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Shannon N, Raymond C, Palmer C, Homa S, Bonini M, Seward D, Cunniff B. Miro1 expression alters global gene expression, ERK1/2 phosphorylation, oxidation and cell cycle progression. J Cell Sci 2025; 138:jcs263554. [PMID: 40067243 PMCID: PMC11993262 DOI: 10.1242/jcs.263554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 02/26/2025] [Indexed: 03/19/2025] Open
Abstract
Mitochondrial positioning supports localized energy and signaling requirements. Miro1 is necessary for attachment of mitochondria to microtubule motor proteins for trafficking. When Miro1 is deleted (Miro1-/-) from mouse embryonic fibroblasts (MEFs), mitochondria become sequestered to the perinuclear space, disrupting subcellular signaling gradients. Here, we show that Miro1-/- MEFs grow slower than Miro1+/+ and Miro1-/- MEFs stably re-expressing a Myc-Miro1 plasmid. Miro1-/- MEFs have a decreased percentage of cells in G1 and increased percentage of cells in S phase. We conducted the first ever RNA sequencing experiment dependent upon Miro1 expression and found differentially expressed genes related to MAPK signaling, cell proliferation and migration. ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) phosphorylation is elevated both spatially and temporally following serum stimulation in Miro1-/- MEFs, whereas the expression levels and oxidation of the dual specificity phosphatases (DUSP1-DUSP6) is unchanged. Finally, we found the oxidation status of ERK1/2 is increased in Miro1-/- MEFs compared to that seen in Miro1+/+ and Myc-Miro1 MEFs. These results highlight transcriptional control based off Miro1 expression and demonstrate the dynamic regulation of ERK1/2 upon deletion of Miro1 which might support the observed cell cycle and proliferation defects.
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Affiliation(s)
- Nathaniel Shannon
- Department of Pathology and Laboratory Medicine, University of Vermont Cancer Center, Larner College of Medicine, Burlington, VT 05405, USA
| | - Cory Raymond
- Department of Pathology and Laboratory Medicine, University of Vermont Cancer Center, Larner College of Medicine, Burlington, VT 05405, USA
| | - Chloe Palmer
- Department of Pathology and Laboratory Medicine, University of Vermont Cancer Center, Larner College of Medicine, Burlington, VT 05405, USA
| | - Silver Homa
- Department of Medicine and Biochemistry, Feinberg School of Medicine Northwestern University, Chicago, IL 60611, USA
| | - Marcelo Bonini
- Department of Medicine and Biochemistry, Feinberg School of Medicine Northwestern University, Chicago, IL 60611, USA
| | - David Seward
- Department of Pathology and Laboratory Medicine, University of Vermont Cancer Center, Larner College of Medicine, Burlington, VT 05405, USA
| | - Brian Cunniff
- Department of Pathology and Laboratory Medicine, University of Vermont Cancer Center, Larner College of Medicine, Burlington, VT 05405, USA
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Kong F, Yang S, Shi R, Peng Y. The Up-Regulated Expression of Mitochondrial Membrane Molecule RHOT1 in Gastric Cancer Predicts the Prognosis of Patients and Promotes the Malignant Biological Behavior of Cells. Mol Biotechnol 2025; 67:1095-1108. [PMID: 38448731 DOI: 10.1007/s12033-024-01107-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Accepted: 01/30/2024] [Indexed: 03/08/2024]
Abstract
Gastric cancer (GC) remains a major disease of high morbidity and mortality worldwide despite advances in diagnosis and treatment. Ras homolog family member T1 (RHOT1) plays an important role in several cancers. Our study aimed to analyze RHOT1 expression, to assess the relationship between its expression and the prognosis of patients, and know the impact of RHOT1 on GC cells. The Cancer Genome Atlas (TCGA) RNA-seq data was used for gene expression analysis, survival and prognostic analysis. Nomograms were created to analyze the pathological factors of GC patients. RHOT1 expression was up-regulated by analyzed TCGA-Stomach adenocarcinoma (STAD) data and verified by Polymerase Chain Reaction (PCR) assay in GC tissues and cell lines. Furthermore, RHOT1 up-regulation was significantly associated with shorter survival of GC patients. At last, after silencing the expression of RHOT1 in AGS cell lines, we found that the proliferative ability of the cells was significantly reduced, the cell invasion ability was significantly inhibited, the cell migration ability was also significantly weakened, the cell cycle was arrested in the G0/G1 phase, and apoptosis was significantly increased. So RHOT1 could impact the apoptosis, proliferation, invasion, and migration behavior of GC cells. We trust RHOT1 has the potential to become a new oncogene biomarker for diagnosis and prognosis as well as a new therapeutic target in GC.
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Affiliation(s)
- Fanhao Kong
- Shenyang Medical College, Shenyang, Liaoning, People's Republic of China
| | - Siwen Yang
- Shenyang Medical College, Shenyang, Liaoning, People's Republic of China
| | - Ruimeng Shi
- Shenyang Medical College, Shenyang, Liaoning, People's Republic of China
| | - Yanyu Peng
- Department of Histology and Embryology, Shenyang Medical College, Shenyang, Liaoning, People's Republic of China.
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Reshkin SJ, Cardone RA, Koltai T. Genetic Signature of Human Pancreatic Cancer and Personalized Targeting. Cells 2024; 13:602. [PMID: 38607041 PMCID: PMC11011857 DOI: 10.3390/cells13070602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/13/2024] Open
Abstract
Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.
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Affiliation(s)
- Stephan J. Reshkin
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Tomas Koltai
- Oncomed, Via Pier Capponi 6, 50132 Florence, Italy
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Anstadt EJ, Carmona R, Berlin E, Yegya-Raman N, Venigalla S, Reddy V, Williams GR, Leibensperger MR, Wojcieszynski A, Baumann BC, Lee MK, Plastaras JP, Furth EE, Mell LK, Metz JM, Ben-Josef E. SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma. Cancer 2024; 130:476-484. [PMID: 37823514 DOI: 10.1002/cncr.35058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/20/2023] [Accepted: 08/08/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. METHODS Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. RESULTS In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p = .19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p = .009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). CONCLUSIONS In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.
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Affiliation(s)
- Emily J Anstadt
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Ruben Carmona
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Eva Berlin
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Nikhil Yegya-Raman
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sriram Venigalla
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Vishruth Reddy
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Graeme R Williams
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Mark R Leibensperger
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Andrzej Wojcieszynski
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Brian C Baumann
- Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Major K Lee
- Division of Gastrointestinal Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - John P Plastaras
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Emma E Furth
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Loren K Mell
- Department of Radiation Medicine and Applied Sciences, University of California San Diego School of Medicine, La Jolla, California, USA
| | - James M Metz
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Edgar Ben-Josef
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Kirkegård J, Ladekarl M, Johannsen IR, Mortensen F. Effect of adjuvant chemotherapy after pancreatectomy in patients with node-negative pancreatic cancer: target trial emulation. Br J Surg 2024; 111:znad398. [PMID: 38006324 DOI: 10.1093/bjs/znad398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/07/2023] [Accepted: 11/09/2023] [Indexed: 11/27/2023]
Abstract
BACKGROUND The effect of adjuvant therapy in node-negative pancreatic cancer is uncertain. The aim of this study was to estimate the effect of adjuvant chemotherapy on survival after surgery for pancreatic cancer in patients with node-negative (pN0) and node-positive (pN+) disease using target trial emulation. METHODS This was an observational cohort study emulating a hypothetical RCT by the clone-censor-weight approach using population-based Danish healthcare registries. The study included Danish patients undergoing curative-intent surgery for pancreatic cancer during 2008-2021, who were discharged alive no more than 4 weeks after surgery. At the time of discharge after surgery, the data for each patient were duplicated; one copy was assigned to the adjuvant chemotherapy strategy and the other to the no adjuvant chemotherapy strategy of the hypothetical trial. Copies were censored when the assigned treatment was no longer compatible with the observed treatment. To account for informative censoring, uncensored patients were weighted according to measured confounders. The primary outcomes were absolute difference in 2-year survival and median overall survival, comparing adjuvant with no adjuvant chemotherapy. RESULTS Some 424 patients with pN0 and 953 with pN+ disease were included. Of these, 62.0 and 74.6% respectively initiated adjuvant chemotherapy within the 8-week grace period. Among patients with pN0 tumours, the difference in 2-year survival between those with and without adjuvant therapy was -2.2 (95% c.i. -11.8 to 7.4)%. In those with pN+ disease, the difference in 2-year survival was 9.9 (1.6 to 18.1)%. Median overall survival was 24.9 (i.q.r. 12.8-49.4) and 15.0 (8.0-34.0) months for patients having adjuvant and no adjuvant therapy respectively. CONCLUSION In a target trial emulation using observational data, adjuvant chemotherapy did not improve survival after surgery for node-negative pancreatic cancer.
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Affiliation(s)
- Jakob Kirkegård
- Department of Surgery, Hepatopancreatobiliary Section, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Morten Ladekarl
- Department of Oncology and Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | | | - Frank Mortensen
- Department of Surgery, Hepatopancreatobiliary Section, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Aryanti C, Uwuratuw JA, Labeda I, Raharjo W, Lusikooy RE, Abdul Rauf M, Mappincara A, Sampetoding S, Kusuma MI, Syarifuddin E. The Mutation Portraits of Oncogenes and Tumor Supressor Genes in Predicting the Overall Survival in Pancreatic Cancer: A Bayesian Network Meta-Analysis. Asian Pac J Cancer Prev 2023; 24:2895-2902. [PMID: 37642079 PMCID: PMC10685232 DOI: 10.31557/apjcp.2023.24.8.2895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 08/07/2023] [Indexed: 08/31/2023] Open
Abstract
INTRODUCTION In pancreatic cancer, the carcinogenesis can not be separated from genetics mutations. The portraits of genes alterations majorily including oncogenes (KRAS, HER2, PD-L1) and tumor supressor genes (P53, CDKN2A, SMAD4). Besides being notorious a screening marker, the genetic mutations were related to the prognosis of pancreatic cancer. The aim of this study is to determine the genetic mutations portrait in predicting the overall survival in pancreatic cancer. METHODS The network meta analysis (NMA) was registered in PROSPERO (CRD42023397976) and conducted in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) in addition of NMA extension guidance. Comprehensive searches were done including all studies which reported the overall survival of pancreatic cancer subjects with KRAS, HER2, PD-L1, P53, CDKN2A, SMAD4. Data were collected and analysis will be done based on Bayesian method, Markov Chain Monte Carlo algorithm, using BUGSnet package in R studio. Transivity was controlled by methods and consistency of the NMA will be fitted by deviance information criterion. Data analysis in NMA were presented in Sucra plot, league table, and forest plot. RESULTS Twenty-four studies were included in this NMA with 4613 total subjects. The NMA was conducted in random-effects, consistent, and convergence model. Relative to control, the genetic mutation of SMAD4 (HR 1.84; 95%CI 1.39-2.46), HER2 (HR 1.76; 95%CI 1.14-2.71), and KRAS (HR 1.7; 95%CI 1.19-2.48) were significant to have worse survival. The mutations of PD-L1, P53, and CDKN2A also showed poor survival, but not statistically significant compared to control. CONCLUSION In pancreatic cancer, the mutation of SMAD4 predicted the worst overall survival, compared to control, also mutation of HER2, KRAS, PD-L1, P53, and CDKN2A.
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Affiliation(s)
- Citra Aryanti
- Digestive Surgery Training Program, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
| | - Julianus Aboyaman Uwuratuw
- Division of Digestive Surgery, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
| | - Ibrahim Labeda
- Division of Digestive Surgery, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
| | - Warsinggih Raharjo
- Division of Digestive Surgery, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
| | - Ronald Erasio Lusikooy
- Division of Digestive Surgery, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
| | - Murny Abdul Rauf
- Division of Digestive Surgery, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
| | - Andi Mappincara
- Division of Digestive Surgery, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
| | - Samuel Sampetoding
- Division of Digestive Surgery, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
| | - M. Ihwan Kusuma
- Division of Digestive Surgery, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
| | - Erwin Syarifuddin
- Division of Digestive Surgery, Department of Surgery, Hasanuddin University, Dr. Wahidin Sudirohusodo General Hospital, Makassar, Sulawesi Selatan, Indonesia.
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Mirza-Aghazadeh-Attari M, Madani SP, Shahbazian H, Ansari G, Mohseni A, Borhani A, Afyouni S, Kamel IR. Predictive role of radiomics features extracted from preoperative cross-sectional imaging of pancreatic ductal adenocarcinoma in detecting lymph node metastasis: a systemic review and meta-analysis. Abdom Radiol (NY) 2023; 48:2570-2584. [PMID: 37202642 DOI: 10.1007/s00261-023-03940-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/20/2023]
Abstract
Lymph node metastases are associated with poor clinical outcomes in pancreatic ductal adenocarcinoma (PDAC). In preoperative imaging, conventional diagnostic modalities do not provide the desired accuracy in diagnosing lymph node metastasis. The current review aims to determine the pooled diagnostic profile of studies examining the role of radiomics features in detecting lymph node metastasis in PDAC. PubMed, Google Scholar, and Embase databases were searched for relevant articles. The quality of the studies was examined using the Radiomics Quality Score and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tools. Pooled results for sensitivity, specificity, likelihood, and odds ratios with the corresponding 95% confidence intervals (CIs) were calculated using a random-effect model (DerSimonian-Liard method). No significant publication bias was detected among the studies included in this meta-analysis. The pooled sensitivity of the validation datasets included in the study was 77.4% (72.7%, 81.5%) and pooled specificity was 72.4% (63.8, 79.6%). The diagnostic odds ratio of the validation datasets was 9.6 (6.0, 15.2). No statistically significant heterogeneity was detected for sensitivity and odds ratio (P values of 0.3 and 0.08, respectively). However, there was significant heterogeneity concerning specificity (P = 0.003). The pretest probability of having lymph node metastasis in the pooled databases was 52% and a positive post-test probability was 76% after the radiomics features were used, showing a net benefit of 24%. Classifiers trained on radiomics features extracted from preoperative images can improve the sensitivity and specificity of conventional cross-sectional imaging in detecting lymph node metastasis in PDAC.
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Affiliation(s)
- Mohammad Mirza-Aghazadeh-Attari
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 600 North Wolfe Street, MRI 143, Baltimore, MD, 21287, USA
| | - Seyedeh Panid Madani
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 600 North Wolfe Street, MRI 143, Baltimore, MD, 21287, USA
| | - Haneyeh Shahbazian
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 600 North Wolfe Street, MRI 143, Baltimore, MD, 21287, USA
| | - Golnoosh Ansari
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 600 North Wolfe Street, MRI 143, Baltimore, MD, 21287, USA
| | - Alireza Mohseni
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 600 North Wolfe Street, MRI 143, Baltimore, MD, 21287, USA
| | - Ali Borhani
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 600 North Wolfe Street, MRI 143, Baltimore, MD, 21287, USA
| | - Shadi Afyouni
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 600 North Wolfe Street, MRI 143, Baltimore, MD, 21287, USA
| | - Ihab R Kamel
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 600 North Wolfe Street, MRI 143, Baltimore, MD, 21287, USA.
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Mahmoudian RA, Akhlaghipour I, Lotfi M, Shahidsales S, Moghbeli M. Circular RNAs as the pivotal regulators of epithelial-mesenchymal transition in gastrointestinal tumor cells. Pathol Res Pract 2023; 245:154472. [PMID: 37087995 DOI: 10.1016/j.prp.2023.154472] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/11/2023] [Accepted: 04/18/2023] [Indexed: 04/25/2023]
Abstract
Gastrointestinal (GI) cancers, as the most common human malignancies are always considered one of the most important health challenges in the world. Late diagnosis in advanced tumor stages is one of the main reasons for the high mortality rate and treatment failure in these patients. Therefore, investigating the molecular pathways involved in GI tumor progression is required to introduce the efficient markers for the early tumor diagnosis. Epithelial-mesenchymal transition (EMT) is one of the main cellular mechanisms involved in the GI tumor metastasis. Non-coding RNAs (ncRNAs) are one of the main regulatory factors in EMT process. Circular RNAs (circRNAs) are a group of covalently closed loop ncRNAs that have higher stability in body fluids compared with other ncRNAs. Considering the importance of circRNAs in regulation of EMT process, in the present review we discussed the role of circRNAs in EMT process during GI tumor invasion. It has been reported that circRNAs mainly affect the EMT process through the regulation of EMT-specific transcription factors and signaling pathways such as WNT, PI3K/AKT, TGF-β, and MAPK. This review can be an effective step in introducing a circRNA/EMT based diagnostic panel marker for the early tumor detection among GI cancer patients.
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Affiliation(s)
- Reihaneh Alsadat Mahmoudian
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Lotfi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Nahacka Z, Novak J, Zobalova R, Neuzil J. Miro proteins and their role in mitochondrial transfer in cancer and beyond. Front Cell Dev Biol 2022; 10:937753. [PMID: 35959487 PMCID: PMC9358137 DOI: 10.3389/fcell.2022.937753] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 07/04/2022] [Indexed: 11/24/2022] Open
Abstract
Mitochondria are organelles essential for tumor cell proliferation and metastasis. Although their main cellular function, generation of energy in the form of ATP is dispensable for cancer cells, their capability to drive their adaptation to stress originating from tumor microenvironment makes them a plausible therapeutic target. Recent research has revealed that cancer cells with damaged oxidative phosphorylation import healthy (functional) mitochondria from surrounding stromal cells to drive pyrimidine synthesis and cell proliferation. Furthermore, it has been shown that energetically competent mitochondria are fundamental for tumor cell migration, invasion and metastasis. The spatial positioning and transport of mitochondria involves Miro proteins from a subfamily of small GTPases, localized in outer mitochondrial membrane. Miro proteins are involved in the structure of the MICOS complex, connecting outer and inner-mitochondrial membrane; in mitochondria-ER communication; Ca2+ metabolism; and in the recycling of damaged organelles via mitophagy. The most important role of Miro is regulation of mitochondrial movement and distribution within (and between) cells, acting as an adaptor linking organelles to cytoskeleton-associated motor proteins. In this review, we discuss the function of Miro proteins in various modes of intercellular mitochondrial transfer, emphasizing the structure and dynamics of tunneling nanotubes, the most common transfer modality. We summarize the evidence for and propose possible roles of Miro proteins in nanotube-mediated transfer as well as in cancer cell migration and metastasis, both processes being tightly connected to cytoskeleton-driven mitochondrial movement and positioning.
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Affiliation(s)
- Zuzana Nahacka
- Laboratory of Molecular Therapy, Institute of Biotechnology, Czech Academy of Sciences, Prague, Czechia
- *Correspondence: Zuzana Nahacka, ; Jiri Neuzil,
| | - Jaromir Novak
- Laboratory of Molecular Therapy, Institute of Biotechnology, Czech Academy of Sciences, Prague, Czechia
- Faculty of Science, Charles University, Prague, Czechia
| | - Renata Zobalova
- Laboratory of Molecular Therapy, Institute of Biotechnology, Czech Academy of Sciences, Prague, Czechia
| | - Jiri Neuzil
- Laboratory of Molecular Therapy, Institute of Biotechnology, Czech Academy of Sciences, Prague, Czechia
- School of Pharmacy and Medical Science, Griffith University, Southport, QLD, Australia
- *Correspondence: Zuzana Nahacka, ; Jiri Neuzil,
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Peng YY, Sun D, Xin Y. Hsa_circ_0005230 is up-regulated and promotes gastric cancer cell invasion and migration via regulating the miR-1299/RHOT1 axis. Bioengineered 2022; 13:5046-5063. [PMID: 35170374 PMCID: PMC8973856 DOI: 10.1080/21655979.2022.2036514] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 01/22/2023] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world. Circular RNAs (circRNAs) are a class of non-coding RNAs that are widely expressed in eukaryotic cells. However, their role has been poorly understood in GC. This report aimed to explore the biological functions of hsa_circ_0005230 and its action mechanism in GC. This study validated that hsa_circ_0005230 was significantly up-regulated in 130 cases of GC tissues using qRT-PCR, and clinicopathological feature analysis revealed that its high expression was positively associated with histological grade, lymph node metastasis, TNM stages, and poor prognosis. In vitro, functional experiments showed that silencing hsa_circ_0005230 significantly decreased GC cell proliferation, invasion and migration capabilities. In addition, the major proteins of EMT (epithelial-mesenchymal transition) relevance have changed. In mechanism studies, bioinformatics analyses were used to predict the hsa_circ_0005230/miR-1299/RHOT1 axis and hsa_circ_0005230 may serve as a sponge for miR-1299 and indirectly regulate the expression of RHOT1. The regulated relationships between the molecules on the axis were verified using qRT-PCR and correlation analysis. Dual-luciferase reporter gene assay has been used to verify the binding site between miR-1299 and RHOT1. WB (Western blotting) and IHC (Immunohistochemical) were used to verify that RHOT1 may play the role of oncoprotein and affect the biological behavior of GC. Overall, hsa_circ_0005230 could enhance the EMT phenotype by promoting RHOT1 expression through sponging miR-1299, thus affecting the biological behavior of GC. Hsa_circ_0005230 can be easily identified as a potential diagnostic biomarker and assessment prognosis target for GC.
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Affiliation(s)
- Yan-Yu Peng
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Dan Sun
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yan Xin
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
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11
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The Role of SMAD4 Inactivation in Epithelial-Mesenchymal Plasticity of Pancreatic Ductal Adenocarcinoma: The Missing Link? Cancers (Basel) 2022; 14:cancers14040973. [PMID: 35205719 PMCID: PMC8870198 DOI: 10.3390/cancers14040973] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is currently one of the deadliest cancers. Despite the progress that has been made in the research of patient care and the understanding of pancreatic cancer, the survival rate remains mediocre. SMAD4, a tumor-suppressor gene, is specifically inactivated in 50–55% of pancreatic cancers. The role of SMAD4 protein loss in PDAC remains controversial, but seems to be associated with worse overall survival and metastasis. Here, we review the function of SMAD4 inactivation in the context of a specific biological process called epithelial–mesenchymal transition, as it has been increasingly associated with tumor formation, metastasis and resistance to therapy. By improving our understanding of these molecular mechanisms, we hope to find new targets for therapy and improve the care of patients with PDAC. Abstract Pancreatic ductal adenocarcinoma (PDAC) presents a five-year survival rate of 10% and its incidence increases over the years. It is, therefore, essential to improve our understanding of the molecular mechanisms that promote metastasis and chemoresistance in PDAC, which are the main causes of death in these patients. SMAD4 is inactivated in 50% of PDACs and its loss has been associated with worse overall survival and metastasis, although some controversy still exists. SMAD4 is the central signal transducer of the transforming growth factor-beta (TGF-beta) pathway, which is notably known to play a role in epithelial–mesenchymal transition (EMT). EMT is a biological process where epithelial cells lose their characteristics to acquire a spindle-cell phenotype and increased motility. EMT has been increasingly studied due to its potential implication in metastasis and therapy resistance. Recently, it has been suggested that cells undergo EMT transition through intermediary states, which is referred to as epithelial–mesenchymal plasticity (EMP). The intermediary states are characterized by enhanced aggressiveness and more efficient metastasis. Therefore, this review aims to summarize and analyze the current knowledge on SMAD4 loss in patients with PDAC and to investigate its potential role in EMP in order to better understand its function in PDAC carcinogenesis.
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12
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Su H, Wang C. Prognostic value of SMAD4 in resectable pancreatic cancer. POSTEP HIG MED DOSW 2022; 76:324-332. [DOI: 10.2478/ahem-2022-0036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
Introduction
The tumor gene SMAD4 was genetically inactivated in approximately half of pancreatic cancer (PC) patients. The correlation of SMAD4 gene expression in PC and its prognosis remains inconclusive. The aim of this study was to evaluate the association between loss of SMAD4 expression and the outcome of resectable PC.
Materials and Methods
A systematic review of the relevant electronic databases was conducted between SMAD4 expression and the outcome of PC patients until December 2020, including PubMed, Web of Science, and the China Journal Net. A meta-analysis was performed using STATA 12.0 and pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the strength of the association between SMAD4 gene expression and the prognosis of PC patients.
Results
Twelve studies were included. Our meta-analysis illustrated that there were no significant associations between the loss of SMAD4 gene expression and overall survival in resectable PC (HR=1.38, 95% CI 0.98–1.81). In addition, there was no evidence of publication bias, as showed by Begg's and Egger's test. There was no correlation between the loss of SMAD4 expression and local recurrence (OR=0.97, 95% CI 0.52–1.80, p=0.914), while the loss of SMAD4 gene expression was associated with increased risk of distant recurrence (OR=1.36, 95% CI 1.08–1.70, p=0.008).
Conclusions
After PC resection, the loss of SMAD4 gene expression was correlated with higher risk of distant recurrence, but not with local recurrence nor overall survival.
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Affiliation(s)
- Hui Su
- Department of Gastrointestinal Surgery , First Affiliated Hospital of Jinan University , Guangzhou , China
- Department of General Surgery, Hwa Mei Hospital , University of Chinese Academy of Sciences , Ningbo , China
- Ningbo Institute of Life and Health Industry , University of Chinese Academy of Sciences
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province
| | - Cunchuan Wang
- Department of Gastrointestinal Surgery , First Affiliated Hospital of Jinan University , Guangzhou , China
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13
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Principe DR, Timbers KE, Atia LG, Koch RM, Rana A. TGFβ Signaling in the Pancreatic Tumor Microenvironment. Cancers (Basel) 2021; 13:5086. [PMID: 34680235 PMCID: PMC8533869 DOI: 10.3390/cancers13205086] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/05/2021] [Accepted: 10/08/2021] [Indexed: 12/27/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor β (TGFβ) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFβ is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFβ signaling can have potent tumor-suppressive effects in epithelial cells, TGFβ signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFβ signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFβ pathway, as well as past and present attempts to advance TGFβ inhibitors in the treatment of PDAC patients.
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Affiliation(s)
- Daniel R. Principe
- Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL 60612, USA
- Department of Surgery, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.E.T.); (L.G.A.); (R.M.K.)
| | - Kaytlin E. Timbers
- Department of Surgery, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.E.T.); (L.G.A.); (R.M.K.)
| | - Luke G. Atia
- Department of Surgery, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.E.T.); (L.G.A.); (R.M.K.)
| | - Regina M. Koch
- Department of Surgery, University of Illinois at Chicago, Chicago, IL 60607, USA; (K.E.T.); (L.G.A.); (R.M.K.)
| | - Ajay Rana
- Jesse Brown Veterans Affairs Hospital, Chicago, IL 60612, USA
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14
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Gits HC, Tang AH, Harmsen WS, Bamlet WR, Graham RP, Petersen GM, Smyrk TC, Mahipal A, Kowalchuk RO, Ashman JB, Rule WG, Owen D, Neben Wittich MA, McWilliams RR, Halfdanarson T, Ma WW, Sio TT, Cleary SP, Truty MJ, Haddock MG, Hallemeier CL, Merrell KW. Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy. J Gastrointest Oncol 2021; 12:2275-2286. [PMID: 34790392 PMCID: PMC8576222 DOI: 10.21037/jgo-21-55] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 06/08/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy. METHODS A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models. RESULTS One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P<0.01, 95% confidence interval: 2.8-18.0) but not distant recurrence (P=0.06) or overall survival (P=0.73). On multivariable analysis, SMAD4 expression (hazard ratio 9.6, P<0.01, 95% confidence interval: 3.7-24.8) and adjuvant chemoradiotherapy (hazard ratio 0.3, P=0.01, 95% confidence interval: 0.1-0.8) were associated with higher and lower locoregional recurrence, respectively. CONCLUSIONS In patients with upfront resected pancreas cancer, SMAD4 expression was associated with an increased risk of locoregional recurrence. Prospective evaluation of the frequency of SMAD4 expression and validation of its predictive utility is warranted.
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Affiliation(s)
- Hunter C. Gits
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - Amy H. Tang
- Leroy T. Canoles Jr. Cancer Research Center, Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA
| | - William S. Harmsen
- Department of Biostatistics and Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - William R. Bamlet
- Department of Biostatistics and Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Rondell P. Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Gloria M. Petersen
- Department of Epidemiology and Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Thomas C. Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Amit Mahipal
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | | | | | - William G. Rule
- Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA
| | - Dawn Owen
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | | | | | | | - Wen Wee Ma
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Terence T. Sio
- Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA
| | - Sean P. Cleary
- Department of Hepatobiliary & Pancreas Surgery, Mayo Clinic, Rochester, MN, USA
| | - Mark J. Truty
- Department of Hepatobiliary & Pancreas Surgery, Mayo Clinic, Rochester, MN, USA
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15
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Qu L, Pan C, He SM, Lang B, Gao GD, Wang XL, Wang Y. The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases. Front Mol Neurosci 2019; 12:121. [PMID: 31213978 PMCID: PMC6555388 DOI: 10.3389/fnmol.2019.00121] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 04/25/2019] [Indexed: 12/22/2022] Open
Abstract
The small GTPases from the Ras superfamily play crucial roles in basic cellular processes during practically the entire process of neurodevelopment, including neurogenesis, differentiation, gene expression, membrane and protein traffic, vesicular trafficking, and synaptic plasticity. Small GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Different subfamilies of small GTPases have been linked to a number of non-neoplastic cerebral diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), intellectual disability, epilepsy, drug addiction, Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and a large number of idiopathic cerebral diseases. Here, we attempted to make a clearer illustration of the relationship between Ras superfamily GTPases and non-neoplastic cerebral diseases, as well as their roles in the neural system. In future studies, potential treatments for non-neoplastic cerebral diseases which are based on small GTPase related signaling pathways should be explored further. In this paper, we review all the available literature in support of this possibility.
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Affiliation(s)
- Liang Qu
- Department of Neurosurgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, China
| | - Chao Pan
- Beijing Institute of Biotechnology, Beijing, China
| | - Shi-Ming He
- Department of Neurosurgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, China.,Department of Neurosurgery, Xi'an International Medical Center, Xi'an, China
| | - Bing Lang
- The School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.,Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Guo-Dong Gao
- Department of Neurosurgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, China
| | - Xue-Lian Wang
- Department of Neurosurgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, China
| | - Yuan Wang
- Department of Neurosurgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, China
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16
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Tomasello G, Ghidini M, Costanzo A, Ghidini A, Russo A, Barni S, Passalacqua R, Petrelli F. Outcome of head compared to body and tail pancreatic cancer: a systematic review and meta-analysis of 93 studies. J Gastrointest Oncol 2019; 10:259-269. [PMID: 31032093 DOI: 10.21037/jgo.2018.12.08] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Even when resectable pancreatic cancer (PC) is associated with a dismal prognosis. Initial presentation varies according with primary tumor location. Aim of this systematic review and meta-analysis was to evaluate the prognosis associated with site (head versus body/tail) in patients with PC. Methods We searched PubMed, Cochrane Library, SCOPUS, Web of Science, EMBASE, Google Scholar, LILACS, and CINAHL databases from inception to March 2018. Studies reporting information on the independent prognostic role of site in PC and comparing overall survival (OS) in head versus body/tail tumors were selected. Data were aggregated using hazard ratios (HRs) for OS of head versus body/tail PC according to fixed- or random-effect model. Results A total of 93 studies including 254,429 patients were identified. Long-term prognosis of head was better than body/tail cancers (HR =0.96, 95% CI: 0.92-0.99; P=0.02). A pooled HR of 0.95 (95% CI: 0.92-0.99, P=0.02) from multivariate analysis only (n=77 publications) showed that head site was an independent prognostic factor for survival. Conclusions Primary tumor location in the head of the pancreas at the time of diagnosis is a predictor of better survival. Such indicator should be acknowledged when designing future studies, in particular in the operable and neoadjuvant setting.
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Affiliation(s)
| | - Michele Ghidini
- Oncology Department, ASST Ospedale di Cremona, Cremona, Italy
| | - Antonio Costanzo
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | | | - Alessandro Russo
- Surgical Oncology Unit, Surgery Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | - Sandro Barni
- Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy
| | | | - Fausto Petrelli
- Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy
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17
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Furnish M, Caino MC. Altered mitochondrial trafficking as a novel mechanism of cancer metastasis. Cancer Rep (Hoboken) 2019; 3:e1157. [PMID: 32671955 DOI: 10.1002/cnr2.1157] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 12/07/2018] [Accepted: 01/07/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Mammalian cells must constantly reprogram the distribution of mitochondria in order to meet the local demands for energy, calcium, redox balance, and other mitochondrial functions. Mitochondrial localization inside the cell is a result of a combination of movement along the microtubule tracks plus anchoring to actin filaments. RECENT FINDINGS Recent advances show that subcellular distribution of mitochondria can regulate tumor cell growth, proliferation/motility plasticity, metastatic competence, and therapy responses in tumors. In this review, we discuss our current understanding of the mechanisms by which mitochondrial subcellular distribution is regulated in tumor cells. CONCLUSIONS Mitochondrial trafficking is dysregulated in tumors. Accumulation of mitochondria at the leading edge of the cell supports energy expensive processes of focal adhesion dynamics, cell membrane dynamics, migration, and invasion.
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Affiliation(s)
- Madison Furnish
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - M Cecilia Caino
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, USA
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18
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Chen Q, Zeng X, Huang D, Qiu X. Identification of differentially expressed miRNAs in early-stage cervical cancer with lymph node metastasis across The Cancer Genome Atlas datasets. Cancer Manag Res 2018; 10:6489-6504. [PMID: 30568508 PMCID: PMC6276827 DOI: 10.2147/cmar.s183488] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background and aim Previous studies have suggested that lymph node metastasis (LNM) in early-stage cervical cancer (CESC) may affect the prognosis of patients and the outcomes of subsequent adjuvant therapy. However, research focused on miRNA expression in early-stage CESC patients with LNM remains limited. Therefore, it is necessary to identify prognostic miRNAs and determine their molecular mechanisms. Methods We evaluated the differentially expressed genes in early-stage CESC patients with LNM compared to patients without LNM and evaluated the prognostic significance of these differentially expressed genes by analyzing a public dataset from The Cancer Genome Atlas. Potential molecular mechanisms were investigated by gene ontology, the Kyoto Encyclopedia of Genes and Genomes, and protein–protein interaction network analyses. Results According to the The Cancer Genome Atlas data, hsa-miR-508, hsa-miR-509-2, and hsa-miR-526b expression levels were significantly lower in early-stage CESC patients with LNM than in patients without LNM. A multivariate analysis suggested that three miRNAs were prognostic factors for CESC (P<0.05). The target genes were identified to be involved in the MAPK, cAMP, PI3K/Akt, mTOR, and estrogen cancer signaling pathways. Protein–protein interaction network analysis showed that TP53, MMP1, NOTCH1, SMAD4, and NFKB1 were the most significant hub proteins. Conclusion Our results indicate that hsa-miR-508, hsa-miR-509-2, and hsa-miR-526b may be potential diagnostic biomarkers for early-stage CESC with LNM, and serve as prognostic predictors for patients with CESC.
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Affiliation(s)
- Qian Chen
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiaoyun Zeng
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China,
| | - Dongping Huang
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China,
| | - Xiaoqiang Qiu
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China,
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19
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Shen K, Xi Z, Xie J, Wang H, Xie C, Lee CS, Fahey P, Dong Q, Xu H. Guttiferone K suppresses cell motility and metastasis of hepatocellular carcinoma by restoring aberrantly reduced profilin 1. Oncotarget 2018; 7:56650-56663. [PMID: 27494863 PMCID: PMC5302942 DOI: 10.18632/oncotarget.10992] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 07/18/2016] [Indexed: 12/27/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignancy and the 5-year survival rate of advanced HCC is < 10%. Guttiferone K (GUTK) isolated from the Garcinia genus inhibited HCC cells migration and invasion in vitro and metastasis in vivo without apparent toxicity. Proteomic analysis revealed that actin-binding protein profilin 1 (PFN1) was markedly increased in the presence of GUTK. Over-expression of PFN1 mimicked the effect of GUTK on HCC cell motility and metastasis. The effect of GUTK on cell motility was diminished when PFN1 was over-expressed or silenced. Over-expression of PFN1 or incubation with GUTK decreased F-actin levels and the expression of proteins involved in actin nucleation, branching and polymerization. Moreover, a reduction of PFN1 protein levels was common in advanced human HCC and associated with poor survival rate. In conclusion, GUTK effectively suppresses the motility and metastasis of HCC cells mainly by restoration of aberrantly reduced PFN1 protein expression.
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Affiliation(s)
- Kaikai Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhichao Xi
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianling Xie
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Hua Wang
- Stanley Ho Center for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China
| | - Chanlu Xie
- School of Science and Health, The University of Western Sydney, Sydney, Australia
| | - C Soon Lee
- School of Science and Health, The University of Western Sydney, Sydney, Australia.,Central Clinical School and Bosch Institute, The University of Sydney, Sydney, Australia
| | - Paul Fahey
- School of Science and Health, The University of Western Sydney, Sydney, Australia
| | - Qihan Dong
- School of Science and Health, The University of Western Sydney, Sydney, Australia.,Central Clinical School and Bosch Institute, The University of Sydney, Sydney, Australia.,Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Hongxi Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Guanghua Integrative Medicine Hospital/ Shanghai University of T.C.M, Shanghai, China.,Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
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20
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Ormanns S, Haas M, Remold A, Kruger S, Holdenrieder S, Kirchner T, Heinemann V, Boeck S. The Impact of SMAD4 Loss on Outcome in Patients with Advanced Pancreatic Cancer Treated with Systemic Chemotherapy. Int J Mol Sci 2017; 18:E1094. [PMID: 28534865 PMCID: PMC5455003 DOI: 10.3390/ijms18051094] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 04/19/2017] [Accepted: 05/15/2017] [Indexed: 02/04/2023] Open
Abstract
The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and outcome in PC patients receiving palliative chemotherapy. Using immunohistochemistry, we examined SMAD4 expression in tumor tissue of 143 aPC pts treated within completed prospective clinical and biomarker trials. In uni- and multivariate analyses, SMAD4 expression status was correlated to clinicopathological patient characteristics and outcome. At chemotherapy initiation, 128 pts had metastatic PC; most pts (n = 99) received a gemcitabine-based regimen. SMAD4 loss was detected in 92 pts (64%); patient characteristics such as gender, age, tumor grading, disease stage or number of metastatic sites had no significant impact on tumoral SMAD4 status. In univariate analyses, SMAD4 loss had no impact on overall survival (hazard ratio (HR) 1.008, p = 0.656); however, we observed a prolonged progression-free survival (HR 1.565, p = 0.038) in pts with tumoral SMAD4 loss. This finding was confirmed in multivariate analyses (HR 1.790, p = 0.040), but only for gemcitabine-treated pts. In contrast to previous studies in resectable PC, loss of SMAD4 expression was not associated with a negative outcome in patients with advanced PC receiving systemic chemotherapy.
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Affiliation(s)
- Steffen Ormanns
- Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Str. 36, 80337 Munich, Germany.
| | - Michael Haas
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany.
| | - Anna Remold
- Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Str. 36, 80337 Munich, Germany.
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany.
| | - Stephan Kruger
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany.
| | - Stefan Holdenrieder
- Institute of Laboratory Medicine, German Heart Centre Munich, Technische Universität München, 80333 Munich, Germany.
- Institute of Clinical Chemistry and Clinical Pharmacology, Universitätsklinikum Bonn, 53127 Bonn, Germany.
| | - Thomas Kirchner
- Institute of Pathology, Ludwig-Maximilians Universität München, Thalkirchner Str. 36, 80337 Munich, Germany.
- Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
| | - Volker Heinemann
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany.
- Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
| | - Stefan Boeck
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Marchioninistr. 15, 81377 Munich, Germany.
- Deutsches Konsortium für Translationale Krebsforschung (DKTK, German Cancer Consortium), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
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Schorn S, Demir IE, Haller B, Scheufele F, Reyes CM, Tieftrunk E, Sargut M, Goess R, Friess H, Ceyhan GO. The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma - A systematic review and meta-analysis. Surg Oncol 2017; 26:105-115. [PMID: 28317579 DOI: 10.1016/j.suronc.2017.01.007] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/28/2017] [Accepted: 01/31/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVES To assess the impact of neural invasion/NI on overall survival/OS and tumor recurrence in pancreatic ductal adenocarcinoma/PDAC. SUMMARY BACKGROUND DATA NI is a histopathological hallmark of PDAC. Although some studies suggested an important role for NI on OS, disease-free/DFS and progression-free survival/PFS in PDAC, there is still no consensus on the actual role of NI on survival and local recurrence in PDAC. METHODS Pubmed, Cochrane library, Ovid and Google Scholar were screened for the terms "pancreatic ductal adenocarcinoma", "pancreatic cancer", "survival", "tumor recurrence" and "perineural invasion". The Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were used for systematic review and meta-analysis. Articles meeting predefined criteria were critically analysed on relevance, and meta-analyses were performed by pooling univariate and multivariate hazard ratios/HR. RESULTS A total number of 25 studies on the influence of NI on tumor recurrence, and 121 studies analysing the influence of NI on survival were identified by systematic review. The HR of the univariate (HR 1.88; 95%-CI 1.71-2.07; p < 0.00001) and multivariate meta-analysis (HR 1.68; 95%-CI 1.47-1.92; p < 0.00001) showed a major impact of NI on OS. Likewise, NI was associated with decreased DFS (HR 2.53; 95%-CI: 1.67-3.83; p = 0.0001) and PFS (HR 2.41; 95%-CI: 1.73-3.37: p < 0.00001) multivariate meta-analysis. CONCLUSIONS Although the power of this study is limited by missing pathological procedures to assess the true incidence of NI, NI appears to be an independent prognostic factor for OS, DFS and PFS in PDAC. Therefore, NI should be increasingly considered in patient stratification and in the development of novel therapeutic algorithms.
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Affiliation(s)
- Stephan Schorn
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Bernhard Haller
- Institute of Medical Statistics and Epidemiology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Florian Scheufele
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Carmen Mota Reyes
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Elke Tieftrunk
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Mine Sargut
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Ruediger Goess
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Güralp Onur Ceyhan
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Germany.
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22
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Słotwiński R, Słotwińska SM. Diagnostic value of selected markers and apoptotic pathways for pancreatic cancer. Cent Eur J Immunol 2017; 41:392-403. [PMID: 28450803 PMCID: PMC5382885 DOI: 10.5114/ceji.2016.65139] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 09/26/2016] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer occupies the fourth place as a cause of death from cancer, and the mortality rate is similar to the number of newly detected cases. Due to the late diagnosis, only 5-6% of patients with pancreatic cancer survive for five years. Given that early diagnosis is critical for improving patients' survival rates, there is an urgent need for the discovery and validation of new biomarkers with sufficient sensitivity and specificity to help diagnose pancreatic cancer early. Detection of serum tumor markers (CA19-9, CEA, CA125 and CA242) is conducive to the early diagnosis of pancreatic cancer. The combination of miR-16, miR-196a and CA19-9 plasma level was more effective, especially in early tumor screening. Furthermore, recent studies reported that mainly miR-21, miR-155 and miR-196 were dysregulated in IPMN (intraductal papillary mucinous neoplasms) and PanIN (pancreatic intraepithelial neoplasia) lesions, suggesting their usefulness as early biomarkers of these diseases. The reduced rate of apoptosis plays a crucial role in carcinogenesis, and it is one of the most important characteristics acquired by pancreatic cancer cells, which protects them from attack by the immune system and reduces the effectiveness of pharmacological treatment. This review summarizes the data concerning the clinical utility of selected biomarkers in pancreatic cancer patients. The review mainly focuses on the genetic aspects of signaling pathway disorders associated with apoptosis in the pathogenesis and diagnosis of pancreatic cancer.
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Affiliation(s)
- Robert Słotwiński
- Department of Surgical Research and Transplantology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Poland
- Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw, Poland
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23
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Yan L, Jiao D, Hu H, Wang J, Tang X, Chen J, Chen Q. Identification of lymph node metastasis-related microRNAs in lung adenocarcinoma and analysis of the underlying mechanisms using a bioinformatics approach. Exp Biol Med (Maywood) 2016; 242:709-717. [PMID: 28299977 DOI: 10.1177/1535370216677353] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
This study aimed to screen lymphatic metastasis-related microRNAs (miRNAs) in lung adenocarcinoma and explore their underlying mechanisms using bioinformatics. The miRNA expression in primary lung adenocarcinoma, matched adjacent non-tumorigenic and lymph node metastasis tissues of patients were profiled via microarray. The screened metastasis-related miRNAs were then validated using quantitative real-time PCR in a second cohort of lung adenocarcinoma patients with lymphatic metastasis. Significance was determined using a paired t-test. Target genes of the metastasis-related miRNAs were predicted using TargetScan, and transcription factors (TFs) were predicted based on the TRANSFAC and ENCODE databases. Furthermore, the related long non-coding RNAs (lncRNAs) were screened with starBase v2.0. The miRNA-TF-mRNA and lncRNA-miRNA-mRNA networks were constructed to determine the key interactions associated with lung adenocarcinoma metastasis. According to the miRNA microarray results, there were 10 miRNAs that were differentially expressed in metastatic tissues compared with primary tumor and adjacent non-tumorigenic tissues. Among them were increased levels of miR-146a-5p, miR-342-3p, and miR-150-5p, which were validated in the second cohort. Based on the miRNA-TF-mRNA network, vascular endothelial growth factor A and transcription factors (TFs) including TP53, SMAD4, and EP300 were recognized as critical targets of the three miRNAs. Interactions involving SNHG16-miR-146a-5p-SMAD4 and RP6-24A23.7-miR-342-3p/miR-150-5p-EP300 were highlighted according to the lncRNA-miRNA-mRNA network. miR-146a-5p, miR-342-3p, and miR-150-5p are lymphatic metastasis-related miRNAs in lung adenocarcinoma. Bioinformatics analyses demonstrated that SNHG16 might inhibit the interaction between miR-146a-5p and SMAD4, while RP6-24A23.7 might weaken miR-342-3p-EP300 and miR-150-5p-EP300 interactions in metastasis.
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Affiliation(s)
- Li Yan
- 1 Department of Oncology, The 117th Hospital of PLA, Hangzhou 310013, P.R. China
| | - Demin Jiao
- 2 Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou 310013, P.R. China
| | - Huizhen Hu
- 2 Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou 310013, P.R. China
| | - Jian Wang
- 2 Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou 310013, P.R. China
| | - Xiali Tang
- 2 Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou 310013, P.R. China
| | - Jun Chen
- 2 Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou 310013, P.R. China
| | - Qingyong Chen
- 2 Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou 310013, P.R. China
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Maggi JC, Hogg ME, Zureikat AH, Zeh HJ. Update on the Management of Pancreatic Cancer: Determinants for Surgery and Widening the Therapeutic Window of Surgical Resection. CURRENT SURGERY REPORTS 2016. [DOI: 10.1007/s40137-016-0146-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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25
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Roeder F. Neoadjuvant radiotherapeutic strategies in pancreatic cancer. World J Gastrointest Oncol 2016; 8:186-197. [PMID: 26909133 PMCID: PMC4753169 DOI: 10.4251/wjgo.v8.i2.186] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 10/12/2015] [Accepted: 12/11/2015] [Indexed: 02/05/2023] Open
Abstract
This review summarizes the current status of neoadjuvant radiation approaches in the treatment of pancreatic cancer, including a description of modern radiation techniques, and an overview on the literature regarding neoadjuvant radio- or radiochemotherapeutic strategies both for resectable and irresectable pancreatic cancer. Neoadjuvant chemoradiation for locally-advanced, primarily non- or borderline resectable pancreas cancer results in secondary resectability in a substantial proportion of patients with consecutively markedly improved overall prognosis and should be considered as possible alternative in pretreatment multidisciplinary evaluations. In resectable pancreatic cancer, outstanding results in terms of response, local control and overall survival have been observed with neoadjuvant radio- or radiochemotherapy in several phase I/II trials, which justify further evaluation of this strategy. Further investigation of neoadjuvant chemoradiation strategies should be performed preferentially in randomized trials in order to improve comparability of the current results with other treatment modalities. This should include the evaluation of optimal sequencing with newer and more potent systemic induction therapy approaches. Advances in patient selection based on new molecular markers might be of crucial interest in this context. Finally modern external beam radiation techniques (intensity-modulated radiation therapy, image-guided radiation therapy and stereotactic body radiation therapy), new radiation qualities (protons, heavy ions) or combinations with alternative boosting techniques widen the therapeutic window and contribute to the reduction of toxicity.
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Shugang X, Hongfa Y, Jianpeng L, Xu Z, Jingqi F, Xiangxiang L, Wei L. Prognostic Value of SMAD4 in Pancreatic Cancer: A Meta-Analysis. Transl Oncol 2016; 9:1-7. [PMID: 26947875 PMCID: PMC4800056 DOI: 10.1016/j.tranon.2015.11.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 11/08/2015] [Accepted: 11/10/2015] [Indexed: 12/15/2022] Open
Abstract
PURPOSE: The prognostic value of SMAD4 in pancreatic cancer has been evaluated in several studies. However, the conclusions remain controversial. Therefore, we aimed to evaluate the association between SMAD4 expression and the outcome of pancreatic cancer patients by performing a meta-analysis. METHODS: We systematically searched for relevant studies evaluating the relationship between SMAD4 expression and the outcome of pancreatic cancer patients until May 2015. A meta-analysis was performed using STATA 12.0, and pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the strength of the association between SMAD4 expression and the prognosis of pancreatic cancer patients. RESULTS: The analysis included 1762 patients from 14 studies, with 1401 patients from 11 studies and 927 patients from 8 studies included in the univariate and multivariate analyses, respectively. Loss of SMAD4 expression was found to be significantly correlated with poor overall survival, with the combined HR (95% CI) of 1.20 (1.03-1.40). After adjusting for potential confounders using the Cox regression model, the pooled HR (95% CI) was 1.88 (1.31-2.70). In subgroup analysis, study region, number of patients, follow-up duration, and cutoff value were found to affect the significance of the association between loss of SMAD4 expression and poor prognosis. In addition, there was no evidence of publication bias, as suggested by Begg’s and Egger’s test. CONCLUSIONS: Loss of SMAD4 was associated with poor survival and was a negative prognostic indicator in patients with pancreatic cancer.
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Affiliation(s)
- Xing Shugang
- The Key Laboratory of Pathobiology, Ministry of Education, the College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yang Hongfa
- Department of Neurosurgery, The First Clinical Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Liu Jianpeng
- Department of Neurosurgery, The First Clinical Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Zheng Xu
- Department of Neurosurgery, The First Clinical Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Feng Jingqi
- The Key Laboratory of Pathobiology, Ministry of Education, the College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Li Xiangxiang
- The Key Laboratory of Pathobiology, Ministry of Education, the College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Li Wei
- The Key Laboratory of Pathobiology, Ministry of Education, the College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.
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Ahn DH, Williams TM, Goldstein DA, El-Rayes B, Bekaii-Saab T. Adjuvant therapy for pancreas cancer in an era of value based cancer care. Cancer Treat Rev 2016; 42:10-7. [PMID: 26620819 PMCID: PMC4976619 DOI: 10.1016/j.ctrv.2015.11.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 11/08/2015] [Accepted: 11/12/2015] [Indexed: 12/16/2022]
Abstract
In resected pancreas cancer, adjuvant therapy improves outcomes and is considered the standard of care for patients who recover sufficiently post operatively. Chemotherapy or combined chemotherapy and radiation therapy (chemoradiation; CRT) are strategies used in the adjuvant setting. However, there is a lack of evidence to suggest whether the addition of RT to chemotherapy translates to an improvement in clinical outcomes. This is true even when accounting for the subset of patients with a higher risk for recurrence, such as those with R1 and lymph node positive disease. When considering the direct and indirect costs, impact on quality of life and questionable added clinical benefit, the true "net health benefit" from added RT to chemotherapy becomes more uncertain. Future directions, including the utilization of modern RT, integration of novel therapies, and intensifying chemotherapy regimens may improve outcomes in resected pancreas cancer.
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Affiliation(s)
- Daniel H Ahn
- The Ohio State University Wexner Medical Center, 310 W. 10th Ave, Columbus, OH, United States
| | - Terence M Williams
- The Ohio State University Wexner Medical Center, 310 W. 10th Ave, Columbus, OH, United States
| | - Daniel A Goldstein
- Winship Cancer Institute, Emory University, 1365-C Clifton Rd NE, Atlanta, GA, United States
| | - Bassel El-Rayes
- Winship Cancer Institute, Emory University, 1365-C Clifton Rd NE, Atlanta, GA, United States
| | - Tanios Bekaii-Saab
- The Ohio State University Wexner Medical Center, 310 W. 10th Ave, Columbus, OH, United States.
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Li Q, Yao L, Wei Y, Geng S, He C, Jiang H. Role of RHOT1 on migration and proliferation of pancreatic cancer. Am J Cancer Res 2015; 5:1460-1470. [PMID: 26101710 PMCID: PMC4473323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 03/12/2015] [Indexed: 06/04/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most malignant tumors. Rho GTPases can affect several types of human cancers, including PC. In this study, we investigated the role of Ras homolog family member T1 (RHOT1), a new member of Rho GTPases in PC. IHC results showed that RHOT1 was expressed significantly higher in PC tissues than paracancerous tissues (P<0.01) and SMAD family member 4 (SMAD4) was expressed lower in PC tissues (P<0.01). RHOT1 was widely expressed in PC cell lines analyzed by reverse transcription PCR (RT-PCR), real-time quantitative PCR (RT-qPCR) and western blotting (WB). SiRNA-RHOT1 significantly suppressed the proliferation and migration of SW1990 cells. Moreover, SMAD4 was identified as an effector of RHOT1. Our findings suggest that RHOT1 can regulate cell migration and proliferation by suppressing the expression of SMAD4 in PC, which may provide a novel sight to explore the mechanism and therapeutic strategy for PC.
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Affiliation(s)
- Qingqing Li
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of MedicineShanghai 200120, China
| | - Lei Yao
- Department of Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of MedicineShanghai 200120, China
| | - Youzhen Wei
- Department of Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of MedicineShanghai 200120, China
| | - Shasha Geng
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of MedicineShanghai 200120, China
| | - Chengzhi He
- Department of Gastroenterology, Institute of Digestive Diseases, Tongji Hospital Affiliated to Tongji UniversityShanghai 200065, China
| | - Hua Jiang
- Department of Geriatrics, Shanghai East Hospital, Tongji University School of MedicineShanghai 200120, China
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Tamburrino D, Partelli S, Crippa S, Manzoni A, Maurizi A, Falconi M. Selection criteria in resectable pancreatic cancer: A biological and morphological approach. World J Gastroenterol 2014; 20:11210-11215. [PMID: 25170205 PMCID: PMC4145759 DOI: 10.3748/wjg.v20.i32.11210] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 02/19/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive tumors with a low rate of survival. Surgery is the only curative treatment for PDA, although only 20% of patients are resectable at diagnosis. During the last decade there was an improvement in survival in patients affected by PDA, possibly explained by the advances in cancer therapy and by improve patient selection by pancreatic surgeons. It is necessary to select patients not only on the basis of surgical resectability, but also on the basis of the biological nature of the tumor. Specific preoperative criteria can be identified in order to select patients who will benefit from surgical resection. Duration of symptoms and level of carbohydrate antigen 19.9 in resectable disease should be considered to avoid R1 resection and early relapse. Radiological assessment can help surgeons to distinguish resectable disease from borderline resectable disease and locally advanced pancreatic cancer. Better patient selection can increase survival rate and neoadjuvant treatment can help surgeons select patients who will benefit from surgery.
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30
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Boone BA, Sabbaghian S, Zenati M, Marsh JW, Moser AJ, Zureikat AH, Singhi AD, Zeh HJ, Krasinskas AM. Loss of SMAD4 staining in pre-operative cell blocks is associated with distant metastases following pancreaticoduodenectomy with venous resection for pancreatic cancer. J Surg Oncol 2014; 110:171-175. [PMID: 24665063 DOI: 10.1002/jso.23606] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 03/01/2014] [Indexed: 01/03/2025]
Abstract
BACKGROUND AND OBJECTIVES Venous resection of locally advanced pancreatic cancer is associated with increased morbidity and mortality; therefore identification of patients most likely to benefit from this aggressive surgical approach is an important goal. Loss of SMAD4 staining on resected specimens has been associated with outcomes. Few studies have evaluated the prognostic significance of SMAD4 staining of pre-operative cell blocks, which would be useful in clinical decision making for patients with locally advanced disease. METHODS Clinical data were retrospectively evaluated from all patients undergoing pancreaticoduodenectomy with venous resection. Immunohistochemical staining for SMAD4 was performed on pre-operative cell blocks and subsequent post-operative resections. RESULTS One hundred seventeen patients underwent pancreaticoduodenectomy with venous resection. Sixty had sufficient specimens available for SMAD4 staining. SMAD4 loss was observed in 70% of resections and was associated with earlier time to metastatic disease. Pre-operative SMAD4 loss correlated well with post-operative staining and was associated with six times higher likelihood of developing metastases. CONCLUSION In this pilot study, preoperative SMAD4 staining showed a strong correlation with postoperative staining and predicted metastases in locally advanced cancer. Preoperative SMAD4 status may be considered as one of several factors when selecting patients most likely to benefit from aggressive en bloc venous resection.
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Affiliation(s)
- Brian A Boone
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
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Jazieh KA, Foote MB, Diaz LA. The clinical utility of biomarkers in the management of pancreatic adenocarcinoma. Semin Radiat Oncol 2014; 24:67-76. [PMID: 24635863 DOI: 10.1016/j.semradonc.2013.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and survival rates have seen minimal improvement over the past few decades. Although results are poor, surgical resection is considered the only curative therapeutic intervention for pancreatic cancer, thereby emphasizing the significance of effective diagnostic and prognostic tools to improve outcomes. As such, biomarkers play a promising role in the development of personalized treatments for patients with pancreatic cancer. Prognostic biomarkers, such as serum carbohydrate antigen 19-9 in particular, as well as cancer stem cell markers, provide valuable insight into the biological processes of an individual and their likely course of disease. This, consequently, allows for the assessment of optimal therapeutic intervention. Furthermore, current efforts target putative predictive biomarkers such as BRCA2, PALB2, and SPARC so as to determine their influence on tumor response on targeted therapies. As research progresses, more evidence will provide clinicians with guidelines on the utilization of biomarkers to accurately stage and tailor personalized treatment to the needs of specific patients with pancreatic cancer.
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Affiliation(s)
- Khalid A Jazieh
- The Swim Across America Laboratory, The Ludwig Center for Cancer Genetics and Therapeutics, Baltimore, MD; The Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
| | - Michael B Foote
- The Swim Across America Laboratory, The Ludwig Center for Cancer Genetics and Therapeutics, Baltimore, MD; The Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
| | - Luis A Diaz
- The Swim Across America Laboratory, The Ludwig Center for Cancer Genetics and Therapeutics, Baltimore, MD; The Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.
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Xiao Z, Luo G, Liu C, Wu C, Liu L, Liu Z, Ni Q, Long J, Yu X. Molecular mechanism underlying lymphatic metastasis in pancreatic cancer. BIOMED RESEARCH INTERNATIONAL 2014; 2014:925845. [PMID: 24587996 PMCID: PMC3919106 DOI: 10.1155/2014/925845] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 11/10/2013] [Indexed: 02/07/2023]
Abstract
As the most challenging human malignancies, pancreatic cancer is characterized by its insidious symptoms, low rate of surgical resection, high risk of local invasion, metastasis and recurrence, and overall dismal prognosis. Lymphatic metastasis, above all, is recognized as an early adverse event in progression of pancreatic cancer and has been described to be an independent poor prognostic factor. It should be noted that the occurrence of lymphatic metastasis is not a casual or stochastic but an ineluctable and designed event. Increasing evidences suggest that metastasis-initiating cells (MICs) and the microenvironments may act as a double-reed style in this crime. However, the exact mechanisms on how they function synergistically for this dismal clinical course remain largely elusive. Therefore, a better understanding of its molecular and cellular mechanisms involved in pancreatic lymphatic metastasis is urgently required. In this review, we will summarize the latest advances on lymphatic metastasis in pancreatic cancer.
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Affiliation(s)
- Zhiwen Xiao
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Guopei Luo
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Chen Liu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Chuntao Wu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Liang Liu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Zuqiang Liu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Quanxing Ni
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Jiang Long
- Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China ; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China ; Pancreatic Cancer Institute, Fudan University, No. 270, Dong'An Road, Xuhui District, Shanghai 200032, China
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Xu H, Yu H, Zhang X, Shen X, Zhang K, Sheng H, Dai S, Gao H. UNC51-like kinase 1 as a potential prognostic biomarker for hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2013; 6:711-717. [PMID: 23573318 PMCID: PMC3606861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 02/27/2013] [Indexed: 06/02/2023]
Abstract
Autophagy is a fundamental cell biological process that confers stress tolerance, limits damage, and sustains viability under adverse conditions. Defective autophagy is associated with diverse diseases. The study aimed to investigate the relationship between UNC51-like kinase 1 (ULK1) expression and clinicopathological characteristics as well as survival in patients with hepatocellular carcinoma (HCC). Expression levels of ULK1 in 55 paired HCC and paracancerous tissues were examined using immunohistochemistry. Although not statistically significant, the expression of ULK1 in adjacent peritumoural tissue was lower than those in HCC tissues (P = 0.113). Expression level of ULK1 was significantly associated with tumor size (P = 0.015) after adjusted for age, sex, histologic grade, cirrhosis and TNM. Survival analysis showed that patients with high ULK1 expression had worse survival time than those with low ULK1 expression (hazard rate = 2.684, 95% CI 1.029-7.006, P = 0.044). The findings of the present study provide evidence that ULK1 represents a potential novel prognostic biomarker for HCC patients and may play an important role during the progression of HCC.
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Affiliation(s)
- Hongtao Xu
- Department of Hepatology, Taizhou People’s HospitalJiangsu, China
| | - Hong Yu
- Department of Pathology, Taizhou People’s HospitalJiangsu, China
| | - Xiaoyan Zhang
- National Engineering Center for Biochip at ShanghaiShanghai, China
| | - Xiaoying Shen
- National Engineering Center for Biochip at ShanghaiShanghai, China
| | - Kehao Zhang
- National Engineering Center for Biochip at ShanghaiShanghai, China
- CMC Biobank and Translational medicine InstituteJiangsu, China
| | - Haihui Sheng
- National Engineering Center for Biochip at ShanghaiShanghai, China
- CMC Biobank and Translational medicine InstituteJiangsu, China
| | - Shengbin Dai
- Department of Oncology, Taizhou People’s HospitalJiangsu, China
| | - Hengjun Gao
- Institute of Digestive Disease, Department of Gastroenterology, Tongji Hospital affiliated to Tongji Medical College, Tongji UniversityShanghai, China
- Shanghai Engineering Center for Molecular MedicineShanghai, China
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