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Baj J, Kołodziej M, Kobak J, Januszewski J, Syty K, Portincasa P, Forma A. Significance of Immune and Non-Immune Cell Stroma as a Microenvironment of Hepatocellular Carcinoma-From Inflammation to Hepatocellular Carcinoma Progression. Int J Mol Sci 2024; 25:10233. [PMID: 39408564 PMCID: PMC11475949 DOI: 10.3390/ijms251910233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer as well as the most prevalent cause of death in the adult patient population with cirrhosis. The occurrence of HCC is primarily caused by chronic liver inflammation that might occur because of a viral infection, non-alcoholic fatty liver disease (NAFLD), or various lifestyle-associated factors. The objective of this review was to summarize the current knowledge regarding the microenvironment of HCC, indicating how immune- and non-immune-cell stroma might affect the onset and progression of HCC. Therefore, in the following narrative review, we described the role of tumor-infiltrating neutrophils, bone-marrow-derived cells, tumor-associated mast cells, cancer-associated fibroblasts, tumor-associated macrophages, liver-sinusoidal endothelial cells, lymphocytes, and certain cytokines in liver inflammation and the further progression to HCC. A better understanding of the HCC microenvironment might be crucial to introducing novel treatment strategies or combined therapies that could lead to more effective clinical outcomes.
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Affiliation(s)
- Jacek Baj
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Magdalena Kołodziej
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Joanna Kobak
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Jacek Januszewski
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Kinga Syty
- Institute of Health Sciences, John Paul the II Catholic University of Lublin, Konstantynów 1G, 20-708 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
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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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Lyu ZZ, Li M, Yang MY, Han MH, Yang Z. Exosome-mediated transfer of circRNA563 promoting hepatocellular carcinoma by targeting the microRNA148a-3p/metal-regulatory transcription factor-1 pathway. World J Gastroenterol 2023; 29:6060-6075. [PMID: 38130740 PMCID: PMC10731156 DOI: 10.3748/wjg.v29.i46.6060] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/24/2023] [Accepted: 11/17/2023] [Indexed: 12/13/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) exert anti-oncogenic effects via exosomes containing non-coding RNA (ncRNA), which play important roles in tumor biology. Our preliminary study identified the interaction of the ncRNA hsa_circ_0000563 (circ563) and the circ563-associated miR-148a-3p in exosomes, as miR-148a-3p and its target metal-regulatory transcription factor-1 (MTF-1) are implicated in hepatocellular carcinoma (HCC) progression. AIM To identify the clinical significance, functional implications, and mechanisms of circ563 in HCC. METHODS The expression levels of miR-148a-3p and MTF-1 in exosomes derived from MSC and HCC cells were compared, and their effects on HCC cells were assessed. Using a dual-luciferase reporter assay, miR-148a-3p was identified as an associated microRNA of circ563, whose role in HCC regulation was assessed in vitro and in vivo. RESULTS The silencing of circ563 blocked the HCC cell proliferation and invasion and induced apoptosis. Co-culturing of HCC cells with MSC-derived exosomes following circ563 overexpression promoted cell proliferation and metastasis and elicited changes in miR-148a-3p and MTF-1 expression. The tumor-promoting effects of circ563 were partially suppressed by miR-148a-3p overexpression or MTF-1 depletion. Xenograft experiments performed in nude mice confirmed that circ563-enriched exosomes facilitated tumor growth by upregulating the expression of MTF-1. In HCC tissues, circ563 expression was negatively correlated with miR-148a-3p expression but positively correlated with MTF-1 levels. CONCLUSION MSCs may exhibit anti-HCC activity through the exosomal circ563/miR-148a-3p/MTF-1 pathway, while exosomes can transmit circ563 to promote oncogenic behavior by competitively binding to miR-148a-3p to activate MTF-1.
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Affiliation(s)
- Zhuo-Zhen Lyu
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Meng Li
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Ming-Yu Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Mei-Hong Han
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Zhen Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
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Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy. Mol Ther 2020; 29:788-803. [PMID: 33068779 DOI: 10.1016/j.ymthe.2020.10.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/22/2020] [Accepted: 10/12/2020] [Indexed: 12/13/2022] Open
Abstract
The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6-48 h after or 24-48 h before hyperthermia treatment. Using 123I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of 123I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated 131I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.
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Human umbilical cord perivascular cells-derived extracellular vesicles mediate the transfer of IGF-I to the liver and ameliorate hepatic fibrogenesis in mice. Gene Ther 2019; 27:62-73. [PMID: 31551525 DOI: 10.1038/s41434-019-0102-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 08/08/2019] [Accepted: 08/26/2019] [Indexed: 12/18/2022]
Abstract
Extracellular vesicles (EVs) can mediate mesenchymal stromal cells (MSCs) paracrine effects. We aimed to evaluate the therapeutic potential of human umbilical cord perivascular cells (HUCPVCs) engineered to produce Insulin Growth Factor like-I (IGF-I) in experimental liver fibrosis and the role of EVs in this effect. HUCPVCs were engineered to produce human IGF-I (AdhIGF-I) or green fluorescence protein (AdGFP) using adenoviruses, and EVs were isolated from their conditioned medium (CM). In vitro effects of CM and EVs on hepatic stellate cells and hepatic macrophages were studied. Cells or EVs-based treatments were evaluated in thioacetamide-induced liver fibrosis in mice. The application of AdhIGF-I-HUCPVCs resulted in a further amelioration of liver fibrosis when compared to AdGFP-HUCPVCs and saline. Similarly, treatment with AdhIGF-I-HUCPVCs-derived EVs resulted in a reduction of collagen deposition and gene expression of the fibrogenic related molecules TGF-β1, α-SMA, and COL1A2. In vitro incubation of hepatic stellate cells with EVs-AdhIGF-I-HUCPVCs significantly reduced activation of fibrogenic cells. In addition, EVs-AdhIGF-I-HUCPVCs trigger hepatic macrophages to switch their phenotype towards anti-inflammatory phagocytes, which might be involved in the antifibrotic effect. Consistently, high levels of IGF-I were observed within EVs-AdhIGF-I-HUCPVCs but not in controls EVs. Our results showed that hIGF-I carrying EVs could mediate the paracrine mechanism by which AdhIGF-I-HUCPVCs reduce liver fibrosis.
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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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Perone MJ, Gimeno ML, Fuertes F. Immunomodulatory Properties and Potential Therapeutic Benefits of Muse Cells Administration in Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1103:115-129. [PMID: 30484226 DOI: 10.1007/978-4-431-56847-6_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
It is well established the link between inflammation and the development of insulin resistance and pathogenesis of type 2 diabetes. Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β cells mediated by autoreactive T lymphocytes and pro-inflammatory agents. Therefore, developing new strategies to efficiently control dysregulated inflammation could have substantial benefits in the treatment of diabetes. Recently, a novel population of non-tumorigenic pluripotent stem cells, named multilineage-differentiating stress-enduring (Muse) cells, was discovered. Muse cells secrete significant amounts of TGF-β1, a key cytokine governing down-modulation of T lymphocytes and macrophages. In this chapter, we discuss the immunomodulatory properties of Muse cells as well as the molecular mechanism of TGF-β1 as mediator of Muse cell action. We also describe the role of certain cytokines/growth factors highly expressed in Muse cells as potential mediators of their effects. Finally, we provide evidence of the beneficial effects of adipose tissue-derived Muse cells in an experimental mice model of type 1 diabetes.
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Affiliation(s)
- Marcelo Javier Perone
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
| | - María Laura Gimeno
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina
| | - Florencia Fuertes
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina
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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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Qin Y, Zhuo L, Cai J, He X, Liu B, Feng C, Zhang L. In vivo monitoring of magnetically labeled mesenchymal stem cells homing to rabbit hepatic VX2 tumors using magnetic resonance imaging. Mol Med Rep 2017; 17:452-458. [PMID: 29115453 DOI: 10.3892/mmr.2017.7902] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 07/20/2017] [Indexed: 11/05/2022] Open
Abstract
Although mesenchymal stem cells (MSCs) have been demonstrated to possess a tumor‑homing feature, their tropism to liver tumors has not been delineated in a visible manner. The aim of the present study was to evaluate the tumor‑homing capacity of MSCs and to investigate the spatial and temporal distributions of MSCs in liver tumors using magnetic resonance imaging (MRI). MSCs were colabeled with superparamagnetic iron oxide (SPIO) particles and 4',6‑diamidino‑2‑phenylindole (DAPI), and then transplanted into rabbits with VX2 liver tumors through intravenous injections. The rabbits were subjected to MRI before and at 3, 7 and 14 days after cell transplantation using a clinical 1.5‑T MRI system. Immediately after the MRI examination, histological analyses were performed using fluorescence and Prussian blue staining. At 3 days after injection with labeled MSCs, heterogeneous hypointensity was detected on the MRI images of the tumor. At 7 days after transplantation, the tumor exhibited anisointense MRI signal, whereas a hypointense ring was detected at the border of the tumor. At 14 days after transplantation, the MRI signal recovered the hyperintensity. As demonstrated in the histological analyses, the distribution of the iron particles visualized with Prussian blue staining was consistent with the DAPI‑stained bright fluorescent nuclei, and the particles corresponded to the hypointense region on the MR images. Thus, systemically administered MSCs could localize to liver tumors with high specificity and possessed a migration feature with active tumor growth. These results demonstrated that the targeting and distribution of the magnetically labeled stem cells in the tumor could be tracked for 7 days in vivo using a clinical 1.5‑T MRI scanner.
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Affiliation(s)
- Yong Qin
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Lisha Zhuo
- Outpatient Department, 77100 Troops, Chinese People's Liberation Army, Chongqing 400020, P.R. China
| | - Jinhua Cai
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Xiaoya He
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Bo Liu
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Chuan Feng
- Department of Radiology, Children's Hospital of Chongqing Medical University, Chongqing 400014, P.R. China
| | - Lin Zhang
- Department of Radiology, Xinan Hospital of Third Military Medical University, Chongqing 400038, P.R. China
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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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Wu N, Zhang YL, Wang HT, Li DW, Dai HJ, Zhang QQ, Zhang J, Ma Y, Xia Q, Bian JM, Hang HL. Overexpression of hepatocyte nuclear factor 4α in human mesenchymal stem cells suppresses hepatocellular carcinoma development through Wnt/β-catenin signaling pathway downregulation. Cancer Biol Ther 2017; 17:558-65. [PMID: 27124543 DOI: 10.1080/15384047.2016.1177675] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) hold promise as cellular vehicles for the delivery of therapeutic gene products because they can be isolated, expanded, and genetically modified in vitro and possess tumor-oriented homing capacity in vivo. (1) Hepatocyte nuclear factor 4α (HNF4α) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis (HCC). (2,3) We have previously demonstrated that overexpression of HNF4α activates various hepatic-specific genes and enhances MSC differentiation. (4) However, the extent that overexpression of HNF4α in MSCs influences HCC progression has yet to be examined. Here we sought to investigate what effect MSCs overexpressing HNF4α (MSC-HNF4α) have on human hepatoma cells in vitro and in vivo. Conditioned medium collected from in vitro MSC-HNF4α cultures significantly inhibited hepatoma cell growth and metastasis compared with controls. Additionally, nude mice administered MSC-HNF4α exhibited significantly smaller tumors compared with controls in vivo. Immunoblot analysis of HCC cells treated with MSC-HNF4α displayed downregulated β-catenin, cyclinD1, c-Myc, MMP2 and MMP9. Taken together, our results demonstrate that MSC-HNF4α inhibits HCC progression by reducing hepatoma cell growth and metastasis through downregulation of the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Ning Wu
- a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China.,b Department of General Surgery , Nanjing Hospital Affiliated to Nanjing Medical University , Nanjing , China
| | | | - Hai-Tian Wang
- b Department of General Surgery , Nanjing Hospital Affiliated to Nanjing Medical University , Nanjing , China
| | - Da-Wei Li
- a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Hui-Juan Dai
- a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Qi-Qi Zhang
- a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Jiang Zhang
- a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Yong Ma
- b Department of General Surgery , Nanjing Hospital Affiliated to Nanjing Medical University , Nanjing , China
| | - Qiang Xia
- a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Jian-Min Bian
- b Department of General Surgery , Nanjing Hospital Affiliated to Nanjing Medical University , Nanjing , China
| | - Hua-Lian Hang
- a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
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Zhu X, Zhou H, Luo J, Cui Y, Li H, Zhang W, Fang F, Li Q, Zhang T. Different but synergistic effects of bone marrow-derived VEGFR2 + and VEGFR2 -CD45 + cells during hepatocellular carcinoma progression. Oncol Lett 2016; 13:63-68. [PMID: 28123523 PMCID: PMC5244973 DOI: 10.3892/ol.2016.5411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 08/19/2016] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-associated mortality worldwide in men. Bone marrow-derived cells (BMDCs), including circulating endothelial progenitor cells, have been reported to be involved in the progression of HCC. The complexity of BMDCs inspires further interest in the study of HCC. In the present study, highly metastatic HCC models with BM function deficiency/reconstruction were established by sublethal irradiation/BM transplantation. The effects of vascular endothelial growth factor receptor-2 (VEGFR2)+ or VEGFR2−/cluster of differentiation 45 (CD45)+ BMDCs on HCC growth were evaluated. VEGFR2+ and VEGFR2−CD45+ BMDCs facilitated the recovery of BM function and promoted tumor growth, while the enhancement of tumor growth by VEGFR2−CD45+ BMDCs was independent of VEGFR2+ BMDCs. BM-derived CD45+CD133+ and VEGFR2+CD133+ cells synergistically played a role in the different stages during HCC progression. In conclusion, different types of BMDCs exhibit effects on HCC tumor growth in a coordinated manner.
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Affiliation(s)
- Xiaolin Zhu
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Hongyuan Zhou
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Jingtao Luo
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Yunlong Cui
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Huikai Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Wei Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Feng Fang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Qiang Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
| | - Ti Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
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Human endometrial mesenchymal stem cells exhibit intrinsic anti-tumor properties on human epithelial ovarian cancer cells. Sci Rep 2016; 6:37019. [PMID: 27845405 PMCID: PMC5109482 DOI: 10.1038/srep37019] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 10/24/2016] [Indexed: 12/25/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the most lethal tumor of all gynecologic tumors. There is no curative therapy for EOC thus far. The tumor-homing ability of adult mesenchymal stem cells (MSCs) provide the promising potential to use them as vehicles to transport therapeutic agents to the site of tumor. Meanwhile, studies have showed the intrinsic anti-tumor properties of MSCs against various kinds of cancer, including epithelial ovarian cancer. Human endometrial mesenchymal stem cells (EnSCs) derived from menstrual blood are a novel source for adult MSCs and exert restorative function in some diseases. Whether EnSCs endow innate anti-tumor properties on EOC cells has never been reported. By using tumor-bearing animal model and ex vivo experiments, we found that EnSCs attenuated tumor growth by inducing cell cycle arrest, promoting apoptosis, disturbing mitochondria membrane potential and decreasing pro-angiogenic ability in EOC cells in vitro and/or in vivo. Furthermore, EnSCs decreased AKT phosphorylation and promoted nuclear translocation of Forkhead box O-3a (FoxO3a) in EOC cells. Collectively, our findings elucidated the potential intrinsic anti-tumor properties of EnSCs on EOC cells in vivo and in vitro. This research provides a potential strategy for EnSC-based anti-cancer therapy against epithelial ovarian cancer.
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Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives. Stem Cell Rev Rep 2016; 11:586-97. [PMID: 25820543 DOI: 10.1007/s12015-015-9585-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem/stromal cells (MSCs) are progenitors which share plastic-adherence capacity and cell surface markers but have different properties according to their cell and tissue sources and to culture conditions applied. Many recent publications suggest that MSCs can differentiate into hepatic-like cells, which can be a consequence of either a positive selection of rare in vivo pluripotent cells or of the original plasticity of some cells contributing to MSC cultures. A possible role of MSCs in hereditary transmission of obesity and/or diabetes as well as properties of MSCs regarding immunomodulation, cell fusion and exosome release capacities are discussed according to recent literature. Limitations in methods used to track MSCs in vivo especially in the context of liver cirrhosis are addressed as well as strategies explored to enhance their migratory, survival and proliferation properties, which are known to be relevant for their future clinical use. Current knowledge regarding mechanisms involved in liver cirrhosis amelioration mediated by naïve and genetically modified MSCs as well as the effects of applying preconditioning and combined strategies to improve their therapeutic effects are evaluated. Finally, first reports of GMP guidelines and biosafety issues in MSCs applications are discussed.
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15
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Jeng KS, Jeng CJ, Jeng WJ, Sheen IS, Li SY, Hung ZH, Hsiau HI, Yu MC, Chang CF. Liver epithelial cells inhibit proliferation and invasiveness of hepatoma cells. Oncol Rep 2015; 35:1622-8. [PMID: 26647726 DOI: 10.3892/or.2015.4478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 10/31/2015] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a worldwide malignancy with poor prognosis. Liver progenitors or stem cells could be a potential therapy for HCC treatment since they migrate toward tumors. Rat liver epithelial (RLE) cells have both progenitor and stem cell-like properties. Therefore, our study elucidated the therapeutic effect of RLE cells in rat hepatoma cells. RLE cells were isolated from 10-day old rats and characterized for stem cell marker expression. RLE cells and rat hepatoma cells (H4-IIE-C3 cells) were co-cultured and divided into four groups with different ratios of RLE and hepatoma cells. Group A had only rat hepatoma cells as a control group. The ratios of rat hepatoma and RLE cells in group B, C and D were 5:1, 1:1 and 1:5, respectively. Effective inhibition of cell proliferation and migration was found in group D when compared to group A. There was a significant decrease in Bcl2 expression and increase in late apoptosis of rat hepatoma cells when adding more RLE cells. RLE cells reduced cell proliferation and migration of rat hepatoma cells. These results suggested that RLE cells could be used as a potential cell therapy.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan, R.O.C
| | - Chi-Juei Jeng
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan, R.O.C
| | - Wen-Juei Jeng
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang-Gung University, Taipei, Taiwan, R.O.C
| | - I-Shyan Sheen
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang-Gung University, Taipei, Taiwan, R.O.C
| | - Shih-Yun Li
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan, R.O.C
| | - Zih-Hang Hung
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan, R.O.C
| | - Hsin-I Hsiau
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan, R.O.C
| | - Ming-Che Yu
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan, R.O.C
| | - Chiung-Fang Chang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan, R.O.C
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16
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Zhang L, Su XS, Ye JS, Wang YY, Guan Z, Yin YF. Bone marrow mesenchymal stem cells suppress metastatic tumor development in mouse by modulating immune system. Stem Cell Res Ther 2015; 6:45. [PMID: 25889932 PMCID: PMC4425902 DOI: 10.1186/s13287-015-0039-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 01/21/2015] [Accepted: 03/05/2015] [Indexed: 12/14/2022] Open
Abstract
Introduction Bone marrow mesenchymal stem cells (BMSCs) have been studied extensively because of their potential use in clinical therapy, regenerative medicine, and tissue engineering. However, their application in tumor therapy remains yet in preclinical stage because of the distinct results from different researches and vagueness of their functional mechanism. In this study, the influence of BMSCs on tumor growth was observed and the potential mechanism was investigated. Method Two animal models, H22 ascitogenous hepatoma in BALb/c mouse and B16-F10 pulmonary metastatic melanoma in C57 mouse, were adopted in experience in vivo and treated with BMSCs by intravenous injection. The percentage of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) and IFN-γ+ T cells were observed in peripheral blood (PB) and bone marrow (BM) by Flow Cytometry. BMSCs were co-cultured in vitro with tumor cells and MDSCs in a tumor conditioned medium separately in order to illustrate the mechanism. Results Our results demonstrated that BMSCs treatment caused a delayed tumor growth and a prolonged survival in both tumor models, the homing fraction of BMSCs in BM was 2% - 5% in 24–72 hours after transfusion and the percentage of Gr-1+CD11b+ MDSCs was downregulated in peripheral blood and BM. Meanwhile, IFN-γ+ T lymphocytes in PB increased. In vitro co-culture showed that BMSCs inhibited the induction and proliferation of MDSCs in tumor conditioned medium, whereas they didn’t affect the proliferation of B16-F10 and H22 cells by in vitro co-culture. Both in vivo and in vitro results showed that BMSCs have a systemic suppressive effect on MDSCs. Conclusion Our data suggest that BMSCs has suppressive effect on tumor and is feasible to be applied in cancer treatment. BMSCs inhibiting MDSCs induction and proliferation is likely one of the mechanism.
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Affiliation(s)
- Lei Zhang
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Xiao San Su
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Jun Song Ye
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Yi Yin Wang
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Zheng Guan
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
| | - Yan Feng Yin
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, PR China.
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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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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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