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Rasouli M, Alavi M, D'Angelo A, Sobhani N, Roudi R, Safari F. Exploring the dichotomy of the mesenchymal stem cell secretome: Implications for tumor modulation via cell-signaling pathways. Int Immunopharmacol 2024; 143:113265. [PMID: 39353385 DOI: 10.1016/j.intimp.2024.113265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 09/16/2024] [Accepted: 09/24/2024] [Indexed: 10/04/2024]
Abstract
Current cancer therapeutic strategies for the treatment of cancer are often unsuccessful due to unwanted side effects and drug resistance. Therefore, the design and development of potent, new anticancer platforms, such as stem-cell treatments, have attracted much attention. Distinctive biological properties of stem cells include their capacity to secrete bioactive factors, their limited immunogenicity, and their capacity for renewing themselves. Mesenchymal stem cells (MSCs) are one of several kinds of stem cells that are conveniently extracted and are able to be cultivated in vitro utilizing various sources. The secretome of stem cells contains many trophic factors, including cytokines, chemokines, growth factors, and microRNA molecules that can either promote or inhibit the formation of tumors, based on the cell environment. In the current review, we focused on the secretome of mesenchymal stem cells. These stem cells act as a double-edged sword in the regulation of cell signal transduction pathways in that they can either suppress or promote tumors.
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Affiliation(s)
- Mohammad Rasouli
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Mana Alavi
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
| | - Alberto D'Angelo
- Oncology Department, Royal United Hospital, Bath BA1 3NG, United Kingdom
| | - Navid Sobhani
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Raheleh Roudi
- Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, CA 94305, USA.
| | - Fatemeh Safari
- Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran.
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Lin HC, Hsu KH, Wang JY, Chen WM, Tung YC, Su YP. Malignancy progression and treatment efficacy estimation of osteosarcoma patients based on in vitro cell culture model and analysis. J Formos Med Assoc 2024:S0929-6646(24)00307-3. [PMID: 39060210 DOI: 10.1016/j.jfma.2024.07.004] [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: 10/01/2023] [Revised: 02/22/2024] [Accepted: 07/02/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Osteosarcoma (OS) usually happens in patients under 20 years old and is notorious for its low survivorship and limb loss. Personalized medicine is a viable approach to increase the efficiency of chemotherapy which is the main prognostic factor for survivorship after surgical treatment. METHODS In this five-year prospective observational study, we collected primary cells of osteosarcoma from 15 patients, and examined the correlation between clinical characters of patients and cell properties characterized using various in vitro assays. The properties including genes expression, pro-angiogenic capability and anti-cancer drug response are characterized respectively by using RT-PCR, tube formation assay, osteogenesis assay and drug testing on 3D tumor spheroid model. RESULT The results suggest that OS patients with higher MMP9 expression levels have higher probability to develop skip metastasis (p = 0.041). The 3D tumor spheroid test based on the median lethal dose from 2D culture provides some prognostic value. Patients do not response well to methotrexate (MTX) show higher percentage of high pathology grade (p = 0.009) and lung metastasis (p = 0.044). Also, patients respond well to ifosfamide (IFO) have higher probability to achieve high tumor necrosis rate (p = 0.007). CONCLUSION The association between cell properties and clinical characters of patients provided by our data can act as potential prognostic factors to help physicians to develop effective personalized chemotherapy for osteosarcoma treatments.
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Affiliation(s)
- Hsi-Chieh Lin
- Research Center for Applied Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Kuei-Hsiang Hsu
- Department of Orthopedic and Traumatology, Taipei Veterans General Hospital, Taipei, 11217, Taiwan; Department of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Jir-You Wang
- Department of Orthopedic and Traumatology, Taipei Veterans General Hospital, Taipei, 11217, Taiwan
| | - Wei-Ming Chen
- Department of Orthopedic and Traumatology, Taipei Veterans General Hospital, Taipei, 11217, Taiwan; Department of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan
| | - Yi-Chung Tung
- Research Center for Applied Sciences, Academia Sinica, Taipei, 11529, Taiwan
| | - Yu-Ping Su
- Department of Orthopedic and Traumatology, Taipei Veterans General Hospital, Taipei, 11217, Taiwan; Department of Medicine, National Yang Ming Chiao Tung University, Taipei, 11221, Taiwan.
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Macrophage Repolarization as a Therapeutic Strategy for Osteosarcoma. Int J Mol Sci 2023; 24:ijms24032858. [PMID: 36769180 PMCID: PMC9917837 DOI: 10.3390/ijms24032858] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Macrophages are versatile immune cells and can adapt to both external stimuli and their surrounding environment. Macrophages are categorized into two major categories; M1 macrophages release pro-inflammatory cytokines and produce protective responses that lead to antimicrobial or antitumor activity. M2 or tumor-associated macrophages (TAM) release anti-inflammatory cytokines that support tumor growth, invasion capacity, and metastatic potential. Since macrophages can be re-polarized from an M2 to an M1 phenotype with a variety of strategies, this has emerged as an innovative anti-cancer approach. Osteosarcoma (OS) is a kind of bone cancer and consists of a complex niche, and immunotherapy is not very effective. Therefore, immediate attention to new strategies is required. We incorporated the recent studies that have used M2-M1 repolarization strategies in the aspect of treating OS cancer.
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Jin X, Yin H, Bao J, Song X, Lu F, Liang J. ML792 inhibits growth and TGF-β1-induced EMT of osteosarcoma cells via TGF-β1/Smad and PI3K/AKT pathways. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2154856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Xiangang Jin
- Taizhou Hospital of Zhejiang Procince affiliated to Wenzhou Medical University, Linhai City, People’s Republic of China
| | - Hua Yin
- Taizhou Hospital of Zhejiang Procince affiliated to Wenzhou Medical University, Linhai City, People’s Republic of China
| | - Jiaqian Bao
- Taizhou Hospital of Zhejiang Procince affiliated to Wenzhou Medical University, Linhai City, People’s Republic of China
| | - Xiaoting Song
- Taizhou Hospital of Zhejiang Procince affiliated to Wenzhou Medical University, Linhai City, People’s Republic of China
| | - Feng Lu
- Taizhou Hospital of Zhejiang Procince affiliated to Wenzhou Medical University, Linhai City, People’s Republic of China
| | - Junbo Liang
- Taizhou Hospital of Zhejiang Procince affiliated to Wenzhou Medical University, Linhai City, People’s Republic of China
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Han X, Zhang Y, Lu F, Feng J, Zhang C, Wang G. Hypermethylated PODN represses the progression of osteosarcoma by inactivating the TGF-β/Smad2/3 pathway. Pathol Res Pract 2022; 238:154075. [PMID: 36037657 DOI: 10.1016/j.prp.2022.154075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 08/10/2022] [Accepted: 08/10/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND PODN is reported to be an promising biomarker for prognosis of osteosarcoma (OS), while the specific function of PODN has not been explored in OS. This study is designed to explore the function and underlying mechanism of PODN in OS. METHODS The mRNA expression of PODN was determined using qRT-PCR. Protein levels of PODN, DNMT1, DNMT3A, DNMT3B, TGF-β1, Smad2/3 and p-Smad2/3 were detected using western blot. The methylation of PODN was determined with methylation-specific PCR. Moreover, CCK-8 assay and colony formation assay were used for assessing the proliferation of OS cells. Transwell assay was used to evaluate migration and invasion abilities of OS cells. Immunohistochemical staining was performed to determine the protein expression of Ki67 and PODN in tumor tissues. For constructing a xenograft tumor model, MG-63 cells were introduced into the right side of the mouse back via subcutaneous injection. RESULTS PODN was lowly expressed and was hypermethylated in OS tissues and cells. PODN overexpression prevented OS cells from proliferating, migrating and invading, and inhibited tumorigenesis in xenograft mice. After PODN overexpression, protein levels of TGF-β1 and p-Smad2/3 were decreased in OS cells. Meantime, the suppressive effects of PODN overexpression on proliferation, migration and invasion of OS cells as well as mouse tumorigenesis were partly counteracted by TGF-β1 overexpression. CONCLUSIONS PODN overexpression inactivated the TGF-β/Smad2/3 pathway to suppress OS development in vitro and in vivo.
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Affiliation(s)
- Xiuxin Han
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yan Zhang
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Feng Lu
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Jinyan Feng
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Chao Zhang
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
| | - Guowen Wang
- Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
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Dios-Barbeito S, González R, Cadenas M, García LF, Victor VM, Padillo FJ, Muntané J. Impact of nitric oxide in liver cancer microenvironment. Nitric Oxide 2022; 128:1-11. [DOI: 10.1016/j.niox.2022.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 07/16/2022] [Accepted: 07/19/2022] [Indexed: 11/25/2022]
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Rodrigues J, Sarmento B, Pereira CL. Osteosarcoma tumor microenvironment: the key for the successful development of biologically relevant 3D in vitro models. IN VITRO MODELS 2022; 1:5-27. [PMID: 39872973 PMCID: PMC11756501 DOI: 10.1007/s44164-022-00008-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 01/09/2022] [Accepted: 01/09/2022] [Indexed: 01/30/2025]
Abstract
Osteosarcoma (OS) is the most common primary bone cancer in children and young adults. This type of cancer is characterized by a high mortality rate, especially for patients with resistant lung metastases. Given its low incidence, high genetic heterogeneity, the lack of effective targets, and poor availability of relevant in vitro and in vivo models to study the tumor progression and the metastatic cascade, the pathophysiology of OS is still poorly understood and the translation of novel drugs into the market has become stagnant. Due to the importance of the tumor microenvironment (TME) in the development of metastases and the growing interest in targeting TME-specific pathways for novel therapeutics in cancer, models that closely represent these interactions are crucial for a better understanding of cancer-related events. In OS research, most studies rely on oversimplified two-dimensional (2D) assays and complex animal models that do not faithfully recapitulate OS development and progression. In turn, three-dimensional (3D) models are able to mimic not only the physical 3D environment in which cancer cells grow but also involve interactions with the TME, including its extracellular matrix, and thus are promising tools for drug screening studies. In this review, the existing and innovative OS in vitro 3D models are highlighted, focusing on how the TME is crucial to develop effective platforms for OS tumor and metastasis modeling in a physiologically relevant context. Graphical abstract
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Affiliation(s)
- João Rodrigues
- Instituto de Investigação E Inovação Em Saúde (i3S), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Instituto de Engenharia Biomédica (INEB), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Instituto Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo 228, 4150-180 Porto, Portugal
- Faculdade de Engenharia da Universidade Do Porto (FEUP), University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal
| | - Bruno Sarmento
- Instituto de Investigação E Inovação Em Saúde (i3S), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Instituto de Engenharia Biomédica (INEB), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- CESPU, Instituto de Investigação E Formação Avançada Em Ciências E Tecnologias da Saúde, Rua Central da Gandra 1317, 4585-116 Gandra, Portugal
| | - Catarina Leite Pereira
- Instituto de Investigação E Inovação Em Saúde (i3S), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
- Instituto de Engenharia Biomédica (INEB), University of Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
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Brozovich AA, Lenna S, Paradiso F, Serpelloni S, McCulloch P, Weiner B, Yustein JT, Taraballi F. Osteogenesis in the presence of chemotherapy: A biomimetic approach. J Tissue Eng 2022; 13:20417314221138945. [PMID: 36451687 PMCID: PMC9703557 DOI: 10.1177/20417314221138945] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/29/2022] [Indexed: 07/13/2024] Open
Abstract
Osteosarcoma (OS) is the most common bone tumor in pediatrics. After resection, allografts or metal endoprostheses reconstruct bone voids, and systemic chemotherapy is used to prevent recurrence. This urges the development of novel treatment options for the regeneration of bone after excision. We utilized a previously developed biomimetic, biodegradable magnesium-doped hydroxyapatite/type I collagen composite material (MHA/Coll) to promote bone regeneration in the presence of chemotherapy. We also performed experiments to determine if human mesenchymal stem cells (hMSCs) seeded on MHA/Coll scaffold migrate less toward OS cells, suggesting that hMSCs will not contribute to tumor growth and therefore the potential of oncologic safety in vitro. Also, hMSCs seeded on MHA/Coll had increased expression of osteogenic genes (BGLAP, SPP1, ALP) compared to hMSCs in the 2D condition, even when exposed to chemotherapeutics. This is the first study to demonstrate that a highly osteogenic scaffold can potentially be oncologically safe because hMSCs on MHA/Coll tend to differentiate and lose the ability to migrate toward tumor cells. Therefore, hMSCs on MHA/Coll could potentially be utilized for bone regeneration after OS excision.
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Affiliation(s)
- Ava A Brozovich
- Texas A&M College of Medicine, Bryan, TX, USA
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Stefania Lenna
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Francesca Paradiso
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
- Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School, Singleton Park, Swansea, UK
| | - Stefano Serpelloni
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
- Politecnico di Milano, Department of Electronics, Informatics, and Bioengineering (DEIB), Milan, Italy
| | - Patrick McCulloch
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Bradley Weiner
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Jason T Yustein
- Texas Children’s Cancer and Hematology Center and The Faris D. Virani Ewing Sarcoma Center, Baylor College of Medicine, Houston, TX, USA
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston, TX, USA
- Houston Methodist Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
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Mesenchymal Stem Cell Senescence and Osteogenesis. Medicina (B Aires) 2021; 58:medicina58010061. [PMID: 35056369 PMCID: PMC8779043 DOI: 10.3390/medicina58010061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/25/2021] [Accepted: 12/27/2021] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are stem cells with the potential ability to differentiate into various cells and the ability to self-renew and resemble fibroblasts. These cells can adhere to plastic to facilitate the culture process. MSCs can be used in research into tissue biotechnology and rejuvenation medicine. MSCs are also beneficial in recipient tissue and differentiate as a breakthrough strategy through paracrine activity. Many databases have shown MSC-based treatment can be beneficial in the reduction of osteogenesis induced by senescence. In this article, we will discuss the potential effect of MSCs in senescence cells related to osteogenesis.
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Senamontree S, Lakthan T, Charoenpanich P, Chanchao C, Charoenpanich A. Betulinic acid decreases lipid accumulation in adipogenesis-induced human mesenchymal stem cells with upregulation of PGC-1α and UCP-1 and post-transcriptional downregulation of adiponectin and leptin secretion. PeerJ 2021; 9:e12321. [PMID: 34721992 PMCID: PMC8520689 DOI: 10.7717/peerj.12321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/25/2021] [Indexed: 12/24/2022] Open
Abstract
Background Controlling cellular functions, including stem cell growth and differentiation, can be the key for the treatment of metabolic disorders, such as type II diabetes mellitus (T2DM). Previously identified as peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, betulinic acid (BA) may have the capability to control stem cell homeostasis, benefiting T2DM treatment. In this study, the effects of BA on osteogenesis and adipogenesis mechanisms of human mesenchymal stem cells (hMSCs) were investigated. Results We observed that BA increased hMSC osteogenesis by enhancing the alkaline phosphatase activity, calcium deposition, and mRNA expressions of osteogenic markers, namely, runt-related transcription factor 2, osteocalcin, and osteopontin. In addition, BA decreased hMSC adipogenesis with the decrease in glycerol-3-phosphate dehydrogenase activity, reduced intracellular lipid accumulations, down-regulated CCAAT-enhancer-binding protein alpha, and suppressed post-transcriptional adiponectin and leptin secretion. BA increased the brown adipocyte characteristics with the increase in the ratio of small lipid droplets and glucose uptake. Furthermore, the mRNA expressions of brown adipocyte markers, namely, PPARγ coactivator one alpha, uncoupling protein 1, and interleukin-6 increased. Conclusions Our results uncovered the mechanisms of how BA improved glucose and lipid metabolisms by decreasing white adipogenesis and increasing brown adipogenesis. Altogether, BA may be used for balancing glucose metabolisms without the potential side effects on bone loss or weight gain.
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Affiliation(s)
- Sasithon Senamontree
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
| | - Thitiporn Lakthan
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
| | - Pornsri Charoenpanich
- Department of Food Technology, Faculty of Engineering and Industrial Technology, Silpakorn University, Nakhon Pathom, Thailand
| | - Chanpen Chanchao
- Department of Biology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | - Adisri Charoenpanich
- Department of Biology, Faculty of Science, Silpakorn University, Nakhon Pathom, Thailand
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Sarhadi VK, Daddali R, Seppänen-Kaijansinkko R. Mesenchymal Stem Cells and Extracellular Vesicles in Osteosarcoma Pathogenesis and Therapy. Int J Mol Sci 2021; 22:11035. [PMID: 34681692 PMCID: PMC8537935 DOI: 10.3390/ijms222011035] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/01/2021] [Accepted: 10/09/2021] [Indexed: 12/29/2022] Open
Abstract
Osteosarcoma (OS) is an aggressive bone tumor that mainly affects children and adolescents. OS has a strong tendency to relapse and metastasize, resulting in poor prognosis and survival. The high heterogeneity and genetic complexity of OS make it challenging to identify new therapeutic targets. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into adipocytes, osteoblasts, or chondroblasts. OS is thought to originate at some stage in the differentiation process of MSC to pre-osteoblast or from osteoblast precursors. MSCs contribute to OS progression by interacting with tumor cells via paracrine signaling and affect tumor cell proliferation, invasion, angiogenesis, immune response, and metastasis. Extracellular vesicles (EVs), secreted by OS cells and MSCs in the tumor microenvironment, are crucial mediators of intercellular communication, driving OS progression by transferring miRNAs/RNA and proteins to other cells. MSC-derived EVs have both pro-tumor and anti-tumor effects on OS progression. MSC-EVs can be also engineered to deliver anti-tumor cargo to the tumor site, which offers potential applications in MSC-EV-based OS treatment. In this review, we highlight the role of MSCs in OS, with a focus on EV-mediated communication between OS cells and MSCs and their role in OS pathogenesis and therapy.
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Menéndez ST, Gallego B, Murillo D, Rodríguez A, Rodríguez R. Cancer Stem Cells as a Source of Drug Resistance in Bone Sarcomas. J Clin Med 2021; 10:jcm10122621. [PMID: 34198693 PMCID: PMC8232081 DOI: 10.3390/jcm10122621] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022] Open
Abstract
Bone sarcomas are commonly characterized by a high degree of intra-tumor heterogeneity, which in part is due to the presence of subpopulations of tumor cells presenting stem cell properties. Similar to normal stem cells, these cancer stem cells (CSCs) display a drug resistant phenotype and therefore are responsible for relapses and tumor dissemination. Drug resistance in bone sarcomas could be enhanced/modulated during tumor evolution though the acquisition of (epi)-genetic alterations and the adaptation to changing microenvironments, including drug treatments. Here we summarize findings supporting the involvement of pro-stemness signaling in the development of drug resistance in bone sarcomas. This include the activation of well-known pro-stemness pathways (Wnt/β-Cat, NOTCH or JAT/STAT pathways), changes in the metabolic and autophagic activities, the alteration of epigenetic pathways, the upregulation of specific non-coding RNAs and the crosstalk with different microenvironmental factors. This altered signaling is expected to be translated to the clinic in the form of biomarkers of response and new therapies able to overcome drug resistance.
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Affiliation(s)
- Sofía T. Menéndez
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma s/n, 33011 Oviedo, Spain; (B.G.); (D.M.); (A.R.)
- Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain
- CIBER en Oncología (CIBERONC), 28029 Madrid, Spain
- Correspondence: (S.T.M.); (R.R.)
| | - Borja Gallego
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma s/n, 33011 Oviedo, Spain; (B.G.); (D.M.); (A.R.)
| | - Dzohara Murillo
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma s/n, 33011 Oviedo, Spain; (B.G.); (D.M.); (A.R.)
| | - Aida Rodríguez
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma s/n, 33011 Oviedo, Spain; (B.G.); (D.M.); (A.R.)
| | - René Rodríguez
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma s/n, 33011 Oviedo, Spain; (B.G.); (D.M.); (A.R.)
- Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain
- CIBER en Oncología (CIBERONC), 28029 Madrid, Spain
- Correspondence: (S.T.M.); (R.R.)
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Mahmood* A, Elsafadi* M, Manikandan M, Alfayez M. IL-1 β-mediated TGFβ/SMAD signaling pathway inactivation impaired ex vivo osteogenic activity of human bone marrow-derived stromal cells. BIOTECHNOL BIOTEC EQ 2021. [DOI: 10.1080/13102818.2021.1939784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Affiliation(s)
- Amer Mahmood*
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mona Elsafadi*
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Muthurangan Manikandan
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Musaad Alfayez
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
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14
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Jongsomchai K, Leardkamolkarn V, Mahatheeranont S. A rice bran phytochemical, cyanidin 3-glucoside, inhibits the progression of PC3 prostate cancer cell. Anat Cell Biol 2020; 53:481-492. [PMID: 32839357 PMCID: PMC7769112 DOI: 10.5115/acb.20.085] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 06/08/2020] [Accepted: 07/13/2020] [Indexed: 12/13/2022] Open
Abstract
Prostate cancer is one of the high incidences and the most invasive cancer that is also highly resistant to chemotherapy. Currently, several natural products have been considering using as the supplements for anti-cancer therapy. This study aims to identify the potential active anti-cancer ingredients in the bran extracts of the native Thai rice (Luempua cultivar). Rice bran fraction enriched in anthocyanins was successively isolated and processed until the major purified compound obtained. The sub-fractions and the purified, rice bran, cyanidin 3-glucoside (RBC3G), were studied for biological effects (cell viability, migration, and invasion assays) on human prostatic cancer (PC3) cells using immunohistochemical-staining and immuno-blotting approaches. The sub-fractions and the purified RBC3G inhibited epithelial mesenchymal transition (EMT) characteristics of PC3 cells by blocking the expression of several cytoskeletal associate proteins in a concentration dependent manner, leading to decreasing of the cancer cell motility. RBC3G reduced the expression of Smad/Snail signaling molecules but enhanced the expression of cell surface protein, E-cadherin, leading to a delay tumor transformation. The RBC3G also inhibited matrix metalloproteinase-9 and nuclear factor-kappa B expression levels and the enzymes activity in PC3 cells, leading to a slow cell migration/invasion process. The results suggested that RBC3G blunt and/or delay the progressive cancer cell behaviors by inhibit EMT through Smad signaling pathway(s) mediating Snail/E-cadherin expression.
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Affiliation(s)
- Kamonwan Jongsomchai
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | | | - Sugunya Mahatheeranont
- Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
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15
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Czarnecka AM, Synoradzki K, Firlej W, Bartnik E, Sobczuk P, Fiedorowicz M, Grieb P, Rutkowski P. Molecular Biology of Osteosarcoma. Cancers (Basel) 2020; 12:E2130. [PMID: 32751922 PMCID: PMC7463657 DOI: 10.3390/cancers12082130] [Citation(s) in RCA: 212] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/29/2020] [Accepted: 07/30/2020] [Indexed: 12/19/2022] Open
Abstract
Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or Diamond-Blackfan anemia. TP53 is the most frequently altered gene in osteosarcoma. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK-ERK pathways. Several genomic studies showed frequent alterations in the RB gene in pediatric OS patients. Osteosarcoma driver mutations have been reported in NOTCH1, FOS, NF2, WIF1, BRCA2, APC, PTCH1 and PRKAR1A genes. Some miRNAs such as miR-21, -34a, -143, -148a, -195a, -199a-3p and -382 regulate the pathogenic activity of MAPK and PI3K/Akt-signaling pathways in osteosarcoma. CD133+ osteosarcoma cells have been shown to exhibit stem-like gene expression and can be tumor-initiating cells and play a role in metastasis and development of drug resistance. Although currently osteosarcoma treatment is based on adriamycin chemoregimens and surgery, there are several potential targeted therapies in development. First of all, activity and safety of cabozantinib in osteosarcoma were studied, as well as sorafenib and pazopanib. Finally, novel bifunctional molecules, of potential imaging and osteosarcoma targeting applications may be used in the future.
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Affiliation(s)
- Anna M Czarnecka
- Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Centre, 02-781 Warsaw, Poland
| | - Kamil Synoradzki
- Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Wiktoria Firlej
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Centre, 02-781 Warsaw, Poland
- Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Ewa Bartnik
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Pawel Sobczuk
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Centre, 02-781 Warsaw, Poland
- Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Michal Fiedorowicz
- Small Animal Magnetic Resonance Imaging Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland
- Interinstitute Laboratory of New Diagnostic Applications of MRI, Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, 02-109 Warsaw, Poland
| | - Pawel Grieb
- Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Centre, 02-781 Warsaw, Poland
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16
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Cersosimo F, Lonardi S, Bernardini G, Telfer B, Mandelli GE, Santucci A, Vermi W, Giurisato E. Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy. Int J Mol Sci 2020; 21:E5207. [PMID: 32717819 PMCID: PMC7432207 DOI: 10.3390/ijms21155207] [Citation(s) in RCA: 140] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/20/2020] [Accepted: 07/21/2020] [Indexed: 12/20/2022] Open
Abstract
Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors.
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Affiliation(s)
- Francesca Cersosimo
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
| | - Silvia Lonardi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.L.); (G.E.M.); (W.V.)
| | - Giulia Bernardini
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
| | - Brian Telfer
- Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK;
| | - Giulio Eugenio Mandelli
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.L.); (G.E.M.); (W.V.)
| | - Annalisa Santucci
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
| | - William Vermi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (S.L.); (G.E.M.); (W.V.)
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Emanuele Giurisato
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy; (F.C.); (G.B.); (A.S.)
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK
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17
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Dewhurst RM, Scalzone A, Buckley J, Mattu C, Rankin KS, Gentile P, Ferreira AM. Development of Natural-Based Bone Cement for a Controlled Doxorubicin-Drug Release. Front Bioeng Biotechnol 2020; 8:754. [PMID: 32733869 PMCID: PMC7363953 DOI: 10.3389/fbioe.2020.00754] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 06/12/2020] [Indexed: 12/22/2022] Open
Abstract
Osteosarcoma (OS) accounts for 60% of all global bone cancer diagnoses. Intravenous administration of Doxorubicin Hydrochloride (DOXO) is the current form of OS treatment, however, systemic delivery has been linked to the onset of DOXO induced cardiomyopathy. Biomaterials including calcium phosphate cements (CPCs) and nanoparticles (NPs) have been tested as localized drug delivery scaffolds for OS cells. However, the tumor microenvironment is critical in cancer progression, with mesenchymal stem cells (MSCs) thought to promote OS metastasis and drug resistance. The extent of MSC assisted survival of OS cells in response to DOXO delivered by CPCs is unknown. In this study, we aimed at investigating the effect of DOXO release from a new formulation of calcium phosphate-based bone cement on the viability of OS cells cocultured with hMSC in vitro. NPs made of PLGA were loaded with DOXO and incorporated in the formulated bone cement to achieve local drug release. The inclusion of PLGA-DOXO NPs into CPCs was also proven to increase the levels of cytotoxicity of U2OS cells in mono- and coculture after 24 and 72 h. Our results demonstrate that a more effective localized DOXO delivery can be achieved via the use of CPCs loaded with PLGA-DOXO NPs compared to CPCs loaded with DOXO, by an observed reduction in metabolic activity of U2OS cells in indirect coculture with hMSCs. The presence of hMSCs offer a degree of DOXO resistance in U2OS cells cultured on PLGA-DOXO NP bone cements. The consideration of the tumor microenvironment via the indirect inclusion of hMSCs in this study can act as a starting point for future direct coculture and in vivo investigations.
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Affiliation(s)
- Rebecca Marie Dewhurst
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Annachiara Scalzone
- School of Engineering, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Joseph Buckley
- School of Engineering, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Clara Mattu
- Department of Mechanical and Aerospace, Politecnico di Torino, Turin, Italy
| | - Kenneth S Rankin
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Piergiorgio Gentile
- School of Engineering, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Ana Marina Ferreira
- School of Engineering, Newcastle University, Newcastle upon Tyne, United Kingdom
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18
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de Azevedo JWV, de Medeiros Fernandes TAA, Fernandes JV, de Azevedo JCV, Lanza DCF, Bezerra CM, Andrade VS, de Araújo JMG, Fernandes JV. Biology and pathogenesis of human osteosarcoma. Oncol Lett 2019; 19:1099-1116. [PMID: 31966039 PMCID: PMC6955653 DOI: 10.3892/ol.2019.11229] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 09/10/2019] [Indexed: 12/26/2022] Open
Abstract
Osteosarcoma (OS) is a bone tumor of mesenchymal origin, most frequently occurring during the rapid growth phase of long bones, and usually located in the epiphyseal growth plates of the femur or the tibia. Its most common feature is genome disorganization, aneuploidy with chromosomal alterations, deregulation of tumor suppressor genes and of the cell cycle, and an absence of DNA repair. This suggests the involvement of surveillance failures, DNA repair or apoptosis control during osteogenesis, allowing the survival of cells which have undergone alterations during differentiation. Epigenetic events, including DNA methylation, histone modifications, nucleosome remodeling and expression of non-coding RNAs have been identified as possible risk factors for the tumor. It has been reported that p53 target genes or those genes that have their activity modulated by p53, in addition to other tumor suppressor genes, are silenced in OS-derived cell lines by hypermethylation of their promoters. In osteogenesis, osteoblasts are formed from pluripotent mesenchymal cells, with potential for self-renewal, proliferation and differentiation into various cell types. This involves complex signaling pathways and multiple factors. Any disturbance in this process can cause deregulation of the differentiation and proliferation of these cells, leading to the malignant phenotype. Therefore, the origin of OS seems to be multifactorial, involving the deregulation of differentiation of mesenchymal cells and tumor suppressor genes, activation of oncogenes, epigenetic events and the production of cytokines.
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Affiliation(s)
| | | | | | | | | | - Christiane Medeiros Bezerra
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, 59072-970 Natal, RN, Brazil
| | - Vânia Sousa Andrade
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, 59072-970 Natal, RN, Brazil
| | | | - José Veríssimo Fernandes
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, 59072-970 Natal, RN, Brazil
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19
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Cancer Stem Cells and Osteosarcoma: Opportunities and Limitations. Tech Orthop 2019. [DOI: 10.1097/bto.0000000000000408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
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20
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Izadpanah S, Shabani P, Aghebati-Maleki A, Baghbanzadeh A, Fotouhi A, Bisadi A, Aghebati-Maleki L, Baradaran B. Prospects for the involvement of cancer stem cells in the pathogenesis of osteosarcoma. J Cell Physiol 2019; 235:4167-4182. [PMID: 31709547 DOI: 10.1002/jcp.29344] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 08/26/2019] [Indexed: 12/31/2022]
Abstract
Osteosarcoma (OS) is one of the most common bone tumors in children and adolescents that cause a high rate of mortality in this age group and tends to be metastatic, in spite of chemotherapy and surgery. The main reason for this can be returned to a small group of malignant cells called cancer stem cells (CSCs). OS-CSCs play a key role in the resistance to treatment and relapse and metastasis through self-renewal and differentiation abilities. In this review, we intend to go through the different aspects of this malignant disease, including the cancer stem cell-phenotype, methods for isolating CSCs, signaling pathways, and molecular markers in this disease, and drugs showing resistance in treatment efforts of OS.
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Affiliation(s)
- Sama Izadpanah
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parastoo Shabani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Fotouhi
- Department of Orthopedic Surgery, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Bisadi
- Department of Orthopedic Surgery, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leili Aghebati-Maleki
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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21
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Zhang C, Ma K, Li WY. IL-6 Promotes Cancer Stemness and Oncogenicity in U2OS and MG-63 Osteosarcoma Cells by Upregulating the OPN-STAT3 Pathway. J Cancer 2019; 10:6511-6525. [PMID: 31777581 PMCID: PMC6856881 DOI: 10.7150/jca.29931] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
Background: Cancer stem cells (CSCs) are associated with tumor development, chemoresistance, recurrence, metastasis, and even prognosis. Interleukin (IL)-6 overexpression has been implicated in the development of various cancers, including osteosarcoma. This study aimed to investigate the role of IL-6 in modulating clinicopathological features, malignant traits, and stemness in osteosarcoma, and to determine the mechanisms underlying IL-6-mediated osteosarcoma progression. Methods: Patients with osteosarcoma (n = 54) and healthy controls (n = 50) were selected. No patients received any pre-operative cancer treatment. Serum levels of IL-6 were determined in patients with osteosarcoma by ELISA and their relationship with pathological features and prognosis analyzed. The 3-(4,5-dimethyl -2-thiazolyl)- 2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays were used to evaluate cell proliferation, transwell assays were used to assess the invasive potential of cells, and cell migration rates were analyzed using a wound healing assay. Tumor self-renewal was detected using a spheroid formation assay and CD133 and CD44 expression assessed by flow cytometry. Protein levels of NANOG, SOX2, OCT3/4, OPN, and epithelial-to-mesenchymal transition (EMT)-related markers, and the phosphorylation status of STAT3, were determined by western blotting. Finally, cell viability was determined with or without cisplatin (cis-dichlorodiammineplatinum [DDP])/adriamycin (ADR) treatment. Xenograft tumor models were established by subcutaneous injection of osteosarcoma spheroids, with or without IL-6. Results: Serum IL-6 levels were higher in osteosarcoma patients than controls. There was no significant association of serum IL-6 level with age, sex and tumor size; however, it was associated with TNM stage, and lung metastasis (P < 0. 05). IL-6 significantly increased proliferation and colony formation of osteosarcoma cells, and enhanced their invasion and migratory potential, thus promoting an EMT-like phenotype and elevated chemoresistance of to DDP/ADR. Spheroid size/proportion of CD133+CD44+ cells and SOX2, OCT3/4, and NANOG protein levels were elevated by IL-6 treatment in a time-dependent manner; however, IL-6 did not substantially influence any of these features in hFOB 1.19 and T98G cells. Knockdown of IL-6 reduced cell viability, colony formation, and invasion/migration ability, and reversed EMT, whereas it increased chemosensitivity to DDP/ADR. Blocking IL-6 expression with siRNA also caused loss of stemness, including reducing self-renewal ability, and reduced the proportion of CD133/CD44-positive cells, and expression of stemness-related genes. Pretreatment with the STAT3 inhibitor, S3I-201, decreased sphere size, and downregulated NANOG, SOX2, and OCT3/4 protein levels, compared with IL-6 treatment alone. Furthermore, OPN levels were elevated in response to IL-6 and an anti-OPN antibody effectively blocked IL-6-induced spheroid formation and STAT3 phosphorylation. In vivo, tumor size and weight were higher in IL-6 treated mice than controls. Conclusions: IL-6 mediates promotion of osteosarcoma spheroid stemness by activating OPN/STAT3 signaling.
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Affiliation(s)
- Chuan Zhang
- Luoyang Orthopaedic-Traumatological Hospital and Henan Orthopaedic Hospital, Luoyang, Henan 471002, China
| | - Kun Ma
- Luoyang Orthopaedic-Traumatological Hospital and Henan Orthopaedic Hospital, Luoyang, Henan 471002, China
| | - Wu-Yin Li
- Luoyang Orthopaedic-Traumatological Hospital and Henan Orthopaedic Hospital, Luoyang, Henan 471002, China
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22
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Yin W, Chen J, Wang G, Zhang D. MicroRNA‑106b functions as an oncogene and regulates tumor viability and metastasis by targeting LARP4B in prostate cancer. Mol Med Rep 2019; 20:951-958. [PMID: 31173237 PMCID: PMC6625195 DOI: 10.3892/mmr.2019.10343] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 03/07/2019] [Indexed: 01/10/2023] Open
Abstract
Prostate cancer (PCa) is the most common malignancy among males worldwide, and is one of the leading causes of cancer‑related mortality. MicroRNAs (miRs) are a type of endogenous, noncoding RNA that serve a key role in pathological processes, and have been demonstrated to be involved in the formation and progression of PCa. Previous studies have reported that miR‑106b acts as an oncogene; however, the specific effects of miR‑106b on PCa have not been fully elucidated. The present study aimed to investigate the role and underlying molecular mechanisms of miR‑106b in the initiation and progression of PCa. In this study, miR‑106b was reported to be overexpressed and la‑related protein 4B (LARP4B) was downregulated in PCa tissues compared with paracancerous tissues. In addition, LARP4B was identified as a target gene of miR‑106b by bioinformatics prediction analysis and a dual luciferase reporter gene assay. Furthermore, MTT, wound healing and Transwell assays were performed to evaluate PCa cell viability, and migration and invasive abilities. The data revealed that inhibition of miR‑106b significantly suppressed the viability, migration and invasion of PCa cells. In addition, inhibition of miR‑106b significantly suppressed the mRNA and protein expression of cancer‑related genes, including matrix metalloproteinase‑2, cluster of differentiation 44 and Ki‑67, and increased that of the tumor suppressor, mothers against decapentaplegic homolog 2. Collectively, the findings of the present study indicated that miR‑106b may target LAR4B to inhibit cancer cell viability, migration and invasion, and may be considered as a novel therapeutic target in PCa.
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Affiliation(s)
- Weiqi Yin
- Department of Urology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Junfeng Chen
- Department of Urology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Guoyao Wang
- Department of Urology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Dongxu Zhang
- Department of Urology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China
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23
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Tian H, Zhou T, Chen H, Li C, Jiang Z, Lao L, Kahn SA, Duarte MEL, Zhao J, Daubs MD, Buser Z, Brochmann EJ, Wang JC, Murray SS. Bone morphogenetic protein-2 promotes osteosarcoma growth by promoting epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin signaling pathway. J Orthop Res 2019; 37:1638-1648. [PMID: 30737824 DOI: 10.1002/jor.24244] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Accepted: 01/29/2019] [Indexed: 02/04/2023]
Abstract
The correlation between BMP-2 and osteosarcoma growth has gained increased interest in the recent years, however, there is still no consensus. In this study, we tested the effects of BMP-2 on osteosarcoma cells through both in vitro and in vivo experiments. The effect of BMP-2 on the proliferation, migration and invasion of osteosarcoma cells was tested in vitro. Subcutaneous and intratibial tumor models were used for the in vivo experiments in nude mice. The effects of BMP-2 on EMT of osteosarcoma cells and the Wnt/β-catenin signaling pathway were also tested using a variety of biochemical methods. In vitro tests did not show a significant effect of BMP-2 on tumor cell proliferation. However, BMP-2 increased the mobility of tumor cells and the invasion assay demonstrated that BMP-2 promoted invasion of osteosarcoma cells in vitro. In vivo animal study showed that BMP-2 dramatically enhanced tumor growth. We also found that BMP-2 induced EMT of osteosarcoma cells. The expression levels of Axin2 and Dkk-1 were both down regulated by BMP-2 treatment, while β-catenin, c-myc and Cyclin-D1 were all upregulated. The expression of Wnt3α and p-GSK-3β were also significantly upregulated indicating that the Wnt/β-catenin signaling pathway was activated during the EMT of osteosarcoma driven by BMP-2. From this study, we can conclude that BMP-2 significantly promotes growth of osteosarcoma cells (143B, MG63), and enhances mobility and invasiveness of tumor cells as demonstrated in vitro. The underlying mechanism might be that BMP-2 promotes EMT of osteosarcoma through the Wnt/β-catenin signaling pathway. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1638-1648, 2019.
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Affiliation(s)
- Haijun Tian
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tangjun Zhou
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongfang Chen
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenshuang Li
- Section of Orthodontics, Division of Growth and Development, School of Dentistry, University of California, Los Angeles, California
| | - Ziyue Jiang
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Lifeng Lao
- Department of Orthopaedic Surgery, University of California, Los Angeles, California
| | - Suzana Assad Kahn
- Research Division, National Institute of Traumatology and Orthopaedics, Rio de Janeiro, Brazil.,Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford University, Stanford, California
| | | | - Jie Zhao
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Michael D Daubs
- Division of Orthopaedic Surgery, Department of Surgery, University of Nevada School of Medicine, Las Vegas, Neveda
| | - Zorica Buser
- Department of Orthopaedic Surgery, Keck School of Medicine of USC, Los Angeles, California
| | - Elsa J Brochmann
- Research Service, VA Greater Los Angeles Healthcare System, North Hills, California.,Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, North Hills, California.,Department of Medicine, University of California, Los Angeles, California
| | - Jeffrey C Wang
- Department of Orthopaedic Surgery, Keck School of Medicine of USC, Los Angeles, California
| | - Samuel S Murray
- Research Service, VA Greater Los Angeles Healthcare System, North Hills, California.,Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, North Hills, California.,Department of Medicine, University of California, Los Angeles, California
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24
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Jiang X, Zhang Z, Song C, Deng H, Yang R, Zhou L, Sun Y, Zhang Q. Glaucocalyxin A reverses EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma. Chem Biol Interact 2019; 307:158-166. [PMID: 31059706 DOI: 10.1016/j.cbi.2019.05.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 04/27/2019] [Accepted: 05/03/2019] [Indexed: 02/07/2023]
Abstract
Metastatic osteosarcoma usually has an unsatisfactory response to the current standard chemotherapy and causes poor prognosis. Currently, epithelial-mesenchymal transition (EMT) is reported as a critical event in osteosarcoma metastasis. Glaucocalyxin A, a bioactive ent-kauranoid diterpenoid, exerts anti-cancer effect on osteosarcoma by inducing apoptosis in previous study. However, the effect of Glaucocalyxin A on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the potential mechanisms of Glaucocalyxin A on EMT and metastasis of osteosarcoma. We found that Glaucocalyxin A inhibited migration and invasion of MG-63 and 143B cells. Moreover, Glaucocalyxin A increased the protein and mRNA levels of E-cadherin and decreased the protein and transcription expression of N-cadherin, Vimentin. Glaucocalyxin A also inhibited the protein and mRNA levels of EMT-associated transcription factor including Snail and Slug. Furthermore, Glaucocalyxin A inhibited transforming growth factor-β1 (TGF-β1)-induced migration, invasion and EMT of low-metastatic osteosarcoma U2OS cells. Glaucocalyxin A inhibited TGF-β-induced phosphorylation of Smad 2/3 in osteosarcoma U2OS cells. Finally, we established transplanted metastatic models of highly metastatic osteosarcoma 143B cells. Glaucocalyxin A inhibited lung metastasis in vivo. Interestingly, Glaucocalyxin A increased the protein expression of E-cadherin and reduced the protein expression of N-cadherin and Vimentin. Glaucocalyxin A inhibited the protein expression of Snail and Slug in vivo. In summary, this study demonstrated that Glaucocalyxin A inhibited EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma. Therefore, Glaucocalyxin A might be a promising candidate against the metastasis of human osteosarcoma.
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Affiliation(s)
- Xiubo Jiang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Zhenhao Zhang
- The First Clinical Medical College, Nanjing Medical University, 101Longmian Avenue, Jiangning District, Nanjing 211166, People's Republic of China
| | - Changqin Song
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Hanzhi Deng
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Runyu Yang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Lvqi Zhou
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China
| | - Yang Sun
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
| | - Qi Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, People's Republic of China.
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25
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Avnet S, Lemma S, Cortini M, Di Pompo G, Perut F, Baldini N. Pre-clinical Models for Studying the Interaction Between Mesenchymal Stromal Cells and Cancer Cells and the Induction of Stemness. Front Oncol 2019; 9:305. [PMID: 31114753 PMCID: PMC6502984 DOI: 10.3389/fonc.2019.00305] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 04/02/2019] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stromal cells (MSC) have essential functions in building and supporting the tumour microenvironment, providing metastatic niches, and maintaining cancer hallmarks, and it is increasingly evident that the study of the role of MSC in cancer is crucial for paving the way to clinical opportunities for novel anti-cancer therapies. To date, the vast majority of preclinical models that have been used for studying the effect of reactive MSC on cancer growth, metastasis, and response to therapy has been mainly based on in vitro flat biology, including the co-culturing with cell compartmentalization or with cell-to-cell contact, and on in vivo cancer models with different routes of MSC inoculation. More complex in vitro 3D models based on spheroid structures that are formed by intermingled MSC and tumour cells are also capturing the interest in cancer research. These are innovative culture systems tailored on the specific tumour type and that can be combined with a synthetic extracellular matrix, or included in in silico technologies, to more properly mimic the in vivo biological, spatial, biochemical, and biophysical features of tumour tissues. In this review, we summarized the most popular and currently available preclinical models for evaluating the role of MSC in cancer and their specific suitability, for example, in assaying the MSC-driven induction of epithelial-to-mesenchymal transition or of stem-like traits in cancer cells. Finally, we enlightened the need to carefully consider those parameters that might unintentionally strongly affect the secretome in MSC-cancer interplay and introduce confounding variables for the interpretation of results.
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Affiliation(s)
- Sofia Avnet
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Silvia Lemma
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Margherita Cortini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Gemma Di Pompo
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Francesca Perut
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Nicola Baldini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.,Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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26
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Zamborsky R, Kokavec M, Harsanyi S, Danisovic L. Identification of Prognostic and Predictive Osteosarcoma Biomarkers. Med Sci (Basel) 2019; 7:medsci7020028. [PMID: 30754703 PMCID: PMC6410182 DOI: 10.3390/medsci7020028] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 01/22/2019] [Accepted: 02/05/2019] [Indexed: 02/06/2023] Open
Abstract
Both adolescents and children suffer from osteosarcoma, localized in the metaphysis of the long bones. This is the most common primary high-grade bone tumor in this patient group. Early tumor detection is the key to ensuring effective treatment. Improved osteosarcoma outcomes in clinical trials have been contingent on biomarker discovery and an evolving understanding of molecules and their complex interactions. In this review, we present a short overview of biomarkers for osteosarcoma, and highlight advances in osteosarcoma-related biomarker research. Many studies show that several biomarkers undergo critical changes with osteosarcoma progression. Growing knowledge about osteosarcoma-related markers is expected to positively impact the development of therapeutics for osteosarcoma, and ultimately of clinical care. It has also become important to develop new biomarkers, which can identify vulnerable patients who should be treated with more intensive and aggressive therapy after diagnosis.
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Affiliation(s)
- Radoslav Zamborsky
- Department of Orthopedics, Faculty of Medicine, Comenius University, Limbova 1, 833 40 Bratislava, Slovakia.
| | - Milan Kokavec
- Department of Orthopedics, Faculty of Medicine, Comenius University, Limbova 1, 833 40 Bratislava, Slovakia.
| | - Stefan Harsanyi
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia.
| | - Lubos Danisovic
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia.
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27
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Singe nucleotide polymorphisms in osteosarcoma: Pathogenic effect and prognostic significance. Exp Mol Pathol 2019; 106:63-77. [PMID: 30528563 DOI: 10.1016/j.yexmp.2018.12.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 08/14/2018] [Accepted: 12/05/2018] [Indexed: 12/26/2022]
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28
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Liu F, Wang K, Zhang L, Yang YL. Bone morphogenetic protein and activin membrane-bound inhibitor suppress bone cancer progression in MG63 and SAOS cells via regulation of the TGF-β-induced EMT signaling pathway. Oncol Lett 2018; 16:5113-5121. [PMID: 30250579 PMCID: PMC6144885 DOI: 10.3892/ol.2018.9268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 05/30/2018] [Indexed: 12/03/2022] Open
Abstract
Bone cancer is one of the most common tumor types that occurs in bones and their affiliated tissues. The prognosis remains poor due to the limited number of effective therapeutic targets. Downregulation of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) has been observed in human cancer cells and BAMBI reconstitution can inhibit growth and metastasis of human cancer cells. In the present study, a potential mechanism mediated by BAMBI in osteosarcoma cells was investigated. The data demonstrated that BAMBI reconstitution suppressed the cell growth, migration and invasion of the osteosarcoma cell lines SAOS2 and MG63. Alterations to the epithelial-to-mesenchymal transition (EMT) marker expression were observed in BAMBI-treated osteosarcoma SAOS2 and MG63 cells. The apoptosis rate of SAOS2 and MG63 cells induced by cisplatin were increased in BAMBI-treated osteosarcoma SAOS2 and MG63 cells via downregulation of the anti-apoptosis genes P16, P21 and B-cell lymphoma 2. The potential mechanism investigated indicated that BAMBI administration downregulated the transforming growth factor-β (TGF-β) signaling pathway, whilst knockdown of BAMBI upregulated the TGF-β signaling pathway in SAOS2 and MG63 cells. Reconstitution of BAMBI in SAOS2 and MG63 cells resulted in a notable reduction of TGF-β-induced EMT, cell growth, migration and invasion in vitro. In conclusion, the results demonstrated that BAMBI reconstitution inhibited growth and invasiveness of osteosarcoma, as well as promoted the apoptotic sensibility, which indicated that the TGF-β-induced EMT signaling pathway may be regarded as a potential target for osteosarcoma therapy.
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Affiliation(s)
- Fengsong Liu
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Kai Wang
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Liang Zhang
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Ya-Lin Yang
- Department of Orthopedics, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
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29
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Sun Y, Jiang X, Lu Y, Zhu J, Yu L, Ma B, Zhang Q. Oridonin prevents epithelial-mesenchymal transition and TGF-β1-induced epithelial-mesenchymal transition by inhibiting TGF-β1/Smad2/3 in osteosarcoma. Chem Biol Interact 2018; 296:57-64. [PMID: 30243739 DOI: 10.1016/j.cbi.2018.09.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 08/02/2018] [Accepted: 09/18/2018] [Indexed: 01/08/2023]
Abstract
Osteosarcoma is the most common primary bone tumor with highly invasive characteristic and low long-term survival. Recently, epithelial-mesenchymal transition (EMT) is reported as a key event in cancer invasion and metastasis. Oridonin, a bioactive diterpenoid, has been proved to possess anti-cancer effects. However, the effect of oridonin on EMT and metastasis of osteosarcoma is unclear. In this study, we investigated the underlying mechanism of oridonin on EMT and metastasis of osteosarcoma. We found that oridonin inhibited migration and invasion of MG-63 and 143B cells. Moreover, oridonin increased the protein expression of E-cadherin and decreased that of N-cadherin and Vimentin. Oridonin upregulated the transcription of E-cadherin and downregulated N-cadherin and Vimentin. Oridonin inhibited the protein and mRNA levels of Snail and Slug. Furthermore, oridonin inhibited TGF-β-induced phosphorylation of Smad 2/3, prevented Smad dimer translocation into the nucleus. Finally, we established metastatic models of osteosarcoma 143B cells, and found that oridonin inhibited lung metastasis in vivo. Oridonin increased the protein expression of E-cadherin and reduced N-cadherin and Vimentin. Oridonin inhibited the protein expression of Snail and Slug as well as Smad 2/3 activation. In conclusion, our study demonstrated that oridonin inhibited EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma.
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Affiliation(s)
- Yang Sun
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing, 211816, PR China.
| | - Xiubo Jiang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing, 211816, PR China
| | - Ying Lu
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing, 211816, PR China
| | - Jianwei Zhu
- Key Laboratory of Flexible Electronics (KLOFE), Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing, 211816, PR China
| | - Lisha Yu
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing, 211816, PR China
| | - Bo Ma
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing, 211816, PR China
| | - Qi Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing, 211816, PR China.
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30
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Du L, Han XG, Tu B, Wang MQ, Qiao H, Zhang SH, Fan QM, Tang TT. CXCR1/Akt signaling activation induced by mesenchymal stem cell-derived IL-8 promotes osteosarcoma cell anoikis resistance and pulmonary metastasis. Cell Death Dis 2018; 9:714. [PMID: 29915309 PMCID: PMC6006172 DOI: 10.1038/s41419-018-0745-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 04/23/2018] [Accepted: 05/29/2018] [Indexed: 12/17/2022]
Abstract
The loss of appropriate cell adhesion normally induces apoptosis via a process termed anoikis. The aim of this study was to investigate the effects of mesenchymal stem cells (MSCs) in the cancer microenvironment on the anoikis resistance and pulmonary metastasis of osteosarcoma (OS) cells, and to evaluate the critical role of the interleukin (IL)-8/C-X-C chemokine receptor (CXCR) 1/Akt-signaling pathway in these processes. Metastatic OS subtype cells, which did or did not interact with MSC-conditioned medium (MSC-CM) in vitro, were isolated from the pulmonary site and named Saos2-lung-M. Both MSC-CM and IL-8 treatment increased the anoikis resistance of Saos2 cells in vitro. Moreover, exogenous MSC-CM promoted the survival and metastasis of Saos2 cells in nude mice. Saos2-lung-M cells were more malignant and resistant to anoikis than parental cells. MSCs secreted IL-8, thereby protecting OS cells from anoikis. Blocking the IL-8/CXCR1/Akt pathway via CXCR1 knockdown inhibited the pulmonary metastasis of Saos2-lung-MSCs and prolonged the survival of tumor-bearing mice. In conclusion, MSCs enhanced OS cell resistance to anoikis and pulmonary metastasis via regulation of the IL-8/CXCR1/Akt pathway. These findings suggest that MSCs can “select for” OS cells with high metastatic potential in vivo, and highlight CXCR1 as a key target in the regulation of pulmonary metastasis of OS cells.
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Affiliation(s)
- Lin Du
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Orthopaedic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiu-Guo Han
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Tu
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Min-Qi Wang
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Han Qiao
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shu-Hong Zhang
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi-Ming Fan
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ting-Ting Tang
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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31
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Pietrovito L, Leo A, Gori V, Lulli M, Parri M, Becherucci V, Piccini L, Bambi F, Taddei ML, Chiarugi P. Bone marrow-derived mesenchymal stem cells promote invasiveness and transendothelial migration of osteosarcoma cells via a mesenchymal to amoeboid transition. Mol Oncol 2018. [PMID: 29517849 PMCID: PMC5928379 DOI: 10.1002/1878-0261.12189] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
There is growing evidence to suggest that bone marrow‐derived mesenchymal stem cells (BM‐MSCs) are key players in tumour stroma. Here, we investigated the cross‐talk between BM‐MSCs and osteosarcoma (OS) cells. We revealed a strong tropism of BM‐MSCs towards these tumour cells and identified monocyte chemoattractant protein (MCP)‐1, growth‐regulated oncogene (GRO)‐α and transforming growth factor (TGF)‐β1 as pivotal factors for BM‐MSC chemotaxis. Once in contact with OS cells, BM‐MSCs trans‐differentiate into cancer‐associated fibroblasts, further increasing MCP‐1, GRO‐α, interleukin (IL)‐6 and IL‐8 levels in the tumour microenvironment. These cytokines promote mesenchymal to amoeboid transition (MAT), driven by activation of the small GTPase RhoA, in OS cells, as illustrated by the in vitro assay and live imaging. The outcome is a significant increase of aggressiveness in OS cells in terms of motility, invasiveness and transendothelial migration. In keeping with their enhanced transendothelial migration abilities, OS cells stimulated by BM‐MSCs also sustain migration, invasion and formation of the in vitro capillary network of endothelial cells. Thus, BM‐MSC recruitment to the OS site and the consequent cytokine‐induced MAT are crucial events in OS malignancy.
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Affiliation(s)
- Laura Pietrovito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Angela Leo
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Valentina Gori
- Transfusion Medicine and Cell Therapy, Meyer Children's Hospital, Florence, Italy
| | - Matteo Lulli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Matteo Parri
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
| | - Valentina Becherucci
- Transfusion Medicine and Cell Therapy, Meyer Children's Hospital, Florence, Italy
| | - Luisa Piccini
- Transfusion Medicine and Cell Therapy, Meyer Children's Hospital, Florence, Italy
| | - Franco Bambi
- Transfusion Medicine and Cell Therapy, Meyer Children's Hospital, Florence, Italy
| | | | - Paola Chiarugi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
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32
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Zheng Y, Wang G, Chen R, Hua Y, Cai Z. Mesenchymal stem cells in the osteosarcoma microenvironment: their biological properties, influence on tumor growth, and therapeutic implications. Stem Cell Res Ther 2018; 9:22. [PMID: 29386041 PMCID: PMC5793392 DOI: 10.1186/s13287-018-0780-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
During tumorigenesis and development, participation of the tumor microenvironment is not negligible. As an important component in the tumor microenvironment, mesenchymal stem cells (MSCs) have been corroborated to mediate proliferation, metastasis, and drug resistance in many cancers, including osteosarcoma. What’s more, because of tumor site tropism, MSCs can be engineered to be loaded with therapeutic agents so that drugs can be precisely delivered to tumor lesions. In this review, we mainly discuss recent advances concerning the functions of MSCs in osteosarcoma and their possible clinical applications in the future.
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Affiliation(s)
- Ying Zheng
- Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road Shanghai, Shanghai, China
| | - Gangyang Wang
- Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road Shanghai, Shanghai, China.
| | - Ruiling Chen
- Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road Shanghai, Shanghai, China
| | - Yingqi Hua
- Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road Shanghai, Shanghai, China.
| | - Zhengdong Cai
- Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road Shanghai, Shanghai, China.
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33
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Papaccio F, Paino F, Regad T, Papaccio G, Desiderio V, Tirino V. Concise Review: Cancer Cells, Cancer Stem Cells, and Mesenchymal Stem Cells: Influence in Cancer Development. Stem Cells Transl Med 2017; 6:2115-2125. [PMID: 29072369 PMCID: PMC5702541 DOI: 10.1002/sctm.17-0138] [Citation(s) in RCA: 212] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 10/04/2017] [Indexed: 12/21/2022] Open
Abstract
Tumors are composed of different types of cancer cells that contribute to tumor heterogeneity. Among these populations of cells, cancer stem cells (CSCs) play an important role in cancer initiation and progression. Like their stem cells counterpart, CSCs are also characterized by self-renewal and the capacity to differentiate. A particular population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into cells of mesodermal characteristics. Several studies have reported the potential pro-or anti-tumorigenic influence of MSCs on tumor initiation and progression. In fact, MSCs are recruited to the site of wound healing to repair damaged tissues, an event that is also associated with tumorigenesis. In other cases, resident or migrating MSCs can favor tumor angiogenesis and increase tumor aggressiveness. This interplay between MSCs and cancer cells is fundamental for cancerogenesis, progression, and metastasis. Therefore, an interesting topic is the relationship between cancer cells, CSCs, and MSCs, since contrasting reports about their respective influences have been reported. In this review, we discuss recent findings related to conflicting results on the influence of normal and CSCs in cancer development. The understanding of the role of MSCs in cancer is also important in cancer management. Stem Cells Translational Medicine 2017;6:2115-2125.
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Affiliation(s)
- Federica Papaccio
- Dipartimento Medico‐Chirurgico di Internistica Clinica e Sperimentale “F. Magrassi”, Università degli Studi della Campania ‘L. Vanvitelli’NaplesItaly
| | - Francesca Paino
- Dipartimento di Medicina Sperimentale, Sezione di Sezione di BiotecnologieIstologia Medica e Biologia Molecolare, Università degli Studi della Campania ‘L. Vanvitelli’NaplesItaly
| | - Tarik Regad
- The John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent UniversityNottinghamUnited Kingdom
- Dipartimento di Biochimica, Biofisica, e Patologia GeneraleUniversità degli Studi della Campania ‘L. Vanvitelli’NaplesItaly
| | - Gianpaolo Papaccio
- Dipartimento di Medicina Sperimentale, Sezione di Sezione di BiotecnologieIstologia Medica e Biologia Molecolare, Università degli Studi della Campania ‘L. Vanvitelli’NaplesItaly
| | - Vincenzo Desiderio
- Dipartimento di Medicina Sperimentale, Sezione di Sezione di BiotecnologieIstologia Medica e Biologia Molecolare, Università degli Studi della Campania ‘L. Vanvitelli’NaplesItaly
| | - Virginia Tirino
- Dipartimento di Medicina Sperimentale, Sezione di Sezione di BiotecnologieIstologia Medica e Biologia Molecolare, Università degli Studi della Campania ‘L. Vanvitelli’NaplesItaly
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34
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Decker AM, Cackowski FC, Jung Y, Taichman RS. Biochemical Changes in the Niche Following Tumor Cell Invasion. J Cell Biochem 2017; 118:1956-1964. [PMID: 27982511 PMCID: PMC5462852 DOI: 10.1002/jcb.25843] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 12/14/2016] [Indexed: 12/15/2022]
Abstract
Metastatic cancer is the leading cause of all cancer related deaths. Prostate cancer (PCa) metastasizes preferentially to the bone marrow, specifically within the endosteal niche. Endosteal cells secrete homing molecules that may recruit PCa cells to the bone marrow. Once there, the biochemical signature of this niche regulates PCa fate including cellular dormancy or cell cycle arrest, reactivation and resistance to chemotherapeutics. Growth factors, interleukins, adhesion molecules, as well as extra-cellular matrix proteins can collectively change the phenotype of PCa cells. Understanding the biochemical signature of endosteal niche parasitism by PCa is imperative for the establishment of new and innovative therapeutic strategies. This review seeks to summarize these important niche signatures and the potential therapeutic approaches to target metastatic PCa within the bone marrow hematopoietic stem cell (HSC) niche. J. Cell. Biochem. 118: 1956-1964, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- A M Decker
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan
| | - F C Cackowski
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan
| | - Y Jung
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan
| | - R S Taichman
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan
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35
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Cortini M, Avnet S, Baldini N. Mesenchymal stroma: Role in osteosarcoma progression. Cancer Lett 2017; 405:90-99. [PMID: 28774797 DOI: 10.1016/j.canlet.2017.07.024] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/19/2017] [Accepted: 07/23/2017] [Indexed: 12/21/2022]
Abstract
The initiation and progression of malignant tumors are supported by their microenvironment: cancer cells per se cannot explain growth and formation of the primary or metastasis, and a combination of proliferating tumor cells, cancer stem cells, immune cells mesenchymal stromal cells and/or cancer-associated fibroblasts all contribute to the tumor bulk. The interaction between these multiple players, under different microenvironmental conditions of biochemical and physical stimuli (i.e. oxygen tension, pH, matrix mechanics), regulates the production and biological activity of several soluble factors, extracellular matrix components, and extracellular vesicles that are needed for growth, maintenance, chemoresistance and metastatization of cancer. In osteosarcoma, a very aggressive cancer of young adults characterized by the extensive need for more effective therapies, this aspect has been only recently explored. In this view, we will discuss the role of stroma, with a particular focus on the mesenchymal stroma, contributing to osteosarcoma progression through inherent features for homing, neovascularization, paracrine cross-feeding, microvesicle secretion, and immune modulation, and also by responding to the changes of the microenvironment that are induced by tumor cells. The most recent advances in the molecular cues triggered by cytokines, soluble factors, and metabolites that are partially beginning to unravel the axis between stromal elements of mesenchymal origin and osteosarcoma cells, will be reviewed providing insights likely to be used for novel therapeutic approaches against sarcomas.
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Affiliation(s)
- Margherita Cortini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Sofia Avnet
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Nicola Baldini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
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Casado-Díaz A, Anter J, Müller S, Winter P, Quesada-Gómez JM, Dorado G. Transcriptomic analyses of the anti-adipogenic effects of oleuropein in human mesenchymal stem cells. Food Funct 2017; 8:1254-1270. [PMID: 28243663 DOI: 10.1039/c7fo00045f] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Extra virgin olive oil has positive effects on health. Oleuropein is a polyphenolic compound present in olive-tree leaves, fruits (olives) and olive oil. It is responsible for the relevant organoleptic and biological properties of olive oil, including antiadipogenic properties. Thus, the effects of oleuropein on the adipogenesis of human bone-marrow mesenchymal stem cells were studied by transcriptomics and differential gene-expression analyses. Oleuropein could upregulate expression of 60% of adipogenesis-repressed genes. Besides, it could activate signaling pathways such as Rho and β-catenin, maintaining cells at an undifferentiated stage. Our data suggest that mitochondrial activity is reduced by oleuropein, mostly during adipogenic differentiation. These results shed light on oleuropein activity on cells, with potential application as a "nutraceutical" for the prevention and treatment of diseases such as obesity and osteoporosis.
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Affiliation(s)
- Antonio Casado-Díaz
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain. and CIBER de Fragilidad y Envejecimiento Saludable, Spain
| | - Jaouad Anter
- Dep. Genética, Universidad de Córdoba, Campus Rabanales C5-1-O1, 14071 Córdoba, Spain
| | - Sören Müller
- GenXPro, Altenhoferallee 3, 60438 Frankfurt Main, Germany
| | - Peter Winter
- GenXPro, Altenhoferallee 3, 60438 Frankfurt Main, Germany
| | - José Manuel Quesada-Gómez
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain. and CIBER de Fragilidad y Envejecimiento Saludable, Spain
| | - Gabriel Dorado
- Dep. Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, 14071 Córdoba, Spain and CIBER de Fragilidad y Envejecimiento Saludable, Spain
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Li Y, Wu Q, Wang Y, Li L, Bu H, Bao J. Senescence of mesenchymal stem cells (Review). Int J Mol Med 2017; 39:775-782. [PMID: 28290609 DOI: 10.3892/ijmm.2017.2912] [Citation(s) in RCA: 183] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 01/13/2017] [Indexed: 02/05/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been used in cell-based therapy for various diseases, due to their immunomodulatory and inflammatory effects. However, the function of MSCs is known to decline with age, a process that is called senescence. To date, the process of MSC senescence remains unknown as in-depth understanding of the mechanisms involved in cellular senescence is lacking. First, senescent MSCs are so heterogeneous that not all of them express the same phenotypic markers. In addition, the genes and signaling pathways which regulate this process in MSCs are still unknown. Thus, an understanding of the molecular processes controlling MSC senescence is crucial to determining the drivers and effectors of age-associated MSC dysfunction. Moreover, the proper use of MSCs for clinical application requires a general understanding of the MSC aging process. Furthermore, such knowledge is essential for the development of therapeutic interventions that can slow or reverse age-related degenerative changes to enhance repair processes and maintain healthy function in aging tissues. To further clarify the properties of senescent cells, as well as to present significant findings from studies on the mechanisms of cellular aging, we summarize these biological features in the senescence of MSCs in this scenario. This review summarizes recent advances in our understanding of the markers and differentiation potential indicating MSC senescence, as well as factors affecting MSC senescence with particular emphasis on the roles of oxidative stress, intrinsic changes in telomere shortening, histone deacetylase and DNA methyltransferase, genes and signaling pathways and immunological properties.
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Affiliation(s)
- Yi Li
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qiong Wu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yujia Wang
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Li Li
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hong Bu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Ji Bao
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Heng L, Jia Z, Bai J, Zhang K, Zhu Y, Ma J, Zhang J, Duan H. Molecular characterization of metastatic osteosarcoma: Differentially expressed genes, transcription factors and microRNAs. Mol Med Rep 2017; 15:2829-2836. [DOI: 10.3892/mmr.2017.6286] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 01/09/2017] [Indexed: 11/05/2022] Open
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JianPi JieDu Recipe Inhibits Epithelial-to-Mesenchymal Transition in Colorectal Cancer through TGF- β/Smad Mediated Snail/E-Cadherin Expression. BIOMED RESEARCH INTERNATIONAL 2017; 2017:2613198. [PMID: 28299321 PMCID: PMC5337333 DOI: 10.1155/2017/2613198] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 12/28/2016] [Accepted: 01/19/2017] [Indexed: 11/17/2022]
Abstract
JPJD was an ideal alternative traditional Chinese medicine compound in the prevention and treatment of CRC, but its underlying mechanisms has not been fully elucidated. In this study, we demonstrated in vitro that TGF-β-induced EMT promoted the invasion and metastasis of CRC cells, reduced the expression of E-cadherin, and elevated the expression of Vimentin. However, JPJD could inhibit the invasive and migratory ability of TGF-β-stimulated CRC cells in a concentration-dependent manner through increasing the expression of E-cadherin and repressing the expression of Vimentin, as well as the inhibition of TGF-β/Smad signaling pathway. Meanwhile, JPJD reduced the transcriptional activities of EMT-associated factors Snail and E-cadherin during the initiation of TGF-β-induced EMT. In vivo, the results demonstrated that JPJD can significantly inhibit the liver and lung metastasis of orthotopic CRC tumor in nude mice, as well as significantly prolonging the survival time of tumor-bearing in a dose-dependent manner. Additionally, JPJD can upregulate the expression of E-cadherin and Smad2/3 in the cytoplasm and downregulate the expression of Vimentin, p-Smad2/3, and Snail in the orthotopic CRC tumor tissues. In conclusions, our new findings provided evidence that JPJD could inhibit TGF-β-induced EMT in CRC through TGF-β/Smad mediated Snail/E-cadherin expression.
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Cortini M, Massa A, Avnet S, Bonuccelli G, Baldini N. Tumor-Activated Mesenchymal Stromal Cells Promote Osteosarcoma Stemness and Migratory Potential via IL-6 Secretion. PLoS One 2016; 11:e0166500. [PMID: 27851822 PMCID: PMC5112800 DOI: 10.1371/journal.pone.0166500] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 10/28/2016] [Indexed: 12/20/2022] Open
Abstract
Osteosarcoma (OS) is an aggressive bone malignancy with a high relapse rate despite combined treatment with surgery and multiagent chemotherapy. As for other cancers, OS-associated microenvironment may contribute to tumor initiation, growth, and metastasis. We consider mesenchymal stromal cells (MSC) as a relevant cellular component of OS microenvironment, and have previously found that the interaction between MSC and tumor cells is bidirectional: tumor cells can modulate their peripheral environment that in turn becomes more favorable to tumor growth through metabolic reprogramming. Here, we determined the effects of MSC on OS stemness and migration, two major features associated with recurrence and chemoresistance. The presence of stromal cells enhanced the number of floating spheres enriched in cancer stem cells (CSC) of the OS cell population. Furthermore, the co-culturing with MSC stimulated the migratory capacity of OS via TGFβ1 and IL-6 secretion, and the neutralizing antibody anti-IL-6 impaired this effect. Thus, stromal cells in combination with OS spheres exploit a vicious cycle where the presence of CSC stimulates mesenchymal cytokine secretion, which in turn increases stemness, proliferation, migration, and metastatic potential of CSC, also through the increase of expression of adhesion molecules like ICAM-1. Altogether, our data corroborate the concept that a comprehensive knowledge of the interplay between tumor and stroma that also includes the stem-like fraction of tumor cells is needed to develop novel and effective anti-cancer therapies.
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Affiliation(s)
- Margherita Cortini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli (IOR), 40136, Bologna, Italy
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126, Bologna, Italy
| | - Annamaria Massa
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli (IOR), 40136, Bologna, Italy
| | - Sofia Avnet
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli (IOR), 40136, Bologna, Italy
| | - Gloria Bonuccelli
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli (IOR), 40136, Bologna, Italy
| | - Nicola Baldini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, Istituto Ortopedico Rizzoli (IOR), 40136, Bologna, Italy
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126, Bologna, Italy
- * E-mail:
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Vallabhaneni KC, Hassler MY, Abraham A, Whitt J, Mo YY, Atfi A, Pochampally R. Mesenchymal Stem/Stromal Cells under Stress Increase Osteosarcoma Migration and Apoptosis Resistance via Extracellular Vesicle Mediated Communication. PLoS One 2016; 11:e0166027. [PMID: 27812189 PMCID: PMC5094708 DOI: 10.1371/journal.pone.0166027] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 10/21/2016] [Indexed: 12/11/2022] Open
Abstract
Studies have shown that mesenchymal stem/stromal cells (MSCs) from bone marrow are involved in the growth and metastasis of solid tumors but the mechanism remains unclear in osteosarcoma (OS). Previous studies have raised the possibility that OS cells may receive support from associated MSCs in the nutrient deprived core of the tumors through the release of supportive macromolecules and growth factors either in vesicular or non-vesicular forms. In the present study, we used stressed mesenchymal stem cells (SD-MSCs), control MSCs and OS cells to examine the hypothesis that tumor-associated MSCs in nutrient deprived core provide pro-proliferative, anti-apoptotic, and metastatic support to nearby tumor cells. Assays to study of the effects of SD-MSC conditioned media revealed that OS cells maintained proliferation when compared to OS cells grown under serum-starved conditions alone. Furthermore, OS cells in MSCs and SD-MSC conditioned media were significantly resistant to apoptosis and an increased wound healing rate was observed in cells exposed to either conditioned media or EVs from MSCs and SD-MSCs. RT-PCR assays of OS cells incubated with extracellular vesicles (EVs) from SD-MSCs revealed microRNAs that could potentially target metabolism and metastasis associated genes as predicted by in silico algorithms, including monocarboxylate transporters, bone morphogenic receptor type 2, fibroblast growth factor 7, matrix metalloproteinase-1, and focal adhesion kinase-1. Changes in the expression levels of focal adhesion kinase, STK11 were confirmed by quantitative PCR assays. Together, these data indicate a tumor supportive role of MSCs in osteosarcoma growth that is strongly associated with the miRNA content of the EVs released from MSCs under conditions that mimic the nutrient deprived core of solid tumors.
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Affiliation(s)
- Krishna C. Vallabhaneni
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America
- Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Meeves-Yoni Hassler
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Anu Abraham
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Jason Whitt
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Yin-Yuan Mo
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America
- Department of Pharmacology-Toxicology, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Azeddine Atfi
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America
- Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Radhika Pochampally
- Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America
- Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, United States of America
- * E-mail:
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Mao CY, Wang YG, Zhang X, Zheng XY, Tang TT, Lu EY. Double-edged-sword effect of IL-1β on the osteogenesis of periodontal ligament stem cells via crosstalk between the NF-κB, MAPK and BMP/Smad signaling pathways. Cell Death Dis 2016; 7:e2296. [PMID: 27415426 PMCID: PMC4973347 DOI: 10.1038/cddis.2016.204] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 06/11/2016] [Accepted: 06/14/2016] [Indexed: 02/08/2023]
Abstract
Microenvironmental conditions can interfere with the functional role and differentiation of mesenchymal stem cells (MSCs). Recent studies suggest that an inflammatory microenvironment can significantly impact the osteogenic potential of periodontal ligament stem cells (PDLSCs), but the precise effects and mechanisms involved remain unclear. Here, we show for the first time that interleukin-1β (IL-1β) has dual roles in the osteogenesis of PDLSCs at concentrations ranging from physiologically healthy levels to those found in chronic periodontitis. Low doses of IL-1β activate the BMP/Smad signaling pathway to promote the osteogenesis of PDLSCs, but higher doses of IL-1β inhibit BMP/Smad signaling through the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, inhibiting osteogenesis. These results demonstrate that crosstalk between NF-κB, MAPK and BMP/Smad signaling mediates this dual effect of IL-1β on PDLSCs. We also show that the impaired osteogenesis of PDLSCs results in more inflammatory cytokines and chemokines being released, inducing the chemotaxis of macrophages, which further clarifies the role of PDLSCs in the pathogenesis of periodontitis.
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Affiliation(s)
- C-Y Mao
- Department of Prosthodontics, Shanghai Key Laboratory of Stomatology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai, China
| | - Y-G Wang
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai, China
| | - X Zhang
- Department of Prosthodontics, Shanghai Key Laboratory of Stomatology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai, China
| | - X-Y Zheng
- Department of Prosthodontics, Shanghai Key Laboratory of Stomatology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai, China
| | - T-T Tang
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedics Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai, China
| | - E-Y Lu
- Department of Prosthodontics, Shanghai Key Laboratory of Stomatology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, 639 Zhizaoju Road, Shanghai, China
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Suda Y, Neri S, Hashimoto H, Higuchi Y, Ishibashi M, Sugano M, Masutomi K, Tsuboi M, Ochiai A, Ishii G. Clonal heterogeneity in osteogenic potential of lung cancer-associated fibroblasts: promotional effect of osteogenic progenitor cells on cancer cell migration. J Cancer Res Clin Oncol 2016; 142:1487-98. [PMID: 27119516 DOI: 10.1007/s00432-016-2171-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 04/18/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND Cancer-associated fibroblasts (CAFs) consist of heterogeneous cell population in terms of their differentiation potential. The functional differences in tumor progression between CAFs with mesenchymal stem/progenitor cells (MSCs/MPCs) characteristics and CAFs without MSCs/MPCs characteristics are not clarified. METHODS CAFs and vascular adventitial fibroblasts (VAFs, which contain MSCs/MPCs) were isolated from nine primary lung cancers and were cultured in osteogenic or adipogenic medium to assess their multi-lineage differentiation. Next, we established nine single-cell-derived clones from the primary culture of CAFs and examined their differentiation potential. The effects of each single-cell-derived clone on the proliferation and migration of lung adenocarcinoma cell line, A549, were analyzed. RESULTS The nine samples of VAFs and CAFs showed various degrees of osteogenic differentiation. Although the VAFs displayed the ability to undergo adipogenic differentiation, all cases of the CAFs did not. CAFs clones presented varying degrees of osteogenic differentiation. Four clones displayed comparable levels of osteogenic potential with that of the VAFs, and two clones were completely negative. As compared to the CAFs clones that possessed lower osteogenic potential, CAFs clones with higher osteogenic potential did not confer proliferative activity in A549 cells. On the contrary, these clones significantly promoted the migration of A549 cells as compared to the clones with lower osteogenic potential. CONCLUSION Our studies clearly indicate that CAFs derived from lung cancer are heterogeneous population that consists of cells with varying osteogenic potentials and that CAFs with higher osteogenic potential have a greater tumor-promoting function through the enhancement of cancer cell migration.
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Affiliation(s)
- Yoshitaka Suda
- Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Shinya Neri
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Hiroko Hashimoto
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Youichi Higuchi
- Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Masayuki Ishibashi
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Masato Sugano
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Kenkichi Masutomi
- Division of Cancer Stem Cell, National Cancer Center Research Institute, Tsukiji, Tokyo, Japan
| | - Masahiro Tsuboi
- Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Atsushi Ochiai
- Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Genichiro Ishii
- Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
- Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
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Guo Y, Chen YH, Cheng ZH, Ou-Yang HN, Luo C, Guo ZL. Tectorigenin inhibits osteosarcoma cell migration through downregulation of matrix metalloproteinases in vitro. Anticancer Drugs 2016; 27:540-6. [PMID: 26991068 PMCID: PMC4881729 DOI: 10.1097/cad.0000000000000362] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Accepted: 02/22/2016] [Indexed: 01/30/2023]
Abstract
Tectorigenin (Tec) is an effective component of the traditional Chinese medicine Belamcanda chinensis, which has been reported to exert beneficial effects in various types of cancer. However, the activity and mechanism of Tec in osteosarcoma (OS) have not been investigated to date. The aim of the present study was to examine the inhibitory effect of Tec on OS and its underlying mechanism of action. OS cells (Saos2 and U2OS) were treated with various concentrations of Tec for 24, 48, and 72 h. Cell proliferation was evaluated using an CCK-8 assay. Cell migration and invasion ability were measured using the Transwell assay. The expressions of MMP1, MMP2, MMP9, and cleaved caspase3 were measured using real-time PCR and/or western blot analysis. We found that Tec inhibited the proliferation of OS cells (Saos2 and U2OS) in a dose-dependent and time-dependent manner. In addition, Tec significantly inhibited migration and invasion in OS cells (P<0.05). Tec upregulated the expression of cleaved caspase3, while downregulating the expression of MMP1, MMP2, and MMP9. Taken together, the present study provided fundamental evidence for the application of Tec in chemotherapy against OS.
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Affiliation(s)
- Yu Guo
- Departments of aNeurosurgery bPlastic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Wu T, Chen JM, Xiao TG, Shu XB, Xu HC, Yang LL, Xing LJ, Zheng PY, Ji G. Qinggan Huoxue Recipe suppresses epithelial-to-mesenchymal transition in alcoholic liver fibrosis through TGF-β1/Smad signaling pathway. World J Gastroenterol 2016; 22:4695-4706. [PMID: 27217701 PMCID: PMC4870076 DOI: 10.3748/wjg.v22.i19.4695] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 03/03/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mechanism by which Qinggan Huoxue Recipe (QGHXR) inhibits epithelial-to-mesenchymal transition (EMT) in rats with alcoholic liver fibrosis (ALF).
METHODS: A total of 75 male SD rats were used to induce ALF. Serum biochemical indicators, including alanine aminotransferase, aspartate aminotransferase, laminin and hyaluronidase, were measured. Liver histopathological changes were evaluated using hematoxylin-eosin and Sirius red staining. EMT was examined by analyzing the expression of the epithelial marker E-cadherin and the mesenchymal markers vimentin and fibronectin using RT-PCR and Western blot. The inhibitory effect of QGHXR on EMT markers, as well as its effect on molecules associated with the transforming growth factor (TGF)-β1/Smad signaling pathway, including TGF-β1, Smad3, snail, occludin, ZO-1 and claudin, was also examined.
RESULTS: Compared with normal control rats, ALF rats exhibited a decrease in E-cadherin levels (mRNA: ALF 0.16 ± 0.05 vs control 1.00 ± 0.08; protein: ALF 0.09 ± 0.05 vs control 0.70 ± 0.17, P < 0.01) and an increase in vimentin and fibronectin levels (mRNA: 11.43 ± 0.39 vs 1.00 ± 0.19 and 9.91 ± 0.34 vs 1.00 ± 0.44, respectively, P < 0.01; protein: 1.13 ± 0.42 vs 0.09 ± 0.03 and 1.16 ± 0.43 vs 0.09 ± 0.00, respectively, P < 0.01). This indicates that EMT occurred in ALF rats. In addition, the TGF-β1/Smad signaling pathway was activated in ALF rats, as evidenced by the increase in TGF-β1 and snail levels (mRNA: 1.76 ± 0.12 vs 1.00 ± 0.05 and 6.98 ± 0.41 vs 1.00 ± 0.10, respectively, P < 0.01; protein: 1.43 ± 0.05 vs 0.12 ± 0.03 and 1.07 ± 0.29 vs 0.07 ± 0.02, respectively, P < 0.01) and the decrease in Smad3 levels (mRNA: 0.05 ± 0.01 vs 1.00 ± 0.12, P < 0.01; protein: 0.06 ± 0.05 vs 0.89 ± 0.12, P < 0.01). Furthermore, levels of the tight junction markers occludin, ZO-1 and claudin decreased in ALF rats compared with healthy control rats (mRNA: 0.60 ± 0.09 vs 1.00 ± 0.12, 0.11 ± 0.00 vs 1.00 ± 0.12 and 0.60 ± 0.01 vs 1.00 ± 0.08, respectively, P < 0.01; protein: 0.05 ± 0.01 vs 0.87 ± 0.40, 0.09 ± 0.05 vs 0.89 ± 0.18 and 0.04 ± 0.03 vs 0.95 ± 0.21, respectively, P < 0.01). In ALF rats treated with QGHXR, E-cadherin levels increased (mRNA: QGHXR 0.67 ± 0.04 vs ALF model 0.16 ± 0.05, P < 0.01; protein: QGHXR 0.66 ± 0.21 vs ALF model 0.09 ± 0.05, P < 0.01), and vimentin and fibronectin levels decreased (mRNA: 6.57 ± 1.05 vs 11.43 ± 0.39 and 1.45 ± 1.51 vs 9.91 ± 0.34, respectively, P < 0.01; protein: 0.09 ± 0.03 vs 1.13 ± 0.42 and 0.10 ± 0.01 vs 1.16 ± 0.43, respectively, P < 0.01). In addition, QGHXR inhibited the expression of TGF-β1 and increased the expression of Smad3 (mRNA: 1.03 ± 0.11 vs 1.76 ± 0.12, 0.70 ± 0.10 vs 0.05 ± 0.01, respectively, P < 0.05 and P < 0.01; protein: 0.12 ± 0.03 vs 1.43 ± 0.05 and 0.88 ± 0.20 vs 0.06 ± 0.05, respectively, P < 0.01). QGHXR treatment also reduced the levels of the EMT-inducing transcription factor snail (mRNA: 2.28 ± 0.33 vs 6.98 ± 0.41, P < 0.01; protein: 0.08 ± 0.02 vs 1.07 ± 0.29, P < 0.01) and increased the occludin, ZO-1 and claudin levels (mRNA: 0.73 ± 0.05 vs 0.60 ± 0.09, 0.57 ± 0.04 vs 0.11 ± 0.00 and 0.68 ± 0.03 vs 0.60 ± 0.01, respectively, P < 0.01, P < 0.01 and P < 0.05; protein: 0.92 ± 0.50 vs 0.05 ± 0.01, 0.94 ± 0.22 vs 0.09 ± 0.05 and 0.94 ± 0.29 vs 0.04 ± 0.03, respectively, P < 0.01). The effects of QGR and HXR on the TGF-β1/Smad signaling pathway were similar to that of QGHXR; however, the QGR- and HXR-induced changes in vimentin mRNA levels, the QGR-induced changes in fibronectin mRNA levels and the HXR-induced changes in snail and TGF-β1 mRNA levels were not significant.
CONCLUSION: Qinggan Huoxue Recipe inhibits EMT in ALF rats by modulating the TGF-β1/Smad signaling pathway, suggesting that the mechanism underlying the amelioration of ALF induced by QGHXR is associated with this pathway.
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Yan GN, Lv YF, Guo QN. Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets. Cancer Lett 2016; 370:268-74. [DOI: 10.1016/j.canlet.2015.11.003] [Citation(s) in RCA: 119] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 11/03/2015] [Accepted: 11/03/2015] [Indexed: 12/15/2022]
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Macrophages derived from THP-1 promote the osteogenic differentiation of mesenchymal stem cells through the IL-23/IL-23R/β-catenin pathway. Exp Cell Res 2015; 339:81-9. [PMID: 26477825 DOI: 10.1016/j.yexcr.2015.10.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 10/11/2015] [Accepted: 10/12/2015] [Indexed: 01/29/2023]
Abstract
Abnormal bone formation is a clinically significant dilemma for many conditions in response to injury, inflammation or genetic disease. However, the effects of inflammation on the osteogenic differentiation of mesenchymal stem cells (MSCs) remain unclear. IL-23 secretion from macrophages might contribute to the development of bone formation. Here, we investigated the stimulatory effects of THP-1 macrophage conditioned medium (MΦ CM) on the osteogenic differentiation of human MSCs and the associated signaling pathways. The osteogenic differentiation of MSCs was induced after exposure to osteogenic differentiation medium (OM). MΦ CM significantly increased alkaline phosphate (ALP) activity and calcium mineralization in MSCs. Osteogenic marker genes, including RUNX2, ALP and osteocalcin (OCN), were also up-regulated in MSCs after exposure to MΦ CM. Moreover, western blotting revealed that MΦ CM treatment induced STAT3 and β-catenin activation in MSCs. Furthermore, blockade of IL-23 in MΦ CM not only impaired the osteogenic-promotion effects of macrophage but also decreased the expression of osteogenic maker genes. However, IL-23R silencing suppressed MΦ CM-induced calcium mineralization and osteogenic maker gene expression in MSCs. These data suggest that macrophages derived from THP-1 promote the osteoblastic differentiation of MSCs through the IL-23/IL-23R/β-catenin pathway and macrophages might contribute to the development of bone formation in inflammation.
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García-Rocha R, Moreno-Lafont M, Mora-García ML, Weiss-Steider B, Montesinos JJ, Piña-Sánchez P, Monroy-García A. Mesenchymal stromal cells derived from cervical cancer tumors induce TGF-β1 expression and IL-10 expression and secretion in the cervical cancer cells, resulting in protection from cytotoxic T cell activity. Cytokine 2015; 76:382-390. [PMID: 26343835 DOI: 10.1016/j.cyto.2015.09.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 08/19/2015] [Accepted: 09/01/2015] [Indexed: 12/31/2022]
Abstract
Cervical cancer (CeCa) tumors are characterized by increased expression of TGF-β1 and IL-10, which are correlated with downregulated expression of major histocompatibility complex class I antigens (HLA-I) on cancer cells and a reduced immune response mediated by cytotoxic T lymphocytes (CTLs). Mesenchymal stromal cells (MSCs) are important components in the tumor microenvironment that have been suggested to contribute to cancer progression through the induction of TGF-β1 and IL-10. In this study, we provided evidence that MSCs derived from cervical tumors (CeCa-MSCs) cocultured with CeCa cells induced significant expression of TGF-β1 and secretion of IL-10 by CeCa cells compared to MSCs derived from the normal cervix (NCx-MSCs) and normal bone marrow (BM-MSCs; gold standard). This increase in expression was associated with a significant downregulation of HLA-I molecules and protection of the cells against specific CTL lysis. Interestingly, the addition of the neutralizing antibody anti-TGF-β to the CeCa/CeCa-MSCs coculture strongly inhibited the expression and production of IL-10 by CeCa cells. Anti-TGF-β as well as anti-IL-10 also abolished HLA-I downregulation, and reversed the inhibition of CTL cytotoxicity. These results provide evidence that TGF-β1 and IL-10 could play an important role in the downregulation of HLA-I molecules on CeCa cells induced by tumor MSCs. Our findings suggest a novel mechanism through which MSCs may protect tumor cells from immune recognition by specific CTLs.
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Affiliation(s)
- R García-Rocha
- Laboratorio de Inmunología y Cáncer, UIMEO CMN S.XXI, IMSS, México, D.F., Mexico; Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, México, D.F., Mexico
| | - M Moreno-Lafont
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN, México, D.F., Mexico
| | - M L Mora-García
- Laboratorio de Inmunobiología FES-Zaragoza, UNAM, México, D.F., Mexico
| | - B Weiss-Steider
- Laboratorio de Inmunobiología FES-Zaragoza, UNAM, México, D.F., Mexico
| | - J J Montesinos
- Laboratorio de Células Troncales Mesenquimales, UIMEO CMN S.XXI, IMSS, México, D.F., Mexico
| | - P Piña-Sánchez
- Laboratorio de Oncología Molecular, UIMEO CMN S.XXI, IMSS, México, D.F., Mexico
| | - A Monroy-García
- Laboratorio de Inmunología y Cáncer, UIMEO CMN S.XXI, IMSS, México, D.F., Mexico; Laboratorio de Inmunobiología FES-Zaragoza, UNAM, México, D.F., Mexico.
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Alfranca A, Martinez-Cruzado L, Tornin J, Abarrategi A, Amaral T, de Alava E, Menendez P, Garcia-Castro J, Rodriguez R. Bone microenvironment signals in osteosarcoma development. Cell Mol Life Sci 2015; 72:3097-113. [PMID: 25935149 PMCID: PMC11113487 DOI: 10.1007/s00018-015-1918-y] [Citation(s) in RCA: 138] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 04/24/2015] [Accepted: 04/27/2015] [Indexed: 02/06/2023]
Abstract
The bone is a complex connective tissue composed of many different cell types such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem/progenitor cells, hematopoietic cells and endothelial cells, among others. The interaction between them is finely balanced through the processes of bone formation and bone remodeling, which regulates the production and biological activity of many soluble factors and extracellular matrix components needed to maintain the bone homeostasis in terms of cell proliferation, differentiation and apoptosis. Osteosarcoma (OS) emerges in this complex environment as a result of poorly defined oncogenic events arising in osteogenic lineage precursors. Increasing evidence supports that similar to normal development, the bone microenvironment (BME) underlies OS initiation and progression. Here, we recapitulate the physiological processes that regulate bone homeostasis and review the current knowledge about how OS cells and BME communicate and interact, describing how these interactions affect OS cell growth, metastasis, cancer stem cell fate and therapy outcome.
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Affiliation(s)
- Arantzazu Alfranca
- Unidad de Biotecnología Celular, Área de Genética Humana, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Lucia Martinez-Cruzado
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, 33006 Oviedo, Spain
| | - Juan Tornin
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, 33006 Oviedo, Spain
| | - Ander Abarrategi
- Unidad de Biotecnología Celular, Área de Genética Humana, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
- Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, UK
| | - Teresa Amaral
- Molecular Pathology Program, Institute of Biomedical Research of Salamanca-Centro de Investigación del Cáncer, Centro de Investigación del Cáncer (IBSAL-CIC), Salamanca, Spain
- Department of Pathology and Biobank, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS), CSIC-Universidad de Sevilla, Seville, Spain
| | - Enrique de Alava
- Molecular Pathology Program, Institute of Biomedical Research of Salamanca-Centro de Investigación del Cáncer, Centro de Investigación del Cáncer (IBSAL-CIC), Salamanca, Spain
- Department of Pathology and Biobank, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS), CSIC-Universidad de Sevilla, Seville, Spain
| | - Pablo Menendez
- Cell Therapy Program, School of Medicine, Josep Carreras Leukemia Research Institute, University of Barcelona, Barcelona, Spain
- Instituciò Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain
| | - Javier Garcia-Castro
- Unidad de Biotecnología Celular, Área de Genética Humana, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Rene Rodriguez
- Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, 33006 Oviedo, Spain
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Ji Q, Liu X, Han Z, Zhou L, Sui H, Yan L, Jiang H, Ren J, Cai J, Li Q. Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC Cancer 2015; 15:97. [PMID: 25884904 PMCID: PMC4362662 DOI: 10.1186/s12885-015-1119-y] [Citation(s) in RCA: 153] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 02/24/2015] [Indexed: 12/02/2022] Open
Abstract
Background Resveratrol extracted from grape has been an ideal alternative drug in the therapy of different cancers including colorectal cancer (CRC). Since the underlying mechanisms of resveratrol on the invasion and metastasis of CRC have not been fully elucidated, and epithelial-to-mesenchymal transition (EMT) is a key process associated with the progression of CRC, here we aimed to investigate the potential mechanism of resveratrol on the inhibition of TGF-β1-induced EMT in CRC LoVo cells. Methods We investigated the anticancer effect of resveratrol against LoVo cells in vitro and in vivo. In vivo, the impact of resveratrol on invasion and metastasis was investigated by mice tail vein injection model and mice orthotopic transplantation tumor model. In vivo imaging was applied to observe the lungs metastases, and hemaoxylin-eosin (HE) staining was used to evaluate metastatic lesions. In vitro, impact of resveratrol on the migration and invasion of LoVo cells was evaluated by transwell assay. Inhibition effect of resveratrol on TGF-β-induced EMT was examined by morphological observation. Epithelial phenotype marker E-cadherin and mesenchymal phenotype marker Vimentin were detected by western blot and immunofluorescence. Promoter activity of E-cadherin was measured using a dual-luciferase assay kit. mRNA expression of Snail and E-cadherin was measured by RT-PCR. Results We demonstrated that, resveratrol inhibited the lung metastases of LoVo cells in vivo. In addition, resveratrol reduced the rate of lung metastases and hepatic metastases in mice orthotopic transplantation. In vitro, TGF-β1-induced EMT promoted the invasion and metastasis of CRC, reduced the E-cadherin expression and elevated the Vimentin expression, and activated the TGF-β1/Smads signaling pathway. But resveratrol could inhibit the invasive and migratory ability of LoVo cells in a concentration-dependent manner, increase the expression of E-cadherin, repress the expression of Vimentin, as well as the inhibition of TGF-β1/Smads signaling pathway. Meanwhile, resveratrol reduced the level of EMT-inducing transcription factors Snail and the transcription of E-cadherin during the initiation of TGF-β1-induced EMT. Conclusions Our new findings provided evidence that, resveratrol could inhibit EMT in CRC through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression, and this might the potential mechanism of resveratrol on the inhibition of invasion and metastases in CRC.
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Affiliation(s)
- Qing Ji
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. .,Research Center for Traditional Chinese Medicine and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Xuan Liu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Zhifen Han
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Lihong Zhou
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hua Sui
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Linlin Yan
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Haili Jiang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Jianlin Ren
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Department of Oncology, Shanghai, 200071, China.
| | - Jianfeng Cai
- Department of Chemistry, University of South Florida, Tampa, FL, 33620, USA.
| | - Qi Li
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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