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1
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Lin SL, Yang SY, Tsai CH, Fong YC, Chen WL, Liu JF, Lin CY, Tang CH. Nerve growth factor promote VCAM-1-dependent monocyte adhesion and M2 polarization in osteosarcoma microenvironment: Implications for larotrectinib therapy. Int J Biol Sci 2024; 20:4114-4127. [PMID: 39247831 PMCID: PMC11379077 DOI: 10.7150/ijbs.95463] [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: 02/19/2024] [Accepted: 07/09/2024] [Indexed: 09/10/2024] Open
Abstract
Osteosarcoma is the most prevalent form of primary malignant bone tumor, primarily affecting children and adolescents. The nerve growth factors (NGF) referred to as neurotrophins have been associated with cancer-induced bone pain; however, the role of NGF in osteosarcoma has yet to be elucidated. In osteosarcoma samples from the Genomic Data Commons data portal, we detected higher levels of NGF and M2 macrophage markers, but not M1 macrophage markers. In cellular experiments, NGF-stimulated osteosarcoma conditional medium was shown to facilitate macrophage polarization from the M0 to the M2 phenotype. NGF also enhanced VCAM-1-dependent monocyte adhesion within the osteosarcoma microenvironment by down-regulating miR-513c-5p levels through the FAK and c-Src cascades. In in vivo xenograft models, the overexpression of NGF was shown to enhance tumor growth, while the oral administration of the TrK inhibitor larotrectinib markedly antagonized NGF-promoted M2 macrophage expression and tumor progression. These results suggest that larotrectinib could potentially be used as a therapeutic agent aimed at mitigating NGF-mediated osteosarcoma progression.
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Affiliation(s)
- Syuan-Ling Lin
- Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Shang-Yu Yang
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
| | - Chun-Hao Tsai
- Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Yi-Chin Fong
- Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
- Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin, Taiwan
| | - Wei-Li Chen
- Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Ju-Fang Liu
- School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei City, Taiwan
| | - Chih-Yang Lin
- Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Chih-Hsin Tang
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
- Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu, Taiwan
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2
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Du J, Qin H. Lipid metabolism dynamics in cancer stem cells: potential targets for cancers. Front Pharmacol 2024; 15:1367981. [PMID: 38994204 PMCID: PMC11236562 DOI: 10.3389/fphar.2024.1367981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 06/10/2024] [Indexed: 07/13/2024] Open
Abstract
Cancer stem cells (CSCs) represent a small subset of heterogeneous cells within tumors that possess the ability to self-renew and initiate tumorigenesis. They serve as potential drivers for tumor initiation, metastasis, recurrence, and drug resistance. Recent research has demonstrated that the stemness preservation of CSCs is heavily reliant on their unique lipid metabolism alterations, enabling them to maintain their own environmental homeostasis through various mechanisms. The primary objectives involve augmenting intracellular fatty acid (FA) content to bolster energy supply, promoting β-oxidation of FA to optimize energy utilization, and elevating the mevalonate (MVA) pathway for efficient cholesterol synthesis. Additionally, lipid droplets (LDs) can serve as alternative energy sources in the presence of glycolysis blockade in CSCs, thereby safeguarding FA from peroxidation. Furthermore, the interplay between autophagy and lipid metabolism facilitates rapid adaptation of CSCs to the harsh microenvironment induced by chemotherapy. In this review, we comprehensively review recent studies pertaining to lipid metabolism in CSCs and provide a concise overview of the indispensable role played by LDs, FA, cholesterol metabolism, and autophagy in maintaining the stemness of CSCs.
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Affiliation(s)
- Juan Du
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Hai Qin
- Department of Clinical Laboratory, Beijing Jishuitan Hospital Guizhou Hospital, Guiyang, China
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3
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ZHAO J, ZHU Q, ZHANG Y, LI G, ZHANG Y, LI F, BIAN L. [Role of COX-2/PGE2/EP4 Axis-induced Macrophage Functional Activation
in NSCLC Development]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2024; 27:245-256. [PMID: 38769827 PMCID: PMC11110263 DOI: 10.3779/j.issn.1009-3419.2024.101.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Indexed: 05/22/2024]
Abstract
BACKGROUND Tumor microenvironment (TME) is one of the important factors in tumorigenesis and progression, in which tumor-associated macrophages (TAMs) play an important role in non-small cell lung cancer (NSCLC) progression. However, the mechanism of TAMs in NSCLC progression remains unclear, so this study aimed to investigate the role of TAMs in NSCLC progression and to find potential therapeutic targets. METHODS Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the expression of prostaglandin E2 receptor 4 (EP4) mRNA in NSCLC and normal lung tissues; the protein expression levels of cyclooxygenase-2 (COX-2), EP4, cluster of differentiation 86 (CD86), CD163 and CD31 were detected by immunohistochemistry (IHC) in 120 NSCLC tissues and 24 paracancerous tissues specimens. The nude mouse lung adenocarcinoma cell A549 and macrophage RAW264.7 co-transplanted tumor model was established. And the samples were collected by gavage with EP4 inhibitor E7046, and then stained with hematoxylin-eosin (HE), IHC, and immunofluorescence (IF), and then detected by Western blot for the epithelial mesenchymal transformation (EMT) of the tumor tissues of the nude mice in each group. Western blot was used to detect the expressions of EMT related protiens in each group of nude mice; full-length transcriptome sequencing was used to screen the key genes causing liver metastasis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed. RESULTS EP4 mRNA expression level in NSCLC tissues was generally lower than that in normal lung tissues (P<0.05); COX-2, EP4, CD163, CD31 proteins were differentially expressed in NSCLC tissues and adjacent tissues, and differences were observed in many clinicopathological parameters of NSCLC patients; RAW264.7 shortened the latency period of tumorigenesis of A549 and promoted the proliferation of tumors and liver metastasis of tumors, and E7046 could reduce tumor cell proliferation activity, tumor tissue vascular density and M2-type macrophage infiltration in nude mice; IF staining showed that macrophages were mainly distributed around the metastatic foci of tumors; Western blot results showed that compared with A549 alone transplantation group, the relative expression of E-cadherin protein in tumor tissues of mice in A549 and RAW264.7 co-transplantation group was significantly decreased, and the difference was statistically significant (P<0.05), while the relative expression of N-cadherin protein was up-regulated, but the difference was not statistically significant (P>0.05); the main pathways enriched in the differential genes of the full-length transcriptome were the PI3K-AKT and MAPK signaling pathways. CONCLUSIONS During NSCLC development, the COX-2/PGE2/EP4 axis may promote tumor progression by inducing macrophage functional activation, and EP4 may be a potential new target for tumor immunotherapy. This study provides new perspectives and ideas for in-depth exploration of the mechanisms of NSCLC development, as well as a theoretical basis for the development of new therapeutic strategies for NSCLC.
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4
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Trivanović D, Mojsilović S, Bogosavljević N, Jurišić V, Jauković A. Revealing profile of cancer-educated platelets and their factors to foster immunotherapy development. Transl Oncol 2024; 40:101871. [PMID: 38134841 PMCID: PMC10776659 DOI: 10.1016/j.tranon.2023.101871] [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: 09/30/2023] [Revised: 12/03/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
Among multiple hemostasis components, platelets hyperactivity plays major roles in cancer progression by providing surface and internal components for intercellular crosstalk as well as by behaving like immune cells. Since platelets participate and regulate immunity in homeostatic and disease states, we assumed that revealing platelets profile might help in conceiving novel anti-cancer immune-based strategies. The goal of this review is to compile and discuss the most recent reports on the nature of cancer-associated platelets and their interference with immunotherapy. An increasing number of studies have emphasized active communication between cancer cells and platelets, with platelets promoting cancer cell survival, growth, and metastasis. The anti-cancer potential of platelet-directed therapy has been intensively investigated, and anti-platelet agents may prevent cancer progression and improve the survival of cancer patients. Platelets can (i) reduce antitumor activity; (ii) support immunoregulatory cells and factors generation; (iii) underpin metastasis and, (iv) interfere with immunotherapy by expressing ligands of immune checkpoint receptors. Mediators produced by tumor cell-induced platelet activation support vein thrombosis, constrain anti-tumor T- and natural killer cell response, while contributing to extravasation of tumor cells, metastatic potential, and neovascularization within the tumor. Recent studies showed that attenuation of immunothrombosis, modulation of platelets and their factors have a good perspective in immunotherapy optimization. Particularly, blockade of intra-tumoral platelet-associated programmed death-ligand 1 might promote anti-tumor T cell-induced cytotoxicity. Collectively, these findings suggest that platelets might represent the source of relevant cancer staging biomarkers, as well as promising targets and carriers in immunotherapeutic approaches for combating cancer.
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Affiliation(s)
- Drenka Trivanović
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr. Subotica 4, PBOX 102, 11129, Belgrade 11000, Serbia.
| | - Slavko Mojsilović
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr. Subotica 4, PBOX 102, 11129, Belgrade 11000, Serbia
| | | | - Vladimir Jurišić
- Faculty of Medical Sciences, University of Kragujevac, Kragujevac 34000, Serbia
| | - Aleksandra Jauković
- Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Dr. Subotica 4, PBOX 102, 11129, Belgrade 11000, Serbia
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Opposing MMP-9 Expression in Mesenchymal Stromal Cells and Head and Neck Tumor Cells after Direct 2D and 3D Co-Culture. Int J Mol Sci 2023; 24:ijms24021293. [PMID: 36674806 PMCID: PMC9861345 DOI: 10.3390/ijms24021293] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/23/2022] [Accepted: 01/07/2023] [Indexed: 01/11/2023] Open
Abstract
Bone marrow-derived mesenchymal stromal cells (BMSCs) respond to a variety of tumor cell-derived signals, such as inflammatory cytokines and growth factors. As a result, the inflammatory tumor microenvironment may lead to the recruitment of BMSCs. Whether BMSCs in the tumor environment are more likely to promote tumor growth or tumor suppression is still controversial. In our experiments, direct 3D co-culture of BMSCs with tumor cells from the head and neck region (HNSCC) results in strong expression and secretion of MMP-9. The observed MMP-9 secretion mainly originates from BMSCs, leading to increased invasiveness. In addition to our in vitro data, we show in vivo data based on the chorioallantoic membrane (CAM) model. Our results demonstrate that MMP-9 induces hemorrhage and increased perfusion in BMSC/HNSCC co-culture. While we had previously outlined that MMP-9 expression and secretion originate from BMSCs, our data showed a strong downregulation of MMP-9 promoter activity in HNSCC cells upon direct contact with BMSCs using the luciferase activity assay. Interestingly, the 2D and 3D models of direct co-culture suggest different drivers for the downregulation of MMP-9 promoter activity. Whereas the 3D model depicts a BMSC-dependent downregulation, the 2D model shows cell density-dependent downregulation. In summary, our data suggest that the direct interaction of HNSCC cells and BMSCs promotes tumor progression by significantly facilitating angiogenesis via MMP-9 expression. On the other hand, data from 3D and 2D co-culture models indicate opposing regulation of the MMP-9 promoter in tumor cells once stromal cells are involved.
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Lasorsa F, di Meo NA, Rutigliano M, Ferro M, Terracciano D, Tataru OS, Battaglia M, Ditonno P, Lucarelli G. Emerging Hallmarks of Metabolic Reprogramming in Prostate Cancer. Int J Mol Sci 2023; 24:ijms24020910. [PMID: 36674430 PMCID: PMC9863674 DOI: 10.3390/ijms24020910] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 12/30/2022] [Accepted: 01/01/2023] [Indexed: 01/06/2023] Open
Abstract
Prostate cancer (PCa) is the most common male malignancy and the fifth leading cause of cancer death in men worldwide. Prostate cancer cells are characterized by a hybrid glycolytic/oxidative phosphorylation phenotype determined by androgen receptor signaling. An increased lipogenesis and cholesterogenesis have been described in PCa cells. Many studies have shown that enzymes involved in these pathways are overexpressed in PCa. Glutamine becomes an essential amino acid for PCa cells, and its metabolism is thought to become an attractive therapeutic target. A crosstalk between cancer and stromal cells occurs in the tumor microenvironment because of the release of different cytokines and growth factors and due to changes in the extracellular matrix. A deeper insight into the metabolic changes may be obtained by a multi-omic approach integrating genomics, transcriptomics, metabolomics, lipidomics, and radiomics data.
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Affiliation(s)
- Francesco Lasorsa
- Urology, Andrology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Nicola Antonio di Meo
- Urology, Andrology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Monica Rutigliano
- Urology, Andrology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Matteo Ferro
- Division of Urology, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Daniela Terracciano
- Department of Translational Medical Sciences, University of Naples “Federico II”, 80131 Naples, Italy
| | - Octavian Sabin Tataru
- The Institution Organizing University Doctoral Studies (I.O.S.U.D.), George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, 540142 Târgu Mureș, Romania
| | - Michele Battaglia
- Urology, Andrology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Pasquale Ditonno
- Urology, Andrology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Giuseppe Lucarelli
- Urology, Andrology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy
- Correspondence: or
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7
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Arjmand B, Hamidpour SK, Alavi-Moghadam S, Yavari H, Shahbazbadr A, Tavirani MR, Gilany K, Larijani B. Molecular Docking as a Therapeutic Approach for Targeting Cancer Stem Cell Metabolic Processes. Front Pharmacol 2022; 13:768556. [PMID: 35264950 PMCID: PMC8899123 DOI: 10.3389/fphar.2022.768556] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 01/13/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) are subpopulation of cells which have been demonstrated in a variety of cancer models and involved in cancer initiation, progression, and development. Indeed, CSCs which seem to form a small percentage of tumor cells, display resembling characteristics to natural stem cells such as self-renewal, survival, differentiation, proliferation, and quiescence. Moreover, they have some characteristics that eventually can demonstrate the heterogeneity of cancer cells and tumor progression. On the other hand, another aspect of CSCs that has been recognized as a central concern facing cancer patients is resistance to mainstays of cancer treatment such as chemotherapy and radiation. Owing to these details and the stated stemness capabilities, these immature progenitors of cancerous cells can constantly persist after different therapies and cause tumor regrowth or metastasis. Further, in both normal development and malignancy, cellular metabolism and stemness are intricately linked and CSCs dominant metabolic phenotype changes across tumor entities, patients, and tumor subclones. Hence, CSCs can be determined as one of the factors that correlate to the failure of common therapeutic approaches in cancer treatment. In this context, researchers are searching out new alternative or complementary therapies such as targeted methods to fight against cancer. Molecular docking is one of the computational modeling methods that has a new promise in cancer cell targeting through drug designing and discovering programs. In a simple definition, molecular docking methods are used to determine the metabolic interaction between two molecules and find the best orientation of a ligand to its molecular target with minimal free energy in the formation of a stable complex. As a comprehensive approach, this computational drug design method can be thought more cost-effective and time-saving compare to other conventional methods in cancer treatment. In addition, increasing productivity and quality in pharmaceutical research can be another advantage of this molecular modeling method. Therefore, in recent years, it can be concluded that molecular docking can be considered as one of the novel strategies at the forefront of the cancer battle via targeting cancer stem cell metabolic processes.
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Affiliation(s)
- Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- *Correspondence: Babak Arjmand, ; Bagher Larijani,
| | - Shayesteh Kokabi Hamidpour
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hanieh Yavari
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ainaz Shahbazbadr
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Kambiz Gilany
- Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
- Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- *Correspondence: Babak Arjmand, ; Bagher Larijani,
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Aggarwal V, Rathod S, Vashishth K, Upadhyay A. Immune Cell Metabolites as Fuel for Cancer Cells. IMMUNO-ONCOLOGY CROSSTALK AND METABOLISM 2022:153-186. [DOI: 10.1007/978-981-16-6226-3_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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9
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Di Somma S, Napolitano F, Portella G, Malfitano AM. Cross Talk of Macrophages with Tumor Microenvironment Cells and Modulation of Macrophages in Cancer by Virotherapy. Biomedicines 2021; 9:biomedicines9101309. [PMID: 34680425 PMCID: PMC8533595 DOI: 10.3390/biomedicines9101309] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/17/2021] [Accepted: 09/21/2021] [Indexed: 02/07/2023] Open
Abstract
Cellular compartments constituting the tumor microenvironment including immune cells, fibroblasts, endothelial cells, and mesenchymal stromal/stem cells communicate with malignant cells to orchestrate a series of signals that contribute to the evolution of the tumor microenvironment. In this study, we will focus on the interplay in tumor microenvironment between macrophages and mesenchymal stem cells and macrophages and fibroblasts. In particular, cell–cell interaction and mediators secreted by these cells will be examined to explain pro/anti-tumor phenotypes induced in macrophages. Nonetheless, in the context of virotherapy, the response of macrophages as a consequence of treatment with oncolytic viruses will be analyzed regarding their polarization status and their pro/anti-tumor response.
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10
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Planat-Benard V, Varin A, Casteilla L. MSCs and Inflammatory Cells Crosstalk in Regenerative Medicine: Concerted Actions for Optimized Resolution Driven by Energy Metabolism. Front Immunol 2021; 12:626755. [PMID: 33995350 PMCID: PMC8120150 DOI: 10.3389/fimmu.2021.626755] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 04/12/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are currently widely used in cell based therapy regarding to their remarkable efficacy in controlling the inflammatory status in patients. Despite recent progress and encouraging results, inconstant therapeutic benefits are reported suggesting that significant breakthroughs in the understanding of MSCs immunomodulatory mechanisms of action remains to be investigated and certainly apprehended from original point of view. This review will focus on the recent findings regarding MSCs close relationship with the innate immune compartment, i.e. granulocytes and myeloid cells. The review will also consider the intercellular mechanism of communication involved, such as factor secretion, cell-cell contact, extracellular vesicles, mitochondria transfer and efferocytosis. Immune-like-properties of MSCs supporting part of their therapeutic effect in the clinical setting will be discussed, as well as their potentials (immunomodulatory, anti-bacterial, anti-inflammatory, anti-oxidant defenses and metabolic adaptation…) and effects mediated, such as cell polarization, differentiation, death and survival on various immune and tissue cell targets determinant in triggering tissue regeneration. Their metabolic properties in term of sensing, reacting and producing metabolites influencing tissue inflammation will be highlighted. The review will finally open to discussion how ongoing scientific advances on MSCs could be efficiently translated to clinic in chronic and age-related inflammatory diseases and the current limits and gaps that remain to be overcome to achieving tissue regeneration and rejuvenation.
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Affiliation(s)
- Valerie Planat-Benard
- RESTORE, University of Toulouse, UMR 1031-INSERM, 5070-CNRS, Etablissement Français du Sang-Occitanie (EFS), Université Paul Sabatier, Toulouse, France
| | - Audrey Varin
- RESTORE, University of Toulouse, UMR 1031-INSERM, 5070-CNRS, Etablissement Français du Sang-Occitanie (EFS), Université Paul Sabatier, Toulouse, France
| | - Louis Casteilla
- RESTORE, University of Toulouse, UMR 1031-INSERM, 5070-CNRS, Etablissement Français du Sang-Occitanie (EFS), Université Paul Sabatier, Toulouse, France
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11
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Yu J, Piazza A, Sparks S, Hind LE, Niles DJ, Ingram PN, Huang W, Ricke WA, Jarrard DF, Huttenlocher A, Basu H, Beebe DJ. A reconfigurable microscale assay enables insights into cancer-associated fibroblast modulation of immune cell recruitment. Integr Biol (Camb) 2021; 13:87-97. [PMID: 33822934 DOI: 10.1093/intbio/zyab004] [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: 02/04/2021] [Accepted: 02/07/2021] [Indexed: 12/12/2022]
Abstract
Innate immune cell infiltration into neoplastic tissue is the first line of defense against cancer and can play a deterministic role in tumor progression. Here, we describe a series of assays, using a reconfigurable microscale assay platform (i.e. Stacks), which allows the study of immune cell infiltration in vitro with spatiotemporal manipulations. We assembled Stacks assays to investigate tumor-monocyte interactions, re-education of activated macrophages, and neutrophil infiltration. For the first time in vitro, the Stacks infiltration assays reveal that primary tumor-associated fibroblasts from specific patients differ from that associated with the benign region of the prostate in their ability to limit neutrophil infiltration as well as facilitate monocyte adhesion and anti-inflammatory monocyte polarization. These results show that fibroblasts play a regulatory role in immune cell infiltration and that Stacks has the potential to predict individual patients' cancer-immune response.
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Affiliation(s)
- Jiaquan Yu
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA.,Koch Institute For Integrative Cancer Research, Massachusetts Institute of Technology, MA 02142, USA
| | - Amber Piazza
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA.,University of Minnesota Medical School, Minneapolis, MN 55455, USAUSA
| | - Sidney Sparks
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Laurel E Hind
- Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA.,Department of Chemical and Biological Engineering, University of Colorado - Boulder, Boulder, CO 80309, USA
| | - David J Niles
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Patrick N Ingram
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Wei Huang
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, WI 53706, USA
| | - William A Ricke
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA.,Department of Urology, University of Wisconsin-Madison, Madison, WI, USA
| | - David F Jarrard
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA.,Department of Urology, University of Wisconsin-Madison, Madison, WI, USA
| | - Anna Huttenlocher
- Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA.,Department of Pediatrics, University of Wisconsin, Madison, WI 53792, USA
| | - Hirak Basu
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA.,MD-Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
| | - David J Beebe
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA.,Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA.,Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA
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12
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Metabolic regulation of prostate cancer heterogeneity and plasticity. Semin Cancer Biol 2020; 82:94-119. [PMID: 33290846 DOI: 10.1016/j.semcancer.2020.12.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/12/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023]
Abstract
Metabolic reprogramming is one of the main hallmarks of cancer cells. It refers to the metabolic adaptations of tumor cells in response to nutrient deficiency, microenvironmental insults, and anti-cancer therapies. Metabolic transformation during tumor development plays a critical role in the continued tumor growth and progression and is driven by a complex interplay between the tumor mutational landscape, epigenetic modifications, and microenvironmental influences. Understanding the tumor metabolic vulnerabilities might open novel diagnostic and therapeutic approaches with the potential to improve the efficacy of current tumor treatments. Prostate cancer is a highly heterogeneous disease harboring different mutations and tumor cell phenotypes. While the increase of intra-tumor genetic and epigenetic heterogeneity is associated with tumor progression, less is known about metabolic regulation of prostate cancer cell heterogeneity and plasticity. This review summarizes the central metabolic adaptations in prostate tumors, state-of-the-art technologies for metabolic analysis, and the perspectives for metabolic targeting and diagnostic implications.
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13
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Zhu X, Chen HH, Gao CY, Zhang XX, Jiang JX, Zhang Y, Fang J, Zhao F, Chen ZG. Energy metabolism in cancer stem cells. World J Stem Cells 2020; 12:448-461. [PMID: 32742562 PMCID: PMC7360992 DOI: 10.4252/wjsc.v12.i6.448] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 05/20/2020] [Indexed: 02/06/2023] Open
Abstract
Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen. In contrast, most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules. Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth. A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells (CSCs). New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells. CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism. The mechanism of the metabolic plasticity of CSCs has not been fully elucidated, and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment. Targeting CSC metabolism may provide new and effective methods for the treatment of tumors. In this review, we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs, and discuss the clinical implications of targeting CSC metabolism.
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Affiliation(s)
- Xuan Zhu
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Hui-Hui Chen
- The Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Chen-Yi Gao
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Xin-Xin Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jing-Xin Jiang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Yi Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jun Fang
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Feng Zhao
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Zhi-Gang Chen
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
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Khandekar D, Amara S, Tiriveedhi V. Immunogenicity of Tumor Initiating Stem Cells: Potential Applications in Novel Anticancer Therapy. Front Oncol 2019; 9:315. [PMID: 31106150 PMCID: PMC6494937 DOI: 10.3389/fonc.2019.00315] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 04/08/2019] [Indexed: 12/15/2022] Open
Abstract
Tumor initiating stem cells (TISCs) are a subset of tumor cells, which are implicated in cancer relapse and resistance to chemotherapy. The metabolic programs that drive TISC functions are exquisitely unique and finely-tuned by various oncogene-driven transcription factors to facilitate pro-cancerous adaptive challenges. While this change in TISC metabolic machinery allows for the identification of associated molecular targets with diagnostic and prognostic value, these molecules also have a potential immunological application. Recent studies have shown that these TISC-associated molecules have strong antigenic properties enabling naïve CD8+T lymphocytes to differentiate into cytotoxic effector phenotype with anticancer potential. In spite of the current challenges, a detailed understanding in this direction offers an immense immunotherapeutic opportunity. In this review, we highlight the molecular targets that characterize TISCs, the metabolic landscape of TISCs, potential antitumor immune cell activation, and the opportunities and challenges they present in the development of new cancer therapeutics.
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Affiliation(s)
- Durga Khandekar
- Department of Biological Sciences, Tennessee State University, Nashville, TN, United States
| | - Suneetha Amara
- Department of Medicine, St. Thomas Hospital-Midtown, Nashville, TN, United States
| | - Venkataswarup Tiriveedhi
- Department of Biological Sciences, Tennessee State University, Nashville, TN, United States.,Department of Pharmacology, Vanderbilt University, Nashville, TN, United States
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15
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Abstract
Over the past decade, advances in systems biology or 'omics techniques have enabled unprecedented insights into the biological processes that occur in cells, tissues, and on the organism level. One of these technologies is the metabolomics, which examines the whole content of the metabolites in a given sample. In a biological system, a stem cell for instance, there are thousands of single components, such as genes, RNA, proteins, and metabolites. These multiple molecular species interact with each other and these interactions may change over the life-time of a cell or in response to specific stimuli, adding to the complexity of the system. Using metabolomics, we can obtain an instantaneous snapshot of the biological status of a cell, tissue, or organism and gain insights on the pattern(s) of numerous analytes, both known and unknown, that result because of a given biological condition. Here, we outline the main methods to study the metabolism of stem cells, including a relatively recent technology of mass spectrometry imaging. Given the abundant and increasing interest in stem cell metabolism in both physiological and pathological conditions, we hope that this chapter will provide incentives for more research in these areas to ultimately reach wide network of applications in biomedical, pharmaceutical, and nutritional research and clinical medicine.
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16
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Wen Q, Xu C, Zhou J, Liu NM, Cui YH, Quan MF, Cao JG, Ren KQ. 8-bromo-7-methoxychrysin suppress stemness of SMMC-7721 cells induced by co-culture of liver cancer stem-like cells with hepatic stellate cells. BMC Cancer 2019; 19:224. [PMID: 30866863 PMCID: PMC6416872 DOI: 10.1186/s12885-019-5419-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 02/27/2019] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Our previous works have demonstrated that 8-bromo-7-methoxychrysin suppressed stemness of human hepatocellular carcinoma (HCC) cell line SMMC-7721 induced by condition medium from hepatic stellate cell line LX-2 that was activated by liver cancer stem-like cells (LCSCs). However, whether and whereby BrMC inhibits the stemness induced by co-culture of LCSCs and LX-2 cells remains to be investigated. METHODS The second-generation spheres by sphere culture were identified and used as SMMC-7721-and MHCC97H-derived LCSLCs. SMMC-7721-and MHCC97-derived LCSCs/LX-2 cells transwell co-culture system was treated with BrMC and its lead compound chrysin. The concentrations of IL-6, IL-8, HGF and PDGF in condition medium from co-culture were measured by enzyme-linked immunosorbent assay (ELISA). The stemness of SMMC-7721 cells was evaluated by sphere formation assay and western blot analysis for expression levels of cancer stem cell markers (CD133 and CD44).The expression levels of cancer-associated fibroblast markers (FAP-α and α-SMA) were employed to evaluate pathologic activation of LX-2 cells. Addition of IL-6 and/or HGF or deletion of IL-6 and/or HGF was conducted to investigate the mechanisms for BrMC and chrysin treatment in SMMC-7721-derived LCSLCs co-cultured with LX-2cells. RESULTS The co-culture of LCSLCs with LX-2 cells increased sphere formation capability as well as expression of CD133 and CD44 in SMMC-7721 cells, meanwhile, upregulated expression of FAP-α in LX-2 cells. ELISA indicated that the concentrations of IL-6 and HGF were significantly elevated in Co-CM than that of condition media from co-cultured SMMC-7721 cells/LX-2 cells. Treatment of BrMC and chrysin with co-cultures of SMMC-7721- and MHCC97H-derived LCSLCs and LX-2 cells effectively inhibited the above responses. Moreover, addition of IL-6 and/or HGF induced stemness of SMMC-7721 cells and activation of LX-2 cells, conversely, deletion of IL-6 and/or HGF suppressed those. Furthermore, the inhibitory effects of BrMC and chrysin on stemness of SMMC-7721 cells and activation of LX-2 cells were attenuated by addition of IL-6 or HGF, and enhanced by deletion of IL-6 or HGF. CONCLUSIONS Our results suggest IL-6 and HGF may be the key communication molecules for the interaction between LCSLCs and HSCs, and BrMC and chrysin could block these effects and be the novel therapeutic candidates for HCC management.
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Affiliation(s)
- Qi Wen
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013 China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013 China
| | - Chang Xu
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013 China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013 China
| | - Jie Zhou
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013 China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013 China
| | - Nuo-Min Liu
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013 China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013 China
| | - Ying-Hong Cui
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013 China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013 China
| | - Mei-Fang Quan
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013 China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013 China
| | - Jian-Guo Cao
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013 China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013 China
| | - Kai-qun Ren
- Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, 410013 China
- Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Changsha, 410013 China
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Talotta R, Rucci F, Canti G, Scaglione F. Pros and cons of the immunogenicity of monoclonal antibodies in cancer treatment: a lesson from autoimmune diseases. Immunotherapy 2019; 11:241-254. [DOI: 10.2217/imt-2018-0081] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The aim of this review is to report the current evidence on immunogenicity of monoclonal antibodies (moAbs) used in cancer compared with autoimmune diseases, focusing on local microenvironment. English abstracts were identified in Medline and www.clinicaltrials.gov . A total of 82 papers were selected. The percentage of immunogenicity of moAbs used for cancer therapy, evaluated as the serum concentration of antidrug antibodies, is significantly lower than that of moAbs used for the treatment of autoimmune diseases. This condition may rely on a different immunologic background characterized by a hyperactivation of immune cells in autoimmune diseases. The formation of complexes between antidrug antibodies and non-neutralizing moAbs bound to neoplastic antigens may allow more efficient elimination of cancer cells, but additional studies are needed.
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Affiliation(s)
- Rossella Talotta
- Postgraduate School of Clinical Pharmacology & Toxicology, University of Milan, 20162, Milan, Italy
- Laboratory of Genetics, ASST ‘Grande Ospedale Metropolitano Niguarda’, 20162, Milan, Italy
| | - Francesco Rucci
- Postgraduate School of Clinical Pharmacology & Toxicology, University of Milan, 20162, Milan, Italy
- Laboratory of Genetics, ASST ‘Grande Ospedale Metropolitano Niguarda’, 20162, Milan, Italy
| | - Gianfranco Canti
- Department of Medical Biotechnology & Traslational Medicine, University of Milan, 20129, Milan, Italy
| | - Francesco Scaglione
- Department of Oncology & Onco-Hematology, University of Milan, 20162, Milan, Italy
- Clinical Pharmacology Unit, ASST ‘Grande Ospedale Metropolitano Niguarda’, 20162, Milan, Italy
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18
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Wang Y, Wang B, Xiao S, Li Y, Chen Q. miR-125a/b inhibits tumor-associated macrophages mediated in cancer stem cells of hepatocellular carcinoma by targeting CD90. J Cell Biochem 2018; 120:3046-3055. [PMID: 30536969 DOI: 10.1002/jcb.27436] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 07/12/2018] [Indexed: 12/12/2022]
Abstract
Cancer stem cells promote tumorigenesis and progression of hepatocellular carcinoma (HCC). Recently, emerging evidence indicates tumor-associated macrophages (TAMs) play an important role in tumor progression. However, TAMs often occurs with unknown mechanisms. As an important mediator in intercellular communications, exosomes secreted by host cells mediate the exchange of genetic materials and proteins, which involves tumor aggressiveness. The aim of the study was to investigate whether exosomes derived from TAMs mediate stem cell properties in HCC. TAMs were isolated from the tissues of HCC. microRNA (miRNA) expression profiles of TAMs were analyzed using miRNA microarray. In vitro cell coculture was further conducted to investigate the crosstalk between TAMs and tumor cells mediated by TAMs exosomes. In this study, we showed that TAMs exosomes promote HCC cell proliferation and stem cell properties. Using miRNA profiles assay, we identified significantly lower levels of miR-125a and miR-125b in exosomes and cell lysate isolated from TAMs. Functional studies revealed that the HCC cells were treated with TAM exosomes or transfected with miR-125a/b suppressed cell proliferation and stem cell properties by targeting CD90, a stem cell marker of HCC stem cells. The study indicated that miR-125a/b targeting CD90 played important roles in cancer stem cells of HCC.
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Affiliation(s)
- Yufeng Wang
- Department of General Surgery, Shanghai Tongji Hospital, Medical School of Tongji University, Shanghai, China
| | - Bingyi Wang
- Department of General Surgery, Shanghai Tongji Hospital, Medical School of Tongji University, Shanghai, China
| | - Shuai Xiao
- Department of General Surgery, Shanghai Tongji Hospital, Medical School of Tongji University, Shanghai, China
| | - Yang Li
- Department of General Surgery, Shanghai Tongji Hospital, Medical School of Tongji University, Shanghai, China
| | - Quanning Chen
- Department of General Surgery, Shanghai Tongji Hospital, Medical School of Tongji University, Shanghai, China
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19
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Hulea L, Gravel SP, Morita M, Cargnello M, Uchenunu O, Im YK, Lehuédé C, Ma EH, Leibovitch M, McLaughlan S, Blouin MJ, Parisotto M, Papavasiliou V, Lavoie C, Larsson O, Ohh M, Ferreira T, Greenwood C, Bridon G, Avizonis D, Ferbeyre G, Siegel P, Jones RG, Muller W, Ursini-Siegel J, St-Pierre J, Pollak M, Topisirovic I. Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides. Cell Metab 2018; 28:817-832.e8. [PMID: 30244971 PMCID: PMC7252493 DOI: 10.1016/j.cmet.2018.09.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 05/18/2018] [Accepted: 08/31/2018] [Indexed: 10/28/2022]
Abstract
There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1α-dependent perturbations in glutamine metabolism, which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapeutic insults that target cancer metabolism.
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Affiliation(s)
- Laura Hulea
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada
| | - Simon-Pierre Gravel
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada
| | - Masahiro Morita
- Department of Molecular Medicine and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Institute of Resource Developmental and Analysis, Kumamoto University, Kumamoto 860-8111, Japan
| | - Marie Cargnello
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada; Centre de Recherche en Cancérologie de Toulouse, 31100 Toulouse, France
| | - Oro Uchenunu
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada
| | - Young Kyuen Im
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada
| | - Camille Lehuédé
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada
| | - Eric H Ma
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3A 1A3, Canada
| | - Matthew Leibovitch
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada
| | - Shannon McLaughlan
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada
| | - Marie-José Blouin
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada
| | - Maxime Parisotto
- Département de Chimie, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | | | - Cynthia Lavoie
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
| | - Ola Larsson
- Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, 171 16 Stockholm, Sweden
| | - Michael Ohh
- Department of Laboratory Medicine and Pathobiology and Department of Biochemistry, University of Toronto, Toronto, ON M5S1A8, Canada
| | - Tiago Ferreira
- McGill University Centre for Research in Neuroscience, Montreal General Hospital, Montreal, QC H3G 1A4, Canada
| | - Celia Greenwood
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC H3A 1A3, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 1A3, Canada
| | - Gaëlle Bridon
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
| | - Daina Avizonis
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
| | - Gerardo Ferbeyre
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada
| | - Peter Siegel
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada
| | - Russell G Jones
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3A 1A3, Canada
| | - William Muller
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada
| | - Josie Ursini-Siegel
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada; Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada
| | - Julie St-Pierre
- Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Michael Pollak
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada; Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
| | - Ivan Topisirovic
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3A 1A3, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
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20
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Tumour microenvironment and metabolic plasticity in cancer and cancer stem cells: Perspectives on metabolic and immune regulatory signatures in chemoresistant ovarian cancer stem cells. Semin Cancer Biol 2018; 53:265-281. [DOI: 10.1016/j.semcancer.2018.10.002] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 10/05/2018] [Accepted: 10/08/2018] [Indexed: 02/06/2023]
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21
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Di Carlo C, Brandi J, Cecconi D. Pancreatic cancer stem cells: Perspectives on potential therapeutic approaches of pancreatic ductal adenocarcinoma. World J Stem Cells 2018; 10:172-182. [PMID: 30631392 PMCID: PMC6325076 DOI: 10.4252/wjsc.v10.i11.172] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/10/2018] [Accepted: 10/17/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive solid tumours of the pancreas, characterised by a five-year survival rate less than 8%. Recent reports that pancreatic cancer stem cells (PCSCs) contribute to the tumorigenesis, progression, and chemoresistance of pancreatic cancer have prompted the investigation of new therapeutic approaches able to directly target PCSCs. In the present paper the non-cancer related drugs that have been proposed to target CSCs that could potentially combat pancreatic cancer are reviewed and evaluated. The role of some pathways and deregulated proteins in PCSCs as new therapeutic targets are also discussed with a focus on selected specific inhibitors. Finally, advances in the development of nanoparticles for targeting PCSCs and site-specific drug delivery are highlighted, and their limitations considered.
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Affiliation(s)
- Claudia Di Carlo
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
| | - Jessica Brandi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy.
| | - Daniela Cecconi
- Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, University of Verona, Verona 37134, Italy
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22
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Wegiel B, Vuerich M, Daneshmandi S, Seth P. Metabolic Switch in the Tumor Microenvironment Determines Immune Responses to Anti-cancer Therapy. Front Oncol 2018; 8:284. [PMID: 30151352 PMCID: PMC6099109 DOI: 10.3389/fonc.2018.00284] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 07/09/2018] [Indexed: 12/11/2022] Open
Abstract
Tumor-induced immune tolerance permits growth and spread of malignant cells. Cancer cells have strong influence on surrounding cells and shape the hypoxic tumor microenvironment (TME) facilitating cancer progression. A dynamic change in glucose metabolism occurring in cancer cells and its influence on the TME are still poorly understood. Indeed, cancer and/or immune cells undergo rapid adaptation in metabolic pathways during cancer progression. Metabolic reprograming affects macrophages, T cells, and myeloid derived suppressor cells (MDSCs) among other immune cells. Their role in the TME depends on a nature and concentration of factors, such as cytokines, reactive oxygen species (ROS), growth factors, and most importantly, diffusible metabolites (i.e., lactate). Further, the amounts of available nutrients and oxygen as well as activity of microbiota may influence metabolic pathways in the TME. The roles of metabolites in regulating of the interaction between immune and cancer cell are highlighted in this review. Targeting metabolic reprogramming or signaling pathways controlling cell metabolism in the TME might be a potential strategy for anti-cancer therapy alone or in combination with current immunotherapies.
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Affiliation(s)
- Barbara Wegiel
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, United States.,Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Marta Vuerich
- Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Saeed Daneshmandi
- Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Pankaj Seth
- Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, United States.,Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States.,Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
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23
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Yang Y, Chen M, Zhou J, Lv J, Song S, Fu L, Chen J, Yang M, Mei C. Interactions between Macrophages and Cyst-Lining Epithelial Cells Promote Kidney Cyst Growth in Pkd1-Deficient Mice. J Am Soc Nephrol 2018; 29:2310-2325. [PMID: 30042193 DOI: 10.1681/asn.2018010074] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 06/21/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Autosomal-dominant polycystic kidney disease (ADPKD) is the leading inherited renal disease worldwide. The proproliferative function of macrophages is associated with late-stage cyst enlargement in mice with PKD; however, the way in which macrophages act on cyst-lining epithelial cells (CLECs) has not been well elucidated. METHODS We generated a rapid-onset PKD mouse model by inactivating Pkd1 on postnatal day 10 (P10) and compared cell proliferation and differential gene expression in kidney tissues of the PKD mice and wild-type (WT) littermates. RESULTS The cystic phenotype was dominant from P18. A distinct peak in cell proliferation in polycystic kidneys during P22-P30 was closely related to late-stage cyst growth. Comparisons of gene expression profiles in kidney tissues at P22 and P30 in PKD and WT mice revealed that arginine metabolism was significantly activated; 204 differentially expressed genes (DEGs), including Arg1, an arginine metabolism-associated gene, were identified in late-stage polycystic kidneys. The Arg1-encoded protein, arginase-1 (ARG1), was predominantly expressed in macrophages in a time-dependent manner. Multiple-stage macrophage depletion verified that macrophages expressing high ARG1 levels accounted for late-stage cyst enlargement, and inhibiting ARG1 activity significantly retarded cyst growth and effectively lowered the proliferative indices in polycystic kidneys. In vitro experiments revealed that macrophages stimulated CLEC proliferation, and that L-lactic acid, primarily generated by CLECs, significantly upregulated ARG1 expression and increased polyamine synthesis in macrophages. CONCLUSIONS Interactions between macrophages and CLECs promote cyst growth. ARG1 is a key molecule involved in this process and is a potential therapeutic target to help delay ADPKD progression.
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Affiliation(s)
- Yang Yang
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China.,Division of Nephrology, Kidney Diagnostic and Therapeutic Center of PLA, Beidaihe Sanatorium of PLA, Qinhuangdao, China; and
| | - Meihan Chen
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Jie Zhou
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Jiayi Lv
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Shuwei Song
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - LiLi Fu
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Jiejian Chen
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China.,Department of Nephrology, The 175th Hospital of PLA, Zhangzhou, China
| | - Ming Yang
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China
| | - Changlin Mei
- Division of Nephrology, Kidney Institution of Chinese People's Liberation Army (PLA), Chang Zheng Hospital, The Second Military Medical University, Shanghai, China;
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Yi M, Li J, Chen S, Cai J, Ban Y, Peng Q, Zhou Y, Zeng Z, Peng S, Li X, Xiong W, Li G, Xiang B. Emerging role of lipid metabolism alterations in Cancer stem cells. J Exp Clin Cancer Res 2018; 37:118. [PMID: 29907133 PMCID: PMC6003041 DOI: 10.1186/s13046-018-0784-5] [Citation(s) in RCA: 161] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/28/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) or tumor-initiating cells (TICs) represent a small population of cancer cells with self-renewal and tumor-initiating properties. Unlike the bulk of tumor cells, CSCs or TICs are refractory to traditional therapy and are responsible for relapse or disease recurrence in cancer patients. Stem cells have distinct metabolic properties compared to differentiated cells, and metabolic rewiring contributes to self-renewal and stemness maintenance in CSCs. MAIN BODY Recent advances in metabolomic detection, particularly in hyperspectral-stimulated raman scattering microscopy, have expanded our knowledge of the contribution of lipid metabolism to the generation and maintenance of CSCs. Alterations in lipid uptake, de novo lipogenesis, lipid droplets, lipid desaturation, and fatty acid oxidation are all clearly implicated in CSCs regulation. Alterations on lipid metabolism not only satisfies the energy demands and biomass production of CSCs, but also contributes to the activation of several important oncogenic signaling pathways, including Wnt/β-catenin and Hippo/YAP signaling. In this review, we summarize the current progress in this attractive field and describe some recent therapeutic agents specifically targeting CSCs based on their modulation of lipid metabolism. CONCLUSION Increased reliance on lipid metabolism makes it a promising therapeutic strategy to eliminate CSCs. Targeting key players of fatty acids metabolism shows promising to anti-CSCs and tumor prevention effects.
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Affiliation(s)
- Mei Yi
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Department of Dermatology, Xiangya hospital of Central South University, Changsha, 410008 China
| | - Junjun Li
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Shengnan Chen
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Jing Cai
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Yuanyuan Ban
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Qian Peng
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Ying Zhou
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Zhaoyang Zeng
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Shuping Peng
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Xiaoling Li
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Wei Xiong
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Guiyuan Li
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
| | - Bo Xiang
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, 410013 Hunan China
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, 410078 China
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Cassano JM, Schnabel LV, Goodale MB, Fortier LA. Inflammatory licensed equine MSCs are chondroprotective and exhibit enhanced immunomodulation in an inflammatory environment. Stem Cell Res Ther 2018; 9:82. [PMID: 29615127 PMCID: PMC5883371 DOI: 10.1186/s13287-018-0840-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 03/07/2018] [Accepted: 03/13/2018] [Indexed: 01/01/2023] Open
Abstract
Background Inflammatory licensed mesenchymal stem cells (MSCs) have the ability to promote functional tissue repair. This study specifically sought to understand how the recipient tissue environment reciprocally affects MSC function. Inflammatory polarized macrophages, modeling an injured tissue environment, were exposed to licensed MSCs, and the resultant effects of MSC immunomodulation and functionality of the MSC secretome on chondrocyte homeostasis were studied. Methods Inflammatory licensed MSCs were generated through priming with either IFN-γ or polyinosinic:polycytidylic acid (poly I:C). Macrophages were polarized to an inflammatory phenotype using IFN-γ. Licensed MSCs were co-cultured with inflammatory macrophages and immunomodulation of MSCs was assessed in a T-cell proliferation assay. MSC gene expression was analyzed for changes in immunogenicity (MHC-I, MHC-II), immunomodulation (IDO, PTGS2, NOS2, TGF-β1), cytokine (IL-6, IL-8), and chemokine (CCL2, CXCL10) expression. Macrophages were assessed for changes in cytokine (IL-6, IL-10, TNF-α, IFN-γ) and chemokine (CCL2, CXCL10) expression. Conditioned medium representing the secretome from IFN-γ or poly I:C-primed MSCs was applied to IL-1β-stimulated chondrocytes, which were analyzed for catabolic (IL-6, TNF-α, CCL2, CXCL10, MMP-13, PTGS2) and matrix synthesis (ACAN, COL2A1) genes. Results IFN-γ-primed MSCs had a superior ability to suppress T-cell proliferation compared to naïve MSCs, and this ability was maintained following exposure to proinflammatory macrophages. In naïve and licensed MSCs exposed to inflammatory macrophages, MHC-I and MHC-II gene expression was upregulated. The secretome from licensed MSCs was chondroprotective and downregulated inflammatory gene expression in IL-1β-stimulated chondrocytes. Conclusions In-vitro inflammatory licensing agents enhanced the immunomodulatory ability of MSCs exposed to inflammatory macrophages, and the resultant secretome was biologically active, protecting chondrocytes from catabolic stimulation. Use of licensing agents produced a more consistent immunomodulatory MSC population compared to exposure to inflammatory macrophages. The clinical implications of this study are that in-vitro licensing prior to therapeutic application could result in a more predictable immunomodulatory and reparative response to MSC therapy compared to in-vivo inflammatory licensing by the recipient environment. Electronic supplementary material The online version of this article (10.1186/s13287-018-0840-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jennifer M Cassano
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Lauren V Schnabel
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA
| | - Margaret B Goodale
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Lisa A Fortier
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
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De Francesco EM, Ózsvári B, Sotgia F, Lisanti MP. [Pollution of the environment with lead]. Front Oncol 1984; 9:615. [PMID: 31440463 PMCID: PMC6692486 DOI: 10.3389/fonc.2019.00615] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 06/21/2019] [Indexed: 12/26/2022] Open
Abstract
Elevated mitochondrial biogenesis and/or metabolism are distinguishing features of cancer cells, as well as Cancer Stem Cells (CSCs), which are involved in tumor initiation, metastatic dissemination, and therapy resistance. In fact, mitochondria-impairing agents can be used to hamper CSCs maintenance and propagation, toward better control of neoplastic disease. Tri-Phenyl-Phosphonium (TPP)-based mitochondrially-targeted compounds are small non-toxic and biologically active molecules that are delivered to and accumulated within the mitochondria of living cells. Therefore, TPP-derivatives may represent potentially “powerful” candidates to block CSCs. Here, we evaluate the metabolic and biological effects induced by the TPP-derivative, termed Dodecyl-TPP (d-TPP) on breast cancer cells. By employing the 3D mammosphere assay in MCF-7 cells, we demonstrate that treatment with d-TPP dose-dependently inhibits the propagation of breast CSCs in suspension. Also, d-TPP targets adherent “bulk” cancer cells, by decreasing MCF-7 cell viability. The analysis of metabolic flux using Seahorse Xfe96 revealed that d-TPP potently inhibits the mitochondrial oxygen consumption rate (OCR), while simultaneously shifting cell metabolism toward glycolysis. Thereafter, we exploited this ATP depletion phenotype and strict metabolic dependency on glycolysis to eradicate the residual glycolytic CSC population, by using additional metabolic stressors. More specifically, we applied a combination strategy based on treatment with d-TPP, in the presence of a selected panel of natural and synthetic compounds, some of which are FDA-approved, that are known to behave as glycolysis (Vitamin C, 2-Deoxy-Glucose) and OXPHOS (Doxycyline, Niclosamide, Berberine) inhibitors. This two-hit scheme effectively decreased CSC propagation, at concentrations of d-TPP toxic only for cancer cells, but not for normal cells, as evidenced using normal human fibroblasts (hTERT-BJ1) as a reference point. Taken together, d-TPP halts CSCs propagation and targets “bulk” cancer cells, without eliciting the relevant undesirable off-target effects in normal cells. These observations pave the way for further exploring the potential of TPP-based derivatives in cancer therapy. Moreover, TPP-based compounds should be investigated for their potential to discriminate between “normal” and “malignant” mitochondria, suggesting that distinct biochemical, and metabolic changes in these organelles could precede specific normal or pathological phenotypes. Lastly, our data validate the manipulation of the energetic machinery as useful tool to eradicate CSCs.
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