in genetic background, it is unclear whether the genetic loci identified by the previous genome-wide association studies (GWAS) of pancreatic cancer also play significant roles in the development of pancreatic cancer among the Taiwanese population. Methods This study aimed to validate the 25 pancreatic cancer GWAS-identified single nucleotide polymorphisms (SNPs) in a case-control study (278 cases and 658 controls) of pancreatic cancer conducted in Taiwan. Statistical analyses were conducted to determine the associations between the GWAS-identified SNPs and pancreatic cancer risk. Gene-environment interaction analysis was conducted to evaluate the interactions between SNPs and environmental factors on pancreatic cancer risk. Results Among the 25 GWAS-identified SNPs, 7 (rs2816938 (~ 11 kb upstream of NR5A2), rs10094872 (~ 28 kb upstream of MYC), rs9581943 (200 bp upstream of PDX1) and 4 chromosome 13q22.1 SNPs: rs4885093, rs9573163, rs9543325, rs9573166) showed a statistically significant association with pancreatic cancer risk in the current study. Additional analyses showed two significant gene-environment interactions (between poor oral hygiene and NR5A2 rs2816938 and between obesity and PDX1 rs9581943) on the risk of pancreatic cancer. Conclusions The current study confirmed the associations between 7 of the 25 GWAS-identified SNPs and pancreatic risk among the Taiwanese population. Furthermore, pancreatic cancer was jointly influenced by lifestyle and medical factors, genetic polymorphisms, and gene-environment interaction. Additional GWAS is needed to determine the genetic polymorphisms that are more relevant to the pancreatic cancer cases occurring in Taiwan.
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Affiliation(s)
- Yan-Shen Shan
- Department of Surgery, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.,Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Ziyou 1st Road, Sanmin District, Kaohsiung, 80756, Taiwan.,Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Jin-Shang Wu
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Yin-Fan Chang
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chih-Ting Lee
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chih-Hsing Wu
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Nai-Jung Chiang
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.,Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Hsin-En Huang
- Department of Family Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chia-Jui Yen
- Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Ying-Jui Chao
- Department of Surgery, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.,Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chiung-Yu Chen
- Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Jui-Wen Kang
- Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Chin-Fu Kuo
- Preventive Medicine Center, Taichung Tzu Chi Hospital, 88 Section 1, Fengxing Road, Tanzi District, Taichung, 427, Taiwan
| | - Chia-Rung Tsai
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan
| | - Ya-Ling Weng
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan
| | - Han-Chien Yang
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan
| | - Hui-Chin Liu
- Department of Nursing, National Cheng Kung University Hospital, National Cheng Kung University, 138 Sheng Li Road, Tainan, 70456, Taiwan
| | - Jeffrey S Chang
- National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.
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13
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Rautenbach A, Williams AA. Metabolomics as an Approach to Characterise the Contrasting Roles of CCR5 in the Presence and Absence of Disease. Int J Mol Sci 2020; 21:E1472. [PMID: 32098198 PMCID: PMC7073144 DOI: 10.3390/ijms21041472] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 02/06/2023] Open
Abstract
Chemokine receptors such as C-C chemokine receptor 5 (CCR5) are activated through interaction with their ligands and are well known for their role in chemotaxis and signal transduction. While serving these roles, cellular responses are effected, hence the immune function of these molecules is established. Given the role of CCR5 in immune function and that the immune and metabolic systems are interlinked, subsequent immune-directed changes should be measurable at a metabolic level. Numerous investigations have reported on metabolic changes associated with CCR5 status in the presence of disease, so as to understand whether specific CCR5 genotypes, frequency and/or levels offer protection to the host or not. However, these metabolic changes were recorded using older conventional techniques. Depending on certain factors such as the disease model, the geography of the samples and/or the ethnic group under study, the role of CCR5 in disease differs. In addition, little is known about CCR5's role in the absence of an enhanced inflammatory state, such as when infection persists. Metabolomics is defined as the study of metabolites and informs on metabolic changes within living organisms as induced by various stimuli, such as the interaction of CCR5 with its ligand. Since metabolomics reflects the underlying biochemical activity and state of cells/tissues, this review proposes it as a tool to clarify the contrasting roles of CCR5.
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Affiliation(s)
| | - Aurelia A. Williams
- Human Metabolomics, North-West University, Private Bag X6001, Box 269, Potchefstroom 2531, South Africa
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14
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Gentiluomo M, Peduzzi G, Lu Y, Campa D, Canzian F. Genetic polymorphisms in inflammatory genes and pancreatic cancer risk: a two-phase study on more than 14 000 individuals. Mutagenesis 2019; 34:395-401. [PMID: 31748817 DOI: 10.1093/mutage/gez040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 10/18/2019] [Indexed: 12/17/2023] Open
Abstract
There is overwhelming evidence that inflammation plays a key role in the pathogenesis of cancer and its progression. Inflammation is regulated through a complex network of genes and polymorphic variants in these genes have been found to be associated to risk of various human cancers, alone or in combination with environmental variables. Despite this, not much is known on the genetic variability of genes that regulate inflammation and risk of pancreatic ductal adenocarcinoma (PDAC). We performed a two-phase association study considering the genetic variability of 76 genes that are key players in inflammatory response. We analysed tagging single nucleotide polymorphisms (SNPs) and regulatory SNPs on 7207 PDAC cases and 7063 controls and observed several associations with PDAC risk. The most significant association was between the carriers of the A allele of the CCL4-rs1719217 polymorphism, which was reported to be also associated with the expression level of the CCL4 gene, and increased risk of developing PDAC (odds ratio = 1.12, 95% confidence interval = 1.06-1.18, P = 3.34 × 10-5). This association was significant also after correction for multiple testing, highlighting the importance of using potentially functional SNPs in order to discover more genetic variants associated with PDAC risk.
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Affiliation(s)
| | | | - Ye Lu
- Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany
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15
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Zhou B, Wu D, Liu H, Du LT, Wang YS, Xu JW, Qiu FB, Hu SY, Zhan HX. Obesity and pancreatic cancer: An update of epidemiological evidence and molecular mechanisms. Pancreatology 2019; 19:941-950. [PMID: 31447281 DOI: 10.1016/j.pan.2019.08.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 07/04/2019] [Accepted: 08/16/2019] [Indexed: 12/11/2022]
Abstract
Despite advances in therapy and achievements in translational research, pancreatic cancer (PC) remains an invariably fatal malignancy. Risk factors that affect the incidence of PC include diabetes, smoking, obesity, chronic pancreatitis, and diet. The growing worldwide obesity epidemic is associated with an increased risk of the most common cancers, including PC. Chronic inflammation, hormonal effects, circulating adipokines, and adipocyte-mediated inflammatory and immunosuppressive microenvironment are involved in the association of obesity with PC. Herein, we systematically review the epidemiology of PC and the biological mechanisms that may account for this association. Included in this review is a discussion of adipokine-mediated inflammation, lipid metabolism, and the interactions of adipocytes with cancer cells. We consider the influence of bariatric surgery on the risk of PC risk as well as potential molecular targets of therapy. Our review leads us to conclude that targeting adipose tissue to achieve weight loss may represent a new therapeutic strategy for preventing and treating PC.
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Affiliation(s)
- Bin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266003, China; Department of Retroperitoneal Tumor Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266003, China
| | - Dong Wu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Han Liu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Lu-Tao Du
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong Province, 250033, China; Tumor Marker Detection Engineering Laboratory of Shandong Province, Jinan, Shandong Province, 250033, China
| | - Yun-Shan Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong Province, 250033, China; Tumor Marker Detection Engineering Laboratory of Shandong Province, Jinan, Shandong Province, 250033, China
| | - Jian-Wei Xu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Fa-Bo Qiu
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266003, China; Department of Retroperitoneal Tumor Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266003, China
| | - San-Yuan Hu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Han-Xiang Zhan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China.
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16
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Zhou X, Liao X, Wang X, Huang K, Yang C, Yu T, Liu J, Han C, Zhu G, Su H, Qin W, Han Q, Liu Z, Huang J, Gong Y, Ye X, Peng T. Clinical significance and prospective molecular mechanism of C‑C motif chemokine receptors in patients with early‑stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy. Oncol Rep 2019; 42:1856-1868. [PMID: 31432181 PMCID: PMC6775805 DOI: 10.3892/or.2019.7277] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 07/08/2019] [Indexed: 12/24/2022] Open
Abstract
The present study aimed to determine the clinical significance and potential molecular mechanisms of C‑C motif chemokine receptor (CCR) genes in patients with early‑stage pancreatic ductal adenocarcinoma (PDAC). The transcriptomic, survival and clinical data of 112 patients with early‑stage PDAC who underwent pancreaticoduodenectomy were obtained from The Cancer Genome Atlas. The prognostic values of the CCR genes involved in early‑stage PDAC were evaluated using Kaplan‑Meier analysis and the multivariate Cox proportional risk regression model, and the potential molecular mechanisms were determined using bioinformatics tools. The identified CCRs closely interacted with each other at both the gene and protein levels. High expression levels of CCR5 [adjusted P=0.012; adjusted hazard ration (HR)=0.478, 95% confidence interval (CI)=0.269‑0.852], CCR6 (adjusted P=0.026; adjusted HR=0.527, 95% CI=0.299‑0.927) and CCR9 (adjusted P=0.001; adjusted HR=0.374, 95% CI=0.209‑0.670) were significantly associated with longer overall survival times in patients with early‑stage PDAC. The contribution of CCR5, CCR6 and CCR9 to the outcome of early‑stage PDAC was also demonstrated. Combined survival analysis of CCR5, CCR6 and CCR9 suggested that patients with high expression levels of these CCRs exhibited the most favorable outcomes. A prognostic signature was constructed in terms of the expression level of CC5, CCR6 and CCR9, and time‑dependent receiver operating characteristic curves indicated that this signature was able to effectively predict the outcome of patients with early‑stage PDAC. The potential molecular mechanisms of CCR5, CC6 and CCR9 in PDAC include its intersection of the P53, nuclear factor (NF)‑κB, generic transcription, mitogen‑activated protein kinase and STAT signaling pathways. Collectively, this highlights that CCR5, CCR6 and CCR9 are potential prognostic biomarkers for early‑stage PDAC.
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Affiliation(s)
- Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Junqi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Quanfa Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Zhengqian Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Jianlv Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Yizhen Gong
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P. R. China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R China
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17
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Dai P, Li J, Li W, Qin X, Wu X, Di W, Zhang Y. Genetic polymorphisms and pancreatic cancer risk: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 2019; 98:e16541. [PMID: 31393355 PMCID: PMC6708677 DOI: 10.1097/md.0000000000016541] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/10/2019] [Accepted: 06/27/2019] [Indexed: 01/09/2023] Open
Abstract
BACKGROUNDS Previous investigations yielded inconsistent results for the associations between pancreatic cancer (PC) risk and genetic polymorphisms. The study aimed to perform a systematic review and meta-analysis of studies exploring association of some genetic polymorphisms and PC risk. METHODS We systematically searched on PubMed and Web of Science for association of genetic polymorphisms and PC risk published from 1969 to January 2019. We computed the multivariate odd ratio (OR) and 95% confidence intervals (CI), comparing different genetic types. RESULTS The present meta-analysis showed significant associations between deoxyribonucleic acid (DNA) repair gene (X-ray repair cross-complementing group 1 (XRCC1) Arg399GIn and Arg194Trp, excision repair cross complementation 1 (ERCC1) rs11615 and rs3212986, ERCC2 rs13181) polymorphisms and PC risk. CONCLUSIONS Because of the limited sample size and ethnicity enrolled in the present meta-analysis, further larger scaled studies should be performed to demonstrate the association.
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Affiliation(s)
- Peng Dai
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
| | - Jing Li
- Department of Microbiology and Immunology, School of Basic Medical Sciences, Shanxi Medical University
| | - Weibin Li
- Department of General Surgery, Shanxi Academy of Medical Sciences, Shanxi Dayi Hospital, Taiyuan, Shanxi, China
| | - Xueliang Qin
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
| | - Xiaoyong Wu
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
| | - Weidong Di
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
| | - Yanzhong Zhang
- Department of Hepato-Biliary-Pancreatic Surgery, Shanxi Provincial People's Hospital Affiliated to Shanxi Medical University
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18
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Zheng Z, Chen Y, Tan C, Ke N, Du B, Liu X. Risk of pancreatic cancer in patients undergoing surgery for chronic pancreatitis. BMC Surg 2019; 19:83. [PMID: 31286902 PMCID: PMC6615265 DOI: 10.1186/s12893-019-0537-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 06/20/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Chronic pancreatitis (CP) is considered to be a risk factor for pancreatic cancer. A retrospective study was conducted to evaluate the incidence of pancreatic cancer after surgery for CP and to determine the risk factors. METHODS The patients who underwent surgery for histologically documented CP between January 2009 and December 2017 were reviewed. The baseline characteristics, operative data, postoperative complications, and follow-up information were analysed. We calculated standardized incidence ratio on the base of the incidence of pancreatic cancer in the standard population in China. The risk factor for pancreatic cancer was assessed using Cox regression. RESULTS Among 650 patients, pancreatic cancer was detected in 12 patients (1.8%) after a median follow-up of 4.4 years. The standardized incidence ratio of pancreatic cancer was 68.12 (95% CI, 35.20-118.99). Two independent risk factors for the development of pancreatic cancer in patients with chronic pancreatitis after surgery were identified: time interval to surgery [HR 1.005, 95% CI (1.002-1.008), P = 0.002] and de novo endocrine insufficiency [HR 10.672, 95% CI (2.567-44.372), P = 0.001]. CONCLUSIONS Patients who require surgery for CP are at a very high risk of developing pancreatic cancer. Early surgical intervention plays a protective role in the development of pancreatic cancer from CP. A high index of suspicion for pancreatic cancer should be maintained in CP patients with de novo postoperative diabetes after surgery.
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Affiliation(s)
- Zhenjiang Zheng
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, GuoXue Lane No.37, Chengdu, 610041, Sichuan Province, China
| | - Yonghua Chen
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, GuoXue Lane No.37, Chengdu, 610041, Sichuan Province, China
| | - Chunlu Tan
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, GuoXue Lane No.37, Chengdu, 610041, Sichuan Province, China
| | - Nengwen Ke
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, GuoXue Lane No.37, Chengdu, 610041, Sichuan Province, China
| | - Binqing Du
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, GuoXue Lane No.37, Chengdu, 610041, Sichuan Province, China
| | - Xubao Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, GuoXue Lane No.37, Chengdu, 610041, Sichuan Province, China.
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19
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Increased risk of pancreatic cancer after acute pancreatitis: A meta-analysis of prospective cohort studies. Clin Res Hepatol Gastroenterol 2019; 43:e39-e41. [PMID: 30392817 DOI: 10.1016/j.clinre.2018.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 09/16/2018] [Accepted: 09/20/2018] [Indexed: 02/04/2023]
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20
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Fatima F, Saleem S, Hameed A, Haider G, Ali Zaidi SA, Kanwal M, Zehra S, Azhar A. Association analysis and allelic distribution of deletion in CC chemokine receptor 5 gene (CCR5Δ32) among breast cancer patients of Pakistan. Mol Biol Rep 2019; 46:2387-2394. [DOI: 10.1007/s11033-019-04699-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 02/12/2019] [Indexed: 12/17/2022]
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Ganne-Carrié N, Nahon P. Hepatocellular carcinoma in the setting of alcohol-related liver disease. J Hepatol 2019; 70:284-293. [PMID: 30658729 DOI: 10.1016/j.jhep.2018.10.008] [Citation(s) in RCA: 245] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 10/01/2018] [Accepted: 10/08/2018] [Indexed: 01/27/2023]
Abstract
Alcohol-related liver disease is the most prevalent type of chronic liver disease worldwide, accounting for 30% of hepatocellular carcinoma (HCC) cases and HCC-specific deaths. Alcohol has been associated with an increased risk of several malignancies, this risk starting at doses as low as 10 g/1 unit/day. The carcinogenic process includes direct acetaldehyde toxicity through the formation of protein and DNA adducts, an increased production of reactive oxygen species, changes to lipid peroxidation and metabolism, inflammation and an impaired immune response and modifications to DNA methylation. A high annual incidence of HCC has been observed in large European cohorts of patients with alcoholic cirrhosis, reaching 2.9%, with numerous host factors modulating this risk (age, gender, liver failure, genetic polymorphisms affecting oncogenic pathways). Because of impaired surveillance and poor patient compliance, HCC is often detected late in patients with chronic liver disease of alcoholic aetiology. This delay in detection, which is frequently made in the context of advanced liver cirrhosis rather than in surveillance programmes, results in more advanced HCC that is less amenable to curative treatment. Consequently, patients with alcohol-related HCC generally have a worse prognosis than those with non-alcoholic HCC.
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Affiliation(s)
- Nathalie Ganne-Carrié
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France; University Paris 13, Sorbonne Paris Cité, "équipe labellisée Ligue Contre le Cancer", F-93000 Bobigny, France; INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010 Paris, France.
| | - Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Liver Unit, Bondy, France; University Paris 13, Sorbonne Paris Cité, "équipe labellisée Ligue Contre le Cancer", F-93000 Bobigny, France; INSERM UMR-1162: Functional Genomics of Solid Tumours, F-75010 Paris, France
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22
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Suenaga M, Stintzing S, Cao S, Zhang W, Yang D, Ning Y, Okazaki S, Berger MD, Miyamoto Y, Schirripa M, Soni S, Barzi A, Heinemann V, Lenz HJ. Role of CCL5 and CCR5 gene polymorphisms in epidermal growth factor receptor signalling blockade in metastatic colorectal cancer: analysis of the FIRE-3 trial. Eur J Cancer 2019; 107:100-114. [PMID: 30554073 PMCID: PMC6367121 DOI: 10.1016/j.ejca.2018.11.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/10/2018] [Accepted: 11/10/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND Epidermal growth factor receptor signalling blockade increases CCL5 expression that regulates either the anti-tumour immune response or tumour progression. We investigated the potential role of CCL5/CCR5 axis in cetuximab-based treatment in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC from the FIRE-3 trial: an evaluation cohort of 244 patients receiving cetuximab plus FOLFIRI and a control cohort of 247 patients receiving bevacizumab plus FOLFIRI. Single-nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analysed by polymerase chain reaction-based direct sequencing. RESULTS Patients in the evaluation cohort with any CCL5 rs2280789G allele had shorter overall survival (OS) compared with those with the A/A variant (hazard ratio 1.56, P = 0.024). Patients carrying any CCR5 rs1799988T allele had a trend toward lower response rate than those with the C/C variant (68 vs. 81%, P = 0.078). In the analysis based on primary tumour location (left-sided [L]: right-sided [R]), remarkable differences in outcomes were observed between patients with L-CCR5 SNPs C/C variant (L-C/C), L-any T, R-T/T and R-any C as follows: median OS, 38.5, 30.6, 27.1 and 15.8 months, P < 0.001; response rate, 91, 66, 92 and 48%, P < 0.001. Median OS for CCL5 SNPs including L-A/A, L-any G, R-A/A and R-any G groups were 38.3, 21.7, 21.9 and 18.3 months, P < 0.001. The findings were not significant in the control cohort. CONCLUSION Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC patients receiving cetuximab-based treatment depending on tumour location.
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Affiliation(s)
- Mitsukuni Suenaga
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
| | - Sebastian Stintzing
- Department of Medicine III, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Dongyun Yang
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Yan Ning
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Satoshi Okazaki
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Martin D Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Yuji Miyamoto
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Marta Schirripa
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Afsaneh Barzi
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
| | - Volker Heinemann
- Department of Medicine III, University Hospital, LMU Munich, Marchioninistrasse 15, 81377 Munich, Germany
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA
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23
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Suenaga M, Cao S, Zhang W, Yang D, Ning Y, Okazaki S, Berger MD, Miyamoto Y, Schirripa M, Soni S, Barzi A, Yamaguchi T, Lenz HJ. Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients. Int J Cancer 2018; 144:2567-2577. [PMID: 30411783 DOI: 10.1002/ijc.31968] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 10/23/2018] [Accepted: 10/29/2018] [Indexed: 01/07/2023]
Abstract
Early VEGF-A reduction (EVR) by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BEV). The CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first-line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n = 48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF-A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24-0.83, p = 0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26-0.95, p = 0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF-A levels at baseline and a greater decrease in VEGF-A levels at day 14 compared to the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first-line treatment for mCRC.
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Affiliation(s)
- Mitsukuni Suenaga
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.,Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Wu Zhang
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Dongyun Yang
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Yan Ning
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Satoshi Okazaki
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Martin D Berger
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Yuji Miyamoto
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Marta Schirripa
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Shivani Soni
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Afsaneh Barzi
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Toshiharu Yamaguchi
- Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Heinz-Josef Lenz
- Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
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24
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Ghosh J, Chowdhury AR, Srinivasan S, Chattopadhyay M, Bose M, Bhattacharya S, Raza H, Fuchs SY, Rustgi AK, Gonzalez FJ, Avadhani NG. Cigarette Smoke Toxins-Induced Mitochondrial Dysfunction and Pancreatitis Involves Aryl Hydrocarbon Receptor Mediated Cyp1 Gene Expression: Protective Effects of Resveratrol. Toxicol Sci 2018; 166:428-440. [PMID: 30165701 PMCID: PMC6260170 DOI: 10.1093/toxsci/kfy206] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
We previously reported that mitochondrial CYP1 enzymes participate in the metabolism of polycyclic aromatic hydrocarbons and other carcinogens leading to mitochondrial dysfunction. In this study, using Cyp1b1-/-, Cyp1a1/1a2-/-, and Cyp1a1/1a2/1b1-/- mice, we observed that cigarette and environmental toxins, namely benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induce pancreatic mitochondrial respiratory dysfunction and pancreatitis. Our results suggest that aryl hydrocarbon receptor (AhR) activation and resultant mitochondrial dysfunction are associated with pancreatic pathology. BaP treatment markedly inhibits pancreatic mitochondrial oxygen consumption rate (OCR), ADP-dependent OCR, and also maximal respiration, in wild-type mice but not in Cyp1a1/1a2-/- and Cyp1a1/1a2/1b1-/- mice. In addition, both BaP and TCDD treatment markedly affected mitochondrial complex IV activity, in addition to causing marked reduction in mitochondrial DNA content. Interestingly, the AhR antagonist resveratrol, attenuated BaP-induced mitochondrial respiratory defects in the pancreas, and reversed pancreatitis, both histologically and biochemically in wild-type mice. These results reveal a novel role for AhR- and AhR-regulated CYP1 enzymes in eliciting mitochondrial dysfunction and cigarette toxin-mediated pancreatic pathology. We propose that increased mitochondrial respiratory dysfunction and oxidative stress are involved in polycyclic aromatic hydrocarbon associated pancreatitis. Resveratrol, a chemo preventive agent and AhR antagonist, and CH-223191, a potent and specific AhR inhibitor, confer protection against BaP-induced mitochondrial dysfunction and pancreatic pathology.
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Affiliation(s)
- Jyotirmoy Ghosh
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- Department of Chemistry, Banwarilal Bhalotia College, Asansol, Ushagram, Asansol-713303, West Bengal, India
| | - Anindya Roy Chowdhury
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Satish Srinivasan
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- Roche Molecular Systems, 1080, US-202, Branchburg, NJ 08876
| | - Mrittika Chattopadhyay
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Moumita Bose
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390
| | - Sabyasachi Bhattacharya
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
- GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426
| | - Haider Raza
- Department of Biochemistry, College of Medicine and Health Sciences, UAE University, Al-Ain, UAE
| | - Serge Y Fuchs
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Anil K Rustgi
- Division of Gastroenterology, Departments of Medicine and Genetics, and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Frank J Gonzalez
- National Cancer Institute, Center for Cancer Research, Bethesda, Maryland 20892
| | - Narayan G Avadhani
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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25
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Inhibition of the CCL5/CCR5 Axis against the Progression of Gastric Cancer. Int J Mol Sci 2018; 19:ijms19051477. [PMID: 29772686 PMCID: PMC5983686 DOI: 10.3390/ijms19051477] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/11/2018] [Accepted: 05/14/2018] [Indexed: 12/14/2022] Open
Abstract
Despite the progress made in molecular and clinical research, patients with advanced-stage gastric cancer (GC) have a bad prognosis and very low survival rates. Furthermore, it is challenging to find the complex molecular mechanisms that are involved in the development of GC, its progression, and its resistance to therapy. The interactions of chemokines, also known as chemotactic cytokines, with their receptors regulate immune and inflammatory responses. However, updated research demonstrates that cancer cells subvert the normal chemokine role, transforming them into fundamental constituents of the tumor microenvironment (TME) with tumor-promoting effects. C-C chemokine ligand 5 (CCL5) is a chemotactic cytokine, and its expression and secretion are regulated in T cells. C-C chemokine receptor type 5 (CCR5) is expressed in T cells, macrophages, other leukocytes, and certain types of cancer cells. The interaction between CCL5 and CCR5 plays an active role in recruiting leukocytes into target sites. This review summarizes recent information on the role of the CCL5 chemokine and its receptor CCR5 in GC cell proliferation, metastasis formation, and in the building of an immunosuppressive TME. Moreover, it highlights the development of new therapeutic strategies to inhibit the CCL5/CCR5 axis in different ways and their possible clinical relevance in the treatment of GC.
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26
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Kirkegård J, Cronin-Fenton D, Heide-Jørgensen U, Mortensen FV. Acute Pancreatitis and Pancreatic Cancer Risk: A Nationwide Matched-Cohort Study in Denmark. Gastroenterology 2018; 154:1729-1736. [PMID: 29432727 DOI: 10.1053/j.gastro.2018.02.011] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 01/29/2018] [Accepted: 02/05/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Acute pancreatitis may be a risk factor for pancreatic cancer; however, findings from studies on this association are conflicting. We investigated the association between acute pancreatitis and increased risk of pancreatic cancer. METHODS We conducted a nationwide, population-based, matched cohort study of all patients admitted to a hospital in Denmark with a diagnosis of acute pancreatitis from January 1, 1980, through October 31, 2012. As many as 5 individuals from the general population without acute pancreatitis were matched for age and sex to each patient with acute pancreatitis. Pancreatic cancer risk was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), calculated using the Cox proportional hazards model. Cox models were stratified by age, sex, and year of pancreatitis diagnosis and adjusted for alcohol- and smoking-related conditions, and Charlson Comorbidity Index score. RESULTS We included 41,669 patients diagnosed with incident acute pancreatitis and 208,340 comparison individuals. Patients with acute pancreatitis had an increased risk of pancreatic cancer compared with the age- and sex-matched general population throughout the follow-up period. The risk decreased over time but remained high after more than 5 years of follow-up (adjusted HR 2.02; 95% CI 1.57-2.61). Two- and 5-year absolute risks of pancreatic cancer among patients with acute pancreatitis were 0.70% (95% CI 0.62%-0.78%) and 0.87% (95% CI 0.78%-0.97), respectively. CONCLUSIONS In a nationwide, population-based, matched cohort study, we observed an association between a diagnosis of acute pancreatitis and long-term risk of pancreatic cancer.
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Affiliation(s)
- Jakob Kirkegård
- Department of Surgery, HPB section, Aarhus University Hospital, Aarhus, Denmark.
| | | | - Uffe Heide-Jørgensen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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27
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Farajzadeh Valilou S, Keshavarz-Fathi M, Silvestris N, Argentiero A, Rezaei N. The role of inflammatory cytokines and tumor associated macrophages (TAMs) in microenvironment of pancreatic cancer. Cytokine Growth Factor Rev 2018; 39:46-61. [PMID: 29373197 DOI: 10.1016/j.cytogfr.2018.01.007] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/24/2017] [Accepted: 01/11/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is considered as one of the most lethal types of cancer due to its poor prognosis and lack of effective therapeutic approaches. Although many studies have been done on pancreatic cancer, the current treatment methods did not exhibit successful results. Hence, novel strategies are needed for treatment of pancreatic cancer. The microenvironment of pancreatic cancer contains many factors such as inflammatory cytokines and tumor associated macrophages (TAMs), which influence the tumor's status. These factors can be upregulated and consequently lead to exacerbation of tumor progression. Understanding the role of pro- and anti-inflammatory cytokines and the function of TAMs in the pancreatic cancer microenvironment might lead to development and improvement of novel strategies in the diagnosis and treatment of pancreatic cancer and may result in promising treatments for this type of cancer.
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Affiliation(s)
- Saeed Farajzadeh Valilou
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahsa Keshavarz-Fathi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Nicola Silvestris
- Medical Oncology Unit and Scientific Directorate, National Cancer Institute IRCCS "Giovanni Paolo II", Bari, Italy; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Bari, Italy
| | - Antonella Argentiero
- Medical Oncology Unit, National Cancer Institute IRCCS "Giovanni Paolo II", Bari, Italy; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Bari, Italy
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK.
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28
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Nahon P, Nault JC. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int 2017; 37:1591-1601. [PMID: 28296015 DOI: 10.1111/liv.13419] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 03/08/2017] [Indexed: 02/13/2023]
Abstract
Exploration of the constitutional genetics of hepatocellular carcinoma (HCC) has identified numerous variants associated with a higher risk of liver cancer in alcoholic cirrhotic patients. Although Genome-Wide Association studies have not been carried out in the field of alcohol-related HCC, common single nucleotide polymorphisms conferring a small increase in the risk of liver cancer risk have been identified and shown to modulate ethanol metabolism, inflammation, oxidative stress, iron or lipid metabolism. Specific patterns of gene mutations including CTNNB1, TERT, ARID1A and SMARCA2 exist in alcohol-related HCC. Moreover, a specific mutational process observed at the nucleotide level by next generation sequencing has revealed cooperation between alcohol and tobacco in the development of HCC. Combining this genetic information with epidemiological and clinical data that might define specific HCC risk classes and refine surveillance strategies needs to be assessed in large prospective cohorts of patients with alcoholic cirrhosis.
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Affiliation(s)
- Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France.,Université Paris 13, Bobigny, France.,Inserm UMR-1162, "Functional Genetics of Solid Tumours", Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Oncoimmunology, Equipe labellisée Ligue contre le Cancer, Paris, France
| | - Jean-Charles Nault
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France.,Université Paris 13, Bobigny, France.,Inserm UMR-1162, "Functional Genetics of Solid Tumours", Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Oncoimmunology, Equipe labellisée Ligue contre le Cancer, Paris, France
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29
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Sun K, Gong C, Peng H, Fang H, Zhou J, Li J, Chen S, Zheng H. High CCL5 expression is associated with osteosarcoma metastasis and poor prognosis of patients with osteosarcoma. Mol Med Rep 2017; 16:6953-6957. [PMID: 28901496 DOI: 10.3892/mmr.2017.7458] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Accepted: 03/02/2017] [Indexed: 11/06/2022] Open
Abstract
Osteosarcoma is the most common primary malignant tumor of the skeletal system and is characterized by an aggressive clinical course and high metastatic potential. Regulated upon Activation Normal T cell Expressed and Secreted, also termed C‑C motif chemokine ligand 5 (CCL5), is associated with metastasis and poor prognosis in various types of cancer. The aim of the current study was to investigate the association between CCL5 expression and clinicopathological features and prognosis in patients with osteosarcoma. Tissue microarrays and reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry were used to examine the expression of CCL5 in human osteosarcoma tissues. The prognostic value of CCL5 expression was evaluated by the Kaplan‑Meier method and Cox proportional hazards regression model. The rate of high CCL5 expression was significantly higher in metastatic osteosarcomas than in osteosarcomas without metastases. The overall survival rates (P=0.001) and the metastasis‑free survival rates (P<0.001) of the low CCL5 expression group were significantly higher than the CCL5 high expression group. Multivariate Cox regression analysis indicated that CCL5 expression had independent predictive value for the prognosis of patients with osteosarcoma. In conclusion, the data of the current study indicated that CCL5 may serve as a biomarker for prognosis of osteosarcoma, and may be a potential molecular target for osteosarcoma therapy.
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Affiliation(s)
- Kai Sun
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Chen Gong
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Hao Peng
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Hongsong Fang
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jianlin Zhou
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jianping Li
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Sen Chen
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Huifeng Zheng
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Chronic Pancreatitis and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. Am J Gastroenterol 2017; 112:1366-1372. [PMID: 28762376 DOI: 10.1038/ajg.2017.218] [Citation(s) in RCA: 341] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 06/02/2017] [Indexed: 12/11/2022]
Abstract
Chronic pancreatitis is a putative risk factor for pancreatic cancer. The aim of this study was to examine the magnitude and temporality of this association. We searched MEDLINE and EMBASE for observational studies investigating the association between chronic pancreatitis and pancreatic cancer. We computed overall effect estimates (EEs) with associated 95% confidence intervals (CIs) using a random-effects meta-analytic model. The EEs were stratified by length of follow-up from chronic pancreatitis diagnosis to pancreatic cancer (lag period). Robustness of the results was examined in sensitivity analyses. We identified 13 eligible studies. Pooled EEs for pancreatic cancer in patients with chronic pancreatitis were 16.16 (95% CI: 12.59-20.73) for patients diagnosed with pancreatic cancer within 2 years from their chronic pancreatitis diagnosis. The risk of pancreatic cancer in patients with chronic pancreatitis decreased when the lag period was increased to 5 years (EE: 7.90; 95% CI: 4.26-14.66) or a minimum of 9 years (EE: 3.53; 95% CI: 1.69-7.38). In conclusion, chronic pancreatitis increases the risk of pancreatic cancer, but the association diminishes with long-term follow-up. Five years after diagnosis, chronic pancreatitis patients have a nearly eight-fold increased risk of pancreatic cancer. We suggest that common practice on inducing a 2-year lag period in these studies may not be sufficient. We also recommend a close follow-up in the first years following a diagnosis of chronic pancreatitis to avoid overlooking a pancreatic cancer.
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-2518 A/G MCP-1 but not -403 G/A RANTES gene polymorphism is associated with enhanced risk of basal cell carcinoma. Postepy Dermatol Alergol 2016; 33:381-385. [PMID: 27881944 PMCID: PMC5110628 DOI: 10.5114/ada.2016.62846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 09/18/2015] [Indexed: 12/24/2022] Open
Abstract
Introduction Polymorphic variants of MCP-1 and RANTES genes and their protein serum levels have been implicated in the increased risk and severity of several malignancies. However, the subject has not been explored in basal cell carcinoma (BCC) patients so far. Aim To investigate the association between monocyte chemoattractant protein 1 (MCP-1) (–2518 A/G) and RANTES (–403 G/A) polymorphism and risk and clinical course of BCC. Material and methods The study group consisted of 150 unrelated patients with BCC and 140 healthy, unrelated, age- and sex-matched volunteers. The polymorphisms were analysed using the amplification refractory mutation system polymerase chain reaction method (ARMS-PCR) and single specific primer-polymerase chain reaction (SSP-PCR). Serum cytokine levels were measured with ELISA. Results The presence of the MCP-1 –2518 GG genotype was statistically more frequent in BCC patients and it increased the risk of BCC (OR = 2.63, p = 0.003). Genotype –330 GG was statistically more common in patients with less advanced tumours (OR = 2.8, p = 0.017). Monocyte chemoattractant protein 1 serum level was statistically higher with GG genotype. In the BCC group MCP-1 serum levels were decreased. Neither polymorphic variants of RANTES nor the chemokine serum concentration differed significantly between the study groups. Conclusions These findings suggest that –2518 A/G MCP-1 polymorphism may be involved in BCC pathogenesis.
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Qidwai T. Chemokine genetic polymorphism in human health and disease. Immunol Lett 2016; 176:128-38. [PMID: 27262929 DOI: 10.1016/j.imlet.2016.05.018] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 05/16/2016] [Accepted: 05/31/2016] [Indexed: 12/11/2022]
Abstract
Chemokine receptor-ligand interaction regulates transmigration of lymphocytes and monocytes from circulation to the inflammatory sites. CC chemokine receptors, chemokine receptor 2(CCR2) and 5 (CCR5) are important in recruitment of immune cells as well as non-immune cells under pathological condition. CCR2, CCR5 and their ligands (CCL2 and CCL5) are major contributor to the autoimmune and inflammatory diseases and cancer. Currently studies are being done to explore genetic variations in chemokine genes and their involvement in diseases that could make clear disease severity and deaths. Conflicting results of studies in different populations and diseases promoted to investigate chemokines genetic polymorphisms in miscellaneous diseases. This study is aimed to evaluate the influence of chemokines genetic polymorphisms in pathogenesis and outcome of prevalent non infectious diseases. Present study demonstrates the likely role played by genetic variations in drug response and evolution. Moreover this study highlights chemokine as therapeutic target and diagnostic biomarker in pathological condition.
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Affiliation(s)
- Tabish Qidwai
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, India.
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Yako YY, Kruger D, Smith M, Brand M. Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review. PLoS One 2016; 11:e0154016. [PMID: 27170998 PMCID: PMC4865360 DOI: 10.1371/journal.pone.0154016] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 04/07/2016] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES A systematic review of the role of cytokines in clinical medicine as diagnostic, prognostic, or predictive biomarkers in pancreatic ductal adenocarcinoma was undertaken. MATERIALS AND METHODS A systematic review was conducted according to the 2009 PRISMA guidelines. PubMed database was searched for all original articles on the topic of interest published until June 2015, and this was supplemented with references cited in relevant articles. Studies were evaluated for risk of bias using the Quality in Prognosis Studies tools. RESULTS Forty one cytokines were investigated with relation to pancreatic ductal adenocarcinoma (PDAC) in 65 studies, ten of which were analyzed by more than three studies. Six cytokines (interleukin[IL]-1β, -6, -8, -10, vascular endothelial growth factor, and transforming growth factor) were consistently reported to be increased in PDAC by more than four studies; irrespective of sample type; method of measurement; or statistical analysis model used. When evaluated as part of distinct panels that included CA19-9, IL-1β, -6 and -8 improved the performance of CA19-9 alone in differentiating PDAC from healthy controls. For example, a panel comprising IL-1β, IL-8, and CA 19-9 had a sensitivity of 94.1% vs 85.9%, specificity of 100% vs 96.3%, and area under the curve of 0.984 vs 0.925. The above-mentioned cytokines were associated with the severity of PDAC. IL-2, -6, -10, VEGF, and TGF levels were reported to be altered after patients received therapy or surgery. However, studies did not show any evidence of their ability to predict treatment response. CONCLUSION Our review demonstrates that there is insufficient evidence to support the role of individual cytokines as diagnostic, predictive or prognostic biomarkers for PDAC. However, emerging evidence indicates that a panel of cytokines may be a better tool for discriminating PDAC from other non-malignant pancreatic diseases or healthy individuals.
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Affiliation(s)
- Yandiswa Yolanda Yako
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
| | - Deirdré Kruger
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
| | - Martin Smith
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
| | - Martin Brand
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
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Sukari A, Muqbil I, Mohammad RM, Philip PA, Azmi AS. F-BOX proteins in cancer cachexia and muscle wasting: Emerging regulators and therapeutic opportunities. Semin Cancer Biol 2016; 36:95-104. [PMID: 26804424 PMCID: PMC4761518 DOI: 10.1016/j.semcancer.2016.01.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 01/17/2016] [Accepted: 01/19/2016] [Indexed: 12/22/2022]
Abstract
Cancer cachexia is a debilitating metabolic syndrome accounting for fatigue, an impairment of normal activities, loss of muscle mass associated with body weight loss eventually leading to death in majority of patients with advanced disease. Cachexia patients undergoing skeletal muscle atrophy show consistent activation of the SCF ubiquitin ligase (F-BOX) family member Atrogin-1 (also known as MAFBx/FBXO32) alongside the activation of the muscle ring finger protein1 (MuRF1). Other lesser known F-BOX family members are also emerging as key players supporting muscle wasting pathways. Recent work highlights a spectrum of different cancer signaling mechanisms impacting F-BOX family members that feed forward muscle atrophy related genes during cachexia. These novel players provide unique opportunities to block cachexia induced skeletal muscle atrophy by therapeutically targeting the SCF protein ligases. Conversely, strategies that induce the production of proteins may be helpful to counter the effects of these F-BOX proteins. Through this review, we bring forward some novel targets that promote atrogin-1 signaling in cachexia and muscle wasting and highlight newer therapeutic opportunities that can help in the better management of patients with this devastating and fatal disorder.
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Affiliation(s)
- Ammar Sukari
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI 48201, USA
| | - Irfana Muqbil
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI 48201, USA
| | - Ramzi M Mohammad
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI 48201, USA; iTRI Hamad Medical Corporation, Doha, Qatar
| | - Philip A Philip
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI 48201, USA
| | - Asfar S Azmi
- Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI 48201, USA.
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Tong GX, Geng QQ, Chai J, Cheng J, Chen PL, Liang H, Shen XR, Wang DB. Association between pancreatitis and subsequent risk of pancreatic cancer: a systematic review of epidemiological studies. Asian Pac J Cancer Prev 2015; 15:5029-34. [PMID: 24998582 DOI: 10.7314/apjcp.2014.15.12.5029] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
This study aimed to summarize published epidemiological evidence for the relationship between pancreatitis and subsequent risk of pancreatic cancer (PC). We searched Medline and Embase for epidemiological studies published by February 5th, 2014 examining the risk of PC in pancreatitis patients using highly inclusive algorithms. Information about first author, year of publication, country of study, recruitment period, type of pancreatitis, study design, sample size, source of controls and attained age of subjects were extracted by two researchers and Stata 11.0 was used to perform the statistical analyses and examine publication bias. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with the random effects model. A total of 17 articles documenting 3 cohort and 14 case-control studies containing 14,667 PC cases and 17,587 pancreatitis cases were included in this study. The pooled OR between pancreatitis and PC risk was 7.05 (95%CI: 6.42-7.75). However, the pooled ORs of case-control and cohort studies were 4.62 (95%CI: 4.08-5.22) and 16.3 (95%CI: 14.3-18.6) respectively. The risk of PC was the highest in patients with chronic pancreatitis (pooled OR=10.35; 95%CI: 9.13-11.75), followed by unspecified type of pancreatitis (pooled OR=6.41; 95%CI: 4.93-8.34), both acute and chronic pancreatitis (pooled OR=6.13; 95%CI: 5.00-7.52), and acute pancreatitis (pooled OR=2.12; 95%CI: 1.59-2.83). The pooled OR of PC in pancreatitis cases diagnosed within 1 year was the highest (pooled OR=23.3; 95%CI: 14.0-38.9); and the risk in subjects diagnosed with pancreatitis for no less than 2, 5 and 10 years were 3.03 (95%CI: 2.41-3.81), 2.82 (95%CI: 2.12-3.76) and 2.25 (95%CI: 1.59-3.19) respectively. Pancreatitis, especially chronic pancreatitis, was associated with a significantly increased risk of PC; and the risk decreased with increasing duration since diagnosis of pancreatitis.
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Affiliation(s)
- Gui-Xian Tong
- Center for Health Management, School of Health Services Management, Anhui Medical University, Hefei, China E-mail :
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Karakaxas D, Gazouli M, Coker A, Agalianos C, Papanikolaou IS, Patapis P, Liakakos T, Dervenis C. Genetic polymorphisms of inflammatory response gene TNF-α and its influence on sporadic pancreatic neuroendocrine tumors predisposition risk. Med Oncol 2014; 31:241. [PMID: 25213764 DOI: 10.1007/s12032-014-0241-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 09/05/2014] [Indexed: 12/17/2022]
Abstract
The diagnosed incidence of pancreatic neuroendocrine tumors (pNETs) is increasing; however, their etiology remains poorly understood. PNETs are a rare, heterogeneous group of tumors arising from the endocrine cells of the pancreas, and genetic risk factors for sporadic pNETs are inadequately understood. It is known that pNETs secrete biogenic amines, hormones and growth factors, tumor necrosis factor-a (TNF-α) being one of them. Furthermore, cytokines and other proinflammatory mediators have been implicated in inflammatory pancreatic diseases including pancreatitis and cancer. The aim of our study was to analyze TNF-α promoter gene polymorphisms as risk factors for pNETs using germline DNA collected in a population-based case-control study of pancreatic cancer [42 pNET cases, 78 pancreatic ductal adenocarcinoma (PDAC) cases, 17 intraductal papillary mucinous neoplasm (IPMN) and 98 healthy controls] conducted in the Athens, Greece and Izmir, Turkey areas. For subsequent analysis, we excluded cases and controls with known genetic syndromes. The CC genotype at the -1031 position was more frequent in pNET and IPMN patients (p=0.0002 and p=0.009, respectively), suggesting its possible role in pNET development. Furthermore, the AA genotype at the -308 position was overrepresented in IPMN cases (p=0.03), and AA genotype at the -238 position was more frequent in PDAC cases (p=0.03) compared to healthy individuals. With regard to tumor characteristics, no statistically significant association was detected. Our findings suggest the putative role of TNF-α -1031 polymorphism in the development of pNET and IPMN, whereas the -308 polymorphism seems to be overrepresented among IPMN cases and -238 polymorphism among PDAC cases.
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Lee YH, Song GG. Association between chemokine receptor 5 delta32 polymorphism and susceptibility to cancer: a meta-analysis. J Recept Signal Transduct Res 2014; 35:509-15. [PMID: 25203595 DOI: 10.3109/10799893.2014.960934] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To explore whether the functional chemokine receptor 5 delta32 (CCR5-Δ32) polymorphism is associated with susceptibility to cancer. METHODS A meta-analysis was conducted on the association between the CCR5-Δ32 polymorphism and cancer using (i) allele contrast and (ii) the dominant model. RESULTS Thirteen articles, including 16 comparative studies on a total of 3087 patients and 3735 controls, were included in the meta-analysis. These studies encompassed breast cancer (n = 3), bladder cancer (n = 3), cervical cancer (n = 2), pancreatic cancer (n = 2), prostate cancer (n = 2), head and neck cancer (n = 2), lymphoma (n = 1), gallbladder cancer (n = 1), skin cancer (n = 1) and mixed cancer (n = 1). The meta-analysis revealed an association between cancer and the CCR5-Δ32 allele (OR = 1.368, 95% CI = 1.064-1.758, p = 0.014), and stratification by ethnicity showed an association between the CCR5-Δ32 allele and cancer in Indians (OR = 2.480, 95% CI = 1.247-4.932, p = 0.010). The meta-analysis also revealed an association between breast cancer and the CCR5-Δ32 allele (OR = 1.689, 95% CI = 1.012-2.821, p = 0.045). However, allele contrast and the dominant model failed to reveal an association between the CCR5-Δ32 polymorphism and bladder cancer, cervical cancer, pancreatic cancer, prostate cancer, and head and neck cancer. CONCLUSIONS This meta-analysis demonstrates that the CCR5-Δ32 polymorphism is associated with susceptibility to cancer in Indians and is associated with breast cancer.
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Affiliation(s)
- Young Ho Lee
- a Division of Rheumatology, Department of Internal Medicine , Korea University College of Medicine , Seoul , Korea
| | - Gwan Gyu Song
- a Division of Rheumatology, Department of Internal Medicine , Korea University College of Medicine , Seoul , Korea
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Ying H, Wang J, Gao X. CCL5-403, CCR5-59029, and Delta32 polymorphisms and cancer risk: a meta-analysis based on 20,625 subjects. Tumour Biol 2014; 35:5895-5904. [PMID: 24687549 DOI: 10.1007/s13277-014-1780-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Accepted: 02/19/2014] [Indexed: 01/18/2023] Open
Abstract
Associations between CCL5-403, CCR5-59029, and Delta32 polymorphisms and cancer risk are inconclusive. To derive a more precise estimation of the association, we performed a meta-analysis by searching PubMed, EMBASE, Google scholar, and WanFang databases. A total of 20 eligible articles with 39 studies were included. Of those studies, there were 21 studies for CCR5-Delta32 polymorphism, 9 studies for CCR5-59029 polymorphism, and 9 studies for CCL5-403 polymorphism. Combined analysis revealed no associations between these polymorphisms and cancer risk. However, subgroup analysis by ethnicity suggested that CCR5-59029 polymorphism was associated with the risk of cancer among Asian populations (A vs. G: odds ratio (OR)=1.36, 95 % confidence interval (CI) 1.13-1.65, P H=0.27; AA vs. GG: OR=2.07, 95 % CI 1.37-3.12, P H=0.17; GA+AA vs. GG: OR=1.35, 95 % CI 1.03-1.77, P H=0.92; AA vs. GA+GG: OR=1.98, 95 % CI 1.01-3.88, P H=0.08), but not among Caucasian populations. CCL5-403 polymorphism was associated with the risk of cancer among African populations (A vs. G: OR=0.68, 95 % CI 0.55-0.83, P H=0.14; AA vs. GG: OR=0.51, 95 % CI 0.33-0.77, P H=0.52; AG vs. GG: OR=0.58, 95 % CI 0.42-0.80, P H=0.14; AG+AA vs. GG: OR=0.56, 95 % CI 0.41-0.75, P H=0.13), but not among Caucasian populations and Asian populations. Overall, this meta-analysis indicated that CCR5-Delta32 was not associated with the risk of cancer. CCR5-59029 polymorphism contributed to cancer risk among Asian populations, and CCL5-403 polymorphism was associated with the decreased risk of cancer among African populations.
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Affiliation(s)
- Houqun Ying
- Department of Clinical Laboratory, Medical College of Southeast University, Nanjing, Jiangsu, 210009, China
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Hocevar BA, Kamendulis LM, Pu X, Perkins SM, Wang ZY, Johnston EL, DeWitt JM, Li L, Loehrer PJ, Klaunig JE, Chiorean EG. Contribution of environment and genetics to pancreatic cancer susceptibility. PLoS One 2014; 9:e90052. [PMID: 24651674 PMCID: PMC3961224 DOI: 10.1371/journal.pone.0090052] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 01/27/2014] [Indexed: 12/20/2022] Open
Abstract
Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00 ± 0.05) versus both healthy unrelated and related controls (0.70 ± 0.06, p<0.001 and 0.82 ± 0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA -308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.
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Affiliation(s)
- Barbara A. Hocevar
- Department of Environmental Health, Indiana University, Bloomington, Indiana, United States of America
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America
| | - Lisa M. Kamendulis
- Department of Environmental Health, Indiana University, Bloomington, Indiana, United States of America
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America
| | - Xinzhu Pu
- Department of Environmental Health, Indiana University, Bloomington, Indiana, United States of America
| | - Susan M. Perkins
- Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America
| | - Zheng-Yu Wang
- Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Erica L. Johnston
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America
| | - John M. DeWitt
- Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Lang Li
- Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America
| | - Patrick J. Loehrer
- Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America
| | - James E. Klaunig
- Department of Environmental Health, Indiana University, Bloomington, Indiana, United States of America
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America
- * E-mail: (JEK); (EGC)
| | - E. Gabriela Chiorean
- Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana, United States of America
- University of Washington, Seattle, Washington, United States of America
- * E-mail: (JEK); (EGC)
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Liu ST, Pham H, Pandol SJ, Ptasznik A. Src as the link between inflammation and cancer. Front Physiol 2014; 4:416. [PMID: 24474940 PMCID: PMC3893689 DOI: 10.3389/fphys.2013.00416] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Accepted: 12/31/2013] [Indexed: 12/11/2022] Open
Abstract
Although a causal link between chronic inflammation and cancer has been established, the exact molecular mechanism linking inflammation to cancer remains largely unknown. It was previously postulated that molecular switches responsible for cancer cell development, and for infiltration of inflammatory cells into cancer, were divided into a distinct set of intracellular proteins and signaling pathways. However, recent evidence suggests that both tumor cells and tumor-infiltrating immune cells utilize the same kinases, mostly that of Src family, to facilitate cancer development and progression. In the past few years several groups have found that Src activation both in cancer and inflammatory cells is mainly driven by pro-inflammatory cytokines within the tumor microenvironment. Here we evaluate the cross talks between Src kinase pathways in immune cells and cancer cells. We conclude that Src might serve as a critical mechanistic link between inflammation and cancer, mediating and propagating a cycle between immune and tissue cells that can ultimately lead to the development and progression of cancer.
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Affiliation(s)
- Sandy T Liu
- Department of Medicine, Cedars-Sinai Medical Center Los Angeles, CA, USA ; Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles CA, USA
| | - Hung Pham
- Department of Medicine, Cedars-Sinai Medical Center Los Angeles, CA, USA
| | - Stephen J Pandol
- Department of Medicine, Cedars-Sinai Medical Center Los Angeles, CA, USA ; Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles CA, USA ; Department of Medicine, Veterans Affairs Los Angeles, CA, USA
| | - Andrzej Ptasznik
- Department of Medicine, Cedars-Sinai Medical Center Los Angeles, CA, USA
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Guo XF, Wang J, Yu SJ, Song J, Ji MY, Cao Z, Zhang JX, Wang J, Dong WG. TNF-α-308 polymorphism and risk of digestive system cancers: A meta-analysis. World J Gastroenterol 2013; 19:9461-9471. [PMID: 24409077 PMCID: PMC3882423 DOI: 10.3748/wjg.v19.i48.9461] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 10/11/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the association between the tumour necrosis factor alpha-308 (TNF-α-308) gene polymorphism and the risk of digestive system cancers.
METHODS: All eligible case-control studies published up to December 2012 were identified by searching PubMed, Web of Science, Embase and China National Knowledge Internet without language restrictions. The risk of digestive system cancers associated with the TNF-α-308 polymorphism was estimated for each study using odds ratio (OR) together with its 95%CI, respectively. Cochrane Collaboration RevMan 5.1 was used to perform the analysis. A χ2-test-based Q statistic test and an I2 test were performed to assess the between-study heterogeneity. When the Q test was significant (P < 0.05) or I2 > 50%, the random effects model was used, otherwise the fixed effects model was used.
RESULTS: Fifty-eight studies from fifty-five publications with a total of 9986 cancer patients and 15511 healthy controls were included. Overall, a significant association was found between the TNF-α-308 polymorphism and the risk of digestive system cancers [dominant model: OR = 1.23, 95%CI: 1.09-1.39, (G/A) vs (G/G): OR = 1.15, 95%CI: 1.02-1.28, (A/A) vs (G/G): OR = 1.44, 95%CI: 1.19-1.73, recessive model: OR = 1.38, 95%CI: 1.15-1.66]. Furthermore, when the analysis was stratified by ethnicity, similar results were observed in both the Asian and Caucasian populations, except for the dominant model and heterozygote comparisons in the Asian population [dominant model: OR = 1.24, 95%CI: 0.99-1.56, (G/A) vs (G/G): OR = 1.09, 95%CI: 0.96-1.24]. When the cancer type subgroups were examined, similar results were detected in gastric and hepatocellular carcinomas; however, no significant association was observed among other digestive system cancers.
CONCLUSION: The TNF-α-308 gene polymorphism may be significantly associated with the risk of gastric and hepatocellular carcinomas, but not colorectal, pancreatic, or oesophageal cancer, in the Asian population.
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Kwon KH, Lee YC, Chung JH, Eun YG. Association Study of Chemokine (C–C motif) Ligand 5 Gene Polymorphism and Papillary Thyroid Cancer. J INVEST SURG 2013; 26:319-24. [DOI: 10.3109/08941939.2013.805857] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Circulating CCL5 Levels in Patients with Breast Cancer: Is There a Correlation with Lymph Node Metastasis? ACTA ACUST UNITED AC 2013. [DOI: 10.1155/2013/453561] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
CC-chemokine ligand 5 (CCL5) was measured in plasma of 238 patients with breast cancer and in serum of 149 of these patients. Mean circulating CCL5 levels tended to be higher in patients with lymph-node-positive breast cancer, larger tumour sizes, the presence of lymphovascular invasion, and multifocal tumours. Additionally, circulating CCL5 levels were higher in the order of stages III, II, and I. The addition of circulating CCL5 concentration to known clinicopathological predictors for lymph node involvement did not allow more precise prediction of the lymph node status. These results suggest that CCL5 is a biomarker for tumour load rather than for lymph node involvement. As such, it might be helpful to identify patients with escape from immunosurveillance who will benefit from therapies to restore immune function.
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Infliximab: protective effect to intestinal barrier function of rat with acute necrosis pancreatitis at early stage. Pancreas 2013; 42:366-7. [PMID: 23407490 DOI: 10.1097/mpa.0b013e31825c5273] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Hertzer KM, Donald GW, Hines OJ. CXCR2: a target for pancreatic cancer treatment? Expert Opin Ther Targets 2013; 17:667-80. [PMID: 23425074 DOI: 10.1517/14728222.2013.772137] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Pancreatic cancer, a leading cause of cancer deaths worldwide, is very aggressive and has minimally effective treatment options. For those who have no surgical options, medical treatments are limited. The chemokine receptor CXCR2 has become the subject of much interest recently because of multiple studies indicating its involvement in cancer and inflammatory conditions. Research now indicates that CXCR2 and its ligands are intimately involved in tumor regulation and growth and that inhibition of its function shows promising results in multiple cancer types, including pancreatic cancer. AREAS COVERED In this study, the authors review basic molecular and structural details of CXCR2, as well as the known functions of CXCR2 and several of its ligands in inflammation and cancer biology with specific attention to pancreatic cancer. Then the future possibilities and questions remaining for pharmacological intervention against CXCR2 in pancreatic cancer are explored. EXPERT OPINION Many current inhibitory strategies already exist for targeting CXCR2 in vitro as well as in vivo. Clinically speaking, CXCR2 is an exciting potential target for pancreatic cancer; however, CXCR2 is functionally important for multiple processes and therapeutic options would benefit from further work toward understanding of these roles as well as structural and target specificity.
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Affiliation(s)
- Kathleen M Hertzer
- Hirshberg Translational Pancreatic Cancer Research Laboratory, David Geffen School of Medicine at UCLA, Department of Surgery , 675 Charles E Young Drive, MRL 2535, Los Angeles, CA 90095 , USA
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Kidd LR, Jones DZ, Rogers EN, Kidd NC, Beache S, Rudd JE, Ragin C, Jackson M, McFarlane-Anderson N, Tulloch-Reid M, Morrison S, Brock GN, Barve SS, Kimbro KS. Chemokine Ligand 5 (CCL5) and chemokine receptor (CCR5) genetic variants and prostate cancer risk among men of African Descent: a case-control study. Hered Cancer Clin Pract 2012; 10:16. [PMID: 23168091 PMCID: PMC3527309 DOI: 10.1186/1897-4287-10-16] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 10/29/2012] [Indexed: 01/20/2023] Open
Abstract
UNLABELLED BACKGROUND Chemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs) are associated with various cancers, their impact on prostate cancer (PCA) among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses. METHODS Sequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls) using Illumina's Goldengate genotyping system. RESULTS Inheritance of CCL5 rs2107538 (AA, GA+AA) and rs3817655 (AA, AG, AG+AA) genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively. CONCLUSIONS In summary, CCL5 (rs2107538, rs3817655) and CCR5 (rs1799988) sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.
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Affiliation(s)
- Lacreis R Kidd
- Department of Pharmacology & Toxicology, University of Louisville Clinical Translational Research Building, 505 South Hancock Street Room 306, Louisville, KY, 40202, USA.
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Infliximab enhances the therapeutic effectiveness of octreotide on acute necrotizing pancreatitis in rat model. Pancreas 2012; 41:849-54. [PMID: 22450369 DOI: 10.1097/mpa.0b013e31823fbdc3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To investigate the synergistic activity of infliximab to the therapeutic effectiveness of octreotide in a rat model of acute necrotizing pancreatitis (ANP). METHODS Forty Sprague-Dawley rats were randomly divided into sham-operated group (SO), ANP group (ANP), octreotide group (OG), infliximab group (IG), and combination group (CG) (n = 8 in each group). The ANP model was induced by biliopancreatic duct injection with 4.5% of sodium taurocholate solution. Rats of the OG, IG, and CG were given a tail vein injection of octreotide (10 μg/kg), infliximab (8 mg/kg), and infliximab (8 mg/kg), respectively, combined with octreotide (10 μg/kg) at 6 hours after modeling. All rats in each group were killed at 24 hours after modeling. Serum biochemical indicator and partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) of rats were determined. Pathological severity score of organs were evaluated. RESULTS The serum biochemical indicator and organs' pathology score of OG , IG, and CG were obviously lower than those in the ANP group, and those in the CG were the lowest (P < 0.05). The PaO2/FiO2 levels in the OG, IG, and CG were significantly higher than that in the ANP group (P < 0.05). CONCLUSION Infliximab could significantly lower the serum biochemical indicator, improve organs' function, and enhance the therapeutic effectiveness of octreotide on ANP.
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Momi N, Kaur S, Ponnusamy MP, Kumar S, Wittel UA, Batra SK. Interplay between smoking-induced genotoxicity and altered signaling in pancreatic carcinogenesis. Carcinogenesis 2012; 33:1617-28. [PMID: 22623649 DOI: 10.1093/carcin/bgs186] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Despite continuous research efforts directed at early diagnosis and treatment of pancreatic cancer (PC), the status of patients affected by this deadly malignancy remains dismal. Its notoriety with regard to lack of early diagnosis and resistance to the current chemotherapeutics is due to accumulating signaling abnormalities. Hoarding experimental and epidemiological evidences have established a direct correlation between cigarette smoking and PC risk. The cancer initiating/promoting nature of cigarette smoke can be attributed to its various constituents including nicotine, which is the major psychoactive component, and several other toxic constituents, such as nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and polycyclic aromatic hydrocarbons. These predominant smoke-constituents initiate a series of oncogenic events facilitating epigenetic alterations, self-sufficiency in growth signals, evasion of apoptosis, sustained angiogenesis, and metastasis. A better understanding of the molecular mechanisms underpinning these events is crucial for the prevention and therapeutic intervention against PC. This review presents various interconnected signal transduction cascades, the smoking-mediated genotoxicity, and genetic polymorphisms influencing the susceptibility for smoking-mediated PC development by modulating pivotal biological aspects such as cell defense/tumor suppression, inflammation, DNA repair, as well as tobacco-carcinogen metabolization. Additionally, it provides a large perspective toward tumor biology and the therapeutic approaches against PC by targeting one or several steps of smoking-mediated signaling cascades.
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Affiliation(s)
- Navneet Momi
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
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Liang CC, Yao P, Zhao ZH. Investigation of risk factors for pancreatic carcinoma and chronic pancreatitis. Shijie Huaren Xiaohua Zazhi 2012; 20:870-874. [DOI: 10.11569/wcjd.v20.i10.870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare risk factors for pancreatic cancer and chronic pancreatitis to find clues to the early diagnosis of pancreatic cancer.
METHODS: The clinical data for 265 patients with pancreatic carcinoma and 294 patients with chronic pancreatitis who were treated at our hospital from January 2005 to October 2010 were analyzed comparatively. Univariate and multivariate analyses were performed to examine factors affecting the incidence of pancreatic carcinoma using logistic regression models.
RESULTS: Univariate analysis showed that age, nation, smoking, smoking >20 cigarettes/day, drinking, alcohol >40 g/d, alcohol >10 years, diabetes, cholelithiasis, blood and urine amylase, fasting blood sugar level, AST level, ALT level, CA19-9 level differed significantly between the two groups. Multivariate analysis showed that age (OR = 1.607, P < 0.05), CA19-9 >35 KU/L (OR = 1.004, P < 0.05), and fasting blood sugar level >6.4 mmol/L (OR = 1.453, P < 0.05) were independent risk factors for pancreatic carcinoma. Using regression analysis, 251 (94.7%) of 265 cases of pancreatic carcinoma and 282 (95.9%) of 294 cases of chronic pancreatitis were predicted. The total accuracy is 95.3%.
CONCLUSION: Chronic pancreatitis patients with significant risk factors for pancreatic cancer should be regularly monitored for early detection of pancreatic cancer.
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Olson SH. Selected medical conditions and risk of pancreatic cancer. Mol Carcinog 2012; 51:75-97. [PMID: 22162233 DOI: 10.1002/mc.20816] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
We review the current evidence for associations of several medical conditions with risk of pancreatic cancer, including allergies, pancreatitis, gall bladder disease, cholecystectomy, ulcers, gastrectomy, appendectomy, and tonsillectomy. There are consistent findings of reduced risk associated with presence of self-reported allergies, particularly hay fever but not asthma; data on other allergies are limited and inconclusive. Several studies provide evidence that patients with pancreatic cancer are more likely than comparison groups to report pancreatitis. Those studies that investigated the time between onset of pancreatitis and diagnosis of pancreatic cancer found that risk estimates declined with longer periods of time; however, increased risks were noted for long-term pancreatitis, indicating that this condition is both a risk factor and a sign of early disease. Increased risk was reported in association with cholelithiasis, but the few studies that considered time before diagnosis of cancer did not find increased risk for cholelithiasis diagnosed in the more distant past. There is weak evidence that cholecystectomy 2 or more years before cancer diagnosis is related to risk, but this is based on only a few studies. There is no consistent association between ulcers and risk, while gastrectomy may increase risk. Overall, study of these conditions, particularly those that are rare, presents methodologic challenges. Time between diagnoses is likely to be important but is not considered in most studies. Lack of adequate control in several studies for risk factors such as smoking and heavy alcohol use also makes it difficult to draw firm conclusions about these results.
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Affiliation(s)
- Sara H Olson
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
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