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Lipreri MV, Totaro MT, Boos JA, Basile MS, Baldini N, Avnet S. A Novel Microfluidic Platform for Personalized Anticancer Drug Screening Through Image Analysis. MICROMACHINES 2024; 15:1521. [PMID: 39770275 PMCID: PMC11677617 DOI: 10.3390/mi15121521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/16/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025]
Abstract
The advancement of personalized treatments in oncology has garnered increasing attention, particularly for rare and aggressive cancer with low survival rates like the bone tumors osteosarcoma and chondrosarcoma. This study introduces a novel PDMS-agarose microfluidic device tailored for generating patient-derived tumor spheroids and serving as a reliable tool for personalized drug screening. Using this platform in tandem with a custom imaging index, we evaluated the impact of the anticancer agent doxorubicin on spheroids from both tumor types. The device produces 20 spheroids, each around 300 µm in diameter, within a 24 h timeframe, facilitating assessments of characteristics and reproducibility. Following spheroid generation, we measured patient-derived spheroid diameters in bright-field images, calcein AM-positive areas/volume, and the binary fraction area, a metric analyzing fluorescence intensity. By employing a specially developed equation that combines viability signal extension and intensity, we observed a substantial decrease in spheroid viability of around 75% for both sarcomas at the highest dosage (10 µM). Osteosarcoma spheroids exhibited greater sensitivity to doxorubicin than chondrosarcoma spheroids within 48 h. This approach provides a reliable in vitro model for aggressive sarcomas, representing a personalized approach for drug screening that could lead to more effective cancer treatments tailored to individual patients, despite some implementation challenges.
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Affiliation(s)
- Maria Veronica Lipreri
- Biomedical Science, Technologies, and Nanobiotecnology Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (M.V.L.)
| | - Marilina Tamara Totaro
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40138 Bologna, Italy;
| | - Julia Alicia Boos
- Bioengineering Laboratory, Department of Biosystems Science and Engineering, ETH Zürich, Klingelbergstrasse 48, 4056 Basel, Switzerland;
| | - Maria Sofia Basile
- Biomedical Science, Technologies, and Nanobiotecnology Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (M.V.L.)
| | - Nicola Baldini
- Biomedical Science, Technologies, and Nanobiotecnology Lab, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; (M.V.L.)
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40138 Bologna, Italy;
| | - Sofia Avnet
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40138 Bologna, Italy;
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2
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Zhu J, Wei R, Hu G, Wang H, Wang W, Wang H, Huang J, Wang Y, Li Y, Meng H. Development of Injectable Thermosensitive Nanocomposite Hydrogel for Ratiometric Drug Delivery to Treat Drug Resistant Chondrosarcoma In Vivo. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2310340. [PMID: 38456789 DOI: 10.1002/smll.202310340] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 02/26/2024] [Indexed: 03/09/2024]
Abstract
Chondrosarcoma(CS), a prevalent primary malignant bone tumor, frequently exhibits chemotherapy resistance attributed to upregulated anti-apoptosis pathways such as the Bcl-2 family. In this manuscript, a new strategy is presented to augment chemosensitivity and mitigate systemic toxicity by harnessing a nano-enabled drug delivery hydrogel platform. The platform utilizes "PLGA-PEG-PLGA", an amphiphilic triblock copolymer combining hydrophilic polyethylene glycol (PEG) and hydrophobic polylactide glycolide (PLGA) blocks, renowned for its properties conducive to crafting a biodegradable, temperature-sensitive hydrogel. This platform is tailored to encapsulate a ratiometrically designed dual-loaded liposomes containing a first-line chemo option for CS, Doxorubicin (Dox), plus a calculated amount of small molecule inhibitor for anti-apoptotic Bcl-2 pathway, ABT-737. In vitro and in vivo evaluations demonstrate successful Bcl-2 suppression, resulting in the restoration of Dox sensitivity, evident through impeded tumor growth and amplified necrosis rates at the tumor site. This delivery system showcases remarkable thermal responsiveness, injectability, and biodegradability, all finely aligned with the clinical demands of CS treatment. Collectively, this study introduces a transformative avenue for tackling drug resistance in CS chemotherapy, offering significant clinical potential.
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Affiliation(s)
- Jiahui Zhu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Ran Wei
- Musculoskeletal Tumor Center, Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People's Hospital, Beijing, 100044, China
| | - Guang Hu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Hui Wang
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Wenbin Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- Academy of Medical Sciences, The First Affiliated Hospital of Zhengzhou University Zhengzhou, Henan, 450052, China
| | - Haiqiang Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Jidan Huang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- USTC Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230000, China
| | - Yu Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China
| | - Yujing Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Huan Meng
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
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Ingangi V, De Chiara A, Ferrara G, Gallo M, Catapano A, Fazioli F, Di Carluccio G, Peranzoni E, Marigo I, Carriero MV, Minopoli M. Emerging Treatments Targeting the Tumor Microenvironment for Advanced Chondrosarcoma. Cells 2024; 13:977. [PMID: 38891109 PMCID: PMC11171855 DOI: 10.3390/cells13110977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/28/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
Chondrosarcoma (ChS), a malignant cartilage-producing tumor, is the second most frequently diagnosed osseous sarcoma after osteosarcoma. It represents a very heterogeneous group of malignant chemo- and radiation-resistant neoplasms, accounting for approximately 20% of all bone sarcomas. The majority of ChS patients have a good prognosis after a complete surgical resection, as these tumors grow slowly and rarely metastasize. Conversely, patients with inoperable disease, due to the tumor location, size, or metastases, represent a great clinical challenge. Despite several genetic and epigenetic alterations that have been described in distinct ChS subtypes, very few therapeutic options are currently available for ChS patients. Therefore, new prognostic factors for tumor progression as well as new treatment options have to be explored, especially for patients with unresectable or metastatic disease. Recent studies have shown that a correlation between immune infiltrate composition, tumor aggressiveness, and survival does exist in ChS patients. In addition, the intra-tumor microvessel density has been proven to be associated with aggressive clinical behavior and a high metastatic potential in ChS. This review will provide an insight into the ChS microenvironment, since immunotherapy and antiangiogenic agents are emerging as interesting therapeutic options for ChS patients.
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Affiliation(s)
- Vincenzo Ingangi
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy; (V.I.); (G.D.C.); (M.M.)
| | - Annarosaria De Chiara
- Histopathology Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy; (A.D.C.); (G.F.)
| | - Gerardo Ferrara
- Histopathology Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy; (A.D.C.); (G.F.)
| | - Michele Gallo
- Musculoskeletal Surgery Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy; (M.G.); (A.C.); (F.F.)
| | - Antonio Catapano
- Musculoskeletal Surgery Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy; (M.G.); (A.C.); (F.F.)
| | - Flavio Fazioli
- Musculoskeletal Surgery Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy; (M.G.); (A.C.); (F.F.)
| | - Gioconda Di Carluccio
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy; (V.I.); (G.D.C.); (M.M.)
| | - Elisa Peranzoni
- Immunology and Molecular Oncology Diagnostics, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy; (E.P.); (I.M.)
| | - Ilaria Marigo
- Immunology and Molecular Oncology Diagnostics, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy; (E.P.); (I.M.)
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padua, Italy
| | - Maria Vincenza Carriero
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy; (V.I.); (G.D.C.); (M.M.)
| | - Michele Minopoli
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy; (V.I.); (G.D.C.); (M.M.)
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Bläsius F, Delbrück H, Hildebrand F, Hofmann UK. Surgical Treatment of Bone Sarcoma. Cancers (Basel) 2022; 14:cancers14112694. [PMID: 35681674 PMCID: PMC9179414 DOI: 10.3390/cancers14112694] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/22/2022] [Accepted: 05/24/2022] [Indexed: 12/24/2022] Open
Abstract
Bone sarcomas are rare primary malignant mesenchymal bone tumors. The three main entities are osteosarcoma, chondrosarcoma, and Ewing sarcoma. While prognosis has improved for affected patients over the past decades, bone sarcomas are still critical conditions that require an interdisciplinary diagnostic and therapeutic approach. While radiotherapy plays a role especially in Ewing sarcoma and chemotherapy in Ewing sarcoma and osteosarcoma, surgery remains the main pillar of treatment in all three entities. After complete tumor resection, the created bone defects need to be reconstructed. Possible strategies are implantation of allografts or autografts including vascularized bone grafts (e.g., of the fibula). Around the knee joint, rotationplasty can be performed or, as an alternative, the implantation of (expandable) megaprostheses can be performed. Challenges still associated with the implantation of foreign materials are aseptic loosening and infection. Future improvements may come with advances in 3D printing of individualized resection blades/implants, thus also securing safe tumor resection margins while at the same time shortening the required surgical time. Faster osseointegration and lower infection rates may possibly be achieved through more elaborate implant surface structures.
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Affiliation(s)
- Felix Bläsius
- Department of Orthopaedic, Trauma and Reconstructive Surgery, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany; (F.B.); (H.D.); (F.H.)
- Centre for Integrated Oncology Aachen Bonn Köln Düsseldorf (CIO), 52074 Aachen, Germany
| | - Heide Delbrück
- Department of Orthopaedic, Trauma and Reconstructive Surgery, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany; (F.B.); (H.D.); (F.H.)
- Centre for Integrated Oncology Aachen Bonn Köln Düsseldorf (CIO), 52074 Aachen, Germany
| | - Frank Hildebrand
- Department of Orthopaedic, Trauma and Reconstructive Surgery, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany; (F.B.); (H.D.); (F.H.)
- Centre for Integrated Oncology Aachen Bonn Köln Düsseldorf (CIO), 52074 Aachen, Germany
| | - Ulf Krister Hofmann
- Department of Orthopaedic, Trauma and Reconstructive Surgery, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074 Aachen, Germany; (F.B.); (H.D.); (F.H.)
- Centre for Integrated Oncology Aachen Bonn Köln Düsseldorf (CIO), 52074 Aachen, Germany
- Correspondence: ; Tel.: +49-(0)241-80-89350
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5
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Meng Y, Sang Y, Liao J, Zhao Q, Qu S, Li R, Jiang J, Wang M, Wang J, Wu D, Cheng C, Wei L. Single cell transcriptional diversity and intercellular crosstalk of human liver cancer. Cell Death Dis 2022; 13:261. [PMID: 35322024 PMCID: PMC8943132 DOI: 10.1038/s41419-022-04689-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 02/09/2022] [Accepted: 02/24/2022] [Indexed: 12/15/2022]
Abstract
Liver cancer arises from the evolutionary selection of the dynamic tumor microenvironment (TME), in which the tumor cell generally becomes more heterogeneous; however, the mechanisms of TME-mediated transcriptional diversity of liver cancer remain unclear. Here, we assess transcriptional diversity in 15 liver cancer patients by single-cell transcriptome analysis and observe transcriptional diversity of tumor cells is associated with stemness in liver cancer patients. Tumor-associated fibroblast (TAF), as a potential driving force behind the heterogeneity in tumor cells within and between tumors, was predicted to interact with high heterogeneous tumor cells via COL1A1-ITGA2. Moreover, COL1A1-mediated YAP-signaling activation might be the mechanistic link between TAF and tumor cells with increased transcriptional diversity. Strikingly, the levels of COL1A1, ITGA2, and YAP are associated with morphological heterogeneity and poor overall survival of liver cancer patients. Beyond providing a potential mechanistic link between the TME and heterogeneous tumor cells, this study establishes that collagen-stimulated YAP activation is associates with transcriptional diversity in tumor cells by upregulating stemness, providing a theoretical basis for individualized treatment targets.
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Affiliation(s)
- Yan Meng
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Street, Nanjing, 210023, China.,Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Yan Sang
- Nursing Department, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, China
| | - Jianping Liao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.,The School of Basic Medical Sciences of Fujian Medical University, Fujian Medical University, Fuzhou, 350108, China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Shuping Qu
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China
| | - Meifeng Wang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.,The School of Basic Medical Sciences of Fujian Medical University, Fujian Medical University, Fuzhou, 350108, China
| | - Jiahong Wang
- The School of Basic Medical Sciences of Fujian Medical University, Fujian Medical University, Fuzhou, 350108, China
| | - Dong Wu
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
| | - Chun Cheng
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Street, Nanjing, 210023, China.
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China.
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Pennington Z, Ehresman J, Pittman PD, Ahmed AK, Lubelski D, McCarthy EF, Goodwin CR, Sciubba DM. Chondrosarcoma of the spine: a narrative review. Spine J 2021; 21:2078-2096. [PMID: 33971325 DOI: 10.1016/j.spinee.2021.04.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 01/19/2021] [Accepted: 04/28/2021] [Indexed: 02/03/2023]
Abstract
Chondrosarcoma is an uncommon primary bone tumor with an estimated incidence of 0.5 per 100,000 patient-years. Primary chondrosarcoma of the mobile spine and sacrum cumulatively account for less than 20% of all cases, most .commonly causing patients to present with focal pain with or without radiculopathy, or myelopathy secondary to neural element compression. Because of the rarity, patients benefit from multidisciplinary care at academic tertiary-care centers. Current standard-of-care consists of en bloc surgical resection with negative margins; for high grade lesions adjuvant focused radiation with ≥60 gray equivalents is taking an increased role in improving local control. Prognosis is dictated by lesion grade at the time of resection. Several groups have put forth survival calculators and epidemiological evidence suggests prognosis is quite good for lesions receiving R0 resection. Future efforts will be focused on identifying potential chemotherapeutic adjuvants and refining radiation treatments as a means of improving local control.
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Affiliation(s)
- Zach Pennington
- Department of Neurosurgery, Mayo Clinic, Rochester, MN USA 55905; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD USA 21287.
| | - Jeff Ehresman
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD USA 21287; Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ USA 85013.
| | - Patricia D Pittman
- Department of Neuropathology, Duke University School of Medicine, Durham, NC USA 27710
| | - A Karim Ahmed
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD USA 21287
| | - Daniel Lubelski
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD USA 21287
| | - Edward F McCarthy
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA 21287
| | - C Rory Goodwin
- Department of Neurosurgery, Duke University School of Medicine, Durham, NC USA 27710
| | - Daniel M Sciubba
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD USA 21287; Department of Neurosurgery, Zucker School of Medicine at Hofstra, Long Island Jewish Medical Center and North Shore University Hospital, Northwell Health, Manhasset, NY USA 11030.
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Tzanakakis GN, Giatagana EM, Berdiaki A, Spyridaki I, Hida K, Neagu M, Tsatsakis AM, Nikitovic D. The Role of IGF/IGF-IR-Signaling and Extracellular Matrix Effectors in Bone Sarcoma Pathogenesis. Cancers (Basel) 2021; 13:cancers13102478. [PMID: 34069554 PMCID: PMC8160938 DOI: 10.3390/cancers13102478] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/27/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Bone sarcomas are mesenchymal origin tumors. Bone sarcoma patients show a variable response or do not respond to chemotherapy. Notably, improving efficient chemotherapy approaches, dealing with chemoresistance, and preventing metastasis pose unmet challenges in sarcoma therapy. Insulin-like growth factors 1 and 2 (IGF-1 and -2) and their respective receptors are a multifactorial system that significantly contributes to bone sarcoma pathogenesis. Most clinical trials aiming at the IGF pathway have had limited success. Developing combinatorial strategies to enhance antitumor responses and better classify the patients that could best benefit from IGF-axis targeting therapies is in order. A plausible approach for developing a combinatorial strategy is to focus on the tumor microenvironment (TME) and processes executed therein. Herewith, we will discuss how the interplay between IGF-signaling and the TME constituents affects bone sarcomas’ basal functions and their response to therapy. Potential direct and adjunct therapeutical implications of the extracellular matrix (ECM) effectors will also be summarized. Abstract Bone sarcomas, mesenchymal origin tumors, represent a substantial group of varying neoplasms of a distinct entity. Bone sarcoma patients show a limited response or do not respond to chemotherapy. Notably, developing efficient chemotherapy approaches, dealing with chemoresistance, and preventing metastasis pose unmet challenges in sarcoma therapy. Insulin-like growth factors 1 and 2 (IGF-1 and -2) and their respective receptors are a multifactorial system that significantly contributes to bone sarcoma pathogenesis. Whereas failures have been registered in creating novel targeted therapeutics aiming at the IGF pathway, new agent development should continue, evaluating combinatorial strategies for enhancing antitumor responses and better classifying the patients that could best benefit from these therapies. A plausible approach for developing a combinatorial strategy is to focus on the tumor microenvironment (TME) and processes executed therein. Herewith, we will discuss how the interplay between IGF-signaling and the TME constituents affects sarcomas’ basal functions and their response to therapy. This review highlights key studies focusing on IGF signaling in bone sarcomas, specifically studies underscoring novel properties that make this system an attractive therapeutic target and identifies new relationships that may be exploited. Potential direct and adjunct therapeutical implications of the extracellular matrix (ECM) effectors will also be summarized.
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Affiliation(s)
- George N. Tzanakakis
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
- Laboratory of Anatomy, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Eirini-Maria Giatagana
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
| | - Aikaterini Berdiaki
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
| | - Ioanna Spyridaki
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
| | - Kyoko Hida
- Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan;
| | - Monica Neagu
- Department of Immunology, Victor Babes National Institute of Pathology, 050096 Bucharest, Romania;
| | - Aristidis M. Tsatsakis
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion, Greece;
| | - Dragana Nikitovic
- Laboratory of Histology-Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece; (G.N.T.); (E.-M.G.); (A.B.); (I.S.)
- Correspondence:
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8
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Papoutsidakis A, Giatagana EM, Berdiaki A, Spyridaki I, Spandidos DA, Tsatsakis A, Tzanakakis GN, Nikitovic D. Lumican mediates HTB94 chondrosarcoma cell growth via an IGF‑IR/Erk1/2 axis. Int J Oncol 2020; 57:791-803. [PMID: 32705211 PMCID: PMC7384848 DOI: 10.3892/ijo.2020.5094] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 06/25/2020] [Indexed: 12/14/2022] Open
Abstract
Chondrosarcoma is a malignant bone tumor characterized by the production of a modified cartilage-type extracellular matrix (ECM). In the present study, the expression levels of the small leucine-rich proteoglycans (SLRPs), decorin, biglycan and lumican, were examined in the HTB94 human chondrosarcoma cell line. HTB94 cells were found to express and secrete the 3 SLRP members. RT-qPCR and western blot analysis demonstrated that lumican was the most abundantly secreted SLRP, whereas decorin and biglycan expression levels were low. The utilization of short interfering RNA specific for the decorin, biglycan, and lumican genes resulted in the efficient downregulation of the respective mRNA levels (P≤0.001). The growth of the HTB94 cells was stimulated by lumican (P≤0.001), whereas their migration and adhesion were not affected (P=NS). By contrast, these cellular functions were not sensitive to a decrease in low endogenous levels of decorin and biglycan. Lumicandeficiency significantly inhibited both basal and insulin-like growth factor I (IGF-I)-induced HTB94 cell growth (P≤0.001 andP≤0.01, respectively). These effects were executed through the insulin-like growth factor I receptor (IGF-IR), whose activation was markedly attenuated (P≤0.01) in lumican-deficient HTB94 cells. The downregulation of lumican induced the substantial inhibition of extracellular regulated kinase (ERK1/2) activation (P≤ 0.01), indicating that ERK1/2 is a necessary component of lumican/IGF-IR-mediated HTB94 cell proliferation. Moreover, the lumican-deficient cells exhibit increased mRNA levels of p53 (P≤0.05), suggesting that lumican facilitates HTB94 cell growth through an IGF-IR/ERK1/2/p53 signaling cascade. On the whole, the findings of the present study demonstrate that endogenous lumican is a novel regulator of HTB94 cell growth.
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Affiliation(s)
- Antonis Papoutsidakis
- Laboratory of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Eirini Maria Giatagana
- Laboratory of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Aikaterini Berdiaki
- Laboratory of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ioanna Spyridaki
- Laboratory of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Demetrios A Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Aristidis Tsatsakis
- Laboratory of Toxicology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - George N Tzanakakis
- Laboratory of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Dragana Nikitovic
- Laboratory of Anatomy‑Histology‑Embryology, School of Medicine, University of Crete, 71003 Heraklion, Greece
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9
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Jana S, Madhu Krishna B, Singhal J, Horne D, Awasthi S, Salgia R, Singhal SS. SOX9: The master regulator of cell fate in breast cancer. Biochem Pharmacol 2020; 174:113789. [PMID: 31911091 PMCID: PMC9048250 DOI: 10.1016/j.bcp.2019.113789] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 12/24/2019] [Indexed: 02/07/2023]
Abstract
SRY-related high-mobility group box 9 (SOX9) is an indispensable transcription factor that regulates multiple developmental pathways related to stemness, differentiation, and progenitor development. Previous studies have demonstrated that the SOX9 protein directs pathways involved in tumor initiation, proliferation, migration, chemoresistance, and stem cell maintenance, thereby regulating tumorigenesis as an oncogene. SOX9 overexpression is a frequent event in breast cancer (BC) subtypes. Of note, the molecular mechanisms and functional regulation underlying SOX9 upregulation during BC progression are still being uncovered. The focus of this review is to appraise recent advances regarding the involvement of SOX9 in BC pathogenesis. First, we provide a general overview of SOX9 structure and function, as well as its involvement in various kinds of cancer. Next, we discuss pathways of SOX9 regulation, particularly its miRNA-mediated regulation, in BC. Finally, we describe the involvement of SOX9 in BC pathogenesis via its regulation of pathways involved in regulating cancer hallmarks, as well as its clinical and therapeutic importance. In general, this review article aims to serve as an ample source of knowledge on the involvement of SOX9 in BC progression. Targeting SOX9 activity may improve therapeutic strategies to treat BC, but precisely inhibiting SOX9 using drugs and/or small peptides remains a huge challenge for forthcoming cancer research.
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Affiliation(s)
- Samir Jana
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - B Madhu Krishna
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Jyotsana Singhal
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - David Horne
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sanjay Awasthi
- Department of Internal Medicine, Division of Hematology & Oncology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ravi Salgia
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
| | - Sharad S Singhal
- Department of Medical Oncology, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA.
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Regional Lymph Node Involvement Is Associated With Poorer Survivorship in Patients With Chondrosarcoma: A SEER Analysis. Clin Orthop Relat Res 2019; 477:2508-2518. [PMID: 31283732 PMCID: PMC6903832 DOI: 10.1097/corr.0000000000000846] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Regional lymph node involvement is thought to be rare in patients with chondrosarcoma, but its actual prevalence is unclear. Additionally, it is often not considered when prognostic factors are analyzed in patients with chondrosarcoma. However, it has been well established that lymph node involvement is a poor prognostic marker in patients with many types of bone and soft tissue sarcoma, including rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma. Although lymph node metastases are rare among all sarcoma types, it is important to consider whether lymph node metastases should be assessed in patients with chondrosarcoma because these metastases may impact survival. QUESTIONS/PURPOSES (1) What is the reported prevalence of regional lymph node involvement in patients with chondrosarcoma? (2) Do patients who have chondrosarcomas with regional lymph node involvement have different clinicopathologic presentations and survival than patients without regional lymph node involvement? (3) Is regional lymph node involvement independently associated with prognosis in patients with chondrosarcoma? METHODS The data of patients with chondrosarcoma registered in the Surveillance Epidemiology and End Results database (SEER) (1988-2015) were analyzed for the reported prevalence of regional lymph node involvement and its relationship with clinicopathologic features and the 5-year overall survival rate. From 1988 to 2015, 5528 patients with chondrosarcoma were registered in the SEER database. After screening by the inclusion criterion-chondrosarcoma as the first primary tumor, diagnosis with histology confirmation, patients with active followup and available information about regional node status-3374 patients met the inclusion criteria and were analyzed. Demographics and clinicopathologic data were compared using chi-square or Fisher's exact tests. Logistic regression analysis was used to assess the adjusted odds ratio. The overall survival rate was estimated with Kaplan-Meier curves and log-rank tests. Univariate and multivariate analyses of overall survival were performed with Cox proportional hazard models. In addition, a series of sensitivity analyses were performed to assess the robustness of the final Cox proportional hazard model. RESULTS Forty-four patients (1.3%) were recorded in the database as having regional lymph node involvement at the time of the primary diagnosis. Lymph node metastases were more likely to be reported in an extraskeletal primary site (3% [13 of 426] versus 1% [31 of 2948], adjusted odds ratio [OR] = 2.9, 95% CI, 1.5-5.8; p = 0.003) for bone primary sites and tumors with maximum diameter ≥ 8 cm (2% [26 of 1045] versus 1% [10 of 1075], adjusted OR = 2.9, 95% CI, 1.3-6.3; p = 0.008) and poorer differentiation (4% [24 of 608] versus 1% [14 of 2308], adjusted OR = 4.0, 95% CI, 2.0-8.2; p < 0.001), and in those with distant metastases (7% [14 of 203] versus 1% [30 of 3148], adjusted OR = 3.5, 95% CI, 1.7-7.1, p = 0.001). The 5-year overall survival rates of patients with and without regional lymph node involvement were 28% (95% CI, 15-42%) and 77% (95% CI, 75-78%), respectively (p < 0.001). After controlling for age, sex, race, grade, metastatic status, size, and histologic subtype, the presence of regional lymph node involvement was associated with poorer survival (hazard ratio, 2.20; 95% CI, 1.50-3.24; p < 0.001); this finding was confirmed in several sensitivity analyses. CONCLUSION The prevalence of regional lymph node involvement in patients with chondrosarcoma was 1.3% in the SEER database. Although chondrosarcomas are rare, patients with chondrosarcomas who have regional node metastases have a poorer prognosis than those who have not reported to have them. This may underrepresent the true proportion of patients with lymph node metastases given the inaccuracies of reporting in this database, but we believe these findings indicate that clinicians should examine patients more carefully for chondrosarcoma with lymph node metastases. Future studies are needed to assess potential treatment strategies to improve the prognosis of these patients. LEVEL OF EVIDENCE Level III, prognostic study.
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Abarrategi A, Gambera S, Alfranca A, Rodriguez-Milla MA, Perez-Tavarez R, Rouault-Pierre K, Waclawiczek A, Chakravarty P, Mulero F, Trigueros C, Navarro S, Bonnet D, García-Castro J. c-Fos induces chondrogenic tumor formation in immortalized human mesenchymal progenitor cells. Sci Rep 2018; 8:15615. [PMID: 30353072 PMCID: PMC6199246 DOI: 10.1038/s41598-018-33689-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 10/03/2018] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal progenitor cells (MPCs) have been hypothesized as cells of origin for sarcomas, and c-Fos transcription factor has been showed to act as an oncogene in bone tumors. In this study, we show c-Fos is present in most sarcomas with chondral phenotype, while multiple other genes are related to c-Fos expression pattern. To further define the role of c-Fos in sarcomagenesis, we expressed it in primary human MPCs (hMPCs), immortalized hMPCs and transformed murine MPCs (mMPCs). In immortalized hMPCs, c-Fos expression generated morphological changes, reduced mobility capacity and impaired adipogenic- and osteogenic-differentiation potentials. Remarkably, immortalized hMPCs or mMPCs expressing c-Fos generated tumors harboring a chondrogenic phenotype and morphology. Thus, here we show that c-Fos protein has a key role in sarcomas and that c-Fos expression in immortalized MPCs yields cell transformation and chondrogenic tumor formation.
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Affiliation(s)
- Ander Abarrategi
- Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, E-28021, Spain
- Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, WC2A 3LY, UK
| | - Stefano Gambera
- Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, E-28021, Spain
| | - Arantzazu Alfranca
- Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, E-28021, Spain
| | | | | | - Kevin Rouault-Pierre
- Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, WC2A 3LY, UK
| | - Alexander Waclawiczek
- Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, WC2A 3LY, UK
| | - Probir Chakravarty
- Bioinformatics Core, The Francis Crick Institute, London, United Kingdom
| | - Francisca Mulero
- Molecular Image Core Unit, Spanish National Cancer Research Centre, Madrid, E-28029, Spain
| | - César Trigueros
- Mesenchymal and Hematopoietic Stem Cell Laboratory, Fundación Inbiomed, San Sebastian, E-20009, Spain
| | - Samuel Navarro
- Pathology Department, University of Valencia, Valencia, E-46010, Spain
| | - Dominique Bonnet
- Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, WC2A 3LY, UK
| | - Javier García-Castro
- Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Madrid, E-28021, Spain.
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12
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Boehme KA, Schleicher SB, Traub F, Rolauffs B. Chondrosarcoma: A Rare Misfortune in Aging Human Cartilage? The Role of Stem and Progenitor Cells in Proliferation, Malignant Degeneration and Therapeutic Resistance. Int J Mol Sci 2018; 19:ijms19010311. [PMID: 29361725 PMCID: PMC5796255 DOI: 10.3390/ijms19010311] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Revised: 01/07/2018] [Accepted: 01/18/2018] [Indexed: 02/07/2023] Open
Abstract
Unlike other malignant bone tumors including osteosarcomas and Ewing sarcomas with a peak incidence in adolescents and young adults, conventional and dedifferentiated chondrosarcomas mainly affect people in the 4th to 7th decade of life. To date, the cell type of chondrosarcoma origin is not clearly defined. However, it seems that mesenchymal stem and progenitor cells (MSPC) in the bone marrow facing a pro-proliferative as well as predominantly chondrogenic differentiation milieu, as is implicated in early stage osteoarthritis (OA) at that age, are the source of chondrosarcoma genesis. But how can MSPC become malignant? Indeed, only one person in 1,000,000 will develop a chondrosarcoma, whereas the incidence of OA is a thousandfold higher. This means a rare coincidence of factors allowing escape from senescence and apoptosis together with induction of angiogenesis and migration is needed to generate a chondrosarcoma. At early stages, chondrosarcomas are still assumed to be an intermediate type of tumor which rarely metastasizes. Unfortunately, advanced stages show a pronounced resistance both against chemo- and radiation-therapy and frequently metastasize. In this review, we elucidate signaling pathways involved in the genesis and therapeutic resistance of chondrosarcomas with a focus on MSPC compared to signaling in articular cartilage (AC).
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Affiliation(s)
- Karen A Boehme
- G.E.R.N. Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Medical Center-Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, 79108 Freiburg, Germany.
| | - Sabine B Schleicher
- Department of Hematology and Oncology, Eberhard Karls University Tuebingen, Children's Hospital, 72076 Tuebingen, Germany.
| | - Frank Traub
- Department of Orthopedic Surgery, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.
| | - Bernd Rolauffs
- G.E.R.N. Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Medical Center-Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, 79108 Freiburg, Germany.
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13
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Liu P, Shen JK, Xu J, Trahan CA, Hornicek FJ, Duan Z. Aberrant DNA methylations in chondrosarcoma. Epigenomics 2016; 8:1519-1525. [PMID: 27686001 DOI: 10.2217/epi-2016-0071] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Chondrosarcoma (CS) is the second most common primary malignant bone tumor. Unlike other bone tumors, CS is highly resistant to conventional chemotherapy and radiotherapy, thus resulting in poor patient outcomes. There is an urgent need to establish alternative therapies for CS. However, the etiology and pathogenesis of CS still remain elusive. Recently, DNA methylation-associated epigenetic changes have been found to play a pivotal role in the initiation and development of human cancers, including CS, by regulating target gene expression in different cellular pathways. Elucidating the mechanisms of DNA methylation alteration may provide biomarkers for diagnosis and prognosis, as well as novel treatment options for CS. We have conducted a critical review to summarize the evidence regarding aberrant DNA methylation patterns as diagnostic biomarkers, predictors of progression and potential treatment strategies in CS.
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Affiliation(s)
- Pei Liu
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital & Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, USA.,Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
| | - Jacson K Shen
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital & Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, USA
| | - Jianzhong Xu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
| | - Carol A Trahan
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital & Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, USA
| | - Francis J Hornicek
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital & Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, USA
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital & Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, MA 02114, USA
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TCF-1 participates in the occurrence of dedifferentiated chondrosarcoma. Tumour Biol 2016; 37:14129-14140. [PMID: 27522523 PMCID: PMC5097086 DOI: 10.1007/s13277-016-5235-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 07/15/2016] [Indexed: 01/03/2023] Open
Abstract
The present study demonstrated that T cell factor 1 (TCF-1) protein, a component of the canonical Wnt/β-catenin signaling pathway, can regulate the expression of runt-related transcription factor 2 (runx2) gene and Sry-related HMG box 9 (sox9) gene, which may participate in the differentiation of chondrosarcoma. Dedifferentiated chondrosarcoma (DDCS) is a special variant of conventional chondrosarcoma (CCS), associated with poor survival and high metastasis rate. However, little is known about the mechanism of its occurrence; thus, no effective treatment is available except surgery. Earlier, high expression of runx2 and low expression of sox9 were found in DDCS compared with CCS. Using Western blot to detect clinical tissue samples (including 8 CCS samples and 8 DDCS samples) and immunohistochemistry to detect 85 different-grade chondrosarcoma specimens, a high expression of TCF-1 in DDCS tissues was found compared with CCS tissues. This difference in expression was related to patients' prognosis. Results of luciferase, chromatin immunoprecipitation, and gel electrophoresis mobility shift assays demonstrated that TCF-1 protein could bind to the promoter of runx2 gene directly and sox9 gene indirectly. Hence, it could regulate expression of runx2 gene positively and sox9 gene negatively. Furthermore, in vitro and in vivo experiments showed that TCF-1 protein was closely related to the phenotype and aggressiveness of chondrosarcoma. In conclusion, this study proved that TCF-1 participates in the dedifferentiation of DDCS, which may be mediated by runx2 gene and sox9 gene. Also, TCF-1 can be of important prognostic value and a promising therapeutic target for DDCS patients.
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15
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Li J, Wang L, Liu Z, Zu C, Xing F, Yang P, Yang Y, Dang X, Wang K. MicroRNA-494 inhibits cell proliferation and invasion of chondrosarcoma cells in vivo and in vitro by directly targeting SOX9. Oncotarget 2016; 6:26216-29. [PMID: 26317788 PMCID: PMC4694896 DOI: 10.18632/oncotarget.4460] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 06/19/2015] [Indexed: 12/20/2022] Open
Abstract
Accumulating evidence indicates that dysregulation of miRNAs could contribute to tumor growth and metastasis of chondrosarcoma by infuencing cell proliferation and invasion. In the current study, we are interested to examine the role of miRNAs in the carcinogenesis and progression of chondrosarcoma. Here, using comparative miRNA profiling of tissues and cells of chondrosarcoma and cartilage, we identified miR-494 as a commonly downregulated miRNA in the tissues of patients with chondrosarcoma and chondrosarcoma cancer cell line, and upregulation of miR-494 could inhibit proliferation and invasion of chondrosarcoma cancer cells in vivo and in vitro. Moreover, our data demonstrated that SOX9, the essential regulator of the process of cartilage differentiation, was the direct target and functional mediator of miR-494 in chondrosarcoma cells. And downregulation of SOX9 could also inhibit migration and invasion of chondrosarcoma cells. In the last, we identified low expression of miR-494 was significantly correlated with poor overall survival and prognosis of chondrosarcoma patients. Thus, miR-494 may be a new common therapeutic target and prognosis biomarker for chondrosarcoma.
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Affiliation(s)
- Jingyuan Li
- Department of Orthopaedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, P.R. China.,Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Lijuan Wang
- Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, P.R. China
| | - Zongzhi Liu
- Department of Orthopaedics, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Chao Zu
- Department of Surgical Oncology, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710068, Shaanxi Province, P.R. China
| | - Fanfan Xing
- Department of Clinical Microbiology and Infection Control, The University of Hong Kong - Shenzhen Hospital, Shenzhen, 518053, Guangdong Province, P.R. China
| | - Pei Yang
- Department of Orthopaedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, P.R. China
| | - Yongkang Yang
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712000, Shaanxi Province, P.R. China
| | - Xiaoqian Dang
- Department of Orthopaedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, P.R. China
| | - Kunzheng Wang
- Department of Orthopaedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, P.R. China
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Akyol S, Cömertoğlu I, Firat R, Çakmak Ö, Yukselten Y, Erden G, Ugurcu V, Demircan K. Effect of insulin on the mRNA expression of procollagen N-proteinases in chondrosarcoma OUMS-27 cells. Oncol Lett 2015; 10:1091-1096. [PMID: 26622631 DOI: 10.3892/ol.2015.3317] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Accepted: 04/14/2015] [Indexed: 12/30/2022] Open
Abstract
Chondrosarcoma is one of the most common bone tumors, and at present, there is no non-invasive treatment option for this cancer. The chondrosarcoma OUMS-27 cell line produces proteoglycan and type II, IX, and XI collagens, which constitutes cartilage tissue. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteases are a group of secreted proteases, which include the procollagen N-proteinases ADAMTS-2, -3 and -14. These procollagen N-proteinases perform a role in the processing of procollagens to collagen and the maturation of type I collagen. The present study aimed to improve the understanding of the causes of metastasis, local invasion and resistance to chemo- and radiotherapy in chondrosarcoma, as well as the effect of insulin on cancer cells. The present study was designed to reveal the effects of insulin on procollagen N-proteinases in chondrosarcoma OUMS-27 cells. The cells were cultured in Dulbecco's modified Eagle's medium (DMEM) alone or in DMEM containing 10 µg/ml insulin. The medium was changed every other day for 11 days. The cells were harvested on days 1, 3, 7 and 11, and total RNA isolation was performed immediately following harvesting. The expression levels of ADAMTS2, ADAMTS3 and ADAMTS14 mRNA were estimated by reverse transcription-quantitative polymerase chain reaction using appropriate primers. ADAMTS2 mRNA expression was found to be decreased on day 7 (P=0.028) and increased at day 11 compared with the control group (P=0.016). The increase in mRNA concentration at day 11 was significantly different compared to the concentrations on days 3 (P=0.047) and 7 (P=0.008). The expression of ADAMTS3 mRNA decreased immediately subsequent to insulin induction on day 1 compared with the control group (P=0.008). The most evident decrease in mRNA concentration was seen at day 7 subsequent to insulin induction (P=0.008). The present results demonstrated that ADAMTS2 and ADAMTS3 may perform a role in the invasion and metastasis of tumors, and may also possess proteolytic activity that results in the breakdown of the extracellular matrix (ECM). Insulin itself can modulate the biosynthesis of ECM macromolecules that are altered in diabetes through various pathways.
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Affiliation(s)
- Sumeyya Akyol
- Department of Medical Biology, Turgut Ozal University School of Medicine, Ankara, Ankara 06170, Turkey
| | - Ismail Cömertoğlu
- Department of Medical Genetics, Faculty of Medicine, Mevlana University, Selcuklu, Konya 42003, Turkey
| | - Ridvan Firat
- Division of Clinical Biochemistry Laboratory, Golbasi Hospital, Ministry of Health, Golbasi, Ankara 06830, Turkey
| | - Özlem Çakmak
- Department of Biology, Faculty of Education, Gazi University, Ankara, Ankara 06500, Turkey
| | - Yunus Yukselten
- Department of Medical Biology, Faculty of Medicine, Ankara University, Sihhiye, Ankara 06100, Turkey
| | - Gönül Erden
- Department of Clinical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Ankara 06100, Turkey
| | - Veli Ugurcu
- Department of Medical Biochemistry, Faculty of Medicine, Dumlupinar University, Kutahya, Kutahya 43266, Turkey
| | - Kadir Demircan
- Department of Medical Biology, Turgut Ozal University School of Medicine, Ankara, Ankara 06170, Turkey
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Mak IW, Singh S, Turcotte R, Ghert M. The Epigenetic Regulation of SOX9 by miR-145 in Human Chondrosarcoma. J Cell Biochem 2014; 116:37-44. [DOI: 10.1002/jcb.24940] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 08/15/2014] [Indexed: 02/01/2023]
Affiliation(s)
- Isabella W.Y. Mak
- Department of Surgery; McMaster University; Hamilton Ontario Canada
- Department of Surgery; Juravinski Cancer Centre; Hamilton Health Sciences; Hamilton Ontario Canada
| | - Shalini Singh
- Department of Surgery; McMaster University; Hamilton Ontario Canada
| | - Robert Turcotte
- Department of Orthopaedic Surgery; McGill University Health Centre; Montreal Quebec Canada
| | - Michelle Ghert
- Department of Surgery; McMaster University; Hamilton Ontario Canada
- Department of Surgery; Juravinski Cancer Centre; Hamilton Health Sciences; Hamilton Ontario Canada
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Safari M, Khoshnevisan A. An overview of the role of cancer stem cells in spine tumors with a special focus on chordoma. World J Stem Cells 2014; 6:53-64. [PMID: 24567788 PMCID: PMC3927014 DOI: 10.4252/wjsc.v6.i1.53] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2013] [Revised: 08/31/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
Primary malignant tumors of the spine are relatively rare, less than 5% of all spinal column tumors. However, these lesions are often among the most difficult to treat and encompass challenging pathologies such as chordoma and a variety of invasive sarcomas. The mechanisms of tumor recurrence after surgical intervention, as well as resistance to radiation and chemotherapy, remain a pervasive and costly problem. Recent evidence has emerged supporting the hypothesis that solid tumors contain a sub-population of cancer cells that possess characteristics normally associated with stem cells. Particularly, the potential for long-term proliferation appears to be restricted to subpopulations of cancer stem cells (CSCs) functionally defined by their capacity to self-renew and give rise to differentiated cells that phenotypically recapitulate the original tumor, thereby causing relapse and patient death. These cancer stem cells present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. The general objective of the current study is to discuss the fundamental concepts for understanding the role of CSCs with respect to chemoresistance, radioresistance, special cell surface markers, cancer recurrence and metastasis in tumors of the osseous spine. This discussion is followed by a specific review of what is known about the role of CSCs in chordoma, the most common primary malignant osseous tumor of the spine.
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Hsu W, Mohyeldin A, Shah SR, Gokaslan ZL, Quinones-Hinojosa A. Role of cancer stem cells in spine tumors: review of current literature. Neurosurgery 2012; 71:117-25. [PMID: 22418583 DOI: 10.1227/neu.0b013e3182532e71] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The management of spinal column tumors continues to be a challenge for clinicians. The mechanisms of tumor recurrence after surgical intervention as well as resistance to radiation and chemotherapy continue to be elucidated. Furthermore, the pathophysiology of metastatic spread remains an area of active investigation. There is a growing body of evidence pointing to the existence of a subset of tumor cells with high tumorigenic potential in many spine cancers that exhibit characteristics similar to those of stem cells. The ability to self-renew and differentiate into multiple lineages is the hallmark of stem cells, and tumor cells that exhibit these characteristics have been described as cancer stem cells (CSCs). The mechanisms that allow nonmalignant stem cells to promote normal developmental programming by way of enhanced proliferation, promotion of angiogenesis, and increased motility may be used by CSCs to fuel carcinogenesis. The purpose of this review is to discuss what is known about the role of CSCs in tumors of the osseous spine. First, this article reviews the fundamental concepts critical to understanding the role of CSCs with respect to chemoresistance, radioresistance, and metastatic disease. This discussion is followed by a review of what is known about the role of CSCs in the most common primary tumors of the osseous spine.
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Affiliation(s)
- Wesley Hsu
- Department of Neurosurgery, Wake Forest Baptist Medical Center, Winston-Salem, NC 27157-1029, USA.
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WU JIANHONG, LIANG XUEAI, WU YUMEI, LI FENGSHUANG, DAI YINMEI. Identification of DNA methylation of SOX9 in cervical cancer using methylated-CpG island recovery assay. Oncol Rep 2012; 29:125-32. [DOI: 10.3892/or.2012.2077] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 09/06/2012] [Indexed: 11/05/2022] Open
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Nikitovic D, Aggelidakis J, Young MF, Iozzo RV, Karamanos NK, Tzanakakis GN. The biology of small leucine-rich proteoglycans in bone pathophysiology. J Biol Chem 2012; 287:33926-33. [PMID: 22879588 DOI: 10.1074/jbc.r112.379602] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The class of small leucine-rich proteoglycans (SLRPs) is a family of homologous proteoglycans harboring relatively small (36-42 kDa) protein cores compared with the larger cartilage and mesenchymal proteoglycans. SLRPs have been localized to most skeletal regions, with specific roles designated during all phases of bone formation, including periods relating to cell proliferation, organic matrix deposition, remodeling, and mineral deposition. This is mediated by key signaling pathways regulating the osteogenic program, including the activities of TGF-β, bone morphogenetic protein, Wnt, and NF-κB, which influence both the number of available osteogenic precursors and their subsequent development, differentiation, and function. On the other hand, SLRP depletion is correlated with degenerative diseases such as osteoporosis and ectopic bone formation. This minireview will focus on the SLRP roles in bone physiology and pathology.
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Affiliation(s)
- Dragana Nikitovic
- Department of Histology-Embryology, Medical School, University of Crete, Greece
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The Bone Niche of Chondrosarcoma: A Sanctuary for Drug Resistance, Tumour Growth and also a Source of New Therapeutic Targets. Sarcoma 2011; 2011:932451. [PMID: 21647363 PMCID: PMC3103994 DOI: 10.1155/2011/932451] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2010] [Revised: 01/28/2011] [Accepted: 02/10/2011] [Indexed: 01/10/2023] Open
Abstract
Chondrosarcomas are malignant cartilage-forming tumours representing around 20% of malignant primary tumours of bone and affect mainly adults in the third to sixth decade of life. Unfortunately, the molecular pathways controlling the genesis and the growth of chondrosarcoma cells are still not fully defined. It is well admitted that the invasion of bone by tumour cells affects the balance between early bone resorption and formation and induces an “inflammatory-like” environment which establishes a dialogue between tumour cells and their environment. The bone tumour microenvironment is then described as a sanctuary that contributes to the drug resistance patterns and may control at least in part the tumour growth. The concept of “niche” defined as a specialized microenvironment that can promote the emergence of tumour stem cells and provide all the required factors for their development recently emerges in the literature. The present paper aims to summarize the main evidence sustaining the existence of a specific bone niche in the pathogenesis of chondrosarcomas.
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Diaz-Romero J, Romeo S, Bovée JVMG, Hogendoorn PCW, Heini PF, Mainil-Varlet P. Hierarchical clustering of flow cytometry data for the study of conventional central chondrosarcoma. J Cell Physiol 2010; 225:601-11. [PMID: 20506378 DOI: 10.1002/jcp.22245] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
We have investigated the use of hierarchical clustering of flow cytometry data to classify samples of conventional central chondrosarcoma, a malignant cartilage forming tumor of uncertain cellular origin, according to similarities with surface marker profiles of several known cell types. Human primary chondrosarcoma cells, articular chondrocytes, mesenchymal stem cells, fibroblasts, and a panel of tumor cell lines from chondrocytic or epithelial origin were clustered based on the expression profile of eleven surface markers. For clustering, eight hierarchical clustering algorithms, three distance metrics, as well as several approaches for data preprocessing, including multivariate outlier detection, logarithmic transformation, and z-score normalization, were systematically evaluated. By selecting clustering approaches shown to give reproducible results for cluster recovery of known cell types, primary conventional central chondrosacoma cells could be grouped in two main clusters with distinctive marker expression signatures: one group clustering together with mesenchymal stem cells (CD49b-high/CD10-low/CD221-high) and a second group clustering close to fibroblasts (CD49b-low/CD10-high/CD221-low). Hierarchical clustering also revealed substantial differences between primary conventional central chondrosarcoma cells and established chondrosarcoma cell lines, with the latter not only segregating apart from primary tumor cells and normal tissue cells, but clustering together with cell lines from epithelial lineage. Our study provides a foundation for the use of hierarchical clustering applied to flow cytometry data as a powerful tool to classify samples according to marker expression patterns, which could lead to uncover new cancer subtypes.
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Affiliation(s)
- Jose Diaz-Romero
- Osteoarticular Research Group, Institute of Pathology, University of Bern, Bern, Switzerland.
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Jambhekar NA, Rekhi B, Thorat K, Dikshit R, Agrawal M, Puri A. Revisiting chordoma with brachyury, a "new age" marker: analysis of a validation study on 51 cases. Arch Pathol Lab Med 2010; 134:1181-7. [PMID: 20670140 DOI: 10.5858/2009-0476-oa.1] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Chordoma is a rare, notochordal tumor with a characteristic histomorphology and immunohistochemical profile. At times, it presents a diagnostic challenge, especially in small biopsies. Brachyury, a nuclear transcription factor, is a recently described immunohistochemical marker for diagnosing chordomas. OBJECTIVE To study the sensitivity and specificity of brachyury in diagnosing chordomas by comparing its expression in axial chordomas with nonchordomatous tumors. DESIGN Fifty-one axial chordomas, accessioned during a 10-year period, and 58 nonchordomatous tumors were subjected to brachyury staining by immunohistochemistry. RESULTS The 51 chordomas occurred in 36 men and 15 women. Sitewise, 34 cases (66.7%) occurred in the sacrococcyx, 9 (17.6%) in the spine, and 8 (15.7%) in the skull base. Histologically, 34 cases (66.7%) were classical chordomas, 13 cases (25.5%) had a dominant chondroid component, and 2 cases each (3.9%) were chondroid chordomas and dedifferentiated chordomas, respectively. Brachyury staining was positive in 46 of the 51 chordomas (90.2%) and negative in all 58 nonchordomatous tumors. The dedifferentiated area in 2 chordomas was negative for brachyury staining. Fourteen of 15 chordomas with chondroid component showed positive brachyury staining. Immunohistochemical expression of other markers, included cytokeratin (positive in 23 of 23 cases; 100%), epithelial membrane antigen (positive in 22 of 22 cases; 100%) and S100 protein (positive in 18 of 21 cases; 85.7%). CONCLUSION Exclusive brachyury expression in more than 90% of chordomas indicates its value as a unique, specific marker with other sensitive markers like cytokeratin, epithelial membrane antigen, and/or S100 protein in substantiating a diagnosis of chordoma, including on small biopsies.
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Cajaiba MM, Jianhua Luo, Goodman MA, Fuhrer KA, Rao UNM. Sox9 expression is not limited to chondroid neoplasms: variable occurrence in other soft tissue and bone tumors with frequent expression by synovial sarcomas. Int J Surg Pathol 2010; 18:319-23. [PMID: 20484142 DOI: 10.1177/1066896910367650] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The transcription factor Sox9 is known to play a crucial role in normal chondrogenesis, and antibodies against Sox9 have been proposed as a diagnostic tool for neoplasms with chondroid differentiation. However, the pattern of Sox9 immunohistochemical expression by other bone and soft tissue neoplasms, as well as its diagnostic specificity, remain unexplored. The authors have performed immunohistochemistry with antibodies against Sox9 in 106 chondroid and nonchondroid bone and soft tissue neoplasms. Moderate to intense Sox9 nuclear staining was observed in 14/20 chondrosarcomas (70%), and in 24/81 (29.6%) cases from a multitumor tissue microarray, which included 16/18 synovial sarcomas, 4/15 osteosarcomas, 2/5 peripheral primitive neuroectodermal tumor (PNET)/Ewing sarcomas, 1/1 mesenchymal chondrosarcoma, and 1/1 chondroblastoma. The results suggest that Sox9 usefulness in the diagnosis of chondroid tumors may be limited because of low sensitivity and specificity. The finding of Sox9 expression by 88.9% of synovial sarcomas represents a novel and striking observation, which deserves further investigation.
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Affiliation(s)
- Mariana M Cajaiba
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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Vincourt JB, Etienne S, Cottet J, Delaunay C, Malanda B, Lionneton F, Sirveaux F, Netter P, Plénat F, Mainard D, Vignaud JM, Magdalou J. C-Propeptides of Procollagens Iα1 and II that Differentially Accumulate in Enchondromas versus Chondrosarcomas Regulate Tumor Cell Survival and Migration. Cancer Res 2010; 70:4739-48. [DOI: 10.1158/0008-5472.can-10-0046] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Fanburg-Smith JC, Auerbach A, Marwaha JS, Wang Z, Rushing EJ. Reappraisal of mesenchymal chondrosarcoma: novel morphologic observations of the hyaline cartilage and endochondral ossification and β-catenin, Sox9, and osteocalcin immunostaining of 22 cases. Hum Pathol 2010; 41:653-62. [DOI: 10.1016/j.humpath.2009.11.006] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2009] [Revised: 10/31/2009] [Accepted: 11/04/2009] [Indexed: 11/24/2022]
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Fanburg-Smith JC, Auerbach A, Marwaha JS, Wang Z, Santi M, Judkins AR, Rushing EJ. Immunoprofile of mesenchymal chondrosarcoma: aberrant desmin and EMA expression, retention of INI1, and negative estrogen receptor in 22 female-predominant central nervous system and musculoskeletal cases. Ann Diagn Pathol 2010; 14:8-14. [DOI: 10.1016/j.anndiagpath.2009.09.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 08/23/2009] [Accepted: 09/03/2009] [Indexed: 01/30/2023]
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Brachyury, SOX-9, and podoplanin, new markers in the skull base chordoma vs chondrosarcoma differential: a tissue microarray-based comparative analysis. Mod Pathol 2008; 21:1461-9. [PMID: 18820665 PMCID: PMC4233461 DOI: 10.1038/modpathol.2008.144] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The distinction between chondrosarcoma and chordoma of the skull base/head and neck is prognostically important; however, both have sufficient morphologic overlap to make delineation difficult. As a result of gene expression studies, additional candidate markers have been proposed to help in separating those entities. We sought to evaluate the performance of new markers: brachyury, SOX-9, and podoplanin alongside the more traditional markers glial fibrillary acid protein, carcinoembryonic antigen, CD24, and epithelial membrane antigen. Paraffin blocks from 103 skull base/head and neck chondroid tumors from 70 patients were retrieved (1969-2007). Diagnoses were made based on morphology and/or whole-section immunohistochemistry for cytokeratin and S100 protein yielding 79 chordomas (comprising 45 chondroid chordomas and 34 conventional chordomas), and 24 chondrosarcomas. A tissue microarray containing 0.6 mm cores of each tumor in triplicate was constructed using a manual array (MTA-1; Beecher Instruments). For visualization of staining, the ImmPRESS detection system (Vector Laboratories) with 2-diaminobenzidine substrate was used. Sensitivities and specificities were calculated for each marker. Core loss from the microarray ranged from 25 to 29% yielding 66-78 viable cases per stain. The classic marker, cytokeratin, still has the best performance characteristics. When combined with brachyury, accuracy improves slightly (sensitivity and specificity for detection of chordoma 98 and 100%, respectively). Positivity for both epithelial membrane antigen and AE1/AE3 had a sensitivity of 90% and a specificity of 100% for detecting chordoma in this study. SOX-9 is apparently common to both notochordal and cartilaginous differentiation, and is not useful in the chordoma-chondrosarcoma differential diagnosis. Glial fibrillary acid protein, carcinoembryonic antigen, CD24, and epithelial membrane antigen did not outperform other markers, and are less useful in the diagnosis of chordoma vs chondrosarcoma. Podoplanin still remains the only positive marker for chondrosarcoma, though its accuracy is less than previously reported.
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Pitsillides A, Ashhurst DE. A critical evaluation of specific aspects of joint development. Dev Dyn 2008; 237:2284-94. [DOI: 10.1002/dvdy.21654] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Machado I, Giner F, Mayordomo E, Carda C, Navarro S, Llombart-Bosch A. Tissue microarrays analysis in chondrosarcomas: light microscopy, immunohistochemistry and xenograft study. Diagn Pathol 2008; 3 Suppl 1:S25. [PMID: 18673514 PMCID: PMC2500106 DOI: 10.1186/1746-1596-3-s1-s25] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background Chondrosarcoma (Chs) is the third most frequent primary malignant tumour of bone and can be primary or secondary, the latter results mainly from the malignant transformation of a benign pre-existing tumour. Methods All the cases diagnosed as Chs (primary tumours, recurrences and/or metastasis and xenotransplanted Chs) from the files of our Department were collected. Only cases with paraffin blocks available were selected (Total 32 cases). Six Tissue Microarrays (TMAs) were performed and all the cases and biopsies were distributed into the following groups: a) only paraffin block available from primary and/or metastatic tumours (3 TMAs), b) paraffin block available from primary and/or metastatic tumours as well as from the corresponding Nude mice xenotransplant (2 TMAs), c) only paraffin block available from xenotransplanted Chs (1 TMA). A reclassification of all the cases was performed; in addition, conventional hematoxylin-eosin as well as immunohistochemistry staining (S100, SOX-9, Ki-67, BCL-2, p53, p16, CK, CD99, Survivin and Caveolin) was analyzed in all the TMA. Results The distribution of the cases according to the histopathological pattern and the location of tumours were as follows: fourteen Grade I Chs (all primaries), two primary Grade II Chs, ten Grade III Chs (all primaries), five dedifferentiated Chs (four primaries and one primary with metastasis), and two Chs from cell cultures (Ch grade III). One recurrent extraskeletal myxoid Chs was included as a control in the TMA. Although there was heterogeneity in immunohistochemistry results of the different material analyzed, S100, SOX-9, Caveolin and Survivin were more expressed. The number of passages in xenotransplants fluctuated between 1 and 13. Curiously, in Grade I Chs, these implanted tumours hardly grew, and the number of passages did not exceed one. Conclusion The study of Chs by means of TMA techniques is very important because it will improve the assessment of different antibodies applied in the immunohistochemical assays. Xenotransplanted tumours in TMA improve knowledge concerning the variability in the morphological pattern shown by these tumours during the evolution in nudes.
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Affiliation(s)
- Isidro Machado
- Department of Pathology, University of Valencia, Valencia, Spain
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32
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Aleman A, Adrien L, Lopez-Serra L, Cordon-Cardo C, Esteller M, Belbin TJ, Sanchez-Carbayo M. Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays. Br J Cancer 2008; 98:466-73. [PMID: 18087279 PMCID: PMC2361432 DOI: 10.1038/sj.bjc.6604143] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2007] [Accepted: 11/19/2007] [Indexed: 02/06/2023] Open
Abstract
CpG island arrays represent a high-throughput epigenomic discovery platform to identify global disease-specific promoter hypermethylation candidates along bladder cancer progression. DNA obtained from 10 pairs of invasive bladder tumours were profiled vs their respective normal urothelium using differential methylation hybridisation on custom-made CpG arrays (n=12 288 clones). Promoter hypermethylation of 84 clones was simultaneously shown in at least 70% of the tumours. SOX9 was selected for further validation by bisulphite genomic sequencing and methylation-specific polymerase chain reaction in bladder cancer cells (n=11) and primary bladder tumours (n=101). Hypermethylation was observed in bladder cancer cells and associated with lack of gene expression, being restored in vitro by a demethylating agent. In primary bladder tumours, SOX9 hypermethylation was present in 56.4% of the cases. Moreover, SOX9 hypermethylation was significantly associated with tumour grade and overall survival. Thus, this high-throughput epigenomic strategy has served to identify novel hypermethylated candidates in bladder cancer. In vitro analyses supported the role of methylation in silencing SOX9 gene. The association of SOX9 hypermethylation with tumour progression and clinical outcome suggests its relevant clinical implications at stratifying patients affected with bladder cancer.
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Affiliation(s)
- A Aleman
- Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain
| | - L Adrien
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - L Lopez-Serra
- Epigenetics Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain
| | - C Cordon-Cardo
- Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, NY, USA
| | - M Esteller
- Epigenetics Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain
| | - T J Belbin
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - M Sanchez-Carbayo
- Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain
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Romeo S, Oosting J, Rozeman LB, Hameetman L, Taminiau AHM, Cleton-Jansen AM, Bovée JVMG, Hogendoorn PCW. The role of noncartilage-specific molecules in differentiation of cartilaginous tumors: lessons from chondroblastoma and chondromyxoid fibroma. Cancer 2007; 110:385-94. [PMID: 17559135 DOI: 10.1002/cncr.22798] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Chondroblastoma (CB) and chondromyxoid fibroma (CMF) are benign tumors of bone morphologically recapitulating cartilage differentiation. CMF can resemble high-grade central chondrosarcoma (HGCCS) because of its cellular atypia. The mechanism that drives this morphologic spectrum of cartilage differentiation is unclear. METHODS CMFs and CBs were hybridized on a complementary DNA microarray that was enriched for cartilage-specific genes. Data were analyzed by Linear Model for Microarray Analysis and were compared with previous data on osteochondromas and HGCCS. Verification was performed in an extended series. RESULTS None of the 68 genes that were differentially expressed in CB versus CMF, including several extracellular matrix (ECM) and ECM-degradation genes, were related specifically to cartilage. Perlecan, versican, collagen 4A2 (Col4A2), and cell-cell adhesion genes, such as CD166, were significantly higher in CMF. Sixty genes were expressed differentially in CMF versus HGCCS. Higher expression levels of CD166, cyclin D1 (CCND1), and p16INK4A were observed in CMF. CONCLUSIONS The current findings indicated that differential expression of adhesion and ECM molecules, such as CD166, versican, perlecan, and Col4A2, may interfere with cartilaginous differentiation. The decreased expression of CCND1, p16INK4A, and CD166 in HGCCS reflects impairment of cell cycle progression and of cell-cell adhesions in malignant tumors and is of use in the differential diagnosis of CMF.
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Affiliation(s)
- Salvatore Romeo
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
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Tschoep K, Kohlmann A, Schlemmer M, Haferlach T, Issels RD. Gene expression profiling in sarcomas. Crit Rev Oncol Hematol 2007; 63:111-24. [PMID: 17555981 DOI: 10.1016/j.critrevonc.2007.04.001] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2005] [Revised: 02/28/2007] [Accepted: 04/11/2007] [Indexed: 12/30/2022] Open
Abstract
Sarcomas are a heterogeneous group of malignant mesenchymal tumors of difficult classification. There is considerable variability in both histological appearance and responsiveness to therapy. Their overall poor clinical prognosis is reflected by the fact that >65% of patients suffering retroperitoneal soft tissue sarcoma die within 5 years [Heslin MJ, et al. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol 1997;15(8):2832-9]. A greater understanding of the biology of sarcomas is needed in order to increase the potential for identifying new therapeutic targets and strategies. Microarray analysis permits a global approach to gene expression analysis of thousands of genes at the same time and has proven to be useful for further molecular characterization of tumor tissue and cell lines. This article provides a comprehensive review of possible new biomarkers identified in gene expression studies of sarcomas. These markers give new insight into the pathogenesis of sarcomas, such as malignant fibrous histiocytoma [Lee YF, et al. Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Br J Cancer 2003;88(4):510-5], allow a further subclassifcation of tumors like calponin-positive and calponin-negative leiomyosarcoma, or may help to predict treatment responsiveness and prognosis in patients based on an individual gene expression pattern. In some studies candidate targets for possible new treatment strategies were identified. For instance newly identified markers such as ERBB2 [Allander SV, et al. Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation. Am J Pathol 2002;161(5):1587-95] and EGFR [Nielsen TO, et al. Molecular characterization of soft tissue tumours: a gene expression study. Lancet 2002;359(9314):1301-7] might lead to the possible therapeutic use of Trastuzumab, Gefitinib or Cetuximab in synovial sarcoma, comparable to the use of tyrosine kinase inhibitor STI (Gleevec) that is the standard treatment today of CD117-positive gastrointestinal stromal tumors.
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Affiliation(s)
- Katharina Tschoep
- Medizinische Klinik und Poliklinik III, Ludwig-Maximilians-University, Medical Center-Grosshadern, Munich, Germany.
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Zhao C, Bratthauer GL, Barner R, Vang R. Immunohistochemical Analysis of Sox9 in Ovarian Sertoli Cell Tumors and Other Tumors in the Differential Diagnosis. Int J Gynecol Pathol 2007; 26:1-9. [PMID: 17197889 DOI: 10.1097/01.pgp.0000232026.22861.b5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The distinction of ovarian Sertoli cell tumor from other tumors in the histological differential diagnosis, particularly endometrioid carcinoma and carcinoid tumor, may be difficult. Many immunohistochemical markers have been studied for this differential diagnosis, but currently available markers are neither 100% sensitive nor specific. Sox9 is a transcription factor involved in Sertoli cell differentiation in the testis. The role that this molecule plays in the pathogenesis of ovarian Sertoli cell tumors and the potential use as an immunohistochemical marker for differential diagnosis have not been investigated. Immunohistochemical staining for Sox9 was performed in 152 ovarian tumors: pure Sertoli cell tumor (n = 36), endometrioid borderline tumor (n = 38), well-differentiated endometrioid carcinoma (n = 26), sertoliform endometrioid carcinoma (n = 13), and carcinoid tumor (n = 39). Nuclear expression was considered positive. Extent and intensity of staining were semiquantitatively scored. In addition, immunohistochemical composite scores in positive cases (ranging from 1 to 12) were calculated based on the extent score multiplied by the intensity score. Sox9 was expressed in 44% of Sertoli cell tumors, 55% of endometrioid borderline tumors, 65% of well-differentiated endometrioid carcinomas, 39% of sertoliform endometrioid carcinomas, and 10% of carcinoid tumors. The mean Sox9 immunohistochemical composite scores in positive cases were 6.3 for Sertoli cell tumor, 5.3 for endometrioid borderline tumor, 8.0 for well-differentiated endometrioid carcinoma, 2.8 for sertoliform endometrioid carcinoma, and 6.8 for carcinoid tumor. The differences in the mean Sox9 composite scores between Sertoli cell tumor and the other tumor categories were not statistically significant (p values ranged from 0.092 to 0.523). We conclude that Sox9 is variably expressed in ovarian Sertoli cell tumor and other tumors that are in the differential diagnosis and, thus, is not helpful for immunohistochemical distinction. Understanding the role of Sox9 in the pathogenesis of ovarian Sertoli cell tumor requires further study.
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Affiliation(s)
- Chengquan Zhao
- Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.
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Vujovic S, Henderson S, Presneau N, Odell E, Jacques TS, Tirabosco R, Boshoff C, Flanagan AM. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas. J Pathol 2006; 209:157-65. [PMID: 16538613 DOI: 10.1002/path.1969] [Citation(s) in RCA: 399] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Chordomas are malignant tumours that occur along the spine and are thought to derive from notochordal remnants. There is significant morphological variability between and within chordomas, with some showing prominent areas of chondroid differentiation. Our microarray data from a broad range of connective tissue neoplasms indicate that, at the transcriptional level, chordomas resemble cartilaginous neoplasms. Here we show that chordomas express many genes known to be involved in cartilage development, but they also uniquely express genes distinguishing them from chondroid neoplasms. The brachyury transcription factor, known to be involved in notochordal development, is only expressed by chordomas. Using a polyclonal antibody, we show that brachyury is expressed in the embryonic notochord and in all 53 chordomas analysed, labelling both chondroid and chordoid areas of these tumours. In contrast, the protein was not detected in over 300 neoplasms, including 163 chondroid tumours. Brachyury was not detected in the nucleus pulposus, arguing against the hypothesis that this tissue derives directly from the notochord. These data provide compelling evidence that chordomas derive from notochord and demonstrate that brachyury is a specific marker for the notochord and notochord-derived tumours.
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Affiliation(s)
- S Vujovic
- Wolfson Institute for Biomedical Research, University College London, and Department of Oral Pathology, King's College London Dental Institute at Guy's Hospital, WC1E 6BT, UK
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Abstract
Chordoma, and its relationship to the notochord, has intrigued many researchers over the last two centuries. In particular, the morphological overlap with cartilaginous tumours is striking, and developmental biology has shown a tight relationship between cartilage and the notochord. This is reflected in the expression of common genes in chordoid and chondroid tumours. Wide gene expression analyses have led to the identification of key molecules that might play a crucial role in the pathogenesis of chordoma. Brachyury, a key factor in notochord fate, is significantly differentially expressed in chordoma. This not only gives insight into the histogenesis of this tumour but may also point towards new diagnostic tools in the differential diagnosis between chordoid and chondroid tumours.
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Affiliation(s)
- S Romeo
- Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
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Wegrowski Y, Maquart FX. Chondroitin Sulfate Proteoglycans in Tumor Progression. CHONDROITIN SULFATE: STRUCTURE, ROLE AND PHARMACOLOGICAL ACTIVITY 2006; 53:297-321. [PMID: 17239772 DOI: 10.1016/s1054-3589(05)53014-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Yanusz Wegrowski
- CNRS UMR 6198, Faculty of Medicine, IFR-53, 51095 Reims Cedex, France
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Rozeman LB, Hameetman L, van Wezel T, Taminiau AHM, Cleton-Jansen AM, Hogendoorn PCW, Bovée JVMG. cDNA expression profiling of chondrosarcomas: Ollier disease resembles solitary tumours and alteration in genes coding for components of energy metabolism occurs with increasing grade. J Pathol 2005; 207:61-71. [PMID: 16007578 DOI: 10.1002/path.1813] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Conventional central chondrosarcomas are malignant cartilaginous tumours, occasionally arising secondary to either solitary or multiple (Ollier disease) enchondromas. Recurrences may have progressed in grade. The aims of the present study were to identify putative differences in gene expression between solitary and Ollier disease-related tumours, and to elucidate signalling pathways involved in tumour progression by genome-wide cDNA expression analysis. Arrays enriched for cartilage-specific cDNAs and genes involved in general tumourigenesis were used to analyse enchondromas (n = 3, two with Ollier disease), chondrosarcomas of different grades (n = 19, three with Ollier disease), normal resting-zone cartilage (n = 2), and chondrosarcoma cells in culture (n = 7). The arrays were analysed by unsupervised hierarchical clustering, significant analysis of microarray, and T-tests. Confirmation of data was performed by immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Ollier disease cases and solitary tumours revealed similar expression profiles, suggesting that the same signalling pathways are involved in tumourigenesis. Interestingly, JunB protein expression was significantly higher in grade I chondrosarcomas than in enchondromas (p = 0.009), which could be of diagnostic relevance. Upon chondrosarcoma progression, matrix-associated genes are down-regulated, reflecting the histology of high-grade tumours. An increase in glycolysis-associated, and a decrease in oxidative phosphorylation-related, genes was found in high-grade tumours. These findings suggest an adaptation in energy supply upon progression towards higher grade.
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Affiliation(s)
- Leida B Rozeman
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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Oksjoki S, Söderström M, Inki P, Vuorio E, Anttila L. Molecular profiling of polycystic ovaries for markers of cell invasion and matrix turnover. Fertil Steril 2005; 83:937-44. [PMID: 15820804 DOI: 10.1016/j.fertnstert.2004.10.037] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2004] [Revised: 10/08/2004] [Accepted: 10/08/2004] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To study gene expression profiles of connective tissue components in polycystic ovaries using complementary deoxyribonucleic acid (cDNA) array technology. DESIGN Descriptive study of normal and polycystic human ovarian biopsy samples analyzed by cDNA array hybridizations. SETTING Experimental laboratory research. PATIENT(S) Eight women with polycystic ovary syndrome (PCOS) and two normally cycling women treated with electrocauterization and hysterectomy, respectively. INTERVENTIONS Ovarian biopsy samples. MAIN OUTCOME MEASURE(S) Expression levels of 588 genes involved in cellular invasion, extracellular matrix (ECM) turnover, and cell-ECM interactions in polycystic ovaries. RESULT(S) A majority of the 30 genes down-regulated in PCOS ovaries represented those related to cell adhesion and motility, as well as angiogenesis, followed by regulators of cell cycle and growth. The 14 up-regulated genes represented those regulating cell fate and development, growth factors, cytokines, chemokines, and cell-cell interactions. Of the 44 transcripts exhibiting marked changes in the cDNA array analysis, only one - proliferating cell nuclear antigen messenger ribonucleic acid (PCNA mRNA) - was systematically down-regulated; 2 transcripts, for CDC27HS protein and CD9 antigen, were down-regulated in 7 out of 8 PCOS samples. CONCLUSION(S) The present data suggest that gene expression profiling may become a useful tool to classify PCOS patients into subgroups with different etiologies. Genome-wide expression profiling using microarrays should be performed to better understand the metabolic derangement(s) in PCOS.
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Affiliation(s)
- Sanna Oksjoki
- Departments of Medical Biochemistry and Molecular Biology, Turku University Central Hospital, University of Turku, Turku, Finland
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Abstract
Fracture healing requires the cooperation of multiple molecular signaling pathways. To better understand this cascade of transcriptional events, we compared the gene expression profiles between intact bone and fractured bone at days 1, 2, and 4 using a rat femur model of bone healing. Cluster analysis identified several groups of genes with dynamic temporal expression patterns and stage-specific functions. The immediate-response genes are highlighted by binding activity, transporter activity, and energy derivation. We consider these activities as critical signals for initiation of fracture healing. The continuously increased genes are characterized by those directly involved in bone repair, thus, representing bone specific forefront workers. The constantly upregulated genes tend to regulate general cell growth and are enriched with genes that are involved in tumorigenesis, suggesting common pathways between two processes. The constantly downregulated genes predominantly involve immune response, the significance of which remains for further investigation. Knowledge acquired through this analysis of transcriptional activities at the early stage of bone healing will contribute to our understanding of fracture repair and bone-related pathological conditions.
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Affiliation(s)
- Xinmin Li
- Shanxi Agricultural University, Taigu, Shanxi, China 030801
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Abstract
PURPOSE OF REVIEW The burgeoning body of information on the genetic changes present in and underlying the development and biology of human cancers has carried implications regarding the possible genetic events that are responsible for not only the genesis of these cancers but also the hope of the cure for these cancers. Chondrosarcomas are a group of tumors that fall into this category. The purpose of this review is to summarize the genetic findings in these tumors. RECENT FINDINGS The histopathologic variability of chondrosarcomas is reflected in the complexity and lack of specificity of their cytogenetic and molecular genetic findings, except for extraskeletal myxoid chondrosarcomas. These are characterized in the preponderant number of cases by a translocation, t(9;22)(q22;q12), and in a small number of cases by variant translocations t(9;17)(q22;q11) and t(9;15)(q22;q21). These translocations lead to the formation of abnormal fusion genes and gene products (proteins). In each of these translocations, the CHN gene is involved, resulting in the chimeric fusion genes EWS/CHN, RBP56/CHN, and TCF12/CHN, respectively. The specific translocations and their associated molecular genetic changes are diagnostic of extraskeletal myxoid chondrosarcomas. The abnormal proteins resulting from these fusion genes aberrantly affect gene transcription and cellular signaling pathways thought to be responsible for initiating sarcoma formation. In skeletal (central) chondrosarcomas of varying histopathologic types, the cytogenetic and molecular genetic findings are variable, complex, and apparently lacking in specificity. These changes may reflect a stepwise process (or processes) of oncogenesis involving an array of genes. SUMMARY Although some cartilaginous tumors are characterized by specific or recurrent chromosome alterations and molecular genetic changes, much is yet to be learned about the nature and sequence of these genetics events and about their unique role in the stepwise process involved in the development and biology of each tumor type, both malignant and nonmalignant. Until such time, some of the genetic changes, particularly the presence of specific translocations, can be of definite diagnostic value.
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Affiliation(s)
- Avery A Sandberg
- Department of DNA Diagnostics, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.
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Wegrowski Y, Maquart FX. Involvement of stromal proteoglycans in tumour progression. Crit Rev Oncol Hematol 2004; 49:259-68. [PMID: 15036265 DOI: 10.1016/j.critrevonc.2003.10.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2003] [Indexed: 12/12/2022] Open
Abstract
Glycosaminoglycans (GAGs) and proteoglycans (PGs) belong to a class of extracellular macromolecules necessary for the growth of any multicellular structures, including tumours. Transformed cells induce stromal reaction either per se or by activation of the mesenchymal cells. Tumour stroma contains several chondroitin sulphate and heparan sulphate proteoglycans. These proteoglycans and their glycosaminoglycan chains modify cell behaviour by interacting with different molecules such as growth factors, cytokines, chemokines, proteinases and their inhibitors. This review describes the main proteoglycans of tumour stoma and discusses their implication in the regulation of the activity of extracellular proteins and peptides.
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Affiliation(s)
- Yanusz Wegrowski
- Laboratory of Biochemistry, CNRS FRE 2534, Faculty of Medicine, IFR-53, 51095 Reims Cedex, France.
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Martin JA, DeYoung BR, Gitelis S, Weydert JA, Klingelhutz AJ, Kurriger G, Buckwalter JA. Telomerase reverse transcriptase subunit expression is associated with chondrosarcoma malignancy. Clin Orthop Relat Res 2004:117-24. [PMID: 15346061 DOI: 10.1097/01.blo.0000141647.22689.de] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Expression of the telomerase reverse transcriptase subunit telomerase reverse transcriptase gene is associated with most human malignancies. Because telomerase reverse transcriptase is rarely expressed in normal tissue, its presence in pathologic specimens is considered a marker of transformed cells. Moreover, high levels of expression have been correlated with poor prognosis in many cancers. Although telomerase activity has been found in chondrosarcomas, its prognostic significance in these malignant cartilage tumors is unknown. Malignancy in cartilage-derived tumors is assessed routinely by histomorphologic grading, but even well differentiated, low-grade lesions can metastasize. This unpredictable behavior greatly complicates the clinical treatment of cartilage tumors, making better prognostic indicators desirable. To address this issue we used immunohistochemistry to compare telomerase reverse transcriptase expression in a collection of 61 tumors consisting of malignant chondrosarcomas of varying grade and benign enchondromas. Associated case histories were reviewed to test the hypothesis that telomerase reverse transcriptase expression levels correlated with subsequent tumor recurrence. We found that the relative abundance of telomerase reverse transcriptase-expressing cells correlated significantly with grade and recurrence. These findings indicate that telomerase reverse transcriptase immunostaining may be a useful adjunct to the conventional three-level grading system.
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Affiliation(s)
- James A Martin
- Department of Orthopaedics and Rehabilitation, The University of Iowa, Iowa City, IA 52242, USA.
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Davies SR, Li J, Okazaki K, Sandell LJ. Tissue-restricted expression of the Cdrap/Mia gene within a conserved multigenic housekeeping locus. Genomics 2004; 83:667-78. [PMID: 15028289 DOI: 10.1016/j.ygeno.2003.09.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2003] [Accepted: 09/09/2003] [Indexed: 11/25/2022]
Abstract
The mouse cartilage-derived retinoic acid-sensitive protein (Cdrap/Mia) gene is expressed primarily in cartilage. Various promoter motifs that participate in restricted gene expression have been identified. To define mechanisms of regulation further, we determined the DNA sequence of 12 kb flanking this gene. We show that two genes, Snrpa and Rab4b, that have characteristics of housekeeping genes, including ubiquitous expression, closely flank Cdrap/Mia. We found the exon/intron structure and the organization of the gene locus to be conserved between the mouse and the human chromosomes, suggestive of functional relevance. DNase I hypersensitivity assays comparing expressing and nonexpressing cells indicate that the chromatin structure surrounding Cdrap/Mia is not greatly altered for transcription. The tissue-restricted expression of Cdrap/Mia, located between two housekeeping genes, provides a distinctive model for restricted transcriptional regulation from a multigenic locus.
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Affiliation(s)
- Sherri R Davies
- Department of Orthopaedic Surgery, Washington University at Barnes-Jewish Hospital, Mail Stop 90-34-674, 216 South Kingshighway, St. Louis, MO 63110, USA
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Abstract
A mixed population of lymphocytes from a healthy donor co-existed with an established culture of allogeneic chondrosarcoma cells, during which time the tumor cells changed from malignantly transformed to benign fibroblast-like morphology; from multilayered to a monolayered growth pattern; lost their potency to grow in colonies in soft agar; and showed signs of senescence. A discussion of possible molecular mechanisms for this event is offered. If there are as yet undiscovered lymphokines that can induce reversal of the malignant geno/phenotype, the cognate gene(s) should be cloned for genetic engineering and for the mass production of the corresponding molecular mediators for clinical trials.
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Affiliation(s)
- Joseph G Sinkovics
- Cancer Institue, St. Joseph's Hospital, Department of Medicine, The University of South Florida College of Medicine, 3001 W Dr Martinr Luther King Jr Blvd, Tampa, USA
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Shao L, Kasanov J, Hornicek FJ, Morii T, Fondren G, Weissbach L. Ecteinascidin-743 drug resistance in sarcoma cells: transcriptional and cellular alterations. Biochem Pharmacol 2003; 66:2381-95. [PMID: 14637196 DOI: 10.1016/j.bcp.2003.08.033] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
A human chondrosarcoma cell line, CS-1, was treated successively with increasing concentrations of the marine chemotherapeutic Ecteinascidin-743 (ET-743), yielding a variant cell line displaying a significant degree of resistance to the cytotoxic action of this drug. Various experiments were performed to discern molecular aberrations between the parent and resistant cell line, and also identify potential molecular markers indicative of drug resistance. Although no significant differences in the levels of membrane transporters such as P-glycoprotein or multidrug resistance protein 1 (MRP1) were detected, the cell migratory ability of the ET-743-resistant cell variant was reduced, as was its attachment capability to gelatin-coated cell culture dishes. Staining of the actin-containing cytoskeleton with fluorescent-labeled phalloidin revealed marked differences in the cytoskeleton architecture between the parent and ET-743-resistant CS-1 cell lines. Comparison of serum-free conditioned medium from both cell lines showed conspicuous differences in the levels of several proteins, including a quartet of high molecular weight proteins (> or =140 kDa). The protein sequences of two of these high molecular weight proteins, present at significantly higher concentrations in conditioned medium obtained from the parent cell line, corresponded to subunits of types I and IV collagen. Analysis of type I collagen alpha1 chain mRNA revealed a significantly lower level in the ET-743-resistant CS-1 cell line. Thus, prolonged exposure to ET-743 may cause changes in cell function through cytoskeleton rearrangement and/or modulation of collagen levels.
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Affiliation(s)
- Li Shao
- Orthopaedic Research Laboratories, Massachusetts General Hospital and Harvard Medical School, GRJ 1124, 55 Fruit Street, Boston, MA 02114, USA
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Gil-Benso R, Lopez-Gines C, López-Guerrero JA, Carda C, Callaghan RC, Navarro S, Ferrer J, Pellín A, Llombart-Bosch A. Establishment and characterization of a continuous human chondrosarcoma cell line, ch-2879: comparative histologic and genetic studies with its tumor of origin. J Transl Med 2003; 83:877-87. [PMID: 12808123 DOI: 10.1097/01.lab.0000073131.34648.ea] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Chondrosarcomas are malignant cartilage-forming tumors that represent the second most common malignant solid tumor of bone. These biologically poorly understood neoplasms vary considerably in clinical presentation and biologic behavior. Chemotherapy and radiation therapy are generally ineffective. Here we describe the establishment and characterization of a new human chondrosarcoma cell line named ch-2879, and we compare the cell line with its tumor of origin. The cell line was established from a recurrent grade 3 chondrosarcoma of the chest wall and characterized by growth kinetics and morphologic studies. Immunocytochemistry and RT-PCR were performed to examine the expression of cartilage-specific phenotypes. Genetic characterization was performed using cytogenetics, fluorescence in situ hybridization, flow cytometry, and molecular techniques for analysis of the genes implicated in cell cycle control, amplification of MDM2, CDK4, and Cyclin D1, and mutations in the p53 gene. ch-2879 cells were subcultured for more than 80 passages. They expressed vimentin, HNK-1, HBA-71, Ki-67, cyclin D1, Fli-1, S-100, p21, p27, and p53 and were negative for cytokeratin, EMA, p14, p16, MDM2, Rb, and c-erb-b2 antigens. Cytogenetically the recurrent tumor showed a hyperhaploid karyotype with clonal numerical and structural abnormalities. The sole structural abnormality was a chromosome derivative of a t(1;21) translocation. The cell line at passage 3 showed two populations: the hyperhaploid and an exactly duplicated, hypotriploid population. After the 18th passage, only the hypotriploid population was present. The cells expressed collagen 2. Molecular comparison of the primary and recurrent tumor evidenced an in vivo molecular change consisting of a deletion of 9p21 genes in the recurrence, probably caused by a selection process. Because of its gene expression profile, including expression of genes implicated in chondrogenesis in uncoated plastic dishes, this cell line may prove useful for cellular and molecular studies as well as studies of chondrosarcoma characterization and treatment.
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Affiliation(s)
- Rosario Gil-Benso
- Department of Pathology, Medical School, University of Valencia, Valencia, Spain
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