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Liu C, Wu H, Cai D, Yu X. Unraveling the causal relationship between serum minerals and pancreatic cancer: a Mendelian randomization study. Discov Oncol 2024; 15:788. [PMID: 39692823 DOI: 10.1007/s12672-024-01695-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 12/11/2024] [Indexed: 12/19/2024] Open
Abstract
BACKGROUND Pancreatic cancer is among the most lethal malignancies, characterized by a poor prognosis and limited modifiable factors. Emerging evidence indicates that serum mineral levels may influence the likelihood of developing pancreatic cancer. However, the causal relationship between serum minerals and pancreatic cancer remains unclear and warrants further investigation. METHODS This Mendelian randomization (MR) study was conducted to explore the causal effects of serum mineral levels on pancreatic cancer risk. Genetic variants associated with serum mineral levels, including calcium, iron, magnesium, zinc, selenium, and copper, were selected as instrumental variables (IVs) from large-scale genome-wide association study (GWAS) data. Multiple methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weight methods, were employed to perform MR analysis. The effect sizes from the MR analysis, using two independent GWAS summary datasets related to pancreatic cancer, were combined through meta-analysis. The Cochrane Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out test were conducted for sensitivity tests. RESULTS Our MR analysis demonstrated a significant causal effect of genetically predicted serum calcium levels on increased pancreatic cancer risk [OR = 1.64, 95% CI 1.05-2.57, P = 0.029 (discovery cohort); OR = 1.52, 95% CI 1.07-2.15, P = 0.019 (validation cohort)], while no significant associations were found for other serum minerals (P > 0.05). Additional meta-analysis reinforces and substantiates this conclusion (pooled OR = 1.56, 95% CI 1.19-2.06, P = 0.001). No evidence of pleiotropy or heterogeneity was detected across multiple sensitivity tests (P > 0.05). CONCLUSION This study provides new evidence supporting the causal role of certain serum minerals, particularly calcium, in the development of pancreatic cancer. These findings may help inform future research into preventive strategies or therapies aimed at modulating mineral levels in patients at high risk of pancreatic cancer.
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Affiliation(s)
- Cong Liu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Huajun Wu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Dongdong Cai
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Xin Yu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
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Wei H, Han W, Zhang X, Zhang M. Gastroscopic observation and dose-volume histogram parameter study on gastrointestinal mucous injury for pancreatic cancer treated with TOMO. Medicine (Baltimore) 2024; 103:e38469. [PMID: 38905414 PMCID: PMC11191859 DOI: 10.1097/md.0000000000038469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/15/2024] [Indexed: 06/23/2024] Open
Abstract
To explore the relationships between gastrointestinal radiation injuries of pancreatic cancer patients treated with TOMO and dose-volume histogram parameters prospectively. Seventy patients with pancreatic cancer who underwent TOMO were enrolled in this prospective study from February 2015 to May 2020. The clinical and dose-volume histogram parameters of the patients were collected. The optimal dose parameters for gastrointestinal radiation ulcers were confirmed based on the receiver operating characteristic curve (ROC) and the area below the ROC curve. Acute gastrointestinal tract toxic and side effect and injury grading correlation analyzed by Kruskal-Wallis rank sum test. Gastrointestinal injury often occurs during radiotherapy for pancreatic cancer, as observed using gastroscopy. The main adverse reactions were radioactive gastrointestinal inflammation (58.5%), radioactive gastrointestinal ulcers (41.4%), active bleeding (10%), newly-developed gastric retention (8.6%), and gastric varices (5.7%). As for the stomach, Dmean and V10 were related to radiation ulcer injury. ROC curve indicated that for stomach a Dmean of 13.39 Gy (area under ROC curves = 0.74, P = .048) and a V10 of 72.21% (area = 0.74, P = .048) was the tolerated dose for the injury of stomach radiation ulcer. As for duodenum, aV20 and aV25 are related to radiation ulcer injury. ROC curve indicated that aV20 of 22.82 cm3 (area = 0.68, P = .025) and aV25 of 32.04 cm3 (area = 0.66, P < .047) was the tolerated dose for the injury of duodenum radiation ulcer. The acute gastrointestinal tract toxic and side effects have no significant correlation with injury grading under gastroscope. Dmean > 13.39 Gy and V10 > 72.21% were the key dosimetric indices for predicting radiation-induced gastric ulcer, and aV20 > 22.82 cm3 and aV25 > 32.04 cm3 were for duodenal. Gastrointestinal reactions cannot be used as an overall basis for the diagnosis of gastrointestinal injury, and gastroscopy is recommended as a review item after radiotherapy.
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Affiliation(s)
- Hualin Wei
- Department of Oncology, Hebei General Hospital, Shijiazhuang 050051, Hebei, PR China
| | - Wei Han
- Department of Oncology, Hebei General Hospital, Shijiazhuang 050051, Hebei, PR China
| | - Xianbo Zhang
- Department of Oncology, Hebei General Hospital, Shijiazhuang 050051, Hebei, PR China
| | - Ming Zhang
- Department of Oncology, Hebei General Hospital, Shijiazhuang 050051, Hebei, PR China
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Bhattacharyya S, Ghosh H, Covarrubias-Zambrano O, Jain K, Swamy KV, Kasi A, Hamza A, Anant S, VanSaun M, Weir SJ, Bossmann SH, Padhye SB, Dandawate P. Anticancer Activity of Novel Difluorinated Curcumin Analog and Its Inclusion Complex with 2-Hydroxypropyl-β-Cyclodextrin against Pancreatic Cancer. Int J Mol Sci 2023; 24:ijms24076336. [PMID: 37047307 PMCID: PMC10093935 DOI: 10.3390/ijms24076336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/14/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the primary reason for cancer-related deaths in the US. Genetic mutations, drug resistance, the involvement of multiple signaling pathways, cancer stem cells (CSCs), and desmoplastic stroma, which hinders drug penetrance, contribute to poor chemotherapeutic efficacy. Hence, there is a need to identify novel drugs with improved delivery to improve treatment outcomes. Curcumin is one such compound that can inhibit multiple signaling pathways and CSCs. However, curcumin’s clinical applicability for treating PDAC is limited because of its poor solubility in water and metabolic instability. Hence, we developed a difluorinated curcumin (CDF) analog that accumulates selectively in the pancreas and inhibits PDAC growth in vitro and in vivo. In the present work, we developed its 2-hydroxy-propyl-β-cyclodextrin (HCD) inclusion complex to increase its water solubility and hydrolytic stability. The CDFHCD inclusion complex was characterized by spectroscopic, thermal, and microscopic techniques. The inclusion complex exhibited increased aqueous solubility, hydrolytic stability, and antiproliferative activity compared to parent CDF. Moreover, CDF and CDFHCD inhibited colony and spheroid formation, and induced cell cycle and apoptosis in PDAC cell lines. Hence, CDFHCD self-assembly is an efficient approach to increase water solubility and anticancer therapeutic efficacy, which now warrants advancement towards a clinical proof of concept in PDAC patients.
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Affiliation(s)
- Sangita Bhattacharyya
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Hindole Ghosh
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | | | - Krishan Jain
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - K. Venkateswara Swamy
- MIT School of Bioengineering, Sciences & Research, MIT Art, Design and Technology University, Pune 412201, India
| | - Anup Kasi
- Division of Medical Oncology, University of Kansas, Kansas City, KS 66160, USA
| | - Ameer Hamza
- Pathology and Laboratory Medicine, University of Kansas, Kansas City, KS 66160, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Michael VanSaun
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Scott J. Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
- Division of Medical Oncology, University of Kansas, Kansas City, KS 66160, USA
- Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Stefan H. Bossmann
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Subhash B. Padhye
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
- Interdisciplinary Science & Technology Research Academy (ISTRA), Azam Campus, University of Pune, Pune 411001, India
| | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
- Correspondence: ; Tel.: +1-913-945-6336
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Xie D, Jia S, Ping D, Wang D, Cao L. Scaffold-based three-dimensional cell model of pancreatic cancer is more suitable than scaffold-free three-dimensional cell model of pancreatic cancer for drug discovery. Cytotechnology 2022; 74:657-667. [PMID: 36389286 PMCID: PMC9652184 DOI: 10.1007/s10616-022-00553-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 10/03/2022] [Indexed: 11/03/2022] Open
Abstract
Pancreatic cancer is one of the deadliest malignancies. Three-dimensional (3D) pancreatic cancer cell models for drug screening have been established to improve treatment for pancreatic cancer. However, few studies focus on different drug responses and drug-related molecular mechanisms in various types of 3D cell models. In this study, we constructed 3D scaffold-free cell models and 3D scaffold-based cell models of pancreatic cancer, evaluated chemotherapeutic drug responses in different 3D models, assessed clinical relevance of the models, and investigated molecular mechanisms of chemoresistance and drug pathways in different 3D models. Both types of 3D models showed resistance to chemotherapeutic drugs, and scaffold-based pancreatic cancer models could better reflect in vivo drug efficacy than 2D and scaffold-free pancreatic cancer models did. Increased cell adhesion, extracellular matrix (ECM) synthesis and drug transport were essential for drug resistance in 3D models, and anti-apoptosis might contribute to extreme chemoresistance in scaffold-free models. Moreover, scaffold-based pancreatic cancer models were more suitable than scaffold-free models for drug pathway research.
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Affiliation(s)
- Dafei Xie
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000 China
- Department of General Surgery, Zhejiang Hospital, Hangzhou, 310000 China
| | - Shengnan Jia
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000 China
| | - Dongnan Ping
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000 China
| | - Dong Wang
- Department of General Surgery, Zhejiang Hospital, Hangzhou, 310000 China
| | - Liping Cao
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000 China
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Bagias G, Kanavidis P, Vailas M, Despotidis M, Sotiropoulou M, Katsaros I, Maroulis I, Filippou D, Schizas D. Surgical management of familial pancreatic cancer: a systematic review of the literature. ANZ J Surg 2022; 92:2816-2821. [PMID: 35758214 DOI: 10.1111/ans.17834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/30/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is the third most common cause of cancer-related mortality. The fact that the vast majority of patients with PDAC are diagnosed at an advanced stage highlights the need of early diagnosis. As hereditary factors are associated with approximately 5% of all PDAC cases, a screening programme to these high-risk individuals (HRI) has been proposed. The aim of screening methods is to identify selected group of patients with morphological abnormalities at an early stage, in order to be treated promptly. In this study, we evaluate the surgical outcomes and the appropriateness of pancreatic resection in HRIs who were selected for screening. METHODS A systematic literature search of the PubMed, Embase, and Cochrane databases was performed. The clinicopathological features were recorded and evaluated. RESULTS Six studies were selected for data collection. A total number of 77 patients were identified. Twenty-one patients had a germline mutation, with CDKN2A being the most prominent one (15.6%). Distal pancreatectomy was the most common surgical procedure (42.8%), followed by pancreaticoduodenectomy (33.8%). The mean disease-free survival was 23.6 months and tumour recurrence occurred in 9 patients (11.7%). Disease-specific mortality was 17.8%, while overall mortality was 19.5%. The most frequently reported postoperative diagnosis was PDAC (28 cases, 38.9%), followed by IPMN (23 cases, 31.9%), whereas high-grade PanIN lesions were found in 13 patients (18.1%). CONCLUSION High-risk individuals for pancreatic cancer, who are eventually operated may have a relatively uneventful postoperative course, however the oncological outcomes are comparable to the general population.
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Affiliation(s)
- George Bagias
- Third Department of Surgery, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - Prodromos Kanavidis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Michail Vailas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Markos Despotidis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Maria Sotiropoulou
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Ioannis Katsaros
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Ioannis Maroulis
- Department of Surgery, University of Patras Medical School, Patras, Greece
| | - Dimitrios Filippou
- Department of Anatomy and Surgical Anatomy, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
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Characterization of RARRES1 Expression on Circulating Tumor Cells as Unfavorable Prognostic Marker in Resected Pancreatic Ductal Adenocarcinoma Patients. Cancers (Basel) 2022; 14:cancers14184405. [PMID: 36139565 PMCID: PMC9497091 DOI: 10.3390/cancers14184405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/04/2022] [Accepted: 09/01/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Our explorative study used a microfluidic-based approach for circulating tumor cell (CTC) detection in 55 pancreatic ductal adenocarcinoma (PDAC) patients before treatment initiation (baseline) and during follow-up (FUP). For the first time, we assessed the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs. CTCs were detected in 25.5% of patients at baseline, while the detection rate during FUP was higher (45.5%). Especially high CTC counts during FUP in resected patients were associated with early tumor relapse (p = 0.02). Combining CTC detection and RARRES1 protein expression showed that RARRES1-positive patients with high CTCs counts after curative operation during FUP had a worse prognosis (p = 0.001). In conclusion, RARRES1 is a new marker of interest for further research investigations on subtypes of CTCs in PDAC. Abstract Background: In pancreatic ductal adenocarcinoma (PDAC), the characterization of circulating tumor cells (CTCs) opens new insights into cancer metastasis as the leading cause of cancer-related death. Here, we focused on the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs as a novel marker for treatment failure and early relapse. Methods: The stable isotope labeling of amino acids in cell culture (SILAC)—approach was applied for identifying and quantifying new biomarker proteins in PDAC cell lines HPDE and its chemoresistant counterpart, L3.6pl-Res. Fifty-five baseline and 36 follow-up (FUP) peripheral blood samples were processed via a marker-independent microfluidic-based CTC detection approach using RARRES1 as an additional marker. Results: SILAC-based proteomics identified RARRES1 as an abundantly expressed protein in more aggressive chemoresistant PDAC cells. At baseline, CTCs were detected in 25.5% of all PDAC patients, while FUP analysis (median: 11 months FUP) showed CTC detection in 45.5% of the resected patients. CTC positivity (≥3 CTC) at FUP was significantly associated with short recurrence-free survival (p = 0.002). Furthermore, detection of RARRES1 positive CTCs was indicative of an even earlier relapse after surgery (p = 0.001). Conclusions: CTC detection in resected PDAC patients during FUP is associated with a worse prognosis, and RARRES1 expression might identify an aggressive subtype of CTCs that deserves further investigation.
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Wang D, Li Y, Ge H, Ghadban T, Reeh M, Güngör C. The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC. Cancers (Basel) 2022; 14:cancers14163998. [PMID: 36010993 PMCID: PMC9406497 DOI: 10.3390/cancers14163998] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. In this review, we will discuss the effects of the ECM on tumor biological behavior and its molecular impact on the fundamental signaling pathways in PDAC. We will also provide an overview of how the different ECM components are able to modulate CSCs properties and finally discuss the current and ongoing therapeutic strategies targeting the ECM. Given the many challenges facing current targeted therapies for PDAC, a better understanding of molecular events involving the interplay of ECM and CSC will be key in identifying more effective therapeutic strategies to eliminate CSCs and ultimately to improve survival in patients that are suffering from this deadly disease.
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Li B, Feng Y, Hou Q, Fu Y, Luo Y. Antigen Peptide Transporter 1 (TAP1) Promotes Resistance to MEK Inhibitors in Pancreatic Cancers. Int J Mol Sci 2022; 23:7168. [PMID: 35806187 PMCID: PMC9266799 DOI: 10.3390/ijms23137168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/23/2022] [Accepted: 06/25/2022] [Indexed: 12/14/2022] Open
Abstract
Mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors show limited benefit in Kirsten rat sarcoma (KRAS) mutant pancreatic cancer due to drug resistance. To identify mechanisms of resistance to MEK inhibitor (MEKi), we employed a differential expression analysis of MEKi-sensitive versus MEKi-resistant KRAS-mutant pancreatic cancer cell lines. Here, we report that the antigen peptide transporter 1 (TAP1) expression levels of MEKi-resistant cell lines were notably higher than those of MEKi-sensitive cell lines. Suppression of TAP1 significantly sensitized the MEKi-resistant pancreatic ductal adenocarcinoma (PDAC) cells to MEKi and induced higher apoptotic rate in vitro. Moreover, knockdown of TAP1 in MEKi-resistant tumor significantly decreased tumor growth in vivo. Consistently, overexpression of TAP1 in sensitive PDAC cells resulted in increased resistance to MEKi, both in vitro and in vivo. Mechanistic studies demonstrated that TAP1 promoted chemoresistance by enhancing the transport of MEKi out of PDAC cells, leading to reduced intracellular MEKi concentration and attenuated inhibition of KRAS signaling pathways. Moreover, TAP1 expression increased spheroid formation abilities of PDAC cells. These findings suggest that TAP1 could serve as a potential marker for predicting the response of patients to MEKi. Combination of TAP1 suppression and MEKi may provide a novel therapeutic strategy for PDAC treatment.
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Affiliation(s)
- Boya Li
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; (B.L.); (Y.F.); (Q.H.)
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, Beijing 100084, China
| | - Yu Feng
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; (B.L.); (Y.F.); (Q.H.)
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, Beijing 100084, China
| | - Qiaoyun Hou
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; (B.L.); (Y.F.); (Q.H.)
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, Beijing 100084, China
| | - Yan Fu
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; (B.L.); (Y.F.); (Q.H.)
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, Beijing 100084, China
| | - Yongzhang Luo
- Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China; (B.L.); (Y.F.); (Q.H.)
- Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
- The National Engineering Research Center for Protein Technology, Tsinghua University, Beijing 100084, China
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Agarwal D, Covarrubias-Zambrano O, Bossmann SH, Natarajan B. Early Detection of Pancreatic Cancers Using Liquid Biopsies and Hierarchical Decision Structure. IEEE JOURNAL OF TRANSLATIONAL ENGINEERING IN HEALTH AND MEDICINE 2022; 10:4300208. [PMID: 35937463 PMCID: PMC9342860 DOI: 10.1109/jtehm.2022.3186836] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/30/2022] [Accepted: 06/23/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVE Pancreatic cancer (PC) is a silent killer, because its detection is difficult and to date no effective treatment has been developed. In the US, the current 5-year survival rate of 11%. Therefore, PC has to be detected as early as possible. METHODS AND PROCEDURES In this work, we have combined the use of ultrasensitive nanobiosensors for protease/arginase detection with information fusion based hierarchical decision structure to detect PC at the localized stage by means of a simple Liquid Biopsy. The problem of early-stage detection of pancreatic cancer is modelled as a multi-class classification problem. We propose a Hard Hierarchical Decision Structure (HDS) along with appropriate feature engineering steps to improve the performance of conventional multi-class classification approaches. Further, a Soft Hierarchical Decision Structure (SDS) is developed to additionally provide confidences of predicted labels in the form of class probability values. These frameworks overcome the limitations of existing research studies that employ simple biostatistical tools and do not effectively exploit the information provided by ultrasensitive protease/arginase analyses. RESULTS The experimental results demonstrate that an overall mean classification accuracy of around 92% is obtained using the proposed approach, as opposed to 75% with conventional multi-class classification approaches. This illustrates that the proposed HDS framework outperforms traditional classification techniques for early-stage PC detection. CONCLUSION Although this study is only based on 31 pancreatic cancer patients and a healthy control group of 48 human subjects, it has enabled combining Liquid Biopsies and Machine Learning methodologies to reach the goal of earliest PC detection. The provision of both decision labels (via HDS) as well as class probabilities (via SDS) helps clinicians identify instances where statistical model-based predictions lack confidence. This further aids in determining if more tests are required for better diagnosis. Such a strategy makes the output of our decision model more interpretable and can assist with the diagnostic procedure. CLINICAL IMPACT With further validation, the proposed framework can be employed as a decision support tool for the clinicians to help in detection of pancreatic cancer at early stages.
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Affiliation(s)
- Deepesh Agarwal
- Department of Electrical and Computer EngineeringKansas State UniversityManhattanKS66506USA
| | | | - Stefan H. Bossmann
- Department of Cancer BiologyThe University of Kansas Medical CenterKansas CityKS66160USA
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Kpeglo D, Hughes MD, Dougan L, Haddrick M, Knowles MA, Evans SD, Peyman SA. Modeling the mechanical stiffness of pancreatic ductal adenocarcinoma. Matrix Biol Plus 2022; 14:100109. [PMID: 35399702 PMCID: PMC8990173 DOI: 10.1016/j.mbplus.2022.100109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/28/2022] [Accepted: 03/15/2022] [Indexed: 01/18/2023] Open
Abstract
The PDAC stroma stiffness underlines its malignant behavior and drug resistance. 3D in vitro cultures must model the PDAC stroma to effectively drug efficacy. PSCs are responsible for the stroma, and its activity is increased with TGF-β. Develop a 3D culture model of PDAC, which includes PSCs and TGF-β. Assess the mechanical stiffness, stain for collagen, and investigate gemcitabine efficacy. Despite improvements in the understanding of disease biology, pancreatic ductal adenocarcinoma (PDAC) remains the most malignant cancer of the pancreas. PDAC constitutes ∼95% of all pancreatic cancers, and it is highly resistant to therapeutics. The increased tissue rigidity, which stems from the rich fibrotic stroma in the tumor microenvironment, is central to disease development, physiology, and resistance to drug perfusion. Pancreatic stellate cells (PSCs) are responsible for overproduction of extracellular matrix in the fibrotic stroma, and this is exacerbated by the overexpression of transforming growth factor-β (TGF-β). However, there are few in vitro PDAC models, which include both PSCs and TGF-β or mimic in vivo-like tumor stiffness. In this study, we present a three-dimensional in vitro PDAC model, which includes PSCs and TGF-β, and recapitulates PDAC tissue mechanical stiffness. Using oscillatory shear rheology, we show the mechanical stiffness of the model is within range of the PDAC tissue stiffness by day 21 of culture and highlight that the matrix environment is essential to adequately capture PDAC disease. PDAC is a complex, aggressive disease with poor prognosis, and biophysically relevant in vitro PDAC models, which take into account tissue mechanics, will provide improved tumor models for effective therapeutic assessment.
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Affiliation(s)
- Delanyo Kpeglo
- Molecular and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, LS2 9 JT, UK
| | - Matthew D.G. Hughes
- Molecular and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, LS2 9 JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, LS2 9JT, UK
| | - Lorna Dougan
- Molecular and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, LS2 9 JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, LS2 9JT, UK
| | - Malcolm Haddrick
- Medicines Discovery Catapult, Block 35, Mereside Alderley Park, Alderley Edge, SK10 4TG, UK
| | - Margaret A. Knowles
- Leeds Institute of Medical Research at St James’s (LIMR), School of Medicine, University of Leeds, LS2 9 JT, UK
| | - Stephen D. Evans
- Molecular and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, LS2 9 JT, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, LS2 9JT, UK
| | - Sally A. Peyman
- Molecular and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, LS2 9 JT, UK
- Leeds Institute of Medical Research at St James’s (LIMR), School of Medicine, University of Leeds, LS2 9 JT, UK
- Corresponding author at: Molecular and Nanoscale Physics Group, School of Physics and Astronomy, University of Leeds, LS2 9 JT, UK.
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Sun YT, Liu XR, Huang QF, Wang B, Weng YQ, Deng T, Li LH, Qian J, Li Q, Lin KW, Sun DM, Xu SQ, Wang HF, Wu XX. Midkine ameliorates LPS-induced apoptosis of airway smooth muscle cells via the Notch2 pathway. Asian Pac J Trop Biomed 2022. [DOI: 10.4103/2221-1691.363877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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12
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Li Y, Tian M, Zhou Y, Tan F, Liu W, Zhao L, Perez D, Song X, Wang D, Nitschke C, Pei Q, Güngör C. A novel risk-scoring system conducing to chemotherapy decision for patients with pancreatic ductal adenocarcinoma after pancreatectomy. J Cancer 2021; 12:4433-4442. [PMID: 34093844 PMCID: PMC8176415 DOI: 10.7150/jca.57768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 04/28/2021] [Indexed: 12/16/2022] Open
Abstract
Background: Chemotherapy is suggested to use in all stages of pancreatic cancer. Is it reasonable to recommend chemotherapy for all PDAC patients? It is necessary to distinguish low-risk PDAC patients underwent pancreatectomy, who may not lose survival time due to missed chemotherapy and not need to endure pain, nausea, tiredness, drowsiness, and breath shortness caused by chemotherapy. Methods: Nomograms were constructed with basis from the multivariate Cox regression analysis. X-tile software was utilized to perform risk stratification. Survival curves were used to display the effect of chemotherapy in different risk-stratification. Results: All of the significant variables were used to create the nomograms for overall survival (OS). The total risk score of each patient was calculated by summing the scores related to each variable. X-tile software was utilized to classify patients into high-risk (score >283), median-risk (197
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Affiliation(s)
- Yuqiang Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mengxiang Tian
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yuan Zhou
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Fengbo Tan
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Wenxue Liu
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China
- Department of Rheumatology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Lilan Zhao
- Department of Thoracic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Daniel Perez
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Xiangping Song
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Dan Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Nitschke
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Qian Pei
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Cenap Güngör
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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13
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Antibody therapy in pancreatic cancer: mAb-ye we're onto something? Biochim Biophys Acta Rev Cancer 2021; 1876:188557. [PMID: 33945846 DOI: 10.1016/j.bbcan.2021.188557] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/23/2021] [Accepted: 04/25/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer remains an extremely deadly disease, with little improvement seen in treatment or outcomes over the last 40 years. Targeted monoclonal antibody therapy is one area that has been explored in attempts to tackle this disease. This review examines antibodies that have undergone clinical evaluation in pancreatic cancer. These antibodies target a wide variety of molecules, including tumour cell surface, stromal, immune and embryonic pathway targets. We discuss the therapeutic utility of these therapies both as monotherapeutics and in combination with other treatments such as chemotherapy. While antibody therapy for pancreatic cancer has yet to yield significant success, lessons learned from research thus far highlights future directions that may help overcome observed hurdles to yield clinically efficacious results.
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14
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Abstract
OBJECTIVE In our study, we aim to evaluate in terms of patients the quality and reliability of the most relevant and most-watched videos uploaded on YouTube about pancreatic cancer. METHOD Before starting the study, YouTubeTM search terms were determined by consensus by two General Surgeons. Then, on 10/10/2020, the terms such as "pancreatic cancer", "diagnosis of pancreatic cancer" and "treatment of pancreatic cancer" were entered separately in the search bar of YouTube, "relevance" was selected among the filtering options and the most viewed videos were listed. The videos were evaluated with the Global Quality Scale (GQS), the DISCERN scoring system (Quality Criteria for Consumer Health Information, http://www.discern.org.uk), and video power index. RESULTS Among the 50 videos analysed, 19 videos were uploaded by hospital channels, 17 videos by health channels, seven videos by patients, four videos by blog channels, and three videos by doctors. The mean GQS score of the first researcher was 3.24 ± 0.99 and the mean GQS score of the second researcher was 3.18 ± 0.88 with a significantly high agreement between them (r= 0.628). The mean DISCERN score of the first researcher was 3.48 ± 0.77 and the mean DISCERN score of the second researcher was 3.46 ± 1.09 with a significantly high agreement between them (r= 0.814). CONCLUSION In our study, the majority of the videos were found to be of moderate quality. Healthcare professionals should be encouraged to upload more videos with useful content. However, we think that the uploaded videos should definitely go through a professional peer-review process before they are published.
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Affiliation(s)
- Guner Cakmak
- Department of General Surgery, Sakarya Training and Research Hospital, Sakarya, TUR
| | - Baris Mantoglu
- Department of General Surgery, Sakarya Training and Research Hospital, Sakarya, TUR
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15
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Albendazole suppresses cell proliferation and migration and induces apoptosis in human pancreatic cancer cells. Anticancer Drugs 2021; 31:431-439. [PMID: 32044795 DOI: 10.1097/cad.0000000000000914] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
This study aims to investigate the effects of albendazole on pancreatic cancer cells and to explore the possible mechanisms involved. MTT, colony formation, wound healing and Transwell assays and immunocytochemistry analyses of proliferation antigen Ki-67 were employed to evaluate the role of albendazole in pancreatic cancer cell line proliferation and migration. Moreover, flow cytometry cell apoptosis evaluation was used for mechanism analysis. Finally, the in-vivo effects of albendazole were examined in an in-vivo nude mouse xenograft model. Compared to the control treatment, albendazole significantly decreased the growth of the pancreatic cancer cell lines SW1990 and PANC-1 in a time- and dose-dependent manner, as evidenced by decreased MTT absorbance, colony number and Ki-67 levels. Furthermore, albendazole decreased cell migration in 2- and 3-dimensional models in a dose-dependent manner. In addition, albendazole increased the apoptotic cell ratio in a dose-dependent manner. Finally, the in-vivo results confirmed that albendazole could decrease tumor growth. We demonstrated the inhibitory effects of albendazole on pancreatic cell proliferation and migration in vitro and in vivo, which indicate that albendazole might serve as a novel treatment modality for pancreatic cancer.
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16
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Thakur G, Kumar R, Kim SB, Lee SY, Lee SL, Rho GJ. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines 2021; 9:biomedicines9020178. [PMID: 33670230 PMCID: PMC7916947 DOI: 10.3390/biomedicines9020178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine's action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.
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Affiliation(s)
- Gitika Thakur
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173 234, Himachal Pradesh, India;
| | - Saet-Byul Kim
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sang-Yeob Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
- Correspondence:
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17
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Safa AR. Epithelial-mesenchymal transition: a hallmark in pancreatic cancer stem cell migration, metastasis formation, and drug resistance. JOURNAL OF CANCER METASTASIS AND TREATMENT 2020; 6:36. [PMID: 34841087 PMCID: PMC8623975 DOI: 10.20517/2394-4722.2020.55] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Metastasis, tumor progression, and chemoresistance are the major causes of death in patients with pancreatic ductal adenocarcinoma (PDAC). Tumor dissemination is associated with the activation of an epithelial-to-mesenchymal transition (EMT) process, a program by which epithelial cells lose their cell polarity and cell-to-cell adhesion, and acquire migratory and invasive abilities to become mesenchymal stem cells (MSC). These MSCs are multipotent stromal cells capable of differentiating into various cell types and trigger the phenotypic transition from an epithelial to a mesenchymal state. Therefore, EMT promotes migration and survival during cancer metastasis and confers stemness features to particular subsets of cells. Furthermore, a major problem limiting our ability to treat PDAC is the existence of rare populations of pancreatic cancer stem cells (PCSCs) or cancer-initiating cells in pancreatic tumors. PCSCs may represent sub-populations of tumor cells resistant to therapy which are most crucial for driving invasive tumor growth. These cells are capable of regenerating the cellular heterogeneity associated with the primary tumor when xenografted into mice. Therefore, the presence of PCSCs has prognostic relevance and influences the therapeutic response of tumors. PCSCs express markers of cancer stem cells (CSCs) including CD24, CD133, CD44, and epithelial specific antigen as well as the drug transporter ABCG2 grow as spheroids in a defined growth medium. A major difficulty in studying tumor cell dissemination and metastasis has been the identification of markers that distinguish metastatic cancer cells from cells that are normally circulating in the bloodstream or at sites where these cells metastasize. Evidence highlights a linkage between CSC and EMT. In this review, The current understanding of the PCSCs, signaling pathways regulating these cells, PDAC heterogeneity, EMT mechanism, and links between EMT and metastasis in PCSCs are summarised. This information may provide potential therapeutic strategies to prevent EMT and trigger CSC growth inhibition and cell death.
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Affiliation(s)
- Ahmad R Safa
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
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18
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Zhou L, Yang H, Xie L, Sun J, Qian J, Zhu L. Comparison of Image-Guided Iodine-125 Seed Interstitial Brachytherapy and Local Chemotherapy Perfusion in Treatment of Advanced Pancreatic Cancer. J INVEST SURG 2020; 35:1-6. [PMID: 32865062 DOI: 10.1080/08941939.2020.1805057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE To compare the efficacy and safety of iodine-125 seed interstitial brachytherapy and local chemotherapy perfusion in treatment of advanced pancreatic cancer. METHODS The present open prospective randomized control study included a total of 165 cases of advanced pancreatic cancer patients who were admitted in our hospital during December 2016 to April 2019. All patients were randomized into two groups with 84 cases in iodine-125 group and 81 cases in chemotherapy perfusion group. Basic clinical characteristics and demographic data were collected. The main outcome was the tumor efficiency. The pain condition was measured by visual analogue scale (VAS) and the Karnofsky score was also measured at different time points, before the treatment, 1 d, 7 d, 14 d, 1 mon, 2 mon and 3 mon after treatment. Serum levels of CEA, CA19-9 and CA50 were measured by immunochemiluminescence. The overall survival was analyzed by K-M curve. RESULTS The ratio of partial remission patients was significantly higher, and the ratio of stable disease (SD)+progressive disease patients was also remarkably lower in iodine-125 group than the chemotherapy perfusion group. The mean VAS scores decreased markedly after treatment and were significantly lower and the mean Karnofsky scores were remarkably higher in iodine-125 group than the chemotherapy perfusion group. The levels of CA19-9 and CA50 were remarkably lower in iodine-125 group, however no significant difference was found for CEA. The survival analysis by K-M curve showed the iodine-125 patients had longer overall survival time than the chemotherapy perfusion group. No infection, pancreatic fistula, biliary fistula, intestinal fistula, gastrointestinal obstruction or radiation enteritis was found in both groups. CONCLUSION Iodine-125 seed interstitial brachytherapy could achieve better efficacy with no increased side complications than chemotherapy perfusion in advanced pancreatic cancer.
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Affiliation(s)
- Li Zhou
- Department of Oncology, Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Hui Yang
- Department of Oncology, Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Linjun Xie
- Department of Pharmacy, Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jiantong Sun
- Department of Pharmacy, Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jun Qian
- Department of Oncology, Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Lifei Zhu
- Department of Pathology, Suzhou Hospital of Nanjing Medical University, Suzhou, China
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19
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Li Y, Liu W, Zhao L, Xu Y, Yan T, Yang Q, Pei Q, Güngör C. The Main Bottleneck for Non-Metastatic Pancreatic Adenocarcinoma in Past Decades: A Population-Based Analysis. Med Sci Monit 2020; 26:e921515. [PMID: 32358953 PMCID: PMC7212811 DOI: 10.12659/msm.921515] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/03/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Despite recent advancements in surgical techniques, chemotherapy, and radiotherapy, the 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) remains an unsatisfactory ~8%. MATERIAL AND METHODS Data were extracted to identify patients with non-metastatic pancreatic adenocarcinoma diagnosed in the periods 1988-1996 and 2010-2014 in the Surveillance, Epidemiology, and End Results (SEER) database. The statistical analyses were performed with the log-rank test, Pearson's chi-square test, propensity score matching, and Cox regression model. RESULTS The hazard ratio (HR) of surgery was reduced from 0.454 to 0.302 in Cox regression modeling, and there was no overlapping about the 95% confidence intervals (CI) of surgery between the 2 periods. The HR values of radiotherapy, which were new prognostic factor for resectable PDAC in 2010-2014, were reduced in both the resectable and unresectable groups. The upgraded chemotherapy regimen reduced the HR values from 0.738 to 0.689 in all PADC patients, and from 0.656 to 0.588 in unresectable PDAC. The log-rank test results showed that advances in surgery significantly improved the median survival from 13 months to 32 months. Radiotherapeutic and chemotherapeutic advancements extended median survival by 12 months and 11 months, respectively, in resectable PDAC. The median survivals were extended by 3 months for both of radiotherapy and chemotherapy in unresectable PDAC. CONCLUSIONS The development of chemotherapy and radiotherapy has been slow, especially for unresectable PDAC. Although advances in surgery contributed significantly to improved survival for resectable PDAC, lack of early diagnostic tools, which lead to low resection rates, remain a barrier for all PDAC patients.
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Affiliation(s)
- Yuqiang Li
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Wenxue Liu
- Department of Rheumatology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
| | - Lilan Zhao
- Department of Thoracic Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, P.R. China
| | - Yang Xu
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tingyu Yan
- Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Qionghui Yang
- Department of Pediatrics, Yueqing Third People’s Hospital, Yueqing, Zhejiang, P.R. China
| | - Qian Pei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - Cenap Güngör
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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20
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Zhang W, He R, Chen S, Zhang L, Cao G, Yang W, Li J. The JAM-B/c-src/MMP9 pathway is associated with progression and regulates the invasion of pancreatic cancer. J Cancer 2020; 11:3246-3255. [PMID: 32231730 PMCID: PMC7097935 DOI: 10.7150/jca.40953] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 02/10/2020] [Indexed: 12/21/2022] Open
Abstract
Junctional adhesion molecule B (JAM-B) is a multifunctional transmembrane protein that plays an important role in tumor progression. JAM-B is significantly upregulated in gastric cancer, melanoma cell metastasis and oral squamous cell carcinoma. JAM-2 may also function as a putative tumor suppressor in the progression and metastasis of colorectal cancer. The inconsistency of the results in different cancers has led to uncertainty regarding the role of JAM-B in carcinogenesis. For this purpose, the expression levels of JAM-B in pancreatic cancer (PanCa) tissues were associated with T stage and lymph node involvement with significant differences. A relatively high expression of JAM-B was found in PanCa cell lines by immunohistochemistry and western blot analysis. By cell transfection, JAM-B was silenced in tumor cell lines to determine cell invasion and migration abilities. Scratch wound assays and Transwell assays revealed that shJAM-B significantly decreased Panc-1 cell migration and invasion. Experiments were also conducted using a subcutaneous PanCa nude mouse model. A significant difference in tumor diameter at the injection site was found between the control group and the JAM-B low expression group. The expression levels of c-Src and MMP9 were also significantly reduced compared to that in the control group by immunohistochemistry. In conclusion, our results suggest that JAM-B secreted by cancer cells can promote progression and invasion in PanCa by upregulating the c-Src signal and related downstream proteins.
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Affiliation(s)
- Wunai Zhang
- Department of General Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5 th Road, Xi'an, 710004, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Rui He
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West 5 th Road, Xi'an, 710004, China
| | - Shuo Chen
- Department of General Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5 th Road, Xi'an, 710004, China
| | - Li Zhang
- Department of General Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5 th Road, Xi'an, 710004, China
| | - Gang Cao
- Department of General Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5 th Road, Xi'an, 710004, China
| | - Wenbin Yang
- Department of General Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5 th Road, Xi'an, 710004, China
| | - Junhui Li
- Department of General Surgery, Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5 th Road, Xi'an, 710004, China
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21
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Filippou PS, Karagiannis GS, Constantinidou A. Midkine (MDK) growth factor: a key player in cancer progression and a promising therapeutic target. Oncogene 2020; 39:2040-2054. [PMID: 31801970 DOI: 10.1038/s41388-019-1124-8] [Citation(s) in RCA: 156] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 11/15/2019] [Accepted: 11/19/2019] [Indexed: 12/22/2022]
Abstract
Midkine is a heparin-binding growth factor, originally reported as the product of a retinoic acid-responsive gene during embryogenesis, but currently viewed as a multifaceted factor contributing to both normal tissue homeostasis and disease development. Midkine is abnormally expressed at high levels in various human malignancies and acts as a mediator for the acquisition of critical hallmarks of cancer, including cell growth, survival, metastasis, migration, and angiogenesis. Several studies have investigated the role of midkine as a cancer biomarker for the detection, prognosis, and management of cancer, as well as for monitoring the response to cancer treatment. Moreover, several efforts are also being made to elucidate its underlying mechanisms in therapeutic resistance and immunomodulation within the tumor microenvironment. We hereby summarize the current knowledge on midkine expression and function in cancer development and progression, and highlight its promising potential as a cancer biomarker and as a future therapeutic target in personalized cancer medicine.
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Affiliation(s)
- Panagiota S Filippou
- School of Health & Life Sciences, Teesside University, Middlesbrough, TS1 3BX, UK.
- National Horizons Centre, Teesside University, 38 John Dixon Ln, Darlington, DL1 1HG, UK.
| | - George S Karagiannis
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY, USA
- Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Anastasia Constantinidou
- Medical School, University of Cyprus, Nicosia, Cyprus
- Bank of Cyprus Oncology Centre, Nicosia, Cyprus
- Cyprus Cancer Research Institute, Nicosia, Cyprus
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22
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Masoudi M, Seki M, Yazdanparast R, Yachie N, Aburatani H. A genome-scale CRISPR/Cas9 knockout screening reveals SH3D21 as a sensitizer for gemcitabine. Sci Rep 2019; 9:19188. [PMID: 31844142 PMCID: PMC6915784 DOI: 10.1038/s41598-019-55893-2] [Citation(s) in RCA: 6] [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: 01/23/2019] [Accepted: 12/03/2019] [Indexed: 11/17/2022] Open
Abstract
Gemcitabine, 2',2'-difluoro-2'-deoxycytidine, is used as a pro-drug in treatment of variety of solid tumour cancers including pancreatic cancer. After intake, gemcitabine is transferred to the cells by the membrane nucleoside transporter proteins. Once inside the cells, it is converted to gemcitabine triphosphate followed by incorporation into DNA chains where it causes inhibition of DNA replication and thereby cell cycle arrest and apoptosis. Currently gemcitabine is the standard drug for treatment of pancreatic cancer and despite its widespread use its effect is moderate. In this study, we performed a genome-scale CRISPR/Cas9 knockout screening on pancreatic cancer cell line Panc1 to explore the genes that are important for gemcitabine efficacy. We found SH3D21 as a novel gemcitabine sensitizer implying it may act as a therapeutic target for improvement of gemcitabine efficacy in treatment of pancreatic cancer.
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Affiliation(s)
- Mohammad Masoudi
- Molecular Biology Department, Graduate School of Medicine, The University of Tokyo, Tokyo, 153-8904, Japan
- Genome Science Division, Research Center for Advance Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
- Synthetic Biology Division, Research Center for Advance Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
- Molecular Biology Laboratory, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, 13145-1384, Iran
| | - Motoaki Seki
- Synthetic Biology Division, Research Center for Advance Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
| | - Razieh Yazdanparast
- Molecular Biology Laboratory, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, 13145-1384, Iran.
| | - Nozomu Yachie
- Synthetic Biology Division, Research Center for Advance Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan
| | - Hiroyuki Aburatani
- Molecular Biology Department, Graduate School of Medicine, The University of Tokyo, Tokyo, 153-8904, Japan.
- Genome Science Division, Research Center for Advance Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan.
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23
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Petrusel L, Rusu I, Leucuta DC, Seicean R, Suharoschi R, Zamfir P, Seicean A. Relationship between cachexia and perineural invasion in pancreatic adenocarcinoma. World J Gastrointest Oncol 2019; 11:1126-1140. [PMID: 31908718 PMCID: PMC6937437 DOI: 10.4251/wjgo.v11.i12.1126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 09/09/2019] [Accepted: 10/14/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cachexia is responsible for the low quality of life in pancreatic adenocarcinoma (PDAC). The rapid disease progression and patient deterioration seems related to perineural invasion, but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied. As perineural invasion is difficult to be highlighted, a biomarker such as the neurotrophic factor Midkine (MK) which promotes the neuronal differentiation and the cell migration could be helpful. Also, Activin (ACV) has been described as cachexia related to PDAC. However, their role for assessing and predicting the disease course in daily practice is not known. AIM To assess the relationship between perineural invasion and cachexia and their biomarkers, MK and ACV, respectively, and their prognostic value. METHODS This study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies. Patients with other causes of malnutrition were excluded. The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data. These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease. RESULTS The study comprised 114 patients with PDAC, 125 controls and a supplementary group of 14 benign pancreatic tissue samples. ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls (63% vs 32% for ACV, P < 0.001; 47% vs 16% for MK, P < 0.001), with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage (P = 0.006), the presence of metastasis (P = 0.04), perineural invasion (P = 0.03) and diabetes (P = 0.002), but with no influence on survival. No correlation between clinicopathological factors and ACV expression was noted. Cachexia, present in 19% of patients, was unrelated to ACV or MK level. Higher ACV expression was associated with a shorter survival (P = 0.008). CONCLUSION The MK was a biomarker of perineural invasion, associated with tumor stage and diabetes, but without prognostic value as ACV. Cachexia was unrelated to perineural invasion, ACV level or survival.
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Affiliation(s)
- Livia Petrusel
- Department of Gastroenterology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400162, Romania
| | - Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400162, Romania
| | - Daniel Corneliu Leucuta
- Medical Informatics and Biostatistics Department, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400012, Romania
| | - Radu Seicean
- First Surgery Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400006, Romania
| | - Ramona Suharoschi
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Cluj-Napoca 400372, Romania
| | - Paula Zamfir
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca 400162, Romania
| | - Andrada Seicean
- Department of Gastroenterology, Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400162, Romania
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Choi EA, Choi YS, Lee EJ, Singh SR, Kim SC, Chang S. A pharmacogenomic analysis using L1000CDS 2 identifies BX-795 as a potential anticancer drug for primary pancreatic ductal adenocarcinoma cells. Cancer Lett 2019; 465:82-93. [PMID: 31404615 DOI: 10.1016/j.canlet.2019.08.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 08/07/2019] [Accepted: 08/07/2019] [Indexed: 01/18/2023]
Abstract
Pancreatic cancer is one of the leading causes of cancer death, mainly due to the absence of early diagnostic tool and effective therapeutic agents. To identify an effective therapeutic agent for pancreatic ductal adenocarcinoma cells (PDAC), we used 10 Gene Expression Omnibus (GEO) data sets and L1000CDS2 pharmacogenetic search tool and obtained chemical "perturvants" that were predicted to reverse the abnormal gene expression changes in PDAC. Among 20 initial candidates, we measured IC50 for six compounds and identified BX-795, PDK1/TBK1 inhibitor, as a therapeutic candidate. We found that BX-795 inhibits primary PDAC cell proliferation more effectively than normal cells. Following molecular analysis revealed that BX-795 down-regulates mTOR-GSK3β pathway and trigger apoptosis. Moreover, we found that BX-795 suppresses primary PDAC cell migration via downregulation of Snail and Slug. Finally, efficacy test in patient-derived xenograft model of PDAC showed BX-795 can inhibit in vivo tumor growth as efficient as gemcitabine and a combination with trametinib further suppresses tumor growth. Collectively, these results demonstrate the BX-795 as an effective therapeutic candidate for PDAC treatment.
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Affiliation(s)
- Eun A Choi
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea
| | - Yeon-Sook Choi
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea
| | - Eun Ji Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea
| | - Shree Ram Singh
- Basic Research Laboratory, National Cancer Institute, Frederick, MD, 21702, USA.
| | - Song Cheol Kim
- Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.
| | - Suhwan Chang
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea; Department of Physiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.
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25
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Targeting acquired oncogenic burden in resilient pancreatic cancer: a novel benefit from marine polyphenols. Mol Cell Biochem 2019; 460:175-193. [PMID: 31367889 DOI: 10.1007/s11010-019-03579-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 06/21/2019] [Indexed: 02/07/2023]
Abstract
The upsurge of marine-derived therapeutics for cancer treatment is evident, with many drugs in clinical use and in clinical trials. Seaweeds harbor large amounts of polyphenols and their anti-cancer benefit is linear to their anti-oxidant activity. Our studies identified three superlative anti-cancer seaweed polyphenol drug candidates (SW-PD). We investigated the acquisition of oncogenic burden in radiation-resilient pancreatic cancer (PC) that could drive tumor relapse, and elucidated the efficacy of SW-PD candidates as adjuvants in genetically diverse in vitro systems and a mouse model of radiation-residual disease. QPCR profiling of 88 oncogenes in therapy-resilient PC cells identified a 'shared' activation of 40 oncogenes. SW-PD pretreatment inflicted a significant mitigation of acquired (shared) oncogenic burden, in addition to drug- and cell-line-specific repression signatures. Tissue microarray with IHC of radiation-residual tumors in mice signified acquired cellular localization of key oncoproteins and other critical architects. Conversely, SW-PD treatment inhibited the acquisition of these critical drivers of tumor genesis, dissemination, and evolution. Heightened death of resilient PC cells with SW-PD treatment validated the translation aspects. The results defined the acquisition of oncogenic burden in resilient PC and demonstrated that the marine polyphenols effectively target the acquired oncogenic burden and could serve as adjuvant(s) for PC treatment.
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26
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Konczalla L, Perez DR, Wenzel N, Wolters-Eisfeld G, Klemp C, Lüddeke J, Wolski A, Landschulze D, Meier C, Buchholz A, Yao D, Hofmann BT, Graß JK, Spriestersbach SL, Grupp K, Schumacher U, Betzel C, Kapis S, Nuguid T, Steinberg P, Püschel K, Sauter G, Bockhorn M, Uzunoglu FG, Izbicki JR, Güngör C, El Gammal AT. Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer. Int J Cancer 2019; 146:1618-1630. [PMID: 31291468 DOI: 10.1002/ijc.32567] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 05/31/2019] [Accepted: 06/21/2019] [Indexed: 12/14/2022]
Abstract
MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.
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Affiliation(s)
- Leonie Konczalla
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel R Perez
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nadine Wenzel
- Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Gerrit Wolters-Eisfeld
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Clarissa Klemp
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johanna Lüddeke
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Annika Wolski
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dirk Landschulze
- Institute of Organic Chemistry, University of Hamburg, Hamburg, Germany
| | - Chris Meier
- Institute of Organic Chemistry, University of Hamburg, Hamburg, Germany
| | - Anika Buchholz
- Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dichao Yao
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bianca T Hofmann
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julia K Graß
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah L Spriestersbach
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katharina Grupp
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Udo Schumacher
- Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Betzel
- Laboratory for Structural Biology of Infection and Inflammation, Department of Chemistry, c/o DESY, University of Hamburg, Hamburg, Germany
| | - Svetlana Kapis
- Laboratory for Structural Biology of Infection and Inflammation, Department of Chemistry, c/o DESY, University of Hamburg, Hamburg, Germany
| | - Theresa Nuguid
- Laboratory for Structural Biology of Infection and Inflammation, Department of Chemistry, c/o DESY, University of Hamburg, Hamburg, Germany
| | - Pablo Steinberg
- Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Klaus Püschel
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maximillian Bockhorn
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Faik G Uzunoglu
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R Izbicki
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cenap Güngör
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexander T El Gammal
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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27
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Benzel J, Fendrich V. Familial Pancreatic Cancer. Oncol Res Treat 2018; 41:611-618. [PMID: 30269130 DOI: 10.1159/000493473] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/04/2018] [Indexed: 12/13/2022]
Abstract
Familial pancreatic cancer accounts for 10% of all patients with pancreatic cancer. Because the 5-year survival rate of pancreatic cancer is only 7%, screening programs for high-risk individuals are essential and might be advantageous. Pancreatic ductal adenocarcinoma mostly shows symptoms at an advanced state and treatment is not efficient enough to cure most patients. People with hereditary tumor syndromes or their affected relatives can also be included in such screening programs. Besides the collection of data to investigate the background of the disease, these screening programs aim to diagnose and treat precursor lesions so that more dangerous, invasive lesions are prevented. These precursor lesions can be pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. This review summarizes the latest knowledge of pancreatic screening programs, shows the procedure of pancreatic cancer screening, and gives an overview of current guidelines.
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28
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Moriya C, Imai K, Taniguchi H. PRDM14 is overexpressed in chronic pancreatitis prior to pancreatic cancer. FEBS Open Bio 2018; 8:1733-1741. [PMID: 30338223 PMCID: PMC6168686 DOI: 10.1002/2211-5463.12519] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 04/14/2018] [Accepted: 08/23/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer that is typically diagnosed at a later stage with metastases and is difficult to treat. Therefore, investigating the mechanism of PDAC initiation is important to aid early‐stage cancer detection. PRDM14 is a transcription factor that maintains pluripotency in embryonic stem cells and is overexpressed in several cancers. We previously reported that PRDM14 is overexpressed and regulates cancer stem‐like phenotypes in PDAC, and herein, we assess whether PRDM14 expression increases prior to tumorigenesis. Through immunohistochemistry analyses of clinical tissues, we detected PRDM14‐positive cells in precursor pancreatic intraepithelial neoplasia and chronic pancreatitis, which is a risk factor for PDAC, lesions. PRDM14 staining in chronic pancreatitis was as high as that in PDAC and cancer adjacent tissues. We induced pancreatitis in mouse models by cerulein injection, and observed that PRDM14 expression increased in chronic pancreatitis models but not in control or acute pancreatitis mice. Moreover, cerulein treatment increased PRDM14 expression in PK‐1 and AsPC‐1 pancreatic cancer cell lines. Our results suggest that inflammation increases the expression of PRDM14, which regulates cancer stem‐like phenotypes, and this occurs prior to PDAC initiation and progression.
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Affiliation(s)
- Chiharu Moriya
- Center for Antibody and Vaccine Therapy Research Hospital Institute of Medical Science The University of Tokyo Japan
| | - Kohzoh Imai
- Research Hospital Institute of Medical Science The University of Tokyo Japan
| | - Hiroaki Taniguchi
- Center for Antibody and Vaccine Therapy Research Hospital Institute of Medical Science The University of Tokyo Japan
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29
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Abstract
Pancreatic cancer is the fifth most common cause of cancer death in the UK. This disease often remains undiagnosed until it is at a late stage, resulting in the majority of tumours being unsuitable for surgical resection. When a diagnosis of pancreatic cancer is confirmed, early input from the multi-disciplinary team (MDT) is vital. Due to the poor prognosis, the screening and treatment of pancreatic cancer remains a considerable challenge for medicine in the 21st century.
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Affiliation(s)
- Karen Gedge
- Main Theatres, West Suffolk Hospital NHS Foundation Trust, UK
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30
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Does Second Reader Opinion Affect Patient Management in Pancreatic Ductal Adenocarcinoma? Acad Radiol 2018; 25:825-832. [PMID: 29373213 DOI: 10.1016/j.acra.2017.12.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 12/11/2017] [Accepted: 12/13/2017] [Indexed: 02/07/2023]
Abstract
RATIONALE AND OBJECTIVES To determine the impact of second-opinion assessment on cancer staging and patient management in patients with pancreatic ductal adenocarcinoma. METHODS AND MATERIALS This retrospective study was approved by our institutional review board with a waiver of informed consent. Second-opinion reports between January 1, 2009 and December 31, 2013, alongside outside reports for 65 consecutive cases of biopsy-proven pancreatic adenocarcinomas, were presented in random order to two experienced abdominal surgeons who independently reviewed them blinded to the origin of the report, images of the examinations, and patient identifier. Each surgeon filled in a questionnaire for each report recommending cancer staging and patient management. Recommended patient management and staging were evaluated against reference standards (actual patient management at 6 months following second-opinion assessment, and pathology or other clinical and imaging reference standards at 6 months or longer, respectively) using Cohen kappa. RESULTS Cancer staging differed in 13% (9 of 65) of cases for surgeon 1 and in 18.4% (12 of 65) for surgeon 2. Patient management changed in 38.4% (25 of 65) of cases for surgeon 1 and in 20% (13 of 65) for surgeon 2. When compared to the pathologic staging gold standard, second opinion was correct in 85.7% (six of seven) of the time for both surgeons. Recommended patient management from second-opinion reports showed good agreement with the reference standard (weighted k = 0.6467 [0.4014-0.892] and weighted k = 0.6262 [0.3954-0.857] for surgeon 2). CONCLUSION Second-opinion review by subspecialized oncologic radiologists can impact patient care, specifically in terms of management decision.
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Han L, Jiang J, Ma Q, Wu Z, Wang Z. The inhibition of heme oxygenase-1 enhances the chemosensitivity and suppresses the proliferation of pancreatic cancer cells through the SHH signaling pathway. Int J Oncol 2018; 52:2101-2109. [PMID: 29620188 DOI: 10.3892/ijo.2018.4363] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 02/05/2018] [Indexed: 11/05/2022] Open
Abstract
Pancreatic cancer (PC) is a type of cancer associated with a high fatality rate due to a poor prognosis and resistance to treatment. Heme oxygenase-1 (HO-1) is significantly overexpressed in a number of types of cancer and seems to play an important role in cancer progression. In this study, we examined the potential effects of HO-1 on PC cell proliferation and sensivity to gemcitabine (Gem). Furthermore, the role of the sonic hedgehog (SHH) signaling pathway in the regulatory effects of HO-1 on PC progression were examined. For this purpose, the expression of HO-1 was examined in cultured PC cells by real-time PCR, western blot analysis and immunofluorescence. Transfection with small interfering RNA against HO-1 or an overexpression plasmid were used to regulate the expression of HO-1 in the MIA PaCa-2 and PANC-1 cell lines. Cell proliferation was examined by MTT assays in response to the different treatments. The results revealed that HO-1 expression differed significantly in the different PC cells. The overexpression of HO-1 induced PC cell proliferation and the inhibition of HO-1 decreased the cell proliferative ability. Furthermore, HO-1 activated the SHH signaling pathway in the PC cells. In addition, the SHH signaling pathway was found to play a role in HO-1-induced PC cell proliferation. The inhibition of HO-1 enhanced the responsiveness of PC cells to Gem and Gem was found to regulate the expression of HO-1 and the activation of the SHH pathway. On the whole, our findings indicate that HO-1 overexpression in PC cells may be responsible for the increased cell proliferation and the resistance to anticancer therapy. Furthermore, the SHH signaling pathway, the activation of which was initiated by HO-1, may be one of the endogenous mechanisms in this process. Our data shed light into the association between HO-1 and SHH in PC cells, and may aid in the development of novel therapeutic targets for the treatment of patients with PC.
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Affiliation(s)
- Liang Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jie Jiang
- Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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32
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Zhang L, Song X, Shao Y, Wu C, Jiang J. Prognostic value of Midkine expression in patients with solid tumors: a systematic review and meta-analysis. Oncotarget 2018; 9:24821-24829. [PMID: 29872508 PMCID: PMC5973861 DOI: 10.18632/oncotarget.23892] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/13/2017] [Indexed: 12/23/2022] Open
Abstract
Background Accumulated studies have shown the important role of Midkine (MDK) protein in various solid tumors and indicated its correlation with patients' survival. This meta-analysis was performed to further explore the prognostic value of MDK expression in solid tumors. Materials and Methods We collected the literatures through searching PubMed, Embase and the Cochrane Library (last up to April 10, 2017) to assess the effect of MDK on survival in solid tumor patients. The STATA 12.0 software was used for the meta-analysis. Fixed-effects models or random-effects models were used to estimate the pooled hazard ratios (HRs) for overall survival (OS). Results A total of 2097 patients from 17 observational studies were summarized. High expression of MDK was notably associated with worse OS in solid tumor patients. (pooled HR = 1.96; 95% CI = 1.67-2.31). The subgroup analysis of tumor type demonstrated negative impact of elevated MDK on OS in most solid tumor patients (P < 0.05), while MDK had no relevance with OS in the patients with OSCC (pooled HR = 1.68; 95% CI = 0.84-3.36; P = 0.145) or HNSCC (pooled HR = 1.56; 95% CI = 0.96-2.51; P = 0.075). Conclusions The present meta-analysis clarifies that MDK is a potential prognostic biomarker in solid tumor patients. Future large-scale prospective clinical trials are needed to determine the prognostic value of MDK in solid tumor patients.
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Affiliation(s)
- Luo Zhang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Xing Song
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Yingjie Shao
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Changping Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China
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Widder M, Lemke K, Kekeç B, Förster T, Grodrian A, Gastrock G. A modified 384-well-device for versatile use in 3D cancer cell (co-)cultivation and screening for investigations of tumor biology in vitro. Eng Life Sci 2017; 18:132-139. [PMID: 29610566 PMCID: PMC5873453 DOI: 10.1002/elsc.201700008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 06/28/2017] [Accepted: 10/10/2017] [Indexed: 01/12/2023] Open
Abstract
Pancreatic cancer exhibits a worst prognosis owed to an aggressive tumor progression i.a. driven by chemoresistance or tumor‐stroma‐interactions. The identification of candidate genes, which promote this progression, can lead to new therapeutic targets and might improve patient's outcome. The identification of these candidates in a plethora of genes requires suitable screening protocols. The aim of the present study was to establish a universally usable device which ensures versatile cultivation, screening and handling protocols of cancer cells with the 3D spheroid model, an approved model to study tumor biology. By surface modification and alternative handling of a commercial 384‐well plate, a modified device enabling (i) 3D cultivation either by liquid overlay or by a modified hanging drop method for (ii) screening of substances as well as for tumor‐stroma‐interactions (iii) either with manual or automated handling was established. The here presented preliminary results of cell line dependent dose‐response‐relations and a stromal‐induced spheroid‐formation of the pancreatic cancer cells demonstrate the proof‐of‐principle of the versatile functionality of this device. By adapting the protocols to automation, a higher reproducibility and the ability for high‐throughput analyses were ensured.
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Affiliation(s)
- Miriam Widder
- Department of Bioprocess Engineering Institute for Bioprocessing and Analytical Measurement Techniques e.V. Rosenhof Heilbad Heiligenstadt Germany
| | - Karen Lemke
- Department of Bioprocess Engineering Institute for Bioprocessing and Analytical Measurement Techniques e.V. Rosenhof Heilbad Heiligenstadt Germany
| | - Bünyamin Kekeç
- Department of Bioprocess Engineering Institute for Bioprocessing and Analytical Measurement Techniques e.V. Rosenhof Heilbad Heiligenstadt Germany
| | - Tobias Förster
- Department of Bioprocess Engineering Institute for Bioprocessing and Analytical Measurement Techniques e.V. Rosenhof Heilbad Heiligenstadt Germany
| | - Andreas Grodrian
- Department of Bioprocess Engineering Institute for Bioprocessing and Analytical Measurement Techniques e.V. Rosenhof Heilbad Heiligenstadt Germany
| | - Gunter Gastrock
- Department of Bioprocess Engineering Institute for Bioprocessing and Analytical Measurement Techniques e.V. Rosenhof Heilbad Heiligenstadt Germany
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Moriya C, Taniguchi H, Miyata K, Nishiyama N, Kataoka K, Imai K. Inhibition of PRDM14 expression in pancreatic cancer suppresses cancer stem-like properties and liver metastasis in mice. Carcinogenesis 2017; 38:638-648. [PMID: 28498896 DOI: 10.1093/carcin/bgx040] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 05/04/2017] [Indexed: 01/04/2023] Open
Abstract
Pancreatic cancer is one of the most lethal types of cancer, with aggressive properties characterized by metastasis, recurrence and drug resistance. Cancer stem cells are considered to be responsible for these properties. PRDM14, a transcriptional regulator that maintains pluripotency in embryonic stem cells, is overexpressed in some cancers. Here, we assessed PRDM14 expression and the effects of PRDM14 knockdown on cancer stem-like phenotypes in pancreatic cancer. We observed that PRDM14 protein was overexpressed in pancreatic cancer tissues compared with normal pancreatic tissues. Using lentiviral shRNA-transduced pancreatic cancer cells, we found that PRDM14 knockdown decreased sphere formation, number of side population and cell surface marker-positive cells and subcutaneous xenograft tumors and liver metastasis in mice. This was accompanied by upregulation of some microRNAs (miRNAs), including miR-125a-3p. miR-125a-3p, a tumor suppressor that is down-regulated in pancreatic cancer, has been suggested to regulate the expression of the Src-family kinase, Fyn. In PRDM14-knockdown cells, Fyn was expressed at lower levels and downstream proteins were less activated. These changes were considered to cause suppression of the above cancer phenotypes. In addition, we used small interfering RNA (siRNA)-based therapy targeting PRDM14 in a mouse model of liver metastasis induced using MIA-PaCa2 cells, and this treatment significantly decreased metastasis and in vitro migration. Taken together, these results suggest that targeting the overexpression of PRDM14 suppresses cancer stem-like phenotypes, including liver metastasis, via miRNA regulation and siRNA-based therapy targeting it shows promise as a treatment for patients with pancreatic cancer.
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Affiliation(s)
| | | | - Kanjiro Miyata
- Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
| | - Nobuhiro Nishiyama
- Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, Yokohama 226-8503, Japan and
| | - Kazunori Kataoka
- Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan
| | - Kohzoh Imai
- Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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Gemcitabine treatment induces endoplasmic reticular (ER) stress and subsequently upregulates urokinase plasminogen activator (uPA) to block mitochondrial-dependent apoptosis in Panc-1 cancer stem-like cells (CSCs). PLoS One 2017; 12:e0184110. [PMID: 28854261 PMCID: PMC5576696 DOI: 10.1371/journal.pone.0184110] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Accepted: 08/17/2017] [Indexed: 02/05/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates. The presence of cancer stem-like cells (CSCs) is believed to be among the underlying reasons for the aggressiveness of PDAC, which contributes to chemoresistance and recurrence. However, the mechanisms that induce chemoresistance and inhibit apoptosis remain largely unknown. Methods We used serum-free medium to enrich CSCs from panc-1 human pancreatic cancer cells and performed sphere formation testing, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and semi-quantitative western blotting to confirm the stemness of panc-1 CSCs. Hallmarks of endoplasmic reticulum (ER) stress, including IRE1, PERK, ATF4, ATF6α, GRP78 and uPA expression, were detected after gemcitabine treatment. Effects of gemcitabine-induced uPA expression on cell invasion, sphere formation, colony formation and gemcitabine sensitivity were detected. Electrophoretic mobility shift assays (EMSAs) and RNA-immunoprecipitation (RIP) were performed to detect interaction between the uPA mRNA 3’-UTR and mutant p53-R273H expressed by panc-1 CSCs. The effects of upregulated uPA by gemcitabine on apoptosis were detected by Annexin V-FITC/PI staining, and the impact of uPA on small molecule CP-31398-restored mutant p53 transcriptional activity was measured by a luciferase reporter assay. Results Enriched panc-1 CSCs expressing high levels of CD44 and CD133 also produced significantly higher amounts of Oct4 and Nanog. Compared with panc-1 cells, panc-1 CSCs presented chemoresistance to gemcitabine. ER stress gene detections demonstrated effects of gemcitabine-induced ER stress on both the pro-apoptotic and pro-survival branches. ER stress-induced ATF6α upregulated level of uPA by transcriptionally activating GRP78. Gemcitabine-induced uPA promoted invasion, sphere formation and colony formation and attenuated apoptosis induced by gemcitabine in panc-1 CSCs, depending on interaction with mutant p53-R273H. Upregulation of uPA abolished CP-31398-mediated restoration of mutant p53 transcriptional activity in panc-1 CSCs. Conclusion Gemcitabine treatment induced ER stress and promoted mutant p53-R273H stabilization via transcriptionally activated uPA which may contribute to chemoresistance to gemcitabine. Notably, upregulation of uPA by gemcitabine treatment may lead to the failure of CP-31398; thus, a novel strategy for modulating mutant p53 function needs to be developed.
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Aynacıoğlu AŞ, Bilir A, Kadomatsu K. Dual inhibition of P-glycoprotein and midkine may increase therapeutic effects of anticancer drugs. Med Hypotheses 2017; 107:26-28. [PMID: 28915956 DOI: 10.1016/j.mehy.2017.07.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 07/15/2017] [Indexed: 02/06/2023]
Abstract
Multidrug resistance (MDR) to chemotherapy may significantly affect the outcome of cancer treatment. ATP-dependent drug efflux pumps, including P-glycoprotein (P-gp), contribute to the resistance of various chemotherapeutic agents. Overexpression of P-gp in tumor cells induces chemoresistance via pumping the anticancer drugs out of the cells. In addition to taking part in many biological processes such as development, reproduction and repair, midkine (MK) also plays important roles in the pathogenesis of malignant diseases as well as in the regulation of MDR. Although, the mechanisms of action of P-gp and MK are different, overexpression of both proteins prevents the accumulation of many chemotherapeutics in tumor cells, leading to decreased therapeutic effects of anticancer drugs. Therefore, identification of the result of dual inhibition of P-gp and MK in overcoming chemoresistance may enhance the likelihood for a more efficient chemotherapy.
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Affiliation(s)
- A Şükrü Aynacıoğlu
- Department of Medical Pharmacology, İstanbul Aydın University, Medical Faculty, Florya Main Campus, Küçükçekmece, 34295 İstanbul, Turkey.
| | - Ayhan Bilir
- Department of Histology and Embryology, İstanbul Aydın University, Medical Faculty, Florya Main Campus, Küçükçekmece, 34295 İstanbul, Turkey
| | - Kenji Kadomatsu
- Department of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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Yu J, Liu SH, Sanchez R, Nemunaitis J, Rozengurt E, Brunicardi FC. Pancreatic cancer actionable genes in precision medicine and personalized surgery. Surgeon 2017; 15:24-29. [PMID: 27374183 PMCID: PMC5195911 DOI: 10.1016/j.surge.2016.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 05/02/2016] [Accepted: 05/22/2016] [Indexed: 12/17/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an overall 5-year survival rate less than 5% due to the poor early diagnosis and lack of effective therapeutic options. The most effective therapy remains surgery, however post-operative survival could be enhanced with effective adjuvant therapy. The massive information gained from Omics techniques on PDAC at the beginning of the 21st century is a remarkable accomplishment. However, the information gained from the omics data, including next generation sequencing data, has yet to successfully affect care of patients suffering with PDAC. Therefore, we propose the development of an actionable genomic platform that matches a patient's PDAC clinically actionable genes with potential targeted adjuvant therapies. Using this platform, PDX1 has been identified as a potential actionable gene for PDAC, therefore, RNAi therapy, gene therapy and small inhibitory drugs, all targeting PDX1, serve as potential targeted adjuvant therapies. Preclinical studies support the hypothesis that identification of PDAC actionable genes could permit translation of a patient's genomic information into precision targeted adjuvant therapy for PDAC.
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Affiliation(s)
- Juehua Yu
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | - Shi-He Liu
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | - Robbi Sanchez
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | | | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA
| | - F Charles Brunicardi
- Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
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Axtner J, Steele M, Kröz M, Spahn G, Matthes H, Schad F. Health services research of integrative oncology in palliative care of patients with advanced pancreatic cancer. BMC Cancer 2016; 16:579. [PMID: 27485618 PMCID: PMC4971628 DOI: 10.1186/s12885-016-2594-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 07/21/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Pancreatic cancer has a dire prognosis and is associated with a high mortality. Palliative patients have special needs and often seek help in integrative oncological concepts (IO) that combine conventional and complementary therapies. Nevertheless there are few recommendations regarding IO in current cancer guidelines. The aims of this study were to report on implementation of IO in everyday palliative care and to analyze patient survival in advanced pancreatic cancer. METHODS This multicenter observational study investigates the implementation of IO and length of survival of patients suffering from advanced pancreatic cancer (stage IV). We analyzed patient's survival by employing multivariable proportional hazard models using different parametric distribution functions and compared patients receiving chemotherapy only, a combination of chemotherapy and Viscum album (VA) treatment, and VA treatment only. RESULTS Records of 240 patients were analyzed. Complementary therapy showed high acceptance (93 %). Most frequent therapy was VA treatment (74 %) that was often administered concomitantly to chemotherapy (64 %). Both therapies had positive effects on patient survival as they had significant negative effects on the hazard in our log-normal model. A second analysis showed that patients with combined chemotherapy and VA therapy performed significantly better than patients receiving only chemotherapy (12.1 to 7.3 month). Patients receiving only VA therapy showed longer survival than those receiving neither chemotherapy nor VA therapy (5.4 to 2.5 months). Our data demonstrates that IO can be implemented in the everyday care of patients without disregarding conventional treatment. Patients combining VA with chemotherapy showed longest survival. CONCLUSIONS Our data demonstrate the importance and potential of health services research showing that IO treatment can be successfully implemented in the every-day care of patients suffering from advanced pancreatic cancer. Patients combining VA with chemotherapy showed longest survival. To address patients' needs adequately, future cancer guidelines might increasingly include comments on complementary treatment options in addition to conventional therapies. Further studies should investigate the effect of complementary treatments on survival and quality of life in more detail.
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Affiliation(s)
- Jan Axtner
- Forschungsinstitut Havelhöhe gGmbH, Kladower Damm 221, 14089, Berlin, Germany
| | - Megan Steele
- Forschungsinstitut Havelhöhe gGmbH, Kladower Damm 221, 14089, Berlin, Germany.,ihop Research Group, Queensland University of Technology, School of Public Health and Social Work, Victoria Park Road, 4059, Brisbane, Australia
| | - Matthias Kröz
- Forschungsinstitut Havelhöhe gGmbH, Kladower Damm 221, 14089, Berlin, Germany.,Krankenhaus Havelhöhe, Kladower Damm 221, 14089, Berlin, Germany
| | - Günther Spahn
- Institut für Integrative Krebstherapie, Hans-Böckler-Str. 7, 55128, Mainz, Germany
| | - Harald Matthes
- Forschungsinstitut Havelhöhe gGmbH, Kladower Damm 221, 14089, Berlin, Germany.,Krankenhaus Havelhöhe, Kladower Damm 221, 14089, Berlin, Germany
| | - Friedemann Schad
- Forschungsinstitut Havelhöhe gGmbH, Kladower Damm 221, 14089, Berlin, Germany. .,Krankenhaus Havelhöhe, Kladower Damm 221, 14089, Berlin, Germany.
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Primary cultures of human colon cancer as a model to study cancer stem cells. Tumour Biol 2016; 37:12833-12842. [PMID: 27449036 DOI: 10.1007/s13277-016-5214-8] [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] [Received: 12/22/2015] [Accepted: 07/14/2016] [Indexed: 12/24/2022] Open
Abstract
The principal cause of death in cancer involves tumor progression and metastasis. Since only a small proportion of the primary tumor cells, cancer stem cells (CSCs), which are the most aggressive, have the capacity to metastasize and display properties of stem cells, it is imperative to characterize the gene expression of diagnostic markers and to evaluate the drug sensitivity in the CSCs themselves. Here, we have examined the key genes that are involved in the progression of colorectal cancer and are expressed in cancer stem cells. Primary cultures of colorectal cancer cells from a patient's tumors were studied using the flow cytometry and cytological methods. We have evaluated the clinical and stem cell marker expression in these cells, their resistance to 5-fluorouracil and irinotecan, and the ability of cells to form tumors in mice. The data shows the role of stem cell marker Oct4 in the resistance of primary colorectal cancer tumor cells to 5-fluorouracil.
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Huang J, Qian W, Wang L, Wu H, Zhou H, Wang AY, Chen H, Yang L, Mao H. Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer. Int J Nanomedicine 2016; 11:3087-99. [PMID: 27462153 PMCID: PMC4939990 DOI: 10.2147/ijn.s92722] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Engineered nanocarriers have emerged as a promising platform for cancer therapy. However, the therapeutic efficacy is limited by low drug loading efficiency, poor passive targeting to tumors, and severe systemic side effects. Herein, we report a new class of nanoconstructs based on milk protein (casein)-coated magnetic iron oxide (CNIO) nanoparticles for targeted and image-guided pancreatic cancer treatment. The tumor-targeting amino-terminal fragment (ATF) of urokinase plasminogen activator and the antitumor drug cisplatin (CDDP) were engineered on this nanoplatform. High drug loading (~25 wt%) and sustained release at physiological conditions were achieved through the exchange and encapsulation strategy. These ATF-CNIO-CDDP nanoparticles demonstrated actively targeted delivery of CDDP to orthotopic pancreatic tumors in mice. The effective accumulation and distribution of ATF-CNIO-CDDP was evidenced by magnetic resonance imaging, based on the T2-weighted contrast resulting from the specific accumulation of ATF-CNIO-CDDP in the tumor. Actively targeted delivery of ATF-CNIO-CDDP led to improved therapeutic efficacy in comparison with free CDDP and nontargeted CNIO-CDDP treatment. Meanwhile, less systemic side effects were observed in the nanocarrier-treated groups than that in the group treated with free CDDP. Hematoxylin and Eosin and Sirius Red staining of tumor sections revealed the possible disruption of stroma during the treatment with ATF-CNIO-CDDP. Overall, our results suggest that ATF-CNIO-CDDP can be an effective theranostic platform for active targeting-enhanced and image-guided cancer treatment while simultaneously reducing the systemic toxicity.
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Affiliation(s)
- Jing Huang
- Department of Radiology and Imaging Sciences; Center for Systems Imaging
| | - Weiping Qian
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Liya Wang
- Department of Radiology and Imaging Sciences; Center for Systems Imaging
| | - Hui Wu
- Department of Radiology and Imaging Sciences
| | - Hongyu Zhou
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
| | | | - Hongbo Chen
- School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, Guangxi, People's Republic of China
| | - Lily Yang
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Hui Mao
- Department of Radiology and Imaging Sciences; Center for Systems Imaging
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Gemcitabine upregulates ABCG2/BCRP and modulates the intracellular pharmacokinetic profiles of bioluminescence in pancreatic cancer cells. Anticancer Drugs 2016; 27:183-91. [PMID: 26556627 DOI: 10.1097/cad.0000000000000315] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
A lack of methods capable of exploring real-time intracellular drug deposition has since limited the investigation of gemcitabine-induced multidrug resistance in vitro and in vivo. Specifically, resistance induced by D-luciferin, a substrate of the breast cancer resistance protein (ABCG2/BCRP), has recently attracted clinical attention, but further investigation has been limited. Herein, the intracellular pharmacokinetic behavior of D-luciferin was investigated in pancreatic cancer cell lines in real time by using bioluminescence imaging. To achieve this feat, BxPC3 and Panc1 pancreatic cancer cells overexpressing firefly luciferase were treated with gemcitabine in a dose and time gradient manner in vitro. The intracellular pharmacokinetic profiles of each group were then determined through the acquisition of bioluminescent signal intensity of D-luciferin in cells. Simultaneously, key pharmacokinetic parameters including area under the curve, elimination rate constant (K), and mean resident time were calculated according to the noncompartment model. ABCG2 protein levels following gemcitabine treatment were detected through western blot, and gemcitabine showed no significant effect on luciferase activity over dimethyl sulfoxide (DMSO) as a control (P>0.05). However, gemcitabine significantly increased K values while suppressing area under the curve and mean resident time compared with DMSO (P<0.05) and increased ABCG2 expression over DMSO-treated cells. In addition, gemcitabine increased the elimination rate of the ABCG2 substrate, D-luciferin, and decreased D-luciferin accumulation in BxPC3 and Panc1 cells in a dose-response manner. Advances made herein illustrate the versatility of the in-vitro bioluminescent model and its capability to observe the onset of chemoresistance in real time.
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Crawley AS, O'Kennedy RJ. The need for effective pancreatic cancer detection and management: a biomarker-based strategy. Expert Rev Mol Diagn 2016; 15:1339-53. [PMID: 26394703 DOI: 10.1586/14737159.2015.1083862] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Pancreatic cancer (Pa) is generally a very aggressive disease, with few effective approaches available for early diagnosis or therapy. These factors, combined with the aggressiveness and chemoresistance of Pa, results in a bleak outcome post-diagnosis. Cancer-related biomarkers have established capabilities for diagnosis, prognosis and screening and can be exploited to aid in earlier less-invasive diagnosis and optimization of targeted therapies. Pa has only one US FDA-approved biomarker, CA19-9, which has significant limitations. Hence, it is vital that novel biomarkers are identified and validated to diagnose, treat, control and monitor Pa. This review focuses on existing and potential Pa-associated markers and discusses how they may be applied in cohort for improved management of Pa.
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Affiliation(s)
- Aoife S Crawley
- a 1 School of Biotechnology, Dublin City University, Dublin 9, Ireland
| | - Richard J O'Kennedy
- a 1 School of Biotechnology, Dublin City University, Dublin 9, Ireland.,b 2 Biomedical Diagnostics Institute, National Centre for Sensor Research, Dublin City University, Dublin 9, Ireland
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Ma Y, Hu J, Zhang N, Dong X, Li Y, Yang B, Tian W, Wang X. Prediction of Candidate Drugs for Treating Pancreatic Cancer by Using a Combined Approach. PLoS One 2016; 11:e0149896. [PMID: 26910401 PMCID: PMC4765895 DOI: 10.1371/journal.pone.0149896] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 02/05/2016] [Indexed: 01/15/2023] Open
Abstract
Pancreatic cancer is the leading cause of death from solid malignancies worldwide. Currently, gemcitabine is the only drug approved for treating pancreatic cancer. Developing new therapeutic drugs for this disease is, therefore, an urgent need. The C-Map project has provided a wealth of gene expression data that can be mined for repositioning drugs, a promising approach to new drug discovery. Typically, a drug is considered potentially useful for treating a disease if the drug-induced differential gene expression profile is negatively correlated with the differentially expressed genes in the target disease. However, many of the potentially useful drugs (PUDs) identified by gene expression profile correlation are likely false positives because, in C-Map, the cultured cell lines to which the drug is applied are not derived from diseased tissues. To solve this problem, we developed a combined approach for predicting candidate drugs for treating pancreatic cancer. We first identified PUDs for pancreatic cancer by using C-Map-based gene expression correlation analyses. We then applied an algorithm (Met-express) to predict key pancreatic cancer (KPC) enzymes involved in pancreatic cancer metabolism. Finally, we selected candidates from the PUDs by requiring that their targets be KPC enzymes or the substrates/products of KPC enzymes. Using this combined approach, we predicted seven candidate drugs for treating pancreatic cancer, three of which are supported by literature evidence, and three were experimentally validated to be inhibitory to pancreatic cancer celllines.
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Affiliation(s)
- Yanfen Ma
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, P.R. China
- Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi province, P.R. China
| | - Jian Hu
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, P.R. China
| | - Ning Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, P.R. China
- Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi province, P.R. China
| | - Xinran Dong
- Department of Biostatistics and Computational Biology, School of Life Science, Fudan University, Shanghai, China
| | - Ying Li
- Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi province, P.R. China
- SHAANXI Kang Fu Hospital, Xi'an, Shaanxi province, P.R. China
| | - Bo Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, P.R. China
| | - Weidong Tian
- Department of Biostatistics and Computational Biology, School of Life Science, Fudan University, Shanghai, China
| | - Xiaoqin Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, P.R. China
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Chijiiwa Y, Moriyama T, Ohuchida K, Nabae T, Ohtsuka T, Miyasaka Y, Fujita H, Maeyama R, Manabe T, Abe A, Mizuuchi Y, Oda Y, Mizumoto K, Nakamura M. Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL. Int J Oncol 2016; 48:1688-700. [PMID: 26892887 DOI: 10.3892/ijo.2016.3389] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 01/21/2016] [Indexed: 11/05/2022] Open
Abstract
Metastasis is the main cause of cancer-associated death, and metastasis of pancreatic cancer remains difficult to treat because of its aggressiveness. MicroRNAs (miRNAs) play crucial roles in the regulation of various human transcripts, and many miRNAs have been reported to correlate with cancer metastasis. We identified an anti-metastatic miRNA, miR-5100, by investigating differences in miRNA profiling between highly metastatic pancreatic cancer cells and their parental cells. Overexpression of miR-5100 inhibited colony formation (P<0.05), cell migration (P<0.0001) and invasion (P<0.0001) of pancreatic cancer cells. In addition, we identified a possible target of miR-5100, podocalyxin-like 1 (PODXL), and demonstrated miR-5100 directly binds to the 3' untranslated region of PODXL and post-transcriptionally regulates its expression in pancreatic cancer cells. Silencing PODXL resulted in diminished cell migration (P<0.0001) and invasion (P<0.05). We also clarified the close relationship between expression of PODXL in human pancreatic cancer specimens and liver metastasis (P=0.0003), and determined that post-operative survival was longer in the low-PODXL expression group than in the high-PODXL expression group (P<0.05). These results indicate that miR-5100 and PODXL have considerable therapeutic potential for anti-metastatic therapy and could be potential indicators for cancer metastases in patients with pancreatic cancer.
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Affiliation(s)
- Yoshiro Chijiiwa
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Taiki Moriyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshinaga Nabae
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takao Ohtsuka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Miyasaka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hayato Fujita
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryo Maeyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tatsuya Manabe
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsushi Abe
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yusuke Mizuuchi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Sarkar FH. Novel Holistic Approaches for Overcoming Therapy Resistance in Pancreatic and Colon Cancers. Med Princ Pract 2016; 25 Suppl 2:3-10. [PMID: 26228733 PMCID: PMC5588517 DOI: 10.1159/000435814] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 06/08/2015] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal (GI) cancers, such as of the colon and pancreas, are highly resistant to both standard and targeted therapeutics. Therapy-resistant and heterogeneous GI cancers harbor highly complex signaling networks (the resistome) that resist apoptotic programming. Commonly used gemcitabine or platinum-based regimens fail to induce meaningful (i.e. disease-reversing) perturbations in the resistome, resulting in high rates of treatment failure. The GI cancer resistance networks are, in part, due to interactions between parallel signaling and aberrantly expressed microRNAs (miRNAs) that collectively promote the development and survival of drug-resistant cancer stem cells with epithelial-to-mesenchymal transition (EMT) characteristics. The lack of understanding of the resistance networks associated with this subpopulation of cells as well as reductionist, single protein-/pathway-targeted approaches have made 'effective drug design' a difficult task. We propose that the successful design of novel therapeutic regimens to target drug-resistant GI tumors is only possible if network-based drug avenues and agents, in particular 'natural agents' with no known toxicity, are correctly identified. Natural agents (dietary agents or their synthetic derivatives) can individually alter miRNA profiles, suppress EMT pathways and eliminate cancer stem-like cells that derive from pancreatic cancer and colon cancer, by partially targeting multiple yet meaningful networks within the GI cancer resistome. However, the efficacy of these agents as combinations (e.g. consumed in the diet) against this resistome has never been studied. This short review article provides an overview of the different challenges involved in the understanding of the GI resistome, and how novel computational biology can help in the design of effective therapies to overcome resistance.
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Affiliation(s)
- Fazlul H. Sarkar
- *Fazlul H. Sarkar, PhD, Departments of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, 740 HWCRC, Detroit, MI 48201 (USA), E-Mail
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Gibson AF, D'Cruz L, Janda M, Beesley VL, Neale RE, Rowlands IJ. Beyond survivorship? A discursive analysis of how people with pancreatic cancer negotiate identity transitions in their health. J Health Psychol 2015; 21:3060-3071. [PMID: 26194412 DOI: 10.1177/1359105315592050] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
We explored how people negotiate, and respond to, identity transitions following a diagnosis of pancreatic cancer. Interviews with 19 people with pancreatic cancer were analysed using thematic discourse analysis. While discursively negotiating two transitions, 'moving from healthy to ill' and 'moving from active treatment to end-of-life care', participants positioned themselves as 'in control', 'optimistic' and managing their health and illness. In the absence of other discourses or models of life post-cancer, many people draw on the promise of survival. Moving away from 'survivorship' may assist people with advanced cancer to make sense of their lives in a short timeframe.
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Affiliation(s)
- Alexandra F Gibson
- The University of Queensland, Australia .,QIMR Berghofer Medical Research Institute, Australia
| | | | | | | | | | - Ingrid J Rowlands
- The University of Queensland, Australia.,QIMR Berghofer Medical Research Institute, Australia
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Xu C, Zhu S, Wu M, Zhao Y, Han W, Yu Y. The therapeutic effect of rhMK on osteoarthritis in mice, induced by destabilization of the medial meniscus. Biol Pharm Bull 2015; 37:1803-10. [PMID: 25366485 DOI: 10.1248/bpb.b14-00470] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Osteoarthritis (OA) is a worldwide disease in aged people, causing not only physical suffering to the patients themselves, but also a great burden on their families and on society. Here we used a mouse OA model induced by destabilization of the medial meniscus (DMM), and studied the therapeutic effect of recombinant human midkine (rhMK) on this OA model. Our results indicated that the DMM surgery induced mechanical allodynia and locomotor activity obstacles, together with cartilage injury in the C57BL/6 mice. The rhMK treatment mitigated the OA related mechanical allodynia, improved locomotor activity capacity, and prevented degradation of the cartilage. Considering the safety issue of rhMK used as a biologic, we also inspected the main organs in the rhMK treated mice throughout the process and found no pathological change. These results suggest that rhMK could be used as a biologic to treat OA or OA related pain.
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Affiliation(s)
- Chuanying Xu
- School of Agriculture and Biology, Shanghai Jiao Tong University
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48
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Husi H, Skipworth RJE, Cronshaw A, Stephens NA, Wackerhage H, Greig C, Fearon KCH, Ross JA. Programmed cell death 6 interacting protein (PDCD6IP) and Rabenosyn-5 (ZFYVE20) are potential urinary biomarkers for upper gastrointestinal cancer. Proteomics Clin Appl 2015; 9:586-96. [PMID: 25644331 DOI: 10.1002/prca.201400111] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 12/02/2014] [Accepted: 01/27/2015] [Indexed: 12/19/2022]
Abstract
PURPOSE Cancer of the upper digestive tract (uGI) is a major contributor to cancer-related death worldwide. Due to a rise in occurrence, together with poor survival rates and a lack of diagnostic or prognostic clinical assays, there is a clear need to establish molecular biomarkers. EXPERIMENTAL DESIGN Initial assessment was performed on urine samples from 60 control and 60 uGI cancer patients using MS to establish a peak pattern or fingerprint model, which was validated by a further set of 59 samples. RESULTS We detected 86 cluster peaks by MS above frequency and detection thresholds. Statistical testing and model building resulted in a peak profiling model of five relevant peaks with 88% overall sensitivity and 91% specificity, and overall correctness of 90%. High-resolution MS of 40 samples in the 2-10 kDa range resulted in 646 identified proteins, and pattern matching identified four of the five model peaks within significant parameters, namely programmed cell death 6 interacting protein (PDCD6IP/Alix/AIP1), Rabenosyn-5 (ZFYVE20), protein S100A8, and protein S100A9, of which the first two were validated by Western blotting. CONCLUSIONS AND CLINICAL RELEVANCE We demonstrate that MS analysis of human urine can identify lead biomarker candidates in uGI cancers, which makes this technique potentially useful in defining and consolidating biomarker patterns for uGI cancer screening.
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Affiliation(s)
- Holger Husi
- Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.,School of Clinical Sciences, University of Edinburgh, Edinburgh, UK
| | | | - Andrew Cronshaw
- School of Biological Sciences, University of Edinburgh, Edinburgh, UK
| | | | | | - Carolyn Greig
- School of Clinical Sciences, University of Edinburgh, Edinburgh, UK.,School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK
| | | | - James A Ross
- School of Clinical Sciences, University of Edinburgh, Edinburgh, UK
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Tume L, Aquino-Ordinola R. Desregulación de microARN específicos en la progresión del cáncer de páncreas. GACETA MEXICANA DE ONCOLOGÍA 2015. [DOI: 10.1016/j.gamo.2015.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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50
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Cheng S, Swanson K, Eliaz I, McClintick JN, Sandusky GE, Sliva D. Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress. PLoS One 2015; 10:e0122270. [PMID: 25915041 PMCID: PMC4411097 DOI: 10.1371/journal.pone.0122270] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 02/12/2015] [Indexed: 12/17/2022] Open
Abstract
Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effect of PA on human chemotherapy resistant pancreatic cancer. PA triggered apoptosis in gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2. Comparative gene expression array analysis demonstrated that endoplasmic reticulum (ER) stress was induced by PA through activation of heat shock response and unfolded protein response related genes. Induced ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2α. Moreover, ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blocked PA induced apoptosis. In addition, 25 mg kg-1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis and expression of ER stress related proteins in tumor tissues. Taken together, growth inhibition and induction of apoptosis by PA in gemcitabine-resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. PA may be potentially exploited for the use in treatment of chemotherapy resistant pancreatic cancer.
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Affiliation(s)
- Shujie Cheng
- Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America
| | - Kristen Swanson
- Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America
| | - Isaac Eliaz
- Amitabha Medical Clinic and Healing Center, Santa Rosa, California, United States of America
| | - Jeanette N. McClintick
- Departments of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America
| | - George E. Sandusky
- Departments of Pathology, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America
| | - Daniel Sliva
- Cancer Research Laboratory, Methodist Research Institute, Indiana University Health, Indianapolis, Indiana, United States of America
- Departments of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, United States of America
- DSTest Laboratories, Purdue Research Park, Indianapolis, Indiana, United States of America
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