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Macdonald JK, Taylor HB, Wang M, Delacourt A, Edge C, Lewin DN, Kubota N, Fujiwara N, Rasha F, Marquez CA, Ono A, Oka S, Chayama K, Lewis S, Taouli B, Schwartz M, Fiel MI, Drake RR, Hoshida Y, Mehta AS, Angel PM. The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma. J Proteome Res 2024; 23:3791-3805. [PMID: 38980715 PMCID: PMC11385377 DOI: 10.1021/acs.jproteome.4c00099] [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: 05/31/2024] [Accepted: 06/15/2024] [Indexed: 07/10/2024]
Abstract
Hepatocellular carcinoma (HCC) mortality rates continue to increase faster than those of other cancer types due to high heterogeneity, which limits diagnosis and treatment. Pathological and molecular subtyping have identified that HCC tumors with poor outcomes are characterized by intratumoral collagenous accumulation. However, the translational and post-translational regulation of tumor collagen, which is critical to the outcome, remains largely unknown. Here, we investigate the spatial extracellular proteome to understand the differences associated with HCC tumors defined by Hoshida transcriptomic subtypes of poor outcome (Subtype 1; S1; n = 12) and better outcome (Subtype 3; S3; n = 24) that show differential stroma-regulated pathways. Collagen-targeted mass spectrometry imaging (MSI) with the same-tissue reference libraries, built from untargeted and targeted LC-MS/MS was used to spatially define the extracellular microenvironment from clinically-characterized, formalin-fixed, paraffin-embedded tissue sections. Collagen α-1(I) chain domains for discoidin-domain receptor and integrin binding showed distinctive spatial distribution within the tumor microenvironment. Hydroxylated proline (HYP)-containing peptides from the triple helical regions of fibrillar collagens distinguished S1 from S3 tumors. Exploratory machine learning on multiple peptides extracted from the tumor regions could distinguish S1 and S3 tumors (with an area under the receiver operating curve of ≥0.98; 95% confidence intervals between 0.976 and 1.00; and accuracies above 94%). An overall finding was that the extracellular microenvironment has a high potential to predict clinically relevant outcomes in HCC.
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Affiliation(s)
- Jade K. Macdonald
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Harrison B. Taylor
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Mengjun Wang
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Andrew Delacourt
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Christin Edge
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - David N. Lewin
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Naoto Kubota
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Naoto Fujiwara
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Fahmida Rasha
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Cesia A. Marquez
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Atsushi Ono
- Department
of Gastroenterology, Graduate School of
Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Shiro Oka
- Department
of Gastroenterology, Graduate School of
Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan
| | - Kazuaki Chayama
- Hiroshima
Institute of Life Sciences, Hiroshima 734-8553, Japan
- Collaborative
Research Laboratory of Medical Innovation, Research Center for Hepatology
and Gastroenterology, Hiroshima University, Hiroshima 734-8553, Japan
- RIKEN Center
for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Sara Lewis
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - Bachir Taouli
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - Myron Schwartz
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
- Department
of Surgery, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - M Isabel Fiel
- Department
of Radiology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
- Department
of Pathology, Icahn School of Medicine at
Mount Sinai, New York, New York 10029, United States
| | - Richard R. Drake
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Yujin Hoshida
- Liver
Tumor Translational Research Program, Simmons Comprehensive Cancer
Center, Division of Digestive and Liver Diseases, Department of Internal
Medicine, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
| | - Anand S. Mehta
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
| | - Peggi M. Angel
- Department
of Cell and Molecular Pharmacology, Medical
University of South Carolina, Charleston, South Carolina 29425, United States
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Cantero MJ, Bueloni B, Gonzalez Llamazares L, Fiore E, Lameroli L, Atorrasagasti C, Mazzolini G, Malvicini M, Bayo J, García MG. Modified mesenchymal stromal cells by in vitro transcribed mRNA: a therapeutic strategy for hepatocellular carcinoma. Stem Cell Res Ther 2024; 15:208. [PMID: 38992782 PMCID: PMC11241816 DOI: 10.1186/s13287-024-03806-0] [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: 12/29/2023] [Accepted: 06/18/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) tropism for tumours allows their use as carriers of antitumoural factors and in vitro transcribed mRNA (IVT mRNA) is a promising tool for effective transient expression without insertional mutagenesis risk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine with antitumor properties by stimulating the specific immune response. The aim of this work was to generate modified MSCs by IVT mRNA transfection to overexpress GM-CSF and determine their therapeutic effect alone or in combination with doxorubicin (Dox) in a murine model of hepatocellular carcinoma (HCC). METHODS DsRed or GM-CSF IVT mRNAs were generated from a cDNA template designed with specific primers followed by reverse transcription. Lipofectamine was used to transfect MSCs with DsRed (MSC/DsRed) or GM-CSF IVT mRNA (MSC/GM-CSF). Gene expression and cell surface markers were determined by flow cytometry. GM-CSF secretion was determined by ELISA. For in vitro experiments, the J774 macrophage line and bone marrow monocytes from mice were used to test GM-CSF function. An HCC model was developed by subcutaneous inoculation (s.c.) of Hepa129 cells into C3H/HeN mice. After s.c. injection of MSC/GM-CSF, Dox, or their combination, tumour size and mouse survival were evaluated. Tumour samples were collected for mRNA analysis and flow cytometry. RESULTS DsRed expression by MSCs was observed from 2 h to 15 days after IVT mRNA transfection. Tumour growth remained unaltered after the administration of DsRed-expressing MSCs in a murine model of HCC and MSCs expressing GM-CSF maintained their phenotypic characteristic and migration capability. GM-CSF secreted by modified MSCs induced the differentiation of murine monocytes to dendritic cells and promoted a proinflammatory phenotype in the J774 macrophage cell line. In vivo, MSC/GM-CSF in combination with Dox strongly reduced HCC tumour growth in C3H/HeN mice and extended mouse survival in comparison with individual treatments. In addition, the tumours in the MSC/GM-CSF + Dox treated group exhibited elevated expression of proinflammatory genes and increased infiltration of CD8 + T cells and macrophages. CONCLUSIONS Our results showed that IVT mRNA transfection is a suitable strategy for obtaining modified MSCs for therapeutic purposes. MSC/GM-CSF in combination with low doses of Dox led to a synergistic effect by increasing the proinflammatory tumour microenvironment, enhancing the antitumoural response in HCC.
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Affiliation(s)
- María José Cantero
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Barbara Bueloni
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Lucrecia Gonzalez Llamazares
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Esteban Fiore
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Lucia Lameroli
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Catalina Atorrasagasti
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Guillermo Mazzolini
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Mariana Malvicini
- Cancer Immunobiology Laboratory, IIMT, Universidad Austral - CONICET, Buenos Aires, Argentina
| | - Juan Bayo
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Mariana G García
- Experimental Hepatology and Gene Therapy Program, Instituto de Investigaciones en Medicina Traslacional (IIMT), Universidad Austral - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
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Sun H, Ma J, Lu J, Yao ZH, Ran HL, Zhou H, Yuan ZQ, Huang YC, Xiao YY. Fibrinogen-to-albumin ratio predicts overall survival of hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:1662-1672. [PMID: 37746650 PMCID: PMC10514720 DOI: 10.4251/wjgo.v15.i9.1662] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/04/2023] [Accepted: 08/18/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Fibrinogen-to-albumin ratio (FAR) has been found to be of prognostic significance for several types of malignant tumors. However, less is known about the association between FAR and survival outcomes in hepatocellular carcinoma (HCC) patients. AIM To explore the association between FAR and prognosis and survival in patients with HCC. METHODS A total of 366 histologically confirmed HCC patients diagnosed between 2013 and 2018 in a provincial cancer hospital in southwestern China were retrospectively selected. Relevant data were extracted from the hospital information system. The optimal cutoff for baseline serum FAR measured upon disease diagnosis was established using the receiver operating characteristic (ROC) curve. Univariate and multivariate Cox proportional hazards models were used to determine the crude and adjusted associations between FAR and the overall survival (OS) of the HCC patients while controlling for various covariates. The restricted cubic spline (RCS) was applied to estimate the dose-response trend in the FAR-OS association. RESULTS The optimal cutoff value for baseline FAR determined by the ROC was 0.081. Multivariate Cox proportional hazards model revealed that a lower baseline serum FAR level was associated with an adjusted hazard ratio of 2.43 (95% confidence interval: 1.87-3.15) in the OS of HCC patients, with identifiable dose-response trend in the RCS. Subgroup analysis showed that this FAR-OS association was more prominent in HCC patients with a lower baseline serum aspartate aminotransferase or carbohydrate antigen 125 level. CONCLUSION Serum FAR is a prominent prognostic indicator for HCC. Intervention measures aimed at reducing FAR might result in survival benefit for HCC patients.
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Affiliation(s)
- Hao Sun
- NHC Key Laboratory of Drug Addiction Medicine, School of Public Health, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Jie Ma
- The Third Affiliated Hospital, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Jian Lu
- The Third Affiliated Hospital, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Zhi-Hong Yao
- The Third Affiliated Hospital, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Hai-Liang Ran
- NHC Key Laboratory of Drug Addiction Medicine, School of Public Health, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Hai Zhou
- The Third Affiliated Hospital, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Zhong-Qin Yuan
- The Third Affiliated Hospital, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Yun-Chao Huang
- The Third Affiliated Hospital, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Yuan-Yuan Xiao
- NHC Key Laboratory of Drug Addiction Medicine, School of Public Health, Kunming Medical University, Kunming 650500, Yunnan Province, China
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Emran TB, Islam F, Mitra S, Paul S, Nath N, Khan Z, Das R, Chandran D, Sharma R, Lima CMG, Awadh AAA, Almazni IA, Alhasaniah AH, Guiné RPF. Pectin: A Bioactive Food Polysaccharide with Cancer Preventive Potential. Molecules 2022; 27:7405. [PMID: 36364232 PMCID: PMC9657392 DOI: 10.3390/molecules27217405] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 07/30/2023] Open
Abstract
Pectin is an acidic heteropolysaccharide found in the cell walls and the primary and middle lamella of land plants. To be authorized as a food additive, industrial pectins must meet strict guidelines set forth by the Food and Agricultural Organization and must contain at least 65% polygalacturonic acid to achieve the E440 level. Fruit pectin derived from oranges or apples is commonly used in the food industry to gel or thicken foods and to stabilize acid-based milk beverages. It is a naturally occurring component and can be ingested by dietary consumption of fruit and vegetables. Preventing long-term chronic diseases like diabetes and heart disease is an important role of dietary carbohydrates. Colon and breast cancer are among the diseases for which data suggest that modified pectin (MP), specifically modified citrus pectin (MCP), has beneficial effects on the development and spread of malignancies, in addition to its benefits as a soluble dietary fiber. Cellular and animal studies and human clinical trials have provided corroborating data. Although pectin has many diverse functional qualities, this review focuses on various modifications used to develop MP and its benefits for cancer prevention, bioavailability, clinical trials, and toxicity studies. This review concludes that pectin has anti-cancer characteristics that have been found to inhibit tumor development and proliferation in a wide variety of cancer cells. Nevertheless, further clinical and basic research is required to confirm the chemopreventive or therapeutic role of specific dietary carbohydrate molecules.
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Affiliation(s)
- Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Fahadul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
| | - Shyamjit Paul
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
| | - Nikhil Nath
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Zidan Khan
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Rajib Das
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
| | - Deepak Chandran
- Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, Tamil Nadu, India
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India
| | | | - Ahmed Abdullah Al Awadh
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, P.O. Box 1988, Najran 61441, Saudi Arabia
| | - Ibrahim Abdullah Almazni
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, P.O. Box 1988, Najran 61441, Saudi Arabia
| | - Abdulaziz Hassan Alhasaniah
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, P.O. Box 1988, Najran 61441, Saudi Arabia
| | - Raquel P. F. Guiné
- CERNAS Research Centre, Department of Food Industry, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal
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Casadei M, Fiore E, Rubione J, María Domínguez L, Florencia Coronel M, Leiguarda C, García M, Mazzolini G, Villar MJ, Montaner A, Constandil L, Romero-Sandoval A, Brumovsky PR. IMT504 blocks allodynia in rats with spared nerve injury by promoting the migration of mesenchymal stem cells and by favoring an anti-inflammatory milieu at the injured nerve. Pain 2022; 163:1114-1129. [PMID: 34711765 PMCID: PMC8920950 DOI: 10.1097/j.pain.0000000000002476] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 08/31/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT IMT504, a noncoding, non-CpG oligodeoxynucleotide, modulates pain-like behavior in rats undergoing peripheral nerve injury, through mechanisms that remain poorly characterized. Here, we chose the spared nerve injury model in rats to analyze the contribution of mesenchymal stem cells (MSCs) in the mechanisms of action of IMT504. We show that a single subcutaneous administration of IMT504 reverses mechanical and cold allodynia for at least 5 weeks posttreatment. This event correlated with long-lasting increases in the percentage of MSCs in peripheral blood and injured sciatic nerves, in a process seemingly influenced by modifications in the CXCL12-CXCR4 axis. Also, injured nerves presented with reduced tumor necrosis factor-α and interleukin-1β and increased transforming growth factor-β1 and interleukin-10 protein levels. In vitro analysis of IMT504-pretreated rat or human MSCs revealed internalized oligodeoxynucleotide and confirmed its promigratory effects. Moreover, IMT504-pretreatment induced transcript expression of Tgf-β1 and Il-10 in MSCs; the increase in Il-10 becoming more robust after exposure to injured nerves. Ex vivo exposure of injured nerves to IMT504-pretreated MSCs confirmed the proinflammatory to anti-inflammatory switch observed in vivo. Interestingly, the sole exposure of injured nerves to IMT504 also resulted in downregulated Tnf-α and Il-1β transcripts. Altogether, we reveal for the first time a direct association between the antiallodynic actions of IMT504, its promigratory and cytokine secretion modulating effects on MSCs, and further anti-inflammatory actions at injured nerves. The recapitulation of key outcomes in human MSCs supports the translational potential of IMT504 as a novel treatment for neuropathic pain with a unique mechanism of action involving the regulation of neuroimmune interactions.
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Affiliation(s)
- Mailín Casadei
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
| | - Esteban Fiore
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
| | - Julia Rubione
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
| | - Luciana María Domínguez
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
| | - María Florencia Coronel
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
| | - Candelaria Leiguarda
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
| | - Mariana García
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
| | - Guillermo Mazzolini
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
| | - Marcelo J. Villar
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
| | - Alejandro Montaner
- Instituto de Ciencia y Tecnología “Dr. César Milstein”, CONICET, Fundación Pablo Cassará, Ciudad Autónoma de Buenos Aires, Argentina
| | - Luis Constandil
- Laboratorio de Neurobiología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Alfonso Romero-Sandoval
- Department of Anesthesiology, Pain Mechanisms Laboratory, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Pablo R. Brumovsky
- Instituto de Investigaciones en Medicina Traslacional (IIMT), CONICET-Universidad Austral, Av. Juan D. Perón 1500, Derqui, Pilar, Buenos Aires, Argentina
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Wu MC, Meng QH. Current understanding of mesenchymal stem cells in liver diseases. World J Stem Cells 2021; 13:1349-1359. [PMID: 34630867 PMCID: PMC8474713 DOI: 10.4252/wjsc.v13.i9.1349] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 07/01/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Liver diseases caused by various factors have become a significant threat to public health worldwide. Liver transplantation has been considered as the only effective treatment for end-stage liver diseases; however, it is limited by the shortage of donor organs, postoperative complications, long-term immunosuppression, and high cost of treatment. Thus, it is not available for all patients. Recently, mesenchymal stem cells (MSCs) transplantation has been extensively explored for repairing hepatic injury in various liver diseases. MSCs are multipotent adult progenitor cells originated from the embryonic mesoderm, and can be found in mesenchymal tissues including the bone marrow, umbilical cord blood, adipose tissue, liver, lung, and others. Although the precise mechanisms of MSC transplantation remain mysterious, MSCs have been demonstrated to be able to prevent the progression of liver injury and improve liver function. MSCs can self-renew by dividing, migrating to injury sites and differentiating into multiple cell types including hepatocytes. Additionally, MSCs have immune-modulatory properties and release paracrine soluble factors. Indeed, the safety and effectiveness of MSC therapy for liver diseases have been demonstrated in animals. However, pre-clinical and clinical trials are largely required to confirm its safety and efficacy before large scale clinical application. In this review, we will explore the molecular mechanisms underlying therapeutic effects of MSCs on liver diseases. We also summarize clinical advances in MSC-based therapies.
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Affiliation(s)
- Mu-Chen Wu
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Hua Meng
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China
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Artificial cells for the treatment of liver diseases. Acta Biomater 2021; 130:98-114. [PMID: 34126265 DOI: 10.1016/j.actbio.2021.06.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/06/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022]
Abstract
Liver diseases have become an increasing health burden and account for over 2 million deaths every year globally. Standard therapies including liver transplant and cell therapy offer a promising treatment for liver diseases, but they also suffer limitations such as adverse immune reactions and lack of long-term efficacy. Artificial cells that mimic certain functions of a living cell have emerged as a new strategy to overcome some of the challenges that liver cell therapy faces at present. Artificial cells have demonstrated advantages in long-term storage, targeting capability, and tuneable features. This article provides an overview of the recent progress in developing artificial cells and their potential applications in liver disease treatment. First, the design of artificial cells and their biomimicking functions are summarized. Then, systems that mimic cell surface properties are introduced with two concepts highlighted: cell membrane-coated artificial cells and synthetic lipid-based artificial cells. Next, cell microencapsulation strategy is summarized and discussed. Finally, challenges and future perspectives of artificial cells are outlined. STATEMENT OF SIGNIFICANCE: Liver diseases have become an increasing health burden. Standard therapies including liver transplant and cell therapy offer a promising treatment for liver diseases, but they have limitations such as adverse immune reactions and lack of long-term efficacy. Artificial cells that mimic certain functions of a living cell have emerged as a new strategy to overcome some of the challenges that liver cell therapy faces at present. This article provides an overview of the recent progress in developing artificial cells and their potential applications in liver disease treatment, including the design of artificial cells and their biomimicking functions, two systems that mimic cell surface properties (cell membrane-coated artificial cells and synthetic lipid-based artificial cells), and cell microencapsulation strategy. We also outline the challenges and future perspectives of artificial cells.
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8
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Ding Y, Wang C, Sun Z, Wu Y, You W, Mao Z, Wang W. Mesenchymal Stem Cells Engineered by Nonviral Vectors: A Powerful Tool in Cancer Gene Therapy. Pharmaceutics 2021; 13:pharmaceutics13060913. [PMID: 34205513 PMCID: PMC8235299 DOI: 10.3390/pharmaceutics13060913] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/09/2021] [Accepted: 06/16/2021] [Indexed: 12/14/2022] Open
Abstract
Due to their "tumor homing" and "immune privilege" characteristics, the use of mesenchymal stem cells (MSCs) has been proposed as a novel tool against cancer. MSCs are genetically engineered in vitro and then utilized to deliver tumoricidal agents, including prodrugs and bioactive molecules, to tumors. The genetic modification of MSCs can be achieved by various vectors, and in most cases viral vectors are used; however, viruses may be associated with carcinogenesis and immunogenicity, restricting their clinical translational potential. As such, nonviral vectors have emerged as a potential solution to address these limitations and have gradually attracted increasing attention. In this review, we briefly revisit the current knowledge about MSC-based cancer gene therapy. Then, we summarize the advantages and challenges of nonviral vectors for MSC transfection. Finally, we discuss recent advances in the development of new nonviral vectors, which have provided promising strategies to overcome obstacles in the gene modulation of MSCs.
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Affiliation(s)
- Yuan Ding
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Chenyang Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Zhongquan Sun
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Yingsheng Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Wanlu You
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
| | - Zhengwei Mao
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- MOE Key Laboratory, Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
- Correspondence: (Z.M.); (W.W.); Tel.: +86-15168215834 (Z.M.); +86-0571-87783820 (W.W.)
| | - Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; (Y.D.); (C.W.); (Z.S.); (Y.W.); (W.Y.)
- Key Laboratory, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, China
- Research Center, Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province, Hangzhou 310009, China
- Clinical Medicine Innovation Center, Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease, Zhejiang University, Hangzhou 310009, China
- Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310009, China
- Cancer Center, Zhejiang University, Hangzhou 310009, China
- Correspondence: (Z.M.); (W.W.); Tel.: +86-15168215834 (Z.M.); +86-0571-87783820 (W.W.)
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9
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In-Depth Characterization of Stromal Cells within the Tumor Microenvironment Yields Novel Therapeutic Targets. Cancers (Basel) 2021; 13:cancers13061466. [PMID: 33806802 PMCID: PMC8005121 DOI: 10.3390/cancers13061466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 12/23/2022] Open
Abstract
Simple Summary This up-to-date and in-depth review describes fibroblast-derived cells and their role within the tumor microenvironment for tumor progression. Moreover, targets for future antitumor therapies are summarized and potential aspects for future translational research are outlined. Furthermore, this review discusses the challenges and possible obstacles related to certain treatment targets. Abstract Cells within the tumor stroma are essential for tumor progression. In particular, cancer-associated fibroblasts (CAF) and CAF precursor cells (resident fibroblasts and mesenchymal stromal cells) are responsible for the formation of the extracellular matrix in tumor tissue. Consequently, CAFs directly and indirectly mediate inflammation, metastasis, immunomodulation, angiogenesis, and the development of tumor chemoresistance, which is orchestrated by complex intercellular cytokine-mediated crosstalk. CAFs represent a strategic target in antitumor therapy but their heterogeneity hinders effective treatment regimes. In-depth understanding of CAF subpopulations and knowledge of specific functions in tumor progression will ultimately result in more specific and effective cancer treatments. This review provides a detailed description of CAFs and CAF precursor cells and summarizes possible treatment strategies as well as molecular targets of these cells in antitumor therapies.
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10
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Chen Y, Jiang B, Wang W, Su D, Xia F, Li X. Identifying the Transcriptional Regulatory Network Associated With Extrathyroidal Extension in Papillary Thyroid Carcinoma by Comprehensive Bioinformatics Analysis. Front Genet 2020; 11:453. [PMID: 32477405 PMCID: PMC7232969 DOI: 10.3389/fgene.2020.00453] [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] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 04/14/2020] [Indexed: 12/31/2022] Open
Abstract
Extrathyroidal extension (ETE) affects papillary thyroid cancer (PTC) prognosis. The objective of this study was to identify biomarkers for ETE and explore the mechanisms controlling its development in PTC. We performed a comprehensive bioinformatics analysis using several datasets. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) on 58 paired PTC samples from The Cancer Genome Atlas (TCGA) were used to detect ETE-related mRNA and long noncoding (lnc) RNA modules and construct an lncRNA/mRNA network. An independent TCGA dataset containing 438 samples was utilized to validate and characterize the WGCNA results. Functional annotation was used to identify the biological functions and related pathways of ETE modules. Two independent RNA sequencing datasets were combined to crossvalidate relationships between lncRNAs and mRNAs by Pearson correlation analysis. Transcription factors (TFs) for affected genes were predicted using the binding motif data from Ensembl Biomart to construct a TF/lncRNA/mRNA network. Other two independent datasets were used to crossvalidate TF-mRNA associations. Finally, receiver operating characteristic, survival analyses, and Cox proportional hazard regression model were performed to explore the significance of hub genes in ETE diagnosis and PTC prognosis. Three mRNA modules and two lncRNA modules were significantly associated with ETE. Enrichment analysis showed extracellular matrix changes was closely related to the development of ETE. A TF/lncRNA/mRNA regulatory network was constructed containing 33 validated hub genes, 64 lncRNAs, and 64 TFs, all differentially expressed between ETE and non-ETE samples. Unc-5 family C-terminal like [area under the curve (AUC): 0.711], sushi repeat containing protein X-linked 2 (AUC: 0.706), lysyl oxidase (AUC: 0.704), collagen type I alpha 1 chain (AUC: 0.704), and collagen type X alpha 1 chain (AUC: 0.704) were the most highly significant hub genes for ETE diagnosis. The Cox proportional hazard regression model constructed with hub genes showed significant survival differences between low- and high-risk groups (p = 0.00025) and performed good prediction for PTC prognosis(AUC = 0.794; C-index = 0.895). The identification of 33 biomarkers and TF/lncRNA/mRNA regulatory network would provide new insights into the molecular mechanisms of ETE besides the prognosis model may have important clinical implications in the improvement of PTC risk stratification, therapeutic decision-making, and prognosis prediction.
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Affiliation(s)
- Yong Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Bo Jiang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Wenlong Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Duntao Su
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Fada Xia
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xinying Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
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11
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Jones VA, Patel PM, Gibson FT, Cordova A, Amber KT. The Role of Collagen XVII in Cancer: Squamous Cell Carcinoma and Beyond. Front Oncol 2020; 10:352. [PMID: 32266137 PMCID: PMC7096347 DOI: 10.3389/fonc.2020.00352] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/28/2020] [Indexed: 12/12/2022] Open
Abstract
Alterations in the extracellular matrix (ECM) likely facilitate the first steps of cancer cell metastasis and supports tumor progression. Recent data has demonstrated that alterations in collagen XVII (BP180), a transmembrane protein and structural component of the ECM, can have profound effects on cancer invasiveness. Collagen XVII is a homotrimer of three α1 (XVII) chains. Its intracellular domain contains binding sites for plectin, integrin β4, and BP230, while the extracellular domain facilitates interactions between the cell and the ECM. Collagen XVII and its shed ectodomain have been implicated in cell motility and adhesion and are believed to promote tumor development and invasion. A strong association of collagen XVII ectodomain shedding and tumor invasiveness occurs in squamous cell carcinoma (SCC). Aberrant expression of collagen XVII has been reported in many epithelial cancers, ranging from squamous cell carcinoma to colon, pancreatic, mammary, and ovarian carcinoma. Thus, in this review, we focus on collagen XVII's role in neoplasia and tumorigenesis. Lastly, we discuss the importance of targeting collagen XVII and its ectodomain shedding as a novel strategy to curb tumor growth and reduce metastatic potential.
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Affiliation(s)
- Virginia A Jones
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
| | - Payal M Patel
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
| | - Frederick T Gibson
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
| | - Adriana Cordova
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
| | - Kyle T Amber
- Skin Immunology Laboratory, Department of Dermatology, University of Illinois at Chicago, Chicago, IL, United States
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12
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Wang Q, Ma L, Li J, Yuan C, Sun J, Li K, Qin L, Zang C, Zhao Y, Zhao Y, Zhang Y. A Novel Scoring System for Patients with Recurrence of Hepatocellular Carcinoma After Undergoing Minimal Invasive Therapies. Cancer Manag Res 2020; 11:10641-10649. [PMID: 31908536 PMCID: PMC6930388 DOI: 10.2147/cmar.s224711] [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] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 12/08/2019] [Indexed: 12/24/2022] Open
Abstract
Background The higher recurrence rate of hepatocellular carcinoma (HCC) needs to be urgently controlled. However, definitive markers are lacking for patients with recurrence of HCC after undergoing minimal invasive therapies-local ablation combined with transcatheter arterial chemoembolization (TACE). Materials and methods Demographic and clinicopathological data of 234 subjects receiving combined therapies as the initial treatment were retrospectively analyzed. Univariate and multivariate Cox regression analysis was used to assess independent risk factors of recurrence. Selected variables were divided into low-, intermediate-, and high-risk groups of recurrence according to the scores assigned to them based on their respective hazard ratio (HR) values. The area under the curve (AUC) was used to evaluate the predictive value of the scoring system. Cumulative recurrence-free survival (RFS) and overall survival rates were calculated by the Kaplan-Meier estimator. Finally, a correlation analysis was performed on demographic and clinical data among the three groups. Results The AUC of predicting 1-, 2-, and 3-year recurrence rates was 0.680, 0.728, and 0.709, respectively. The cumulative RFS rate in the low-risk group at 1, 2, and 3 years after undergoing combined treatments was 4%, 12.2%, and 30.6%, while that in the intermediate-risk group and high-risk group was 23.4%, 51.6%, 60.0%, and 47.3%, 78.2%, 83.6%, respectively. Gamma-glutamyltransferase (γ-GT), blood urea nitrogen (BUN), and total cholesterol (TC) levels among the three groups were statistically different. Conclusion The scoring system of the present study for patients with the recurrence of HCC after undergoing TACE combined with local ablation may help physicians make a reasonable clinical decision, providing ideal management for diagnosis and treatment.
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Affiliation(s)
- Qi Wang
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Liang Ma
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Jianjun Li
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Chunwang Yuan
- Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Jianping Sun
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Kang Li
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Ling Qin
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Chaoran Zang
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Yanan Zhao
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Yan Zhao
- Clinical Detection Center, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
| | - Yonghong Zhang
- Research Center for Biomedical Resources, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China.,Interventional Therapy Center for Oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, People's Republic of China
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13
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Differential Expression and Diagnostic Significance of Pre-Albumin, Fibrinogen Combined with D-Dimer in AFP-Negative Hepatocellular Carcinoma. Pathol Oncol Res 2019; 26:1669-1676. [PMID: 31578661 DOI: 10.1007/s12253-019-00752-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 09/12/2019] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most malignant cancers with high morbidity and mortality. Nowadays, AFP-negative hepatocellular carcinoma (AFP-NHCC) has been found in many HCC patients and AFP analysis can't be used to screen HCC in these cases. In this study, we have examined the expression patterns of pre-albumin (PA), fibrinogen, D-Dimer and their clinical significance in AFP-NHCC. We recruited 214 AFP-NHCC patients and 210 controls in the study. PA, fibrinogen and D-Dimer levels were detected by turbidimetry, clauss and immunoturbidimetry methods, respectively. Serum PA levels were significantly lower in AFP-NHCC (84.5 ± 24.7 mg/L) than that in the controls (240.6 ± 59.4 mg/L, P < 0.05). For plasma fibrinogen levels, there was no difference between the controls (2.9 ± 0.7 g/L) and AFP-NHCC (2.5 ± 0.7 g/L). Compared with AFP-NHCC (0.8 ± 0.2 mg/L), plasma D-Dimer levels were significantly lower in controls (0.1 ± 0.0 mg/L, P < 0.05). The levels of PA, fibrinogen and D-Dimer were significantly correlated with differentiation (P < 0.01), and the PA and D-Dimer values were correlated with TNM stage (P < 0.05). Moreover, PA levels were correlated with tumor size (P = 0.034). Receiver operating characteristic curve (ROC) analyses elaborated that combination of PA, fibrinogen and D-Dimer possessed a higher sensitivity (93.4%) for differentiating AFP-NHCC from the controls, but the diagnostic specificity was reduced due to the combination of fibrinogen. After adjusting for all significant outcome predictors of the univariate logistic regression analysis, low levels of PA and high levels of D-Dimer were remained independent unfavorable outcome predictors (P < 0.05). Our data suggested that the expression levels of PA, fibrinogen and D-Dimer played critical roles in AFP-NHCC tumorigenesis. Moreover, PA and D-Dimer might be considered as potential diagnostic indicators in AFP-NHCC.
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14
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Mesenchymal Stem Cells in the Adult Human Liver: Hype or Hope? Cells 2019; 8:cells8101127. [PMID: 31546729 PMCID: PMC6830330 DOI: 10.3390/cells8101127] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/18/2019] [Accepted: 09/21/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic liver diseases constitute a significant economic, social, and biomedical burden. Among commonly adopted approaches, only organ transplantation can radically help patients with end-stage liver pathologies. Cell therapy with hepatocytes as a treatment for chronic liver disease has demonstrated promising results. However, quality human hepatocytes are in short supply. Stem/progenitor cells capable of differentiating into functionally active hepatocytes provide an attractive alternative approach to cell therapy for liver diseases, as well as to liver-tissue engineering, drug screening, and basic research. The application of methods generally used to isolate mesenchymal stem cells (MSCs) and maintain them in culture to human liver tissue provides cells, designated here as liver MSCs. They have much in common with MSCs from other tissues, but differ in two aspects-expression of a range of hepatocyte-specific genes and, possibly, inherent commitment to hepatogenic differentiation. The aim of this review is to analyze data regarding liver MSCs, probably another type of liver stem/progenitor cells different from hepatic stellate cells or so-called hepatic progenitor cells. The review presents an analysis of the phenotypic characteristics of liver MSCs, their differentiation and therapeutic potential, methods for isolating these cells from human liver, and discusses issues of their origin and heterogeneity. Human liver MSCs are a fascinating object of fundamental research with a potential for important practical applications.
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15
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Zappa Villar MF, Lehmann M, García MG, Mazzolini G, Morel GR, Cónsole GM, Podhajcer O, Reggiani PC, Goya RG. Mesenchymal stem cell therapy improves spatial memory and hippocampal structure in aging rats. Behav Brain Res 2019; 374:111887. [PMID: 30951751 DOI: 10.1016/j.bbr.2019.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 03/31/2019] [Accepted: 04/01/2019] [Indexed: 12/21/2022]
Abstract
There is a growing interest in the potential of mesenchymal stem cells (MSCs) for implementing regenerative medicine in the brain as they have shown neurogenic and immunomodulatory activities. We assessed the effect of intracerebroventricular (icv) administration of human bone marrow-derived MSCs (hBM-MSCs) on spatial memory and hippocampal morphology of senile (27 months) female rats, using 3-months-old counterparts as young controls. Half of the animals were injected in the lateral ventricles (LV) with a suspension containing 5 × 105hBM-MSCs in 8 μl per side. The other half received no treatment (senile controls). Spatial memory performance was assessed with a modified version of the Barnes maze test. We employed one probe trial, one day after training in order to evaluate learning ability as well as spatial memory retention. Neuroblast (DCX) and microglial (Iba-1 immunoreactive) markers were also immunohistochemically quantitated in the animals by means of an unbiased stereological approach. In addition, hippocampal presynaptic protein expression was assessed by immunoblotting analysis. After treatment, the senile MSC-treated group showed a significant improvement in spatial memory accuracy and extended permanence in a one- and 3-hole goal sectors as compared with senile controls. The MSC treatment increased the number of neuroblasts in the hippocampal dentate gyrus, reduced the number of reactive microglial cells, and restored presynaptic protein levels as compared to senile controls. We conclude that icv injected hBM-MSCs are effective in improving spatial memory in senile rats and that the strategy improves some functional and morphologic brain features typically altered in aging rats.
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Affiliation(s)
- Maria F Zappa Villar
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Marianne Lehmann
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Mariana G García
- Gene Therapy Laboratory, IIMT, School of Medical Science, Austral University, Buenos Aires, Argentina
| | - Guillermo Mazzolini
- Gene Therapy Laboratory, IIMT, School of Medical Science, Austral University, Buenos Aires, Argentina
| | - Gustavo R Morel
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Gloria M Cónsole
- Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Osvaldo Podhajcer
- Laboratory of Molecular and Cellular Therapy, Fundacion Instituto Leloir, Buenos Aires, Argentina
| | - Paula C Reggiani
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina
| | - Rodolfo G Goya
- INIBIOLP-Pathology B, School of Medicine, National University of La Plata, Argentina; Department of Histology and of Embryology B, School of Medicine, National University of La Plata, Argentina.
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16
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Collagen Fiber Array of Peritumoral Stroma Influences Epithelial-to-Mesenchymal Transition and Invasive Potential of Mammary Cancer Cells. J Clin Med 2019; 8:jcm8020213. [PMID: 30736469 PMCID: PMC6406296 DOI: 10.3390/jcm8020213] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 01/29/2019] [Accepted: 02/04/2019] [Indexed: 01/06/2023] Open
Abstract
Interactions of cancer cells with matrix macromolecules of the surrounding tumor stroma are critical to mediate invasion and metastasis. In this study, we reproduced the collagen mechanical barriers in vitro (i.e., basement membrane, lamina propria under basement membrane, and deeper bundled collagen fibers with different array). These were used in 3D cell cultures to define their effects on morphology and behavior of breast cancer cells with different metastatic potential (MCF-7 and MDA-MB-231) using scanning electron microscope (SEM). We demonstrated that breast cancer cells cultured in 2D and 3D cultures on different collagen substrates show different morphologies: i) a globular/spherical shape, ii) a flattened polygonal shape, and iii) elongated/fusiform and spindle-like shapes. The distribution of different cell shapes changed with the distinct collagen fiber/fibril physical array and size. Dense collagen fibers, parallel to the culture plane, do not allow the invasion of MCF-7 and MDA-MB-231 cells, which, however, show increases of microvilli and microvesicles, respectively. These novel data highlight the regulatory role of different fibrillar collagen arrays in modifying breast cancer cell shape, inducing epithelial-to-mesenchymal transition, changing matrix composition and modulating the production of extracellular vesicles. Further investigation utilizing this in vitro model will help to demonstrate the biological roles of matrix macromolecules in cancer cell invasion in vivo.
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17
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Yin Z, Jiang K, Li R, Dong C, Wang L. Multipotent mesenchymal stromal cells play critical roles in hepatocellular carcinoma initiation, progression and therapy. Mol Cancer 2018; 17:178. [PMID: 30593276 PMCID: PMC6309092 DOI: 10.1186/s12943-018-0926-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 12/16/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with high morbidity, relapse and mortality rates. Multipotent mesenchymal stromal cells (MSCs) can be recruited to and become integral components of the HCC microenvironment and can influence tumor progression. This review discusses MSC migration to liver fibrosis and the HCC microenvironment, MSC involvement in HCC initiation and progression and the widespread application of MSCs in HCC-targeted therapy, thus clarifying the critical roles of MSCs in HCC.
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Affiliation(s)
- Zeli Yin
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China.,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China.,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China
| | - Keqiu Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China.,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China.,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China
| | - Rui Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China.,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China.,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China
| | - Chengyong Dong
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China. .,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China. .,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China.
| | - Liming Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, 116027, Liaoning, China. .,Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, Dalian Medical University, Dalian, 116027, Liaoning, China. .,Engineering Technology Research Center for Translational Medicine, Dalian Medical University, Dalian, 116027, Liaoning, China.
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18
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Liang HG, Gao K, Jia R, Li J, Wang C. Prognostic significance of the combination of preoperative fibrinogen and the neutrophil-lymphocyte ratio in patients with non-small cell lung cancer following surgical resection. Oncol Lett 2018; 17:1435-1444. [PMID: 30675197 PMCID: PMC6341855 DOI: 10.3892/ol.2018.9760] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 03/26/2018] [Indexed: 02/07/2023] Open
Abstract
The purpose of the present study was to evaluate the prognostic value of preoperative coagulation factor levels (including fibrinogen and D-dimer) and inflammatory indicators in patients with non-small cell lung cancer (NSCLC). The medical records of 456 patients with NSCLC who had undergone curative resection were retrospectively analysed. The recommended cut-off values for preoperative fibrinogen, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio and lymphocyte-monocyte ratio were determined using receiver operating characteristic curve analyses. The associations between preoperative fibrinogen or D-dimer levels and clinicopathological variables were analysed using the χ2 test. Univariate Kaplan-Meier analysis and a multivariate Cox proportional hazards model were applied to identify which prognostic variables were significantly associated with overall survival (OS) rates. Multivariate analyses revealed that lymph node metastasis (P<0.001), preoperative fibrinogen (P=0.024) and NLR (P=0.028) were effective independent prognostic variables associated with OS. Based on this result, a novel, single inflammation-based combination of fibrinogen and NLR (COF-NLR) score was proposed for the determination of prognosis. Patients with elevated fibrinogen and NLR levels were allocated a score of 2 (n=136), and those that demonstrated elevated levels of one or neither were allocated a score of 1 (n=152) or 0 (n=168), respectively. The 5-year OS rates were significantly poorer for patients with COF-NLR=2 compared with those with COF-NLR=1 or 0 (23.5% vs. 34.2% vs. 50.0%, P<0.001). A subgroup analysis demonstrated that the prognostic significance of COF-NLR was independent of histological subtype, lymph node metastasis and pathological stage. Therefore, COF-NLR has potential as a novel and useful blood marker for predicting tumour progression and the postoperative survival of patients with NSCLC. It may assist clinicians in risk stratification, prognosis predictions and facilitating individualised treatment.
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Affiliation(s)
- Hua-Gang Liang
- Department of Thoracic Surgery, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei 066000, P.R. China
| | - Kun Gao
- Department of Thoracic Surgery, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei 066000, P.R. China
| | - Rui Jia
- Department of Thoracic Surgery, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei 066000, P.R. China
| | - Jian Li
- Department of Thoracic Surgery, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei 066000, P.R. China
| | - Chao Wang
- Department of Thoracic Surgery, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei 066000, P.R. China
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19
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Yang N, Ding Y, Zhang Y, Wang B, Zhao X, Cheng K, Huang Y, Taleb M, Zhao J, Dong WF, Zhang L, Nie G. Surface Functionalization of Polymeric Nanoparticles with Umbilical Cord-Derived Mesenchymal Stem Cell Membrane for Tumor-Targeted Therapy. ACS APPLIED MATERIALS & INTERFACES 2018; 10:22963-22973. [PMID: 29905067 DOI: 10.1021/acsami.8b05363] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Multiple cell plasma membranes have been utilized for surface functionalization of synthetic nanomaterials and construction of biomimetic drug delivery systems for cancer treatment. The natural characters and facile isolation of original cells facilitate the biomedical applications of plasma membranes in functionalizing nanocarriers. Human umbilical cord-derived mesenchymal stem cells (MSCs) have been identified to show tropism toward malignant lesions and have great advantages in ease of acquisition, low immunogenicity, and high proliferative ability. Here, we developed a poly(lactic- co-glycolic acid) (PLGA) nanoparticle with a layer of plasma membrane from umbilical cord MSC coating on the surface for tumor-targeted delivery of chemotherapy. Functionalization of MSC plasma membrane significantly enhanced the cellular uptake efficiency of PLGA nanoparticles, the tumor cell killing efficacy of PLGA-encapsulated doxorubicin, and most importantly the tumor-targeting and accumulation of the nanoparticles. As a result, this MSC-mimicking nanoformulation led to remarkable tumor growth inhibition and induced obvious apoptosis within tumor lesions. This study for the first time demonstrated the great potential of umbilical cord MSC plasma membranes in functionalizing nanocarriers with inherent tumor-homing features and the high feasibility of such biomimetic nanoformulations in cancer therapy.
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Affiliation(s)
- Na Yang
- School of Life Sciences , Shanghai University , No. 333 Nanchen Road , Baoshan District, Shanghai 200444 , China
- CAS Key Laboratory of Bio-Medical Diagnostics , Suzhou Institute of Biomedical Engineering and Technology (SIBET) , No. 88 Keling Road , Suzhou New District , 215163 Jiangsu Province , China
| | - Yanping Ding
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | | | - Bin Wang
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | | | | | - Yixin Huang
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Mohammad Taleb
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Jing Zhao
- School of Life Sciences , Shanghai University , No. 333 Nanchen Road , Baoshan District, Shanghai 200444 , China
| | - Wen-Fei Dong
- CAS Key Laboratory of Bio-Medical Diagnostics , Suzhou Institute of Biomedical Engineering and Technology (SIBET) , No. 88 Keling Road , Suzhou New District , 215163 Jiangsu Province , China
| | - Lirong Zhang
- School of Basic Medical Sciences , Zhengzhou University , Zhengzhou , Henan 450001 , China
| | - Guangjun Nie
- University of Chinese Academy of Sciences , Beijing 100049 , China
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20
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Fiore EJ, Domínguez LM, Bayo J, García MG, Mazzolini GD. Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies. World J Gastroenterol 2018; 24:2427-2440. [PMID: 29930465 PMCID: PMC6010941 DOI: 10.3748/wjg.v24.i23.2427] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 05/08/2018] [Accepted: 06/02/2018] [Indexed: 02/06/2023] Open
Abstract
Cell-based therapies for acute and chronic liver diseases are under continuous progress. Mesenchymal stem/stromal cells (MSCs) are multipotent cells able to migrate selectively to damaged tissue and contribute to its healing and regeneration. The MSC pro-regenerative effect occurs due to their immunomodulatory capacity and their ability to produce factors that promote cell protection and survival. Likewise, it has been observed that part of their paracrine effect is mediated by MSC-derived extracellular vesicles (EVs). EVs contain proteins, lipids and nucleic acids (DNA, mRNA, miRNA, lncRNA) from the cell of origin, allowing for intercellular communication. Recently, different studies have demonstrated that MSC-derived EVs could reproduce, at least in part, the biological effects obtained by MSC-based therapies. Moreover, due to EVs' stability for long periods of time and easy isolation methods they have become a therapeutic option to MSCs treatments. This review summarizes the latest results achieved in clinical trials using MSCs as cell therapy for liver regeneration, the role of EVs in liver physiopathology and the potential of MSCderived EVs as intercellular mediators and therapeutic tools in liver diseases.
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Affiliation(s)
- Esteban Juan Fiore
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
| | - Luciana María Domínguez
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
| | - Juan Bayo
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
| | - Mariana Gabriela García
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
| | - Guillermo Daniel Mazzolini
- Laboratory of Gene Therapy, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Buenos Aires 999071, Argentina
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21
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Ji R, Ren Q, Bai S, Wang Y, Zhou Y. Prognostic significance of pretreatment plasma fibrinogen in patients with hepatocellular and pancreatic carcinomas: A meta-analysis. Medicine (Baltimore) 2018; 97:e10824. [PMID: 29923974 PMCID: PMC6023750 DOI: 10.1097/md.0000000000010824] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 04/25/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The high pretreatment plasma fibrinogen has been widely reported to be a possible biomarker for predicting prognosis in hepatocellular carcinoma (HCC) and pancreatic carcinoma (PC), but persuasive conclusion has not been made yet. Thus, we herein conducted a meta-analysis to comprehensively assess the prognostic value of high pretreatment plasma fibrinogen in patients with HCC and PC. METHOD We systematically searched PubMed, EMBASE, and Web of Science to identify eligible studies from inception to November 10, 2017. RESULTS Finally, a total of 12 publications with 13 studies were included. Of these eligible studies, 5 publications with 6 studies were about pancreatic cancer and 7 were about HCC. The pooled analysis indicated that high plasm fibrinogen level was significantly related to worse overall survival (OS) in HCC [hazard ratio (HR) = 1.87; 95% confidence interval (CI): 1.55-2.24; P < .01]. Similarly, from our result, it was found that high plasm fibrinogen was also significantly associated with worse OS in PC (HR = 1.56; 95% CI: 1.13-2.15; P < .01). CONCLUSION Taken together, our meta-analysis confirmed that high plasma fibrinogen level could predict worse survival in HCC and PC.
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Affiliation(s)
- Rui Ji
- Department of Gastroenterology, the First Hospital of Lanzhou University
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Qian Ren
- Department of Gastroenterology, the First Hospital of Lanzhou University
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Suyang Bai
- Department of Gastroenterology, the First Hospital of Lanzhou University
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Yuping Wang
- Department of Gastroenterology, the First Hospital of Lanzhou University
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
| | - Yongning Zhou
- Department of Gastroenterology, the First Hospital of Lanzhou University
- Key Laboratory for Gastrointestinal Diseases of Gansu Province, Lanzhou University, Lanzhou, China
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22
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Fu SJ, Ji F, Han M, Chen MG, Wang XP, Ju WQ, Zhao Q, Wu LW, Ren QQ, Guo ZY, Wang DP, Zhu XF, Ma Y, He XS. Prognostic value of combined preoperative fibrinogen and neutrophil-lymphocyte ratio in patients with hepatocellular carcinoma after liver transplantation. Oncotarget 2018; 8:4301-4312. [PMID: 27935864 PMCID: PMC5354833 DOI: 10.18632/oncotarget.13804] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 11/02/2016] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Elevated plasma fibrinogen (Fib) correlated with patient's prognosis in several solid tumors. However, few studies have illuminated the relationship between preoperative Fib and prognosis of HCC after liver transplantation. We aimed to clarify the prognostic value of Fib and whether the prognostic accuracy can be enhanced by the combination of Fib and neutrophil-lymphocyte ratio (NLR). RESULTS Fib was correlated with Child-pugh stage, alpha-fetoprotein (AFP), size of largest tumor, macro- and micro-vascular invasion. Univariate analysis showed preoperative Fib, AFP, NLR, size of largest tumor, tumor number, macro- and micro- vascular invasion were significantly associated with disease-free survival (DFS) and overall survival (OS) in HCC patients with liver transplantation. After multivariate analysis, only Fib and macro-vascular invasion were independently correlated with DFS and OS. Survival analysis showed that preoperative Fib > 2.345 g/L predicted poor prognosis of patients HCC after liver transplantation. Preoperative Fib showed prognostic value in various subgroups of HCC. Furthermore, the predictive range was expanded by the combination of Fib and NLR. MATERIALS AND METHODS Data were collected retrospectively from 130 HCC patients who underwent liver transplantation. Preoperative Fib, NLR and clinicopathologic variables were analyzed. The survival analysis was performed by the Kaplan-Meier method, and compared by the log-rank test. Univariate and multivariate analyses were performed to identify the prognostic factors for DFS and OS. CONCLUSIONS Preoperative Fib is an independent effective predictor of prognosis for HCC patients, higher levels of Fib predict poorer outcomes and the combination of Fib and NLR enlarges the prognostic accuracy of testing.
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Affiliation(s)
- Shun-Jun Fu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, China
| | - Fei Ji
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Ming Han
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Mao-Gen Chen
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Xiao-Ping Wang
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Wei-Qiang Ju
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Qiang Zhao
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Lin-Wei Wu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Qing-Qi Ren
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Zhi-Yong Guo
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Dong-Ping Wang
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Xiao-Feng Zhu
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Yi Ma
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Xiao-Shun He
- Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P. R. China
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23
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Müller AM, Schmohl KA, Knoop K, Schug C, Urnauer S, Hagenhoff A, Clevert DA, Ingrisch M, Niess H, Carlsen J, Zach C, Wagner E, Bartenstein P, Nelson PJ, Spitzweg C. Hypoxia-targeted 131I therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated sodium iodide symporter gene delivery. Oncotarget 2018; 7:54795-54810. [PMID: 27458162 PMCID: PMC5342382 DOI: 10.18632/oncotarget.10758] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 07/10/2016] [Indexed: 12/18/2022] Open
Abstract
Adoptively transferred mesenchymal stem cells (MSCs) home to solid tumors. Biologic features within the tumor environment can be used to selectively activate transgenes in engineered MSCs after tumor invasion. One of the characteristic features of solid tumors is hypoxia. We evaluated a hypoxia-based imaging and therapy strategy to target expression of the sodium iodide symporter (NIS) gene to experimental hepatocellular carcinoma (HCC) delivered by MSCs. MSCs engineered to express transgenes driven by a hypoxia-responsive promoter showed robust transgene induction under hypoxia as demonstrated by mCherry expression in tumor cell spheroid models, or radioiodide uptake using NIS. Subcutaneous and orthotopic HCC xenograft mouse models revealed significant levels of perchlorate-sensitive NIS-mediated tumoral radioiodide accumulation by tumor-recruited MSCs using 123I-scintigraphy or 124I-positron emission tomography. Functional NIS expression was further confirmed by ex vivo123I-biodistribution analysis. Administration of a therapeutic dose of 131I in mice treated with NIS-transfected MSCs resulted in delayed tumor growth and reduced tumor perfusion, as shown by contrast-enhanced sonography, and significantly prolonged survival of mice bearing orthotopic HCC tumors. Interestingly, radioiodide uptake into subcutaneous tumors was not sufficient to induce therapeutic effects. Our results demonstrate the potential of using tumor hypoxia-based approaches to drive radioiodide therapy in non-thyroidal tumors.
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Affiliation(s)
- Andrea M Müller
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Kathrin A Schmohl
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Kerstin Knoop
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Christina Schug
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Sarah Urnauer
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Anna Hagenhoff
- Clinical Biochemistry Group, Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Dirk-André Clevert
- Department of Clinical Radiology, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Michael Ingrisch
- Department of Clinical Radiology, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Hanno Niess
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Janette Carlsen
- Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Christian Zach
- Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Ernst Wagner
- Department of Pharmacy, Center of Drug Research, Pharmaceutical Biotechnology, Ludwig Maximilian University of Munich, Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Peter J Nelson
- Clinical Biochemistry Group, Medizinische Klinik und Poliklinik IV, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany
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24
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Jeng KS, Jeng CJ, Jeng WJ, Sheen IS, Li SY, Lu SJ, Chang CF. Tropism of liver epithelial cells toward hepatocellular carcinoma in vitro and in vivo with altering gene expression of cancer stem cells. Am J Surg 2017; 215:735-743. [PMID: 29246405 DOI: 10.1016/j.amjsurg.2017.11.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 11/02/2017] [Accepted: 11/28/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Rat liver epithelial (RLE) cells could inhibit the proliferation and invasiveness of hepatoma cells in vitro. This study is to understand the tropism and the effect of RLE cells on mouse hepatoma cells both in vitro and in vivo. METHODS RLE cells were isolated from new-born rats and characterized their stem cell markers. Co-culture and HCC mouse model was established to detect therapeutic effect of RLE cells. RESULTS RLE cells (including Thy-1+ RLE cells, Thy-1- RLE cells, RLE cells) displayed a selective tropism toward ML-1 hepatoma cells both in vitro and in vivo. They altered the gene expression of some cancer stem cell markers in the liver tumor. CONCLUSION Liver epithelial cells have a selective tropism toward HCC in vitro and in vivo. They could alter the gene expression of cancer stem cells.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
| | - Chi-Juei Jeng
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Juei Jeng
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, Chang-Gung University, Taiwan
| | - I-Shyan Sheen
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, Chang-Gung University, Taiwan
| | - Shih-Yun Li
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Ssu-Jung Lu
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Chiung-Fang Chang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
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25
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Bayo J, Real A, Fiore EJ, Malvicini M, Sganga L, Bolontrade M, Andriani O, Bizama C, Fresno C, Podhajcer O, Fernandez E, Gidekel M, Mazzolini GD, García MG. IL-8, GRO and MCP-1 produced by hepatocellular carcinoma microenvironment determine the migratory capacity of human bone marrow-derived mesenchymal stromal cells without affecting tumor aggressiveness. Oncotarget 2017; 8:80235-80248. [PMID: 29113298 PMCID: PMC5655193 DOI: 10.18632/oncotarget.10288] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 05/22/2016] [Indexed: 12/21/2022] Open
Abstract
New therapies are needed for advanced hepatocellular carcinoma (HCC) and the use of mesenchymal stromal cells (MSCs) carrying therapeutic genes is a promising strategy. HCC produce cytokines recruiting MSCs to the tumor milieu and modifying its biological properties. Our aim was to study changes generated on human MSCs exposed to conditioned media (CM) derived from human HCC fresh samples and xenografts. All CM shared similar cytokines expression pattern including CXCL1-2-3/GRO, CCL2/MCP-1 and CXCL8/IL-8 being the latter with the highest concentration. Neutralizing and knockdown experiments of CCL2/MCP-1, CXCL8/IL-8, CXCR1 and CXCR2 reduced in vitro MSC migration of ≥20%. Simultaneous CXCR1 and CXCR2 neutralization resulted in 50% of MSC migration inhibition. MSC stimulated with CM (sMSC) from HuH7 or HC-PT-5 showed a 2-fold increase of migration towards the CM compared with unstimulated MSC (usMSC). Gene expression profile of sMSC showed ~500 genes differentially expressed compared with usMSC, being 46 genes related with cell migration and invasion. sMSC increased fibroblasts and endothelial cells chemotaxis. Finally, sMSC with HuH7 CM and then inoculated in HCC tumor bearing-mice did not modify tumor growth. In this work we characterized factors produced by HCC responsible for the changes in MSC chemotactic capacity with would have an impact on therapeutic use of MSCs for human HCC.
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Affiliation(s)
- Juan Bayo
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
| | - Alejandrina Real
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
| | - Esteban J. Fiore
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
| | - Mariana Malvicini
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
| | - Leonardo Sganga
- Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina
| | | | - Oscar Andriani
- Liver Unit, Hospital Universitario Austral, Derqui-Pilar, Argentina
| | | | - Cristóbal Fresno
- BioScience Data Mining Group, Catholic University of Córdoba, Córdoba, Argentina
| | | | - Elmer Fernandez
- BioScience Data Mining Group, Catholic University of Córdoba, Córdoba, Argentina
| | - Manuel Gidekel
- Universidad de la Frontera, Temuco, Chile
- Universidad Autónoma de Chile, Santiago, Chile
| | - Guillermo D. Mazzolini
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
- Liver Unit, Hospital Universitario Austral, Derqui-Pilar, Argentina
| | - Mariana G. García
- Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET, Universidad Austral, Buenos Aires, Argentina
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Endaya B, Guan SP, Newman JP, Huynh H, Sia KC, Chong ST, Kok CYL, Chung AYF, Liu BB, Hui KM, Lam PYP. Human mesenchymal stem cells preferentially migrate toward highly oncogenic human hepatocellular carcinoma cells with activated EpCAM signaling. Oncotarget 2017; 8:54629-54639. [PMID: 28903370 PMCID: PMC5589609 DOI: 10.18632/oncotarget.17633] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 02/27/2017] [Indexed: 01/16/2023] Open
Abstract
The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein that is regarded as one of the markers for tumor initiating cells (TIC) in human hepatocellular carcinoma (HCC). Much work has been directed towards targeting these TICs as a mean of placing these master regulators of cell proliferation and drug resistance under control. Human bone marrow-derived mesenchymal stem cells are known to exhibit an innate property of tumor tropism. However, the possible relationship between MSC and TIC is not well understood. In this study, we show that MSC migration to HCC can be effectively inhibited by TACE and γ-secretase inhibitors that stop the activation of EpCAM signaling event. Silencing of EpCAM expression through siRNA and antibody approaches also resulted in impaired MSC migration. By contrast, increase levels of EpICD proteins in HCC cells and HCC mouse xenografts resulted in enhanced MSC migration. Taken together, these findings show that MSC is drawn to the more oncogenic population of HCC, and could potentially serve as a cell-based carrier of therapeutic genes to target EpICD-enriched hepatic tumor cells.
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Affiliation(s)
- Berwini Endaya
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore City, Singapore.,Griffith Health Institute, Griffith University, Southport, Australia
| | - Shou P Guan
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore City, Singapore
| | - Jennifer P Newman
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore City, Singapore
| | - Hung Huynh
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore City, Singapore
| | - Kian C Sia
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore City, Singapore
| | - Siao T Chong
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore City, Singapore
| | - Catherine Y L Kok
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore City, Singapore
| | - Alexander Y F Chung
- Department of General Surgery, Singapore General Hospital, Singapore City, Singapore
| | - Bin B Liu
- Liver Cancer Institute of Fudan University, Shanghai, China
| | - Kam M Hui
- Department of Biochemistry, National University of Singapore, Singapore City, Singapore.,Institute of Molecular and Cell Biology, ASTAR, Singapore City, Singapore.,Cancer and Stem Cells Biology Program, Duke-NUS Graduate Medical School, Singapore City, Singapore
| | - Paula Y P Lam
- Division of Cellular and Molecular Research, National Cancer Centre, Singapore City, Singapore.,Department of Physiology, National University of Singapore, Singapore City, Singapore.,Cancer and Stem Cells Biology Program, Duke-NUS Graduate Medical School, Singapore City, Singapore
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27
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Zhang X, Long Q. Elevated serum plasma fibrinogen is associated with advanced tumor stage and poor survival in hepatocellular carcinoma patients. Medicine (Baltimore) 2017; 96:e6694. [PMID: 28445272 PMCID: PMC5413237 DOI: 10.1097/md.0000000000006694] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Hyperfibrinogenemia has been reported to be a predictor of poor prognosis in cancer patients, and in hepatocellular carcinoma (HCC) patients, survival remains uncertain and unpredictable. The aim of the present study was to evaluate the association between the level of plasma fibrinogen and overall survival in HCC patients.Overall, 308 patients with histologically proven HCC were included in our study. Univariate and multivariate analyses were performed to identify predictive risk factors for the rates of overall survival and tumor recurrence.Patients in the high-fibrinogen-level group were more likely to have advanced stage HCC, portal vein invasion, and tumors that were greater in number and larger in diameter than were patients in the low-fibrinogen-level group (all P < .05). The long-term overall survival rate of patients in the high-fibrinogen group was much lower than that of patients in the normal-fibrinogen group (P = .008), and similar outcomes were observed in the subgroup of patients who underwent radical therapies for HCC (P = .003). The results of the univariate and multivariate analyses indicated that high plasma fibrinogen remained independently associated with poorer overall survival. In addition, high plasma fibrinogen levels were associated with nonresponse to transarterial chemoembolization (TACE) (P < .001).Elevated plasma fibrinogen was independently associated with advanced HCC stage, poor prognosis, and nonresponse to TACE and may, therefore, serve as a valuable clinical biomarker for predicting prognosis in HCC patients.
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28
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Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4/HH signaling loop. Oncotarget 2017; 7:6916-32. [PMID: 26755648 PMCID: PMC4872758 DOI: 10.18632/oncotarget.6870] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 01/01/2016] [Indexed: 12/20/2022] Open
Abstract
The tumor microenvironment is critical to cancer growth and therapy resistance. We previously characterized human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are multi-potent cells that can differentiate into tumor microenvironment components including fibroblasts, myofibroblasts and adipocytes. We previously reported CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We demonstrate here that ovarian tumor cell-secreted Hedgehog (HH) induces CA-MSC BMP4 expression. CA-MSC-derived BMP4 reciprocally increases ovarian tumor cell HH expression indicating a positive feedback loop. Interruption of this loop with a HH pathway inhibitor or BMP4 blocking antibody decreases CA-MSC-derived BMP4 and tumor-derived HH preventing enrichment of CSCs and reversing chemotherapy resistance. The impact of HH inhibition was only seen in CA-MSC-containing tumors, indicating the importance of a humanized stroma. These results are reciprocal to findings in pancreatic and bladder cancer, suggesting HH signaling effects are tumor tissue specific warranting careful investigation in each tumor type. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH and present evidence for the further investigation of HH as a clinical target in ovarian cancer.
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Transforming Growth Factor β1 Promotes Migration and Invasion of Human Hepatocellular Carcinoma Cells Via Up-Regulation of Connective Tissue Growth Factor. Cell Biochem Biophys 2017; 73:775-81. [PMID: 27259324 DOI: 10.1007/s12013-015-0693-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a poor patient survival. Expression of TGF-β1 is up-regulated in HCC and is thought to play a crucial role in the occurrence and development of HCC. However, the mechanism of TGF-β1-mediated facilitation of malignant growth and invasion remains unclear, although some previous studies highlighted a potential involvement of the connective tissue growth factor (CTGF). Here we demonstrate that the in vitro migration of the HCC cell line SMMC-7721 is increased in the presence of recombinant TGF-β1, and that this effect is reversed by the specific inhibitor SB431542. Furthermore, TGF-β1 treatment up-regulated the expression of its own mRNA as well as the expression of CTGF mRNA. The TGF-β1-stimulated migration of SMMC-7721 cells was diminished by siRNA silencing of CTGF. These in vitro observations were validated in a murine xenograft model. In particular, silencing of CTFG diminished the TGF-β1-induced tumorigenesis in experimental animals. In conclusion, TGF-β1 plays a critical role in HCC migration and invasion, and this effect is dependent on CTGF.
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Uehara S, Fukuzawa Y, Matuyama T, Gotoh K. Role of Tyro3, Axl, and Mer Receptors and Their Ligands (Gas6, and Protein S) in Patients with Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2017. [DOI: 10.4236/jct.2017.82010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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31
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Fiore E, Malvicini M, Bayo J, Peixoto E, Atorrasagasti C, Sierra R, Rodríguez M, Gómez Bustillo S, García MG, Aquino JB, Mazzolini G. Involvement of hepatic macrophages in the antifibrotic effect of IGF-I-overexpressing mesenchymal stromal cells. Stem Cell Res Ther 2016; 7:172. [PMID: 27876093 PMCID: PMC5120504 DOI: 10.1186/s13287-016-0424-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 10/07/2016] [Accepted: 10/18/2016] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Cirrhosis is a major health problem worldwide and new therapies are needed. Hepatic macrophages (hMø) have a pivotal role in liver fibrosis, being able to act in both its promotion and its resolution. It is well-known that mesenchymal stromal cells (MSCs) can modulate the immune/inflammatory cells. However, the effects of MSCs over hMø in the context of liver fibrosis remain unclear. We previously described evidence of the antifibrotic effects of in vivo applying MSCs, which were enhanced by forced overexpression of insulin-like growth factor 1 (AdIGF-I-MSCs). The aim of this work was to analyze the effect of MSCs on hMø behavior in the context of liver fibrosis resolution. METHODS Fibrosis was induced in BALB/c mice by chronic administration of thioacetamide (8 weeks). In vivo gene expression analyses, in vitro experiments using hMø isolated from the nonparenchymal liver cells fraction, and in vivo experiments with depletion of Mø were performed. RESULTS One day after treatment, hMø from fibrotic livers of MSCs-treated animals showed reduced pro-inflammatory and pro-fibrogenic gene expression profiles. These shifts were more pronounced in AdIGF-I-MSCs condition. This group showed a significant upregulation in the expression of arginase-1 and a higher downregulation of iNOS expression thus suggesting decreased levels of oxidative stress. An upregulation in IGF-I and HGF expression was observed in hMø from AdIGF-I-MSCs-treated mice suggesting a restorative phenotype in these cells. Factors secreted by hMø, preconditioned with MSCs supernatant, caused a reduction in the expression levels of hepatic stellate cells pro-fibrogenic and activation markers. Interestingly, hMø depletion abrogated the therapeutic effect achieved with AdIGF-I-MSCs therapy. Expression profile analyses for cell cycle markers were performed on fibrotic livers after treatment with AdIGF-I-MSCs and showed a significant regulation in genes related to DNA synthesis and repair quality control, cell cycle progression, and DNA damage/cellular stress compatible with early induction of pro-regenerative and hepatoprotective mechanisms. Moreover, depletion of hMø abrogated such effects on the expression of the most highly regulated genes. CONCLUSIONS Our results indicate that AdIGF-I-MSCs are able to induce a pro-fibrotic to resolutive phenotype shift on hepatic macrophages, which is a key early event driving liver fibrosis amelioration.
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Affiliation(s)
- Esteban Fiore
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
| | - Mariana Malvicini
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) Godoy Cruz 2290, Buenos Aires, Argentina
| | - Juan Bayo
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
| | - Estanislao Peixoto
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
| | - Catalina Atorrasagasti
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) Godoy Cruz 2290, Buenos Aires, Argentina
| | - Romina Sierra
- Developmental Biology and Regenerative Medicine Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
| | - Marcelo Rodríguez
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
| | - Sofia Gómez Bustillo
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
| | - Mariana G. García
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) Godoy Cruz 2290, Buenos Aires, Argentina
| | - Jorge B. Aquino
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) Godoy Cruz 2290, Buenos Aires, Argentina
- Developmental Biology and Regenerative Medicine Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
| | - Guillermo Mazzolini
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Av. Pte. Peron 1500, Derqui-Pilar, Buenos Aires B1629AHJ Argentina
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas) Godoy Cruz 2290, Buenos Aires, Argentina
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Hepatocellular Carcinoma-propagating Cells are Detectable by Side Population Analysis and Possess an Expression Profile Reflective of a Primitive Origin. Sci Rep 2016; 6:34856. [PMID: 27725724 PMCID: PMC5057076 DOI: 10.1038/srep34856] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 09/21/2016] [Indexed: 12/15/2022] Open
Abstract
The recent identification of “Side Population” (SP) cells in a number of unrelated human cancers has renewed interests in the hypothesis of cancer stem cells. Here we isolated SP cells from HepG2 cells and 18 of the 21 fresh hepatocellular carcinoma (HCC) tissue samples. These SP cells have higher abilities of forming spheroids, invasion and migration. Tumors could generate only from SP, not non-SP (NSP), cells in a low dose of subcutaneous injection to the NOD/SCID mice (5 × 102 cells/mouse). The mRNA microarray analysis of the SP vs. NSP cells isolated from HepG2 cells revealed that the SP cells express higher levels of pluripotency- and stem cell-associated transcription factors including Klf4, NF-Ya, SALL4 and HMGA2. Some of the known hepatobiliary progenitor/stem cell markers, such as Sox9 was also up-regulated. RT-qPCR analysis of the gene expression between SP cells and NSP cells isolated from both HepG2 cells and HCC tissue samples showed that most of the tested mRNAs’ changes were in consistent with the microarray data, including the general progenitor/stem cells markers such as Klf4, NF-Ya, SALL4 and HMGA2, which were up-regulated in SP cells. Our data indicates that HCC cancer stem cells exist in HepG2 and HCC fresh tissue samples and can be isolated by SP assay.
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Gao Y, Zhou Z, Lu S, Huang X, Zhang C, Jiang R, Yao A, Sun B, Wang X. Chemokine CCL15 Mediates Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Hepatocellular Carcinoma. Stem Cells 2016; 34:1112-22. [PMID: 26763650 DOI: 10.1002/stem.2275] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 11/12/2015] [Indexed: 12/18/2022]
Abstract
Mesenchymal stem cells (MSCs) possess the ability to migrate toward tumor sites and are regarded as promising gene delivery vehicles for cancer therapeutics. However, the factors that mediate this tropism have yet to be completely elucidated. In this study, through cytokine array analysis, chemokine CCL15 was found to be the most abundant protein differentially expressed in hepatocellular carcinoma (HCC) cell lines compared with a normal liver cell line. Serum CCL15 levels in HCC patients determined by enzyme linked immunosorbent assay were shown to be profoundly elevated compared with healthy controls. Immunohistochemical analysis indicated that CCL15 expression was much stronger in HCC tumor tissues than in adjacent nontumor tissues. Transwell migration assay suggested that CCL15 may be involved in chemotaxis of human MSCs (hMSCs) toward HCC in vitro and that this chemotactic effect of CCL15 is mediated via CCR1 receptors on hMSCs. Orthotopic animal models of HCC were established to investigate the role of CCL15 in hMSCs migration toward HCC in vivo. Both histological and flow cytometric analysis showed that significantly fewer hMSCs localized within 97H-CCL15-shRNA xenografts compared with 97H-green fluorescent protein xenografts after intravenous delivery. Finally, the possible effects of hMSCs on HCC tumor growth were also evaluated. Coculture experiments showed that hMSCs had no apparent effect on the proliferation of HCC cells in vitro In addition, systemic administration of hMSCs did not affect HCC tumor progression in vivo. Our data in this study help to elucidate the mechanism underlying the homing capacity of hMSCs toward HCC.
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MESH Headings
- Animals
- Bone Marrow Cells/cytology
- Bone Marrow Cells/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/therapy
- Cell Line, Tumor
- Cell Movement/genetics
- Chemokines, CC/biosynthesis
- Chemokines, CC/genetics
- Chemokines, CC/therapeutic use
- Chemotaxis/genetics
- Gene Expression Regulation, Neoplastic
- Gene Transfer Techniques
- Green Fluorescent Proteins/genetics
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/therapy
- Macrophage Inflammatory Proteins/biosynthesis
- Macrophage Inflammatory Proteins/genetics
- Macrophage Inflammatory Proteins/therapeutic use
- Mesenchymal Stem Cells/chemistry
- Mesenchymal Stem Cells/cytology
- Mesenchymal Stem Cells/metabolism
- Mice
- RNA, Small Interfering/genetics
- RNA, Small Interfering/therapeutic use
- Receptors, CCR1/biosynthesis
- Receptors, CCR1/genetics
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Yun Gao
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Zhong Zhou
- Department of Orthopaedics, Jiangsu Provincial Hospital of Integrated Chinese and Western Medicine, Nanjing, Jiangsu Province, People's Republic of China
| | - Sen Lu
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Xinli Huang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Chuanyong Zhang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Runqiu Jiang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Aihua Yao
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Beicheng Sun
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
| | - Xuehao Wang
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China
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Uccella S, Cromi A, Vigetti D, Cimetti L, Deleonibus S, Casarin J, Passi A, Riva C, Ghezzi F. Endometrial cancer cells can express fibrinogen: Immunohistochemistry and RT-PCR analysis. J OBSTET GYNAECOL 2015; 36:353-8. [DOI: 10.3109/01443615.2015.1065231] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Li H, Zhao T, Ji X, Liang S, Wang Z, Yang Y, Yin J, Wang R. Hyperfibrinogenemia predicts poor prognosis in patients with advanced biliary tract cancer. Tumour Biol 2015; 37:3535-42. [PMID: 26453118 DOI: 10.1007/s13277-015-4184-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 10/01/2015] [Indexed: 12/11/2022] Open
Abstract
Hyperfibrinogenemia reportedly predicts poor prognosis in several cancers but has not been reviewed for biliary tract cancer (BTC). The aim of the present study was to evaluate associations between baseline plasma fibrinogen concentrations, clinicopathological characteristics, and survival parameters in patients with BTC. Data for 127 patients with BTC diagnosed at the Zhongshan Affiliated Hospital of Dalian University (Liaoning, China) from January 2011 to December 2014 were retrospectively evaluated. Associations between baseline fibrinogen concentrations, selected clinicopathological characteristics, and the prognostic value were examined using SPSS software. Data for 37 patients (29.1 % of study cohort) who had undergone curative intent surgery and 90 (70.9 %) with advanced biliary tract cancer (ABTC) were analyzed. The mean plasma fibrinogen concentration 4.0 ± 0.9 g/L for the entire cohort. The percentages with hyperfibrinogenemia (>4 g/L) were 45.7, 37.8, and 48.9 % overall and in the surgical and ABTC groups, respectively. Hyperfibrinogenemia was associated with performance status (PS) and neutrophil/lymphocyte ratio in the entire cohort but not with other relevant clinicopathological factors. Log-rank test indicated that baseline hyperfibrinogenemia was associated with decreased progression-free survival (PFS) and overall survival (OS) for patients with unresectable ABTC (P > 0.05). Multivariate analysis showed that poor PS and baseline hyperfibrinogenemia were independently associated with worse survival (HR: 1.39, 95 % CI: 1.02-1.90, P = 0.04; HR: 1.75.95 %, 95 % CI: 1.01-3.01, P = 0.04, respectively). Baseline hyperfibrinogenemia is an independent predictor of poor prognosis in patients with ABTC. Baseline plasma fibrinogen concentrations may be a readily available and inexpensive prognostic biomarker in patients with ABTC; this needs further validation in large prospective clinical trials.
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Affiliation(s)
- Heming Li
- Department of Oncology, Zhongshan Hospital of Dalian University, No. 6, Liberation Street, Zhongshan District, Dalian, 116001, People's Republic of China
| | - Tong Zhao
- Department of Oncology, Zhongshan Hospital of Dalian University, No. 6, Liberation Street, Zhongshan District, Dalian, 116001, People's Republic of China
| | - Xuening Ji
- Department of Oncology, Zhongshan Hospital of Dalian University, No. 6, Liberation Street, Zhongshan District, Dalian, 116001, People's Republic of China
| | - Shanshan Liang
- Department of Oncology, Zhongshan Hospital of Dalian University, No. 6, Liberation Street, Zhongshan District, Dalian, 116001, People's Republic of China
| | - Zhe Wang
- Department of Oncology, Zhongshan Hospital of Dalian University, No. 6, Liberation Street, Zhongshan District, Dalian, 116001, People's Republic of China
| | - Yulong Yang
- Department of Oncology, Zhongshan Hospital of Dalian University, No. 6, Liberation Street, Zhongshan District, Dalian, 116001, People's Republic of China
| | - Jiajun Yin
- Department of Oncology, Zhongshan Hospital of Dalian University, No. 6, Liberation Street, Zhongshan District, Dalian, 116001, People's Republic of China
| | - Ruoyu Wang
- Department of Oncology, Zhongshan Hospital of Dalian University, No. 6, Liberation Street, Zhongshan District, Dalian, 116001, People's Republic of China.
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Inhibitory effect of endostar on specific angiogenesis induced by human hepatocellular carcinoma. Gastroenterol Res Pract 2015; 2015:957574. [PMID: 25983751 PMCID: PMC4423035 DOI: 10.1155/2015/957574] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 12/10/2014] [Indexed: 11/21/2022] Open
Abstract
To investigate the effect of endostar on specific angiogenesis induced by human hepatocellular carcinoma, this research systematically elucidated the inhibitory effect on HepG2-induced angiogenesis by endostar from 50 ng/mL to 50000 ng/mL. We employed fluorescence quantitative Boyden chamber analysis, wound-healing assay, flow cytometry examination using a coculture system, quantitative analysis of tube formation, and in vivo Matrigel plug assay induced by HCC conditioned media (HCM) and HepG2 compared with normal hepatocyte conditioned media (NCM) and L02. Then, we found that endostar as a tumor angiogenesis inhibitor could potently inhibit human umbilical vein endothelial cell (HUVEC) migration in response to HCM after four- to six-hour action, inhibit HCM-induced HUVEC migration to the lesion part in a dose-dependent manner between 50 ng/mL and 5000 ng/mL at 24 hours, and reduce HUVEC proliferation in a dose-dependent fashion. Endostar inhibited HepG2-induced tube formation of HUVECs which peaked at 50 ng/mL. In vivo Matrigel plug formation was also significantly reduced by endostar in HepG2 inducing system rather than in L02 inducing system. It could be concluded that, at cell level, endostar inhibited the angiogenesis-related biological behaviors of HUVEC in response to HCC, including migration, adhesion proliferation, and tube formation. At animal level, endostar inhibited the angiogenesis in response to HCC in Matrigel matrix.
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Lejmi E, Perriraz N, Clément S, Morel P, Baertschiger R, Christofilopoulos P, Meier R, Bosco D, Bühler LH, Gonelle-Gispert C. Inflammatory Chemokines MIP-1δ and MIP-3α Are Involved in the Migration of Multipotent Mesenchymal Stromal Cells Induced by Hepatoma Cells. Stem Cells Dev 2015; 24:1223-35. [PMID: 25579056 DOI: 10.1089/scd.2014.0176] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In vivo, bone marrow-derived multipotent mesenchymal stromal cells (MSC) have been identified at sites of tumors, suggesting that specific signals mobilize and activate MSC to migrate to areas surrounding tumors. The signals and migratory mechanisms that guide MSC are not well understood. Here, we investigated the migration of human MSC induced by conditioned medium of Huh-7 hepatoma cells (Huh-7 CM). Using a transwell migration system, we showed that human MSC migration was increased in the presence of Huh-7 CM. Using a human cytokine antibody array, we detected increased levels of MIP-1δ and MIP-3α in Huh-7 CM. Recombinant chemokines MIP-1δ and MIP-3α induced MSC migration. Anti-MIP-1δ and anti-MIP-3α antibodies added to Huh-7 CM decreased MSC migration, further suggesting that MIP-1δ and MIP-3α were implicated in the Huh-7 CM-induced MSC migration. By real-time polymerase chain reaction, we observed an absence of chemokine receptors CCR2 and CXCR2 and low expression of CCR1, CCR5, and CCR6 in MSC. Expression of these chemokine receptors was not regulated by Huh-7 CM. Furthermore, matrix metalloproteinase 1 (MMP-1) expression was strongly increased in MSC after incubation with Huh-7 CM, suggesting that MSC migration depends on MMP-1 activity. The signaling pathway MAPK/ERK was activated by Huh-7 CM but its inhibition by PD98059 did not impair Huh-7 CM-induced MSC migration. Further, long-term incubation of MSC with MIP-1δ increased α-smooth muscle actin expression, suggesting its implication in the Huh-7 CM-induced evolvement of MSC into myofibroblasts. In conclusion, we report that two inflammatory cytokines, MIP-1δ and MIP-3α, are able to increase MSC migration in vitro. These cytokines might be responsible for migration and evolvement of MSC into myofibroblasts around tumors.
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Affiliation(s)
- Esma Lejmi
- 1 Surgical Research Unit, University Hospitals of Geneva , Geneva, Switzerland
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Fiore EJ, Bayo JM, Garcia MG, Malvicini M, Lloyd R, Piccioni F, Rizzo M, Peixoto E, Sola MB, Atorrasagasti C, Alaniz L, Camilletti MA, Enguita M, Prieto J, Aquino JB, Mazzolini G. Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice. Stem Cells Dev 2014; 24:791-801. [PMID: 25315017 DOI: 10.1089/scd.2014.0174] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Liver cirrhosis involves chronic wound healing and fibrotic processes. Mesenchymal stromal cells (MSCs) are multipotent adult progenitor cells that are used as vehicles of therapeutic genes. Insulin growth factor like-I (IGF-I) was shown to counteract liver fibrosis. We aimed at analyzing the effect of applying IGF-I overexpressing mouse bone marrow-derived MSCs on hepatic fibrosis. Fibrosis was induced by chronic thioacetamide application or bile duct ligation. MSCs engineered to produce green fluorescent protein (GFP) (AdGFP-MSCs) or IGF-I (AdIGF-I-MSCs) were applied systemically, and changes in collagen deposition and in the expression of key pro-fibrogenic and pro-regenerative genes/proteins were assessed. In addition, immunogenicity of transduced cells was analyzed. Liver fibrosis was further ameliorated after a single-dose application of AdIGF-I-MSCs when compared with AdGFP-MSCs and/or recombinant IGF-I treatments. Interestingly, an early and transitory upregulation in IGF-I and hepatocyte growth factor (HGF) mRNA expression was found in the liver of MSC-treated animals, which was more pronounced in AdIGF-I-MSCs condition. A reduction in hepatic stellate cell activation status was found after incubation with MSCs conditioned media. In addition, the AdIGF-I-MSCs cell-free supernatant induced the expression of IGF-I and HGF in primary cultured hepatocytes. From day 1 after transplantation, the proliferation marker proliferating cell nuclear antigen was upregulated in the liver of AdIGF-I-MSCs group, mainly in hepatocytes. MSCs were in vivo traced till day 14 after injection. In addition, multiple doses of Ad-IGF-I-MSCs likely suppressed antiviral immune response and it further reduced collagen deposition. Our results uncover early events that are likely involved in the anti-fibrogenic effect of genetically modified MSCs and overall would support the use of AdIGF-I-MSCs in treatment of liver fibrosis.
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Affiliation(s)
- Esteban J Fiore
- 1 Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral , Buenos Aires, Argentina
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Advances in mesenchymal stem cells combined with traditional Chinese medicine therapy for liver fibrosis. JOURNAL OF INTEGRATIVE MEDICINE-JIM 2014; 12:147-55. [PMID: 24861835 DOI: 10.1016/s2095-4964(14)60022-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Liver fibrosis is a primary cause of liver cirrhosis, and even hepatocarcinoma. Recently, the usage of mesenchymal stem cells (MSCs) has been investigated to improve liver fibrosis. It has been reported that the differentiation, proliferation and migration of MSCs can be regulated by traditional Chinese medicine treatment; however, the mechanisms are still unclear. In this article, the authors review the characteristics of MSCs such as multidirectional differentiation and homing, and its application in animal experiments and clinical trials. The authors also list areas that need further investigation, andlook at the future prospects of clinical application of MSCs.
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Hernanda PY, Pedroza-Gonzalez A, Sprengers D, Peppelenbosch MP, Pan Q. Multipotent mesenchymal stromal cells in liver cancer: implications for tumor biology and therapy. Biochim Biophys Acta Rev Cancer 2014; 1846:439-45. [PMID: 25204853 DOI: 10.1016/j.bbcan.2014.08.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 08/01/2014] [Accepted: 08/30/2014] [Indexed: 02/08/2023]
Abstract
Remodeling of tumor microenvironment is a hallmark in the pathogenesis of liver cancer. Being a pivotal part of tumor stroma, multipotent mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells (MSCs), are recruited and enriched in liver tumors. Owing to their tumor tropism, MSCs are now emerging as vehicles for anticancer drug/gene delivery against liver cancer. However, the exact impact of MSCs on liver cancer remains elusive, as a variety of effects of these cells that have been reported included a plethora of tumor-promoting effects and anti-oncogenic properties. This review aims to dissect the mechanistic insight regarding this observed discrepancy in different experimental settings of liver cancer. Furthermore, we call for caution using MSCs to treat liver cancer or even premalignant liver diseases, before conclusive evidence for safety and efficacy having been obtained.
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Affiliation(s)
- Pratika Y Hernanda
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Alexander Pedroza-Gonzalez
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dave Sprengers
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
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41
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Human umbilical cord perivascular cells exhibited enhanced migration capacity towards hepatocellular carcinoma in comparison with bone marrow mesenchymal stromal cells: a role for autocrine motility factor receptor. BIOMED RESEARCH INTERNATIONAL 2014; 2014:837420. [PMID: 25147818 PMCID: PMC4132334 DOI: 10.1155/2014/837420] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 06/17/2014] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Unfortunately, the incidence and mortality associated with HCC are increasing. Therefore, new therapeutic strategies are urgently needed and the use of mesenchymal stromal cells (MSCs) as carrier of therapeutic genes is emerging as a promising option. Different sources of MSCs are being studied for cell therapy and bone marrow-derived cells are the most extensively explored; however, birth associated-tissues represent a very promising source. The aim of this work was to compare the in vitro and in vivo migration capacity between bone marrow MSCs (BM-MSCs) and human umbilical cord perivascular cells (HUCPVCs) towards HCC. We observed that HUCPVCs presented higher in vitro and in vivo migration towards factors released by HCC. The expression of autocrine motility factor (AMF) receptor, genes related with the availability of the receptor on the cell surface (caveolin-1 and -2) and metalloproteinase 3, induced by the receptor activation and important for cell migration, was increased in HUCPVCs. The chemotactic response towards recombinant AMF was increased in HUCPVCs compared to BM-MSCs, and its inhibition in the conditioned medium from HCC induced higher decrease in HUCPVC migration than in BM-MSC. Our results indicate that HUCPVCs could be a useful cellular source to deliver therapeutic genes to HCC.
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Ma WL, Lai HC, Yeh S, Cai X, Chang C. Androgen receptor roles in hepatocellular carcinoma, fatty liver, cirrhosis and hepatitis. Endocr Relat Cancer 2014; 21:R165-82. [PMID: 24424503 PMCID: PMC4165608 DOI: 10.1530/erc-13-0283] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Androgen/androgen receptor (AR) signaling plays important roles in normal liver function and in progression of liver diseases. In studies of noncancerous liver diseases, AR knockout mouse models of liver disease have revealed that androgen/AR signaling suppresses the development of steatosis, virus-related hepatitis, and cirrhosis. In addition, studies have shown that targeting AR in bone marrow-derived mesenchymal stem cells (BM-MSCs) improves their self-renewal and migration potentials, thereby increasing the efficacy of BM-MSC transplantation as a way to control the progression of cirrhosis. Androgen/AR signaling is known to be involved in the initiation of carcinogen- or hepatitis B virus-related hepatocellular carcinoma (HCC). However, studies have demonstrated that AR, rather than androgen, plays the dominant role in cancer initiation. Therefore, targeting AR might be an appropriate therapy for patients with early-stage HCC. In contrast, androgen/AR signaling has been shown to suppress metastasis of HCC in patients with late-stage disease. In addition, there is evidence that therapy comprising Sorafenib and agents that enhance the functional expression of AR may suppress the progression of late-stage HCC.
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Affiliation(s)
- Wen-Lung Ma
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
| | - Hsueh-Chou Lai
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
| | - Shuyuan Yeh
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
| | - Xiujun Cai
- Department of General Surgery, Chawnshang Chang Liver
Cancer Center, Sir Run-run Shaw Hospital, Zhejiang University, Hangzhou, China
- Corresponding author: Chawnshang
Chang () and Xiujun Cai
()
| | - Chawnshang Chang
- Sex Hormone Research Center, Department of
Gastroenterology, and Graduate Institute of Clinical Medical Science, China Medical
University/Hospital, Taichung 404, Taiwan
- George Whipple Lab for Cancer Research, Departments of
Pathology and Urology and The Wilmot Cancer Center, University of Rochester Medical
Center, Rochester, NY 14642, USA
- Corresponding author: Chawnshang
Chang () and Xiujun Cai
()
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Bayo J, Fiore E, Aquino JB, Malvicini M, Rizzo M, Peixoto E, Andriani O, Alaniz L, Piccioni F, Bolontrade M, Podhajcer O, Garcia MG, Mazzolini G. Increased migration of human mesenchymal stromal cells by autocrine motility factor (AMF) resulted in enhanced recruitment towards hepatocellular carcinoma. PLoS One 2014; 9:e95171. [PMID: 24736611 PMCID: PMC3988162 DOI: 10.1371/journal.pone.0095171] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 03/24/2014] [Indexed: 12/26/2022] Open
Abstract
Background and Aims Several reports described the migration of human mesenchymal stromal cells (MSCs) towards tumor-released factors. Autocrine motility factor (AMF) is produced by several tumors including hepatocellular carcinoma (HCC). The aim of this study was to analyze AMF involvement on MSC migration towards human HCC. Methods Production of AMF by HCC tumors was evaluated by western analysis. The effects of AMF on MSCs from different sources (bone marrow, adipose tissue and perivascular cells from umbilical cord) were analyzed using in vitro migration assay; metalloproteinase 2 (MMP2) activity and expression of critical genes were studied by zymography and qRT-PCR, respectively. To assess AMF involvement on the in vivo MSC migration, noninvasive fluorescence imaging was performed. To test the effect of AMF-primed MSCs on tumor development, in vitro proliferation and spheroids growth and in vivo tumor volume were evaluated. Results AMF produced by HCC was found to induce migration of different MSCs in vitro and to enhance their MMP2 activity. Stimulation of MSCs with recombinant AMF (rAMF) also induced the in vitro adhesion to endothelial cells in coincidence with changes in the expression levels of MMP3, AMF receptor, caveolin-1, and -2 and GDI-2. Importantly, stimulation of MSCs with rAMF increased the in vivo migration of MSCs towards experimental HCC tumors. AMF-priming of MSCs did not induce a pro-tumorigenic effect on HCC cells neither in vivo nor in vitro. Conclusion AMF plays a role in MSC recruitment towards HCC. However, its ability to increase MSC migration to HCC for therapeutic purposes merits further evaluation.
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Affiliation(s)
- Juan Bayo
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
| | - Esteban Fiore
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
| | - Jorge B. Aquino
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina
| | - Mariana Malvicini
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
| | - Manglio Rizzo
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
| | - Estanislao Peixoto
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
| | - Oscar Andriani
- Liver Unit, Hospital Universitario Austral, Universidad Austral, Derqui-Pilar, Argentina
| | - Laura Alaniz
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina
| | - Flavia Piccioni
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
| | - Marcela Bolontrade
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina
- Molecular and Cellular Therapy Laboratory, Fundación Instituto Leloir, Buenos Aires, Argentina
| | - Osvaldo Podhajcer
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina
- Molecular and Cellular Therapy Laboratory, Fundación Instituto Leloir, Buenos Aires, Argentina
| | - Mariana G. Garcia
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina
| | - Guillermo Mazzolini
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Buenos Aires, Argentina
- CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina
- Liver Unit, Hospital Universitario Austral, Universidad Austral, Derqui-Pilar, Argentina
- * E-mail:
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Bayo J, Marrodán M, Aquino JB, Silva M, García MG, Mazzolini G. The therapeutic potential of bone marrow-derived mesenchymal stromal cells on hepatocellular carcinoma. Liver Int 2014; 34:330-42. [PMID: 24112437 DOI: 10.1111/liv.12338] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 09/15/2013] [Indexed: 12/11/2022]
Abstract
Mesenchymal stromal cells (MSCs) are more often obtained from adult and extraembryonic tissues, with the latter sources being likely better from a therapeutic perspective. MSCs show tropism towards inflamed or tumourigenic sites. Mechanisms involved in MSC recruitment into tumours are comprehensively analysed, including chemoattractant signalling axes, endothelial adhesion and transmigration. In addition, signals derived from hepatocellular carcinoma (HCC) tumour microenvironment and their influence in MSC tropism and tumour recruitment are dissected, as well as the present controversy regarding their influence on tumour growth and/or metastasis. Finally, evidences available on the use of MSCs and other selected progenitor/stem cells as vehicles of antitumourigenic genes are discussed. A better knowledge of the mechanisms involved in progenitor/stem cell recruitment to HCC tumours is proposed in order to enhance their tumour targeting which may result in improvements in cell-based gene therapy strategies.
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Affiliation(s)
- Juan Bayo
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Universidad Austral, Derqui-Pilar, Argentina
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45
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Yu CY, Wang YM, Li NM, Liu GS, Yang S, Tang GT, He DX, Tan XW, Wei H. In Vitro and in Vivo Evaluation of Pectin-Based Nanoparticles for Hepatocellular Carcinoma Drug Chemotherapy. Mol Pharm 2014; 11:638-44. [DOI: 10.1021/mp400412c] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Cui-Yun Yu
- Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China
| | - Yan-Mei Wang
- Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China
| | - Na-Mei Li
- Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China
| | - Ge-Sha Liu
- Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China
| | - Sa Yang
- Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China
| | - Guo-Tao Tang
- Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China
| | - Dong-Xiu He
- Institute of Pharmacy & Pharmacology, Department of Pharmacy, University of South China, Hengyang 421001, China
| | - Xiang-Wen Tan
- Department
of Laboratory Animal Science, University of South China, Hengyang 421001, China
| | - Hua Wei
- Department
of Bioengineering, University of Washington, Seattle, Washington 98195, United States
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Collagen as a double-edged sword in tumor progression. Tumour Biol 2013; 35:2871-82. [PMID: 24338768 PMCID: PMC3980040 DOI: 10.1007/s13277-013-1511-7] [Citation(s) in RCA: 390] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 12/03/2013] [Indexed: 12/11/2022] Open
Abstract
It has been recognized that cancer is not merely a disease of tumor cells, but a disease of imbalance, in which stromal cells and tumor microenvironment play crucial roles. Extracellular matrix (ECM) as the most abundant component in tumor microenvironment can regulate tumor cell behaviors and tissue tension homeostasis. Collagen constitutes the scaffold of tumor microenvironment and affects tumor microenvironment such that it regulates ECM remodeling by collagen degradation and re-deposition, and promotes tumor infiltration, angiogenesis, invasion and migration. While collagen was traditionally regarded as a passive barrier to resist tumor cells, it is now evident that collagen is also actively involved in promoting tumor progression. Collagen changes in tumor microenvironment release biomechanical signals, which are sensed by both tumor cells and stromal cells, trigger a cascade of biological events. In this work, we discuss how collagen can be a double-edged sword in tumor progression, both inhibiting and promoting tumor progression at different stages of cancer development.
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47
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The fibrotic microenvironment as a heterogeneity facet of hepatocellular carcinoma. FIBROGENESIS & TISSUE REPAIR 2013; 6:17. [PMID: 24350713 PMCID: PMC3849063 DOI: 10.1186/1755-1536-6-17] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 08/28/2013] [Indexed: 02/07/2023]
Abstract
It has long been recognized that hepatocellular carcinoma heterogeneity arises from variation in the microenvironment or from genomic alteration. Only recently it has become clear that non-genetic alterations, such as cytoskeletal rearrangement, protein localization and formation of protein complexes, are also involved in generating phenotype variability. These proteome fluctuations cause genetically identical cells to vary significantly in their responsiveness to microenvironment stimuli. In the cirrhotic liver pre-malignant hepatocytes are continuously exposed to abnormal microenvironments, such as direct contact with activated hepatic stellate cells (HSCs) and extracellular matrix components. These abnormal environments can have pronounced influences on the epigenetic aspects of cells, translating into abnormal phenotypes. Here we discuss non-genetic causes of phenotypic heterogeneity of hepatocellular carcinoma, with an emphasis on variability of membrane protein complexes and transferred functions raising important implications for diagnosis and treatment.
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Xiu M, Liu YH, Brigstock DR, He FH, Zhang RJ, Gao RP. Connective tissue growth factor is overexpressed in human hepatocellular carcinoma and promotes cell invasion and growth. World J Gastroenterol 2012; 18:7070-8. [PMID: 23323010 PMCID: PMC3531696 DOI: 10.3748/wjg.v18.i47.7070] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 11/13/2012] [Accepted: 11/24/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the expression characteristics of connective tissue growth factor (CTGF/CCN2) in human hepatocellular carcinoma (HCC) in histology and to elucidate the roles of CCN2 on hepatoma cell cycle progression and metastasis in vitro.
METHODS: Liver samples from 36 patients (who underwent hepatic resection for the first HCC between 2006 and 2011) and 6 normal individuals were examined for transforming growth factor β1 (TGF-β1) or CCN2 mRNA by in situ hybridization. Computer image analysis was performed to measure integrated optimal density of CCN2 mRNA-positive cells in carcinoma foci and the surrounding stroma. Fibroblast-specific protein-1 (FSP-1) and E-cadherin were examined to evaluate the process of epithelial to mesenchymal transition, α-smooth muscle actin and FSP-1 were detected to identify hepatic stellate cells, and CD34 was measured to evaluate the extent of vascularization in liver tissues by immunohistochemical staining. CCN2 was assessed for its stimulation of HepG2 cell migration and invasion using commercial kits while flow cytometry was used to determine CCN2 effects on HepG2 cell-cycle.
RESULTS: In situ hybridization analysis showed that TGF-β1 mRNA was mainly detected in connective tissues and vasculature around carcinoma foci. In comparison to normal controls, CCN2 mRNA was enhanced 1.9-fold in carcinoma foci (12.36 ± 6.08 vs 6.42 ± 2.35) or 9.4-fold in the surrounding stroma (60.27 ± 28.71 vs 6.42 ± 2.35), with concomitant expression of CCN2 and TGF-β1 mRNA in those areas. Epithelial-mesenchymal transition phenotype related with CCN2 was detected in 12/36 (33.3%) of HCC liver samples at the edges between carcinoma foci and vasculature. Incubation of HepG2 cells with CCN2 (100 ng/mL) resulted in more of the cells transitioning into S phase (23.85 ± 2.35 vs 10.94 ± 0.23), and induced a significant migratory (4.0-fold) and invasive (5.7-fold) effect. TGF-β1-induced cell invasion was abrogated by a neutralizing CCN2 antibody showing that CCN2 is a downstream mediator of TGF-β1-induced hepatoma cell invasion.
CONCLUSION: These data support a role for CCN2 in the growth and metastasis of HCC and highlight CCN2 as a potential novel therapeutic target.
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Bolontrade MF, Sganga L, Piaggio E, Viale DL, Sorrentino MA, Robinson A, Sevlever G, García MG, Mazzolini G, Podhajcer OL. A specific subpopulation of mesenchymal stromal cell carriers overrides melanoma resistance to an oncolytic adenovirus. Stem Cells Dev 2012; 21:2689-702. [PMID: 22462538 DOI: 10.1089/scd.2011.0643] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The homing properties of mesenchymal stromal cells (MSCs) toward tumors turn them into attractive tools for combining cell and gene therapy. The aim of this study was to select in a feasible way a human bone marrow-derived MSC subpopulation that might exhibit a selective ability to target the tumor mass. Using differential in vitro adhesive capacities during cells isolation, we selected a specific MSC subpopulation (termed MO-MSCs) that exhibited enhanced multipotent capacity and increased cell surface expression of specific integrins (integrins α2, α3, and α5), which correlated with an enhanced MO-MSCs adhesiveness toward their specific ligands. Moreover, MO-MSCs exhibited a higher migration toward conditioned media from different cancer cell lines and fresh human breast cancer samples in the presence or not of a human microendothelium monolayer. Further in vivo studies demonstrated increased tumor homing of MO-MSCs toward established 578T and MD-MBA-231 breast cancer and A375N melanoma tumor xenografts. Tumor penetration by MO-MSCs was highly dependent on metallopeptidases production as it was inhibited by the specific inhibitor 1,10 phenantroline. Finally, systemically administered MO-MSCs preloaded with an oncolytic adenovirus significantly inhibited tumor growth in mice harboring established A375N melanomas, overcoming the natural resistance of the tumor to in situ administration of the oncolytic adenovirus. In summary, this work characterizes a novel MSC subpopulation with increased tumor homing capacity that can be used to transport therapeutic compounds.
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Affiliation(s)
- Marcela F Bolontrade
- Laboratory of Molecular and Cellular Therapy, Fundación Instituto Leloir-IIBBA, Buenos Aires, Argentina
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50
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Ye Z, Mahato RI. Combining stem cells and genes for effective therapeutics. Mol Pharm 2011; 8:1443-5. [PMID: 21962294 PMCID: PMC3207237 DOI: 10.1021/mp200437m] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Zhaoyang Ye
- State Key Laboratory of Bioreactor Engineering, School of Bioengineering, East China University of Science and Technology, Shanghai 200237, China
| | - Ram I. Mahato
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38103, USA
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