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Höppener DJ, Grünhagen DJ, Eggermont AMM, van der Veldt AAM, Verhoef C. An Overview of Liver Directed Locoregional Therapies. Hematol Oncol Clin North Am 2025; 39:103-123. [PMID: 39510668 DOI: 10.1016/j.hoc.2024.08.010] [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] [Indexed: 11/15/2024]
Abstract
An overview of all liver-directed locoregional therapies, including surgical resection for melanoma liver metastases (MLMs), is provided. MLM patients are divided by their primary melanoma location; cutaneous, uvea (eye), and mucosal melanoma. If patients with isolated cutaneous MLMs are considered for surgical resection, treatment with systemic therapy should be part of the treatment course. For uveal MLMs, complete surgical or ablative treatment of all MLMs suggests superior results compared with other liver-directed or systemic therapies, based on current evidence, no recommendations for any liver-directed regional therapy in the treatment of mucosal MLMs can be made.
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Affiliation(s)
- Diederik J Höppener
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Dirk J Grünhagen
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Alexander M M Eggermont
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands
| | - Astrid A M van der Veldt
- Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Cornelis Verhoef
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands.
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Xiao H, Wang G, Zhao M, Shuai W, Ouyang L, Sun Q. Ras superfamily GTPase activating proteins in cancer: Potential therapeutic targets? Eur J Med Chem 2023; 248:115104. [PMID: 36641861 DOI: 10.1016/j.ejmech.2023.115104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/06/2023] [Accepted: 01/07/2023] [Indexed: 01/11/2023]
Abstract
To search more therapeutic strategies for Ras-mutant tumors, regulators of the Ras superfamily involved in the GTP/GDP (guanosine triphosphate/guanosine diphosphate) cycle have been well concerned for their anti-tumor potentials. GTPase activating proteins (GAPs) provide the catalytic group necessary for the hydrolysis of GTPs, which accelerate the switch by cycling between GTP-bound active and GDP-bound inactive forms. Inactivated GAPs lose their function in activating GTPase, leading to the continuous activation of downstream signaling pathways, uncontrolled cell proliferation, and eventually carcinogenesis. A growing number of evidence has shown the close link between GAPs and human tumors, and as a result, GAPs are believed as potential anti-tumor targets. The present review mainly summarizes the critically important role of GAPs in human tumors by introducing the classification, function and regulatory mechanism. Moreover, we comprehensively describe the relationship between dysregulated GAPs and the certain type of tumor. Finally, the current status, research progress, and clinical value of GAPs as therapeutic targets are also discussed, as well as the challenges and future direction in the cancer therapy.
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Affiliation(s)
- Huan Xiao
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Guan Wang
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Min Zhao
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Wen Shuai
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China
| | - Qiu Sun
- State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, 610041, China.
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Li WJ, Wu DW, Zhou YF, Zhang CW, Liao XW. Prognostic biomarker replication factor C subunit 5 and its correlation with immune infiltrates in acute myeloid leukemia. Hematology 2022; 27:555-564. [PMID: 35544695 DOI: 10.1080/16078454.2022.2072064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE To determine the role of replication factor C subunit 5 (RFC5) in acute myeloid leukemia (AML) from four aspects: expression, prognosis, biological functions, and its effects on the immune system. METHODS The RFC5 gene expression and survival analyses, biological function analyses including functional enrichment analysis of genes co-expressed with RFC5, RFC5-interacted gene network construction, gene set enrichment analysis (GSEA), and immune infiltration analysis were performed using data based on GDC TCGA and GEO. The CIBERSORT algorithm was employed to quantify immune cell fractions. All the statistical analyses were performed in SPSS software, GraphPad Prism, and R software. RESULTS RFC5 expression was abnormally expressed in AML (P <0.05). Notably, differential RFC5 expression was observed among different FAB AML subtypes and hematopoietic lineages (all P <0.05). More importantly, high RFC5 expression served as an independent prognostic factor for the poor overall survival of AML patients (P <0.001). Enrichment analyses revealed that RFC5 was involved in cell cycle-related pathways in AML. CIBERSORT analysis showed high proportions of M2 macrophages in the high RFC5 expression group. CONCLUSIONS RFC5 might serve as an effective and robust biomarker for the diagnosis and prognosis of AML. RFC5 might be involved in the AML progression via cell cycle regulation. Moreover, the correlation between RFC5 and immune cells might provide potential assistance for AML treatment.
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Affiliation(s)
- Wang-Jun Li
- Department of Pediatric Surgery, Wenzhou Medical University, Wenzhou, People's Republic of China.,Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
| | - Dong-Wei Wu
- Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
| | - Yi-Feng Zhou
- Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
| | - Chen-Wei Zhang
- Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
| | - Xiao-Wei Liao
- Department of Pediatric Surgery, Lishui people's Hospital, Lishui, People's Republic of China
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Wu G, Zhou J, Zhu X, Tang X, Liu J, Zhou Q, Chen Z, Liu T, Wang W, Xiao X, Wu T. Integrative analysis of expression, prognostic significance and immune infiltration of RFC family genes in human sarcoma. Aging (Albany NY) 2022; 14:3705-3719. [PMID: 35483337 PMCID: PMC9085243 DOI: 10.18632/aging.204039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/13/2022] [Indexed: 11/25/2022]
Abstract
Objective: To reveal the expression and prognostic value of replication factor C family genes (RFCs) in patients with sarcoma. Results: The results showed that the mRNA expression levels of RFC2, RFC3, RFC4, and RFC5 were increased in sarcoma tissues. In addition, Cancer Cell Line Encyclopedia (CCLE) dataset analysis indicated that RFC1, RFC2, RFC3, RFC4, and RFC5 were elevated expressed in sarcoma cell lines. Moreover, Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier Plotter showed that highly expressed RFC2-5 were associated with poor overall survival (OS) or relapse-free survival (RFS) in sarcoma patients. The results of the Tumor Immune Estimation Resource (TIMER) database indicated that the expression of RFCs was negatively correlated with the infiltration of CD4+ T cells and macrophages. Conclusions: There were significant differences in the expression of RFCs between normal tissue and sarcoma tissue, and RFC2, RFC3, RFC4, and RFC5 might be promising prognostic biomarkers for sarcoma. Methods: The expression of RFCs was analyzed using the ONCOMINE dataset and GEPIA dataset. CCLE dataset was used to assess the expression of RFCs in the cancer cell line. The prognostic value of RFCs was evaluated by GEPIA and Kaplan-Meier analysis. Furthermore, the association between RFCs and their co-expressed genes were explored via ONCOMINE and GEPIA datasets. We used the TIMER dataset to analyze the immune cell infiltration of RFCs in sarcoma.
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Affiliation(s)
- Gen Wu
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.,Clinical Medicine Eight-Year Program, 02 Class, 2014 Grade, Central South University, Changsha 410013, Hunan Province, China
| | - Jian Zhou
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xi Zhu
- Department of Internal Medicine III, University Hospital, Ludwig Maximilian University, Munich 81377, Germany
| | - Xianzhe Tang
- Department of Orthopedics, Chenzhou No.1 People's Hospital, Chenzhou 423000, Hunan, China
| | - Jie Liu
- Department of Cardiology, The Fourth Hospital of Changsha, Changsha 410006, Hunan, China
| | - Qiong Zhou
- Department of Cardiology, The Fourth Hospital of Changsha, Changsha 410006, Hunan, China
| | - Ziyuan Chen
- Department of Orthopedics, The First People's Hospital of Changde City, Changde 415003, Hunan, China
| | - Tang Liu
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Wanchun Wang
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xungang Xiao
- Department of Orthopedics, Chenzhou No.1 People's Hospital, Chenzhou 423000, Hunan, China
| | - Tong Wu
- Department of Emergency, The First Hospital of Changsha, Changsha 410005, Hunan, China
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Rossi E, Croce M, Reggiani F, Schinzari G, Ambrosio M, Gangemi R, Tortora G, Pfeffer U, Amaro A. Uveal Melanoma Metastasis. Cancers (Basel) 2021; 13:5684. [PMID: 34830841 PMCID: PMC8616038 DOI: 10.3390/cancers13225684] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023] Open
Abstract
Uveal melanoma (UM) is characterized by relatively few, highly incident molecular alterations and their association with metastatic risk is deeply understood. Nevertheless, this knowledge has so far not led to innovative therapies for the successful treatment of UM metastases or for adjuvant therapy, leaving survival after diagnosis of metastatic UM almost unaltered in decades. The driver mutations of UM, mainly in the G-protein genes GNAQ and GNA11, activate the MAP-kinase pathway as well as the YAP/TAZ pathway. At present, there are no drugs that target the latter and this likely explains the failure of mitogen activated kinase kinase inhibitors. Immune checkpoint blockers, despite the game changing effect in cutaneous melanoma (CM), show only limited effects in UM probably because of the low mutational burden of 0.5 per megabase and the unavailability of antibodies targeting the main immune checkpoint active in UM. The highly pro-tumorigenic microenvironment of UM also contributes to therapy resistance. However, T-cell redirection by a soluble T-cell receptor that is fused to an anti-CD3 single-chain variable fragment, local, liver specific therapy, new immune checkpoint blockers, and YAP/TAZ specific drugs give new hope to repeating the success of innovative therapy obtained for CM.
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Affiliation(s)
- Ernesto Rossi
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (E.R.); (G.S.); (G.T.)
| | - Michela Croce
- Laboratory of Biotherapies, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (M.C.); (R.G.)
| | - Francesco Reggiani
- Laboratory of Epigenetics, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (F.R.); (M.A.); (A.A.)
| | - Giovanni Schinzari
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (E.R.); (G.S.); (G.T.)
- Medical Oncology, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Marianna Ambrosio
- Laboratory of Epigenetics, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (F.R.); (M.A.); (A.A.)
| | - Rosaria Gangemi
- Laboratory of Biotherapies, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (M.C.); (R.G.)
| | - Giampaolo Tortora
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (E.R.); (G.S.); (G.T.)
- Medical Oncology, Università Cattolica del S. Cuore, 00168 Rome, Italy
| | - Ulrich Pfeffer
- Laboratory of Epigenetics, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (F.R.); (M.A.); (A.A.)
| | - Adriana Amaro
- Laboratory of Epigenetics, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; (F.R.); (M.A.); (A.A.)
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Bethlehem MS, Katsarelias D, Olofsson Bagge R. Meta-Analysis of Isolated Hepatic Perfusion and Percutaneous Hepatic Perfusion as a Treatment for Uveal Melanoma Liver Metastases. Cancers (Basel) 2021; 13:cancers13184726. [PMID: 34572953 PMCID: PMC8469397 DOI: 10.3390/cancers13184726] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/17/2021] [Accepted: 09/19/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Isolated hepatic perfusion is one of the available treatment options for patients with liver metastases from uveal melanoma. This is an open surgical procedure where the liver is isolated from the circulation and perfused with a chemotherapeutic agent. A modern development is the minimally invasive percutaneous hepatic perfusion, where the liver is endovascularly isolated and then perfused with a chemotherapeutic agent through a catheter in the arterial system. Within this systematic review and meta-analysis, we aim to compare these modalities in terms of overall survival, progression-free survival, complications and response. Abstract Background: Uveal melanoma is the most commonly occurring primary intraocular malignancy in adults, and patients have a high risk of developing metastatic disease, mostly in the liver. Isolated hepatic perfusion (IHP) with melphalan is a liver-directed therapy for patients with liver metastases. Percutaneous hepatic perfusion (PHP), a minimally invasive technique, is available as well. PHP benefits from the fact that the procedure can be repeated and therefore possibly offers better survival. We conducted a systematic review and meta-analysis comparing both techniques. Methods: A systematic literature search was performed using the electronic databases of Scopus, MEDLINE, Web of Science, PubMed and Cochrane CENTRAL. A total of nine articles reporting on eight studies were included in the analysis. Individual survival data were extracted from each study. Results: The median overall survival (OS) was 17.1 months for IHP and 17.3 months for PHP. The median progression-free survival (PFS) was 7.2 months for IHP and 9.6 months for PHP. The median hepatic progression-free survival was 10 months for IHP and 9.5 months for PHP. The complication rate and 30-day mortality rate were 39.1% and 5.5% for IHP and 23.8% and 1.8% for PHP. Conclusion: There was no difference in OS or PFS between IHP and PHP for patients with uveal melanoma liver metastases, but patients have significantly less of a risk for complications and mortality following PHP.
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Affiliation(s)
- Martijn S. Bethlehem
- Department of Surgery, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden; (D.K.); (R.O.B.)
- Institute of Clinical Sciences/Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 413 45 Gothenburg, Sweden
- Correspondence:
| | - Dimitrios Katsarelias
- Department of Surgery, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden; (D.K.); (R.O.B.)
- Institute of Clinical Sciences/Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 413 45 Gothenburg, Sweden
| | - Roger Olofsson Bagge
- Department of Surgery, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden; (D.K.); (R.O.B.)
- Institute of Clinical Sciences/Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, 413 45 Gothenburg, Sweden
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van Kan M, Burns KE, Helsby NA. A systematic review of inter-individual differences in the DNA repair processes involved in melphalan monoadduct repair in relation to treatment outcomes. Cancer Chemother Pharmacol 2021; 88:755-769. [PMID: 34347127 DOI: 10.1007/s00280-021-04340-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/31/2021] [Indexed: 02/03/2023]
Abstract
PURPOSE Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand crosslink. Most studies exploring the role of inherited differences in DNA repair and melphalan outcomes focus on inter-strand crosslink repair, however, monoadduct repair likely plays a key role since it minimises the ultimate production of these crosslinks. The purpose of this systematic review was to assess evidence of an association between variation in monoadduct repair pathways and melphalan response. METHODS A literature search was undertaken using Medline, Embase, Scopus and PubMed databases. Duplicates were removed and only full-text articles were included. To be included for critique in this systematic review, articles were assessed for relevance using strict inclusion/exclusion criteria. RESULTS Fourteen studies were identified that involved patients treated with melphalan, however, in 3, only a minority of the cohort received melphalan. Across the remaining 11 studies, 61 genes/proteins in DNA monoadduct repair pathways were assessed. Both germline SNP (CDKN1A, ERCC1, ERCC2, ERCC4, ERCC6, EXO1, MLH1, MNAT1, MUTYH, PARP4, PCNA, POLE, POLR1G, RAD23B, RFC1, RFC3, RPA1, RPA3, TREX1, UNG, XPC, XRCC1) and somatic expression (CDKN1A, PARP1, PCNA, MGMT, RECQL, RFC5) were associated with melphalan outcomes in ≥ 1 study. CONCLUSION It appears that inherited germline differences in monoadduct repair genes may be a risk factor for poor outcomes. However, the diversity of study design, patient cohorts, genes assessed and lack of replication, preclude any meta-analysis. Further prospective studies are required to validate these findings.
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Affiliation(s)
- Maia van Kan
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
| | - Kathryn E Burns
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Nuala A Helsby
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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Szeligo BM, Ivey AD, Boone BA. Poor Response to Checkpoint Immunotherapy in Uveal Melanoma Highlights the Persistent Need for Innovative Regional Therapy Approaches to Manage Liver Metastases. Cancers (Basel) 2021; 13:3426. [PMID: 34298647 PMCID: PMC8307800 DOI: 10.3390/cancers13143426] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/24/2021] [Accepted: 07/02/2021] [Indexed: 12/12/2022] Open
Abstract
Uveal melanoma is a cancer that develops from melanocytes in the posterior uveal tract. Metastatic uveal melanoma is an extremely rare disease that has a poor long-term prognosis, limited treatment options and a strong predilection for liver metastasis. Median overall survival has been reported to be 6 months and 1 year mortality of 80%. Traditional chemotherapy used in cutaneous melanoma is ineffective in uveal cases. Surgical resection and ablation is the preferred therapy for liver metastasis but is often not feasible due to extent of disease. In this review, we will explore treatment options for liver metastases from uveal melanoma, with a focus on isolated hepatic perfusion (IHP). IHP offers an aggressive regional therapy approach that can be used in bulky unresectable disease and allows high-dose chemotherapy with melphalan to be delivered directly to the liver without systemic effects. Long-term median overall survival has been reported to be as high as 27 months. We will also highlight the poor responses associated with checkpoint inhibitors, including an overview of the biological rationale driving this lack of immunotherapy effect for this disease. The persistent failure of traditional treatments and immunotherapy suggest an ongoing need for regional surgical approaches such as IHP in this disease.
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Affiliation(s)
- Brett M. Szeligo
- Division of Surgical Oncology, Department of Surgery, West Virginia University, Morgantown, WV 26508, USA;
| | - Abby D. Ivey
- Cancer Cell Biology, West Virginia University, Morgantown, WV 26508, USA;
| | - Brian A. Boone
- Division of Surgical Oncology, Department of Surgery, West Virginia University, Morgantown, WV 26508, USA;
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26508, USA
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Tu S, Zhang H, Yang X, Wen W, Song K, Yu X, Qu X. Screening of cervical cancer-related hub genes based on comprehensive bioinformatics analysis. Cancer Biomark 2021; 32:303-315. [PMID: 34151839 DOI: 10.3233/cbm-203262] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Since the molecular mechanisms of cervical cancer (CC) have not been completely discovered, it is of great significance to identify the hub genes and pathways of this disease to reveal the molecular mechanisms of cervical cancer. OBJECTIVE The study aimed to identify the biological functions and prognostic value of hub genes in cervical cancer. METHODS The gene expression data of CC patients were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database. The core genes were screened out by differential gene expression analysis and weighted gene co-expression network analysis (WGCNA). R software, the STRING online tool and Cytoscape software were used to screen out the hub genes. The GEPIA public database was used to further verify the expression levels of the hub genes in normal tissues and tumour tissues and determine the disease-free survival (DFS) rates of the hub genes. The protein expression of the survival-related hub genes was identified with the Human Protein Atlas (HPA) database. RESULTS A total of 64 core genes were screened, and 10 genes, including RFC5, POLE3, RAD51, RMI1, PALB2, HDAC1, MCM4, ESR1, FOS and E2F1, were identified as hub genes. Compared with that in normal tissues, RFC5, POLE3, RAD51,RMI1, PALB2, MCM4 and E2F1 were all significantly upregulated in cervical cancer, ESR1 was significantly downregulated in cervical cancer, and RFC5 expression in CC patients was significantly related to OS. In the DFS analysis, no significant difference was observed in the expression level of RFC5 in cervical cancer patients. Finally, RFC5 protein levels verified by the HPA database were consistently upregulated with mRNA levels in CC samples. CONCLUSIONS RFC5 may play important roles in the occurrence and prognosis of CC. It could be further explored and validated as a potential predictor and therapeutic target for CC.
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Höppener DJ, Grünhagen DJ, Eggermont AMM, van der Veldt AAM, Verhoef C. An Overview of Liver Directed Locoregional Therapies. Surg Oncol Clin N Am 2021; 30:103-123. [PMID: 33220800 DOI: 10.1016/j.soc.2020.09.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
An overview of all liver-directed locoregional therapies, including surgical resection for melanoma liver metastases (MLMs), is provided. MLM patients are divided by their primary melanoma location; cutaneous, uvea (eye), and mucosal melanoma. If patients with isolated cutaneous MLMs are considered for surgical resection, treatment with systemic therapy should be part of the treatment course. For uveal MLMs, complete surgical or ablative treatment of all MLMs suggests superior results compared with other liver-directed or systemic therapies, based on current evidence, no recommendations for any liver-directed regional therapy in the treatment of mucosal MLMs can be made.
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Affiliation(s)
- Diederik J Höppener
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Dirk J Grünhagen
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Alexander M M Eggermont
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands
| | - Astrid A M van der Veldt
- Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Cornelis Verhoef
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands.
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11
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Arulananda S, Parakh S, Palmer J, Goodwin M, Andrews MC, Cebon J. A pilot study of intrahepatic yttrium-90 microsphere radioembolization in combination with intravenous cisplatin for uveal melanoma liver-only metastases. Cancer Rep (Hoboken) 2020; 2:e1183. [PMID: 32721131 DOI: 10.1002/cnr2.1183] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 03/22/2019] [Accepted: 04/03/2019] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Metastatic uveal melanoma is a highly aggressive disease with no standard of care treatment option. A large proportion of patients have liver-only metastatic disease which raises the question if liver-directed therapy can be efficacious in this subpopulation. AIMS The study aims to evaluate the safety and efficacy of radiosensitizing chemotherapy in combination with yttrium-90 microspheres in patients with uveal melanoma with liver-only metastases. METHODS AND RESULTS This single arm, open labeled, non-randomized study enrolled 10 patients with liver-only metastatic uveal melanoma between November 2012 and January 2018. Eligible patients received intrahepatic yttrium-90 microspheres followed by intravenous cisplatin (20 mg/m2) for 5 days. Ten patients were enrolled, but nine patients received treatment who were included in the final analysis with a median follow-up of 30 months (range 7 to 44). Five (50%) were female, five (50%) had an elevated lactate dehydrogenase (LDH), and one (10%) had prior anti-PD-1 therapy. The combination was well tolerated with no greater than or equal to grade 3 toxicity observed. The liver objective response rate (ORR) was 33% (3/9), the median progression-free survival (PFS) in the liver was 3 months (95% CI, 3-NA), and the extrahepatic PFS was 3 months (95% CI, 3-NA). Seventy-eight percent (7/9) received an immune checkpoint inhibitor on disease progression, with no responses seen. The median overall survival (OS) was 10 months (95% CI, 7-NA). CONCLUSION The combination of cisplatin with yttrium-90 microspheres was well tolerated; however, it was associated with intrahepatic disease control of relatively short duration. No responses were seen in patients treated with immune checkpoint inhibitors post radioembolization.
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Affiliation(s)
- Surein Arulananda
- Medical Oncology Unit, Austin Health, Heidelberg, Victoria, Australia.,Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
| | - Sagun Parakh
- Medical Oncology Unit, Austin Health, Heidelberg, Victoria, Australia.,Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
| | - Jodie Palmer
- Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
| | - Mark Goodwin
- Department of Radiology, Austin Hospital, Heidelberg, Victoria, Australia
| | - Miles C Andrews
- Medical Oncology Unit, Austin Health, Heidelberg, Victoria, Australia.,Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.,Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Jonathan Cebon
- Medical Oncology Unit, Austin Health, Heidelberg, Victoria, Australia.,Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
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12
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Cai T, Zhou J, Zeng Y, Du W, Zhang Y, Liu T, Fu Y, Huang JA, Qian Q, Zhu J, Ling C, Liu Z. EVI5 is an oncogene that regulates the proliferation and metastasis of NSCLC cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:84. [PMID: 32393392 PMCID: PMC7212589 DOI: 10.1186/s13046-020-01585-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 04/22/2020] [Indexed: 02/07/2023]
Abstract
Background The Ecotropic viral integration site 5 (EVI5), an important protein in regulating cell cycle, cytokinesis and cellular membrane traffic, functions as a stabilizing factor maintaining anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 in S/G2 phase. However, the mechanism by which EVI5 promotes malignant transformation of non-small cell lung cancer (NSCLC) remains unknown. In the present study, we addressed the role of EVI5 in NSCLC by regulating tumor growth, migration and invasion. Methods The expression levels of EVI5 and miR-486-5p in NSCLC tissues and cells were measured by real-time PCR. Meanwhile, EVI5 and its associated protein expression were analyzed by western blot and co-immunoprecipitation assay. Flow cytometry was performed to determine cell proliferation and apoptosis. CCK-8 and clonogenic assays were used to analyze cell viability. Wound healing, transwell migration and matrigel invasion assays were utilized to assess the motility of tumor cells. To investigate the role of EVI5 in vivo, lung carcinoma xenograft mouse model was applied.. Results EVI5 was upregulated in NSCLC tissues and cell lines when compared with that in normal tissues and cell line. Knockdown of EVI5 in vitro inhibited tumor cell proliferation, migration and invasion in NSCLC cells. Further, inoculation of EVI5-deficient tumor cells into nude mice suppressed tumor proliferation and metastasis compared to control mice inoculated with unmanipulated tumor cells. These data indicated that EVI5 promote the proliferation of NSCLC cells which was consistent with our previous results. Additionally, we showed that EVI5 was directly regulated by miR-486-5p, and miR-486-5p-EVI5 axis affected the NSCLC migration and invasion through TGF-β/Smad signaling pathway by interacting with TGF-β receptor II and TGF-β receptor I. Conclusions Based on these results, we demonstrated a new post-transcriptional mechanism of EVI5 regulation via miR-486-5p and the protumoral function of EVI5 in NSCLC by interacting with Emi1 and/or TGF-β receptors, which provides a new insight into the targeted therapy of NSCLC.
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Affiliation(s)
- Tingting Cai
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China
| | - Jieqi Zhou
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China
| | - Yuanyuan Zeng
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China.,Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China
| | - Wenwen Du
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China
| | - Yang Zhang
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China
| | - Ting Liu
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China
| | - Yulong Fu
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China
| | - Jian-An Huang
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China.,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China.,Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China
| | - Qian Qian
- Department of Medicine, Division of Allergy and Clinical Immunology, National Jewish Health, Denver, CO, 80206, USA
| | - Jianjie Zhu
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China. .,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China. .,Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China.
| | - Chunhua Ling
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China. .,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China. .,Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China.
| | - Zeyi Liu
- Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, China. .,Suzhou Key Laboratory for Respiratory Diseases, Suzhou, 215006, China. .,Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China.
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13
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Wang H, Tang X, Xie L, Dong S, Chen C, Guo W. Stop-Flow Pelvic Chemoperfusion for the Treatment of Malignant Pelvic Bone Tumors: A Preliminary Study. Orthop Surg 2020; 12:741-748. [PMID: 32243077 PMCID: PMC7307261 DOI: 10.1111/os.12666] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/02/2020] [Accepted: 03/04/2020] [Indexed: 01/25/2023] Open
Abstract
Objective To preliminarily study the efficacy and safety of stop‐flow pelvic chemoperfusion, a novel therapeutic strategy for treating pelvic malignancies. Methods Stop‐flow chemoperfusion was performed six times in 5 patients with primary pelvic malignancies. Aortic and vena cave balloons and tourniquets were used to isolate pelvic blood flow from systemic circulation. Cisplatin was then perfused through a transarterial catheter to achieve exposure to a higher drug concentration. Pelvic and peripheral blood samples were collected to determine drug concentration during perfusion. The efficacy of stop‐flow pelvic perfusion was assessed by measuring the change in tumor size, the visual analogue scale, and the tumor necrosis rate after perfusion. Safety was assessed by classifying adverse events according to CTCAE v4.03. Results The mean area under the curve (AUC) and maximum drug concentration in the pelvis during perfusion were 246.23 min μg/mL and 17.29 μg/mL, respectively. These measures were significantly higher than the peripheral mean AUC and maximum drug concentration of 52.08 min μg/mL and 5.14 μg/mL, respectively. All 5 patients showed stable disease in response, with changes in tumor size of −4.7%, −5.4%, +4.7%, −8.4%, and 0.0%. Among the 5 patients, 3 (60%) experienced significant pain relief after perfusion. Three patients underwent surgery, with tumor necrosis of 63%, <60%, and 93%. No severe complications were observed in this study. Conclusions Stop‐flow pelvic chemoperfusion resulted in exposure to drug higher concentration with fewer serious complications. These preliminary results suggest that further studies are required to comprehensively assess the therapeutic potential of stop‐flow pelvic chemoperfusion in pelvic malignancies.
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Affiliation(s)
- Han Wang
- Musculoskeletal Tumor Centre, Peking University People's Hospital, Beijing, China
| | - Xiaodong Tang
- Musculoskeletal Tumor Centre, Peking University People's Hospital, Beijing, China
| | - Lu Xie
- Musculoskeletal Tumor Centre, Peking University People's Hospital, Beijing, China
| | - Sen Dong
- Musculoskeletal Tumor Centre, Peking University People's Hospital, Beijing, China
| | - Chen Chen
- Department of Radiology, Peking University People's Hospital, Beijing, China
| | - Wei Guo
- Musculoskeletal Tumor Centre, Peking University People's Hospital, Beijing, China
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14
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Tang J, Ou J, Xu C, Yi C, Xue F, Xu L, Lai F, Tang J, Li S, Kang T, Ding W, Wang B. EVI5 is a novel independent prognostic predictor in hepatocellular carcinoma after radical hepatectomy. Oncol Rep 2017; 38:2251-2258. [PMID: 28765910 DOI: 10.3892/or.2017.5862] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 07/21/2017] [Indexed: 11/06/2022] Open
Abstract
The present study explored the correlation of ecotropic viral integration site 5 (EVI5) expression with clinicopathological features and prognosis in hepatocellular carcinoma (HCC). A total of 205 HCC patients were included retrospectively. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting were performed to detect the profile of EVI5 expression in HCC cell lines and fresh tissues. Archived paraffin-embedded specimens were investigated for EVI5 expression by immunohistochemistry (IHC). Both the mRNA and protein levels of EVI5 were obviously upregulated in HCC cell lines and tumor tissues. EVI5 protein level was closely associated with the clinicopathological characteristics, including liver function (P=0.013), venous invasion (P=0.015) and TNM stage (P=0.014). Furthermore, univariate analysis showed that the patients with high EVI5 expression indicated shorter overall survival (OS, P<0.001) and recurrence-free survival (RFS, P=0.001) than those with low EVI5 expression. Importantly, high EVI5 expression also exerts predictive power for higher postoperative recurrence rate by stratified analysis. Multivariate Cox regression analysis demonstrated that OS was correlated with both tumor number (P=0.046) and EVI5 expression (P<0.001) and that RFS was correlated with serum AFP (P=0.023), tumor number (P=0.036) and EVI5 expression (P<0.001). Taken together, EVI5 is an useful independent prognostic marker of survival and recurrence in hepatocellular carcinoma.
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Affiliation(s)
- Jintian Tang
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P.R. China
| | - Jianghua Ou
- Department of Breast Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P.R. China
| | - Chunyan Xu
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P.R. China
| | - Chao Yi
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P.R. China
| | - Feng Xue
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P.R. China
| | - Lin Xu
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P.R. China
| | - Fenju Lai
- College of Bioscience and Engineering, Jiangxi Engineering Laboratory for the Development and Utilization of Agricultural Microbial Resources, Jiangxi Agricultural University, Nanchang, Jiangxi, P.R. China
| | - Jianjun Tang
- Department of Gastroenterology, Cancer Hospital of Jiangxi Province, Nanchang, Jiangxi, P.R. China
| | - Shengping Li
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China
| | - Tiebang Kang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. China
| | - Wei Ding
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P.R. China
| | - Boqing Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, P.R. China
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15
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Meng T, Li GQ, Dai MH. Isolated hepatic perfusion for unresectable hepatic malignancies: A systematic review and meta-analysis. World J Meta-Anal 2016; 4:105-117. [DOI: 10.13105/wjma.v4.i5.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 06/24/2016] [Accepted: 08/16/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the efficacy and safety of isolated hepatic perfusion (IHP) in the management of unresectable liver malignancies.
METHODS Studies were identified manually and on-line by using PubMed and EMBASE database. We formulate the eligibility criteria according to the PICOS elements, and accessed the quality of studies using the MINORS instrument. Data from all included studies were carefully investigated. We calculated the pooled response rate and incidences of mortality reported from all eligible studies by using the Meta-Analyst software, and we computed a pooled relative risk (RR) and 95%CI by using the Comprehensive Meta-Analysis software. Heterogeneity was quantified evaluated using I2 statistic.
RESULTS Eight studies, including 502 patients, were selected. Of these, six studies performed IHP, while the other two studies performed percutaneous IHP. The results showed that the pooled response rate was 60.8% (95%CI: 53.1%-68%), I2 = 37.1%. The median overall survival was 20 mo (range: 12.1 to 25 mo) following IHP or PIHP. The pooled mortality rate was 5.4% (95%CI: 2.5%-11.2%), I2 = 37.5%. Prognostic factors predict the response to IHP or survival, and were reported in six studies. Meta-analysis demonstrated that Gender was not associated with overall survival (RR = 0.877, 95%CI: 0.564-1.365); however, carcino-embryonic antigen ≤ 30 ng/mL was associated with a significant improvement in survival outcomes with colorectal cancer patients (RR = 2.082, 95%CI: 1.371-3.163), and there was no significant heterogeneity.
CONCLUSION The present systemic review and meta-analysis suggest that IHP and PIHP are potentially efficient and safe techniques for unresectable liver primary and secondary malignancies.
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Abstract
Isolated hepatic perfusion uses the unique vascular supply of hepatic malignancies to deliver cytotoxic chemotherapy. The procedure involves vascular isolation of the liver and delivery of chemotherapy via the hepatic artery and extraction from retrohepatic vena cava. Benefits of hepatic perfusion have been observed in hepatic metastases of ocular melanoma and colorectal cancer and primary hepatocellular carcinoma. Percutaneous and prophylactic perfusions are avenues of ongoing research.
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Affiliation(s)
- Rahul Rajeev
- Division of Surgical Oncology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
| | - T Clark Gamblin
- Division of Surgical Oncology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
| | - Kiran K Turaga
- Division of Surgical Oncology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA.
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17
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Lin S, Wan D, Chen H, Chen K, Zheng S. Complete resection of isolated hepatic metastatic uveal melanoma with a notably long disease-free period: A case report and review of the literature. Oncol Lett 2015; 10:196-200. [PMID: 26170998 DOI: 10.3892/ol.2015.3217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 04/14/2015] [Indexed: 01/23/2023] Open
Abstract
Although uveal melanoma frequently metastasizes to the liver, cases with a large solitary lesion with spontaneous intratumoral hemorrhage and necrosis are rarely encountered. Here, we report a case of metastatic hepatic melanoma that occurred in a 45-year-old Chinese male. The patient complained of the feeling of a full stomach for a month. Ten years earlier, the patient had undergone left ocular enucleation and artificial eye implantation at a different hospital. Postoperative pathology revealed choroidal melanoma without intrascleral or vascular involvement. Abdominal magnetic resonance imaging and computed tomography scan revealed a solitary lesion measuring 12 cm in diameter. A whole-body F-18-fluoro-2-deoxyglucose (FDG) positron emission tomography/computed tomography scan demonstrated a large solitary nodule with increased FDG uptake. Computed tomography angiography revealed that the huge mass had partially ruptured and was bleeding spontaneously. For diagnostic and therapeutic purposes, right hepatectomy was performed and histological examination revealed that the tumor was metastatic melanoma.
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Affiliation(s)
- Shengzhang Lin
- Department of Hepato-Biliary-Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Dalong Wan
- Department of Hepato-Biliary-Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Haiyong Chen
- Department of Hepato-Biliary-Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Kangjie Chen
- Department of Hepato-Biliary-Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Shusen Zheng
- Department of Hepato-Biliary-Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
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18
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Song X, Kim SY, Lee YJ. Evidence for two modes of synergistic induction of apoptosis by mapatumumab and oxaliplatin in combination with hyperthermia in human colon cancer cells. PLoS One 2013; 8:e73654. [PMID: 24013390 PMCID: PMC3754951 DOI: 10.1371/journal.pone.0073654] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 07/30/2013] [Indexed: 01/01/2023] Open
Abstract
Colorectal cancer is the third leading cause of cancer-related mortality in the world--the main cause of death from colorectal cancer is hepatic metastases, which can be treated with isolated hepatic perfusion (IHP). Searching for the most clinically relevant approaches for treating colorectal metastatic disease by isolated hepatic perfusion (IHP), we developed the application of oxaliplatin concomitantly with hyperthermia and humanized death receptor 4 (DR4) antibody mapatumumab (Mapa), and investigated the molecular mechanisms of this multimodality treatment in human colon cancer cell lines CX-1 and HCT116 as well as human colon cancer stem cells Tu-12, Tu-21 and Tu-22. We showed here, in this study, that the synergistic effect of the multimodality treatment-induced apoptosis was caspase dependent and activated death signaling via both the extrinsic apoptotic pathway and the intrinsic pathway. Death signaling was activated by c-Jun N-terminal kinase (JNK) signaling which led to Bcl-xL phosphorylation at serine 62, decreasing the anti-apoptotic activity of Bcl-xL, which contributed to the intrinsic pathway. The downregulation of cellular FLICE inhibitory protein long isoform (c-FLIPL) in the extrinsic pathway was accomplished through ubiquitination at lysine residue (K) 195 and protein synthesis inhibition. Overexpression of c-FLIPL mutant (K195R) and Bcl-xL mutant (S62A) completely abrogated the synergistic effect. The successful outcome of this study supports the application of multimodality strategy to patients with colorectal hepatic metastases who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway.
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Affiliation(s)
- Xinxin Song
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Seog-Young Kim
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Yong J. Lee
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- * E-mail:
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Lim YS, Tang BL. The Evi5 family in cellular physiology and pathology. FEBS Lett 2013; 587:1703-10. [PMID: 23669355 DOI: 10.1016/j.febslet.2013.04.036] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 04/23/2013] [Accepted: 04/28/2013] [Indexed: 02/03/2023]
Abstract
The Ecotropic viral integration site 5 (Evi5) and Evi5-like (Evi5L) belong to a small subfamily of the Tre-2/Bub2/Cdc16 (TBC) domain-containing proteins with enigmatically divergent roles as modulators of cell cycle progression, cytokinesis, and cellular membrane traffic. First recognized as a potential oncogene and a cell cycle regulator, Evi5 acts as a GTPase Activating Protein (GAP) for Rab11 in cytokinesis. On the other hand, its homologue Evi5L has Rab-GAP activity towards Rab10 as well as Rab23, and has been implicated in primary cilia formation. Recent genetic susceptibility analysis points to Evi5 as an important factor in susceptibility to multiple sclerosis. We discuss below the myriad of cellular functions exhibited by the Evi5 family members, and their associations with disease conditions.
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Affiliation(s)
- Yi Shan Lim
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, Singapore
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20
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Song X, Kim SY, Zhou Z, Lagasse E, Kwon YT, Lee YJ. Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells. Cell Death Dis 2013; 4:e577. [PMID: 23559011 PMCID: PMC3641327 DOI: 10.1038/cddis.2013.104] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Colorectal cancer is the third leading cause of cancer-related mortality in the world; the main cause of death of colorectal cancer is hepatic metastases, which can be treated with hyperthermia using isolated hepatic perfusion (IHP). In this study, we report that mild hyperthermia potently reduced cellular FLIP(long), (c-FLIP(L)), a major regulator of the death receptor (DR) pathway of apoptosis, thereby enhancing humanized anti-DR4 antibody mapatumumab (Mapa)-mediated mitochondria-independent apoptosis. We observed that overexpression of c-FLIP(L) in CX-1 cells abrogated the synergistic effect of Mapa and hyperthermia, whereas silencing of c-FLIP in CX-1 cells enhanced Mapa-induced apoptosis. Hyperthermia altered c-FLIP(L) protein stability without concomitant reductions in FLIP mRNA. Ubiquitination of c-FLIP(L) was increased by hyperthermia, and proteasome inhibitor MG132 prevented heat-induced downregulation of c-FLIP(L). These results suggest the involvement of the ubiquitin-proteasome system in this process. We also found lysine residue 195 (K195) to be essential for c-FLIP(L) ubiquitination and proteolysis, as mutant c-FLIP(L) lysine 195 arginine (arginine replacing lysine) was left virtually un-ubiquitinated and was refractory to hyperthermia-triggered degradation, and thus partially blocked the synergistic effect of Mapa and hyperthermia. Our observations reveal that hyperthermia transiently reduced c-FLIP(L) by proteolysis linked to K195 ubiquitination, which contributed to the synergistic effect between Mapa and hyperthermia. This study supports the application of hyperthermia combined with other regimens to treat colorectal hepatic metastases.
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Affiliation(s)
- X Song
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
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22
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Song X, Kim HC, Kim SY, Basse P, Park BH, Lee BC, Lee YJ. Hyperthermia-enhanced TRAIL- and mapatumumab-induced apoptotic death is mediated through mitochondria in human colon cancer cells. J Cell Biochem 2012; 113:1547-58. [PMID: 22174016 DOI: 10.1002/jcb.24023] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Colorectal cancer is the third leading cause of cancer-related mortality in the world; death usually results from uncontrolled metastatic disease. Previously, we developed a novel strategy of TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) in combination with hyperthermia to treat hepatic colorectal metastases. However, previous studies suggest a potential hepatocyte cytotoxicity with TRAIL. Unlike TRAIL, anti-human TRAIL receptor antibody induces apoptosis without hepatocyte toxicity. In this study, we evaluated the anti-tumor efficacy of humanized anti-death receptor 4 (DR4) antibody mapatumumab (Mapa) by comparing it with TRAIL in combination with hyperthermia. TRAIL, which binds to both DR4 and death receptor 5 (DR5), was approximately tenfold more effective than Mapa in inducing apoptosis. However, hyperthermia enhances apoptosis induced by either agent. We observed that the synergistic effect was mediated through elevation of reactive oxygen species, c-Jun N-terminal kinase activation, Bax oligomerization, and translocalization to the mitochondria, loss of mitochondrial membrane potential, release of cytochrome c to cytosol, activation of caspases, and increase in poly(ADP-ribose) polymerase cleavage. We believe that the successful outcome of this study will support the application of Mapa in combination with hyperthermia to colorectal hepatic metastases.
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Affiliation(s)
- Xinxin Song
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
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Boone BA, Bartlett DL, Zureikat AH. Isolated Hepatic Perfusion for the Treatment of Liver Metastases. Curr Probl Cancer 2012; 36:27-76. [DOI: 10.1016/j.currproblcancer.2011.12.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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