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Cells Apr 2020YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus... (Review)
Review
YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bone Neoplasms; Carcinogenesis; Humans; Osteogenesis; Sarcoma; Signal Transduction; Trans-Activators
PubMed: 32326412
DOI: 10.3390/cells9040972 -
Journal of Nanobiotechnology Sep 2021Bone sarcomas are rare cancers accompanied by metastatic disease, mainly including osteosarcoma, Ewing sarcoma and chondrosarcoma. Extracellular vesicles (EVs) are... (Review)
Review
Bone sarcomas are rare cancers accompanied by metastatic disease, mainly including osteosarcoma, Ewing sarcoma and chondrosarcoma. Extracellular vesicles (EVs) are membrane vesicles released by cells in the extracellular matrix, which carry important signal molecules, can stably and widely present in various body fluids, such as plasma, saliva and scalp fluid, spinal cord, breast milk, and urine liquid. EVs can transport almost all types of biologically active molecules (DNA, mRNA, microRNA (miRNA), proteins, metabolites, and even pharmacological compounds). In this review, we summarized the basic biological characteristics of EVs and focused on their application in bone sarcomas. EVs can be use as biomarker vehicles for diagnosis and prognosis in bone sarcomas. The role of EVs in bone sarcoma has been analyzed point-by-point. In the microenvironment of bone sarcoma, bone sarcoma cells, mesenchymal stem cells, immune cells, fibroblasts, osteoclasts, osteoblasts, and endothelial cells coexist and interact with each other. EVs play an important role in the communication between cells. Based on multiple functions in bone sarcoma, this review provides new ideas for the discovery of new therapeutic targets and new diagnostic analysis.
Topics: Biomarkers; Bone Neoplasms; Collagen Type VI; Extracellular Vesicles; Humans; MicroRNAs; Osteosarcoma; Prognosis; Tumor Microenvironment
PubMed: 34535153
DOI: 10.1186/s12951-021-01028-7 -
Cancer Control : Journal of the Moffitt... 2021The dedifferentiated variant of chondrosarcoma is highly aggressive and carries an especially grim prognosis. While chemotherapeutics has failed to benefit patients with...
BACKGROUND
The dedifferentiated variant of chondrosarcoma is highly aggressive and carries an especially grim prognosis. While chemotherapeutics has failed to benefit patients with dedifferentiated chondrosarcoma significantly, preclinical chemosensitivity studies have been limited by a scarcity of available cell lines. There is, therefore, an urgent need to expand the pool of available cell lines.
METHODS
We report the establishment of a novel dedifferentiated chondrosarcoma cell line DDCS2, which we isolated from the primary tumor specimen of a 60-year-old male patient. We characterized its short tandem repeat (STR) DNA profile, growth potential, antigenic markers, chemosensitivity, and oncogenic spheroid and colony-forming capacity.
RESULTS
DDCS2 showed a spindle to polygonal shape and an approximate 60-hour doubling time. STR DNA profiling revealed a unique genomic identity not matching any existing cancer cell lines within the ATCC, JCRB, or DSMZ databases. There was no detectable contamination with another cell type. Western blot and immunofluorescence assays were consistent with a mesenchymal origin, and our MTT assay revealed relative resistance to conventional chemotherapeutics, which is typical of a dedifferentiated chondrosarcoma. Under three-dimensional (3D) culture conditions, the DDCS2 cells produced spheroid patterns similar to the well-established CS-1 and SW1353 chondrosarcoma cell lines.
CONCLUSION
Our findings confirm DDCS2 is a novel model for dedifferentiated chondrosarcoma and therefore adds to the limited pool of current cell lines urgently needed to investigate the chemoresistance within this deadly cancer.
Topics: Bone Neoplasms; Cell Line, Tumor; Chondrosarcoma; DNA Fingerprinting; Humans; Male; Microsatellite Repeats; Middle Aged
PubMed: 34767468
DOI: 10.1177/10732748211045274 -
The Pan African Medical Journal 2023Extraskeletal myxoid chondrosarcoma is a rare mesenchymal neoplasm of uncertain differentiation, characterized morphologically by abundant myxoid stroma, a multinodular...
Extraskeletal myxoid chondrosarcoma is a rare mesenchymal neoplasm of uncertain differentiation, characterized morphologically by abundant myxoid stroma, a multinodular growth pattern, and uniform cells arranged in strands, clusters, and reticular networks. It usually occurs in adults in the fifth decade, most often in the deep soft tissues of the proximal extremities. The molecular hallmark of this tumor, present in over 90% of cases, is the fusion of NR4A3 with EWSR1 at 22q12.2 or TAF15 at 17q12. Many other tumors with uniform tumor cells embedded in a myxoid matrix can mimic Extraskeletal myxoid chondrosarcoma, and the distinction can be difficult, often requiring immunohistochemistry and/or molecular testing. We herein report the case of an Extraskeletal myxoid chondrosarcoma that occurred in a 74-year-old woman who consulted for a slowly enlarging thigh mass, while highlighting the key morphologic, immunohistochemical, and molecular features of this rare type of soft tissue sarcoma, as well as a summary table gathering diagnostic features of relevance to the differential diagnosis.
Topics: Adult; Female; Humans; Aged; Chondrosarcoma; Neoplasms, Connective and Soft Tissue; Sarcoma; Soft Tissue Neoplasms
PubMed: 37484580
DOI: 10.11604/pamj.2023.44.199.39846 -
Pathology, Research and Practice Nov 2022The detection of mutations of isocitrate dehydrogenase 1 and 2 (IDH 1/2) as tumor driver genes in chondromas and chondrosarcomas more than ten years ago was a first... (Review)
Review
The detection of mutations of isocitrate dehydrogenase 1 and 2 (IDH 1/2) as tumor driver genes in chondromas and chondrosarcomas more than ten years ago was a first major step for better understanding the molecular carcinogenenesis of these rare mesenchymal tumors. Within the TCA cycle, wild-typ IDH1/2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). IDH mutations catalyze the production of a non-physiological metabolite, D-2hydroxyglutarate (D-2HG) from α-KG. D-2HG can inhibit the class of α-KG-dependent enzymes by binding competitively to its receptor. Important enzyme families, such as the Ten-Eleven Translocation (TET) family of 5-methylcytosine hydroxylases and the Jumonji family of histone lysine demethylases are α-KG dependent. Many of the TET and Jumonji family-dependent enzymes regulate epigenetic factors, such as DNA methylation, histone modification, and nucleosome remodeling, underscoring the central role of the epigenome in cancer development. When D-2HG acts with these enzymes instead α-KG their functions will be in disarray with heavily hypermethylated DNA and dysregulations in histone metylation. NcRNAs have increasingly been described as a cornerstone of cancer development. Therefore this review describes exemplarily the oncogenic functions of miRNAs in chondrosarcoma in more detail. Particularly in chondrosarcomas additional carcinogenic features are aquired by interactions of ncRNAs with α-KG-dependent epigenetic regulators. Distinct ncRNAs, miRNAs and lncRNAs alike, are involved in deregulating important cellular signalling pathways and thus contributing further to malignant transformation and development of malignant cellular traits in these rare mesenchymal tumors. This review specially empasizes the complex interactions between the world of ncRNAs and genetics and epigenetics.
Topics: Humans; Isocitrate Dehydrogenase; Epigenesis, Genetic; Chondrosarcoma; Mutation; Carcinogenesis; Ketoglutaric Acids; Bone Neoplasms; MicroRNAs
PubMed: 36274381
DOI: 10.1016/j.prp.2022.154172 -
Oncology Letters Jan 2020Mesenchymal chondrosarcoma (MC) of the kidney is rare. To the best of our knowledge, the current report is the first case of a giant extraskeletal MC that arose...
Mesenchymal chondrosarcoma (MC) of the kidney is rare. To the best of our knowledge, the current report is the first case of a giant extraskeletal MC that arose primarily from the right kidney and mimicked renal cell carcinoma at the locally advanced stage (cT3bN0) with vena cava thrombus and multiple pulmonary arterial tumor emboli. Additionally, the literature on renal EMC is reviewed and the possibilities of oncogenic heterogeneity are discussed. A 64-year-old woman was admitted to Yamagata University Hospital for sudden onset of asymptomatic gross hematuria. CT revealed a 90 mm renal mass without calcification in the right kidney and tumor thrombus extending to the inferior vena cava. Radical nephrectomy with thrombectomy was performed. Lung metastasis was detected 2 months later. The patient received systemic chemotherapy, which was only marginally effective. She died of the malignancy 8 months after surgery. Microscopic examination of the tumor revealed typical histology of MC and a lack of and gene fusions in the tumor tissues. Not all MC patients may exhibit chromosomal alterations in the tumor, suggesting the presence of genetically heterogeneous pathways of MC oncogenesis. Further studies are required to confirm the present findings and reinforce the molecular diagnosis of MC.
PubMed: 31897203
DOI: 10.3892/ol.2019.11143 -
Annals of Diagnostic Pathology Feb 2021Mesenchymal chondrosarcoma is a rare subtype of chondrosarcoma. The tumor has a characteristic bimorphic pattern with areas of poorly differentiated small round cell...
INTRODUCTION
Mesenchymal chondrosarcoma is a rare subtype of chondrosarcoma. The tumor has a characteristic bimorphic pattern with areas of poorly differentiated small round cell component and interspersed islands of well differentiated hyaline cartilage. Histological diagnosis of mesenchymal chondrosarcoma is very challenging especially in small biopsies when tumor presents with little cartilaginous component. In such cases, it is very difficult to distinguish mesenchymal chondrosarcoma from other round blue cell tumors like Ewing's sarcoma, rhabdomyosarcoma, small cell osteosarcoma and desmoplastic round blue cell tumor. Immunohistochemically, mesenchymal chondrosarcoma stains positive for NKX2.2, CD99, S100 and SOX9. This immunoprofile is non-specific and overlaps with other round blue cell tumors. Till recently, there was no reliable immunohistochemical marker to differentiate mesenchymal chondrosarcoma from other round blue cell tumors. NKX3.1, though widely used as a diagnostic biomarker for prostatic adenocarcinoma, has been recently proposed by Yoshida et al. (2020) as a unique marker of mesenchymal chondrosarcoma and EWSR1-NFATC2 sarcoma.
OBJECTIVE
The aim of our study was to further explore utility of NKX3.1 as a diagnostic marker of mesenchymal chondrosarcoma.
MATERIAL & METHODS
We applied NKX3.1 immunohistochemistry to 21 cases of mesenchymal chondrosarcoma and 32 cases of other round blue cell tumors.
RESULTS
14 out of 21 cases (66.7%) of mesenchymal chondrosarcoma stained positive for NKX3.1 with nuclear expression in small round component. Cartilaginous component was predominantly negative. All other round blue cell tumors showed negative results.
CONCLUSION
Based on our study results we suggest that NKX3.1 is a useful immunohistochemical marker in differentiating mesenchymal chondrosarcoma from its histological mimics.
Topics: 12E7 Antigen; Adult; Aged; Biomarkers, Tumor; Biopsy; Bone Neoplasms; Cell Differentiation; Cell Nucleus; Child; Chondrosarcoma, Mesenchymal; Desmoplastic Small Round Cell Tumor; Diagnosis, Differential; Female; Homeobox Protein Nkx-2.2; Homeodomain Proteins; Humans; Hyaline Cartilage; Immunohistochemistry; Male; Middle Aged; NFATC Transcription Factors; Nuclear Proteins; RNA-Binding Protein EWS; Rhabdomyosarcoma; S100 Proteins; SOX9 Transcription Factor; Sarcoma, Ewing; Sarcoma, Small Cell; Transcription Factors
PubMed: 33302222
DOI: 10.1016/j.anndiagpath.2020.151660 -
International Journal of Ophthalmology 2022To evaluate the ophthalmic manifestations, radiographic features, and prognosis of Chinese patients with primary orbital mesenchymal chondrosarcoma (MCS).
AIM
To evaluate the ophthalmic manifestations, radiographic features, and prognosis of Chinese patients with primary orbital mesenchymal chondrosarcoma (MCS).
METHODS
The study included 6 cases with primary orbital MCS treated at Tianjin Eye Hospital from January 2009 to December 2019. Patitent ophthalmic manifestations, radiographic features, diagnosis, pathology, therapeutic regimens, and prognosis were retrospectively reviewed.
RESULTS
Six patitents with primary orbital MCS were identified. The mean age at the first visit was 33y (range, 25-42y). All six patients displayed manifestations of exophthalmos, diplopia, limitation of eye displacement, upper eyelid oedema, decreased visual acuity and ptosis. The mean disease history and range were 5 and 2-8mo, respectively. The tumors were located in the superonasal extraconal compartment (2/6, 33.3%), intraconal compartment (2/6, 33.3%), and bitemporal extraconal compartment (2/6, 33.3%), respectively. Radiographic features were a well-defined, orbital mass with calcification and ossification on computed tomography (CT), and marked heterogenous enhancement on dynamic magnetic resonance imaging (MRI). Five patients were treated with tumor resection and one patient received orbital exenteration. Five patients in the cohort received postoperative radiation therapy, two patients received chemotherapy, and one patient did not receive postoperative adjuvant therapy because he refused. The histopathologic classification revealed a tumour composed of a mixture of mature chondroid tissue surrounded by small, round, and undifferentiated mesenchymal cells. Immunohistochemistry revealed Bcl-2, vimetin, CD99, and S-100 were expressed were expressed. After surgeries, two patients have developed a local recurrence. The median recurrence time of 58mo (52-64mo). One patient had distant recurrence included the lungs occurred 52mo after the initial surgery.
CONCLUSION
The possibilty of orbital MCS need to be considered when a painless, slowly growing orbital mass with calcification and ossification. From our experience, trimodality treatment of radiation therapy, chemotherapy and surgery maybe the best option. Orbital MCS has a high tendency for late recurrence, regular long-term follow-up after complete excision is mandatory.
PubMed: 35186692
DOI: 10.18240/ijo.2022.02.17 -
Cancer Medicine Sep 2023We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs)...
Real-world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study.
OBJECTIVES
We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra-skeletal mesenchymal CS (ESMC).
METHODS
After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.
RESULTS
From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12-76); median starting dose was 60 mg for CABO (n = 37, range 40-60) and 120 mg for REGO (n = 29, range 40-160). Twenty-eight (42.4%) patients required dose reduction: hand-foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7-13.1); 13.4 months (n = 18, 95% CI 3.4-27.2), 8.1 (n = 4, 95% CI 4.1-9.3) and 18.2 (n = 5, 95% CI (10.4-na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8-5), 3.9 (n = 18, 95% CI 2.1-5.9), 5.53 (n = 4. 95% CI 2.13-NA) and 11.4 (n = 5, 95% CI 1.83-14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis.
CONCLUSION
Our real-world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research.
Topics: Humans; Adult; Child; Adolescent; Young Adult; Middle Aged; Aged; Tyrosine Kinase Inhibitors; Neoplasm Recurrence, Local; Canada; Bone Neoplasms; Sarcoma; Sarcoma, Ewing; Osteosarcoma; Chondrosarcoma; Retrospective Studies; Soft Tissue Neoplasms
PubMed: 37724607
DOI: 10.1002/cam4.6515 -
Journal of Orthopaedic Research :... Feb 2020Chondrosarcomas are rare tumors and, historically, investigation of these tumors has been limited to small series and single-institution studies. There have been no...
Chondrosarcomas are rare tumors and, historically, investigation of these tumors has been limited to small series and single-institution studies. There have been no studies that evaluated the identification or comparison of differences in prognostic factors between the five known non-conventional chondrosarcoma subtypes (myxoid, juxtacortical, clear-cell, mesenchymal, and dedifferentiated). The purpose of this paper was to determine the demographic, clinical, incidence, and tumor characteristics of all five known non-conventional chondrosarcoma subtypes, determine the 1-, 5-year, and median survival differences between these subtypes, and to determine the demographic and clinical variables that are significant prognostic indicators for each chondrosarcoma subtypes. We retrospectively reviewed the SEER database for all patients with non-conventional chondrosarcoma. χ testing was used for correlations between clinical variables. Kaplan-Meier and Cox proportional hazard analysis were used to compare survival of the subtypes, and to assess the prognostic value of age group, race, sex, grade, anatomic location, and metastatic involvement. Several demographic characteristics including gender, race, age, and grade varied between chondrosarcoma subtypes. The tumor characteristics showed marked differences in presence of metastasis on presentation between the subtypes with increasing order of rate of metastasis with juxtacortical (2.1%), clear cell (5.7%), myxoid (7.6%), mesenchymal (10.6%), and the highest in dedifferentiated (19.8%). One-, 5-year, and median survival differed significantly between chondrosarcomas subtypes. The highest median survival was found in the juxtacortical subtype (97 months), followed by clear cell (79 months), myxoid (60 months), mesenchymal (33.5 months), and lowest in dedifferentiated (11 months). The only prognostic variable that was shown to significantly impact the survival of each non-conventional chondrosarcoma subtype was a metastatic disease at diagnosis (p = 0.03 to p < 0.001). Subtyping classification of chondrosarcoma should be made whenever possible, given differences in survival and prognostic factors between chondrosarcoma subtypes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:311-319, 2020.
Topics: Adult; Aged; Chondrosarcoma; Female; Humans; Male; Middle Aged; Prognosis; Retrospective Studies; SEER Program; United States
PubMed: 31498474
DOI: 10.1002/jor.24463