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1.
Int J Mol Sci ; 25(10)2024 May 09.
Article in English | MEDLINE | ID: mdl-38791180

ABSTRACT

Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Lymphangiogenesis plays an essential role in cancer metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with VEGF-D generation and lymphangiogenesis in chondrosarcoma remains undetermined. Our results from clinical samples reveal that VEGF-D levels are markedly higher in chondrosarcoma patients than in normal individuals. Visfatin stimulation promotes VEGF-D-dependent lymphatic endothelial cell lymphangiogenesis. We also found that visfatin induces VEGF-D production by activating HIF-1α and reducing miR-2277-3p generation through the Raf/MEK/ERK signaling cascade. Importantly, visfatin controls chondrosarcoma-related lymphangiogenesis in vivo. Therefore, visfatin is a promising target in the treatment of chondrosarcoma lymphangiogenesis.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Hypoxia-Inducible Factor 1, alpha Subunit , Lymphangiogenesis , MicroRNAs , Nicotinamide Phosphoribosyltransferase , Vascular Endothelial Growth Factor D , Humans , Chondrosarcoma/metabolism , Chondrosarcoma/genetics , Chondrosarcoma/pathology , Lymphangiogenesis/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Nicotinamide Phosphoribosyltransferase/metabolism , Nicotinamide Phosphoribosyltransferase/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Vascular Endothelial Growth Factor D/metabolism , Vascular Endothelial Growth Factor D/genetics , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Bone Neoplasms/genetics , Animals , Gene Expression Regulation, Neoplastic , Cell Line, Tumor , Mice , Cytokines/metabolism , Male , Female , MAP Kinase Signaling System
2.
Mod Pathol ; 37(5): 100464, 2024 May.
Article in English | MEDLINE | ID: mdl-38447752

ABSTRACT

Extraskeletal myxoid chondrosarcoma (EMC) is an uncommon mesenchymal neoplasm characteristically composed of uniform-appearing round to spindle-shaped cells with eosinophilic cytoplasm and abundant myxoid extracellular matrix. Although the majority of cases harbor a pathognomonic t(9;22) translocation that fuses EWSR1 with the orphan nuclear receptor NR4A3, there are less common variants that partner NR4A3 with TAF15, TCF12, or TFG. By immunohistochemistry, EMC has features of both cartilaginous and neuroendocrine differentiation, as evidenced by inconsistent expression of S100 protein and synaptophysin or INSM1, respectively, in a subset of cases. Given the limitations of available immunohistochemical stains for the diagnosis of EMC, we analyzed genome-wide gene expression microarray data to identify candidate biomarkers based on differential expression in EMC in comparison with other mesenchymal neoplasms. This analysis pointed to CHRNA6 as the gene with the highest relative expression in EMC (96-fold; P = 8.2 × 10-26) and the only gene with >50-fold increased expression in EMC compared with other tumors. Using RNA chromogenic in situ hybridization, we observed strong and diffuse expression of CHRNA6 in 25 cases of EMC, including both EWSR1-rearranged and TAF15-rearranged variants. All examined cases of histologic mimics were negative for CHRNA6 overexpression; however, limited CHRNA6 expression, not reaching a threshold of >5 puncta or 1 aggregate of chromogen in >25% of cells, was observed in 69 of 685 mimics (10.1%), spanning an array of mesenchymal tumors. Taken together, these findings suggest that, with careful interpretation and the use of appropriate thresholds, CHRNA6 RNA chromogenic in situ hybridization is a potentially useful ancillary histologic tool for the diagnosis of EMC.


Subject(s)
Biomarkers, Tumor , Chondrosarcoma , In Situ Hybridization , Neoplasms, Connective and Soft Tissue , Humans , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Chondrosarcoma/genetics , Chondrosarcoma/pathology , Chondrosarcoma/diagnosis , Chondrosarcoma/metabolism , Neoplasms, Connective and Soft Tissue/genetics , Neoplasms, Connective and Soft Tissue/pathology , Neoplasms, Connective and Soft Tissue/diagnosis , Female , Male , Middle Aged , Aged , In Situ Hybridization/methods , Adult , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Neoplasms, Connective Tissue/genetics , Neoplasms, Connective Tissue/pathology , Neoplasms, Connective Tissue/diagnosis , Aged, 80 and over , Immunohistochemistry
4.
Funct Integr Genomics ; 24(2): 54, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38467932

ABSTRACT

Despite substantial progress in clinical trials of osteoarthritis (OA) gene therapy, the prevalence of OA is still on the rise. MiRNAs have a potential biomarker and therapeutic target for OA. OA cartilage and chondrosarcoma cells were studied to determine the role of miR-29a-3p and PTEN. OA cartilage and human chondrosarcoma cells (SW1353) were obtained. miR-29a-3p and PTEN signature expression was determined by RT-qPCR. The binding relationship between miR-29a-3p and PTEN was investigated by dual-luciferase reporter gene and western blot assay. TUNEL, immunohistochemistry, CCK-8, and flow cytometry were utilized to determine the proliferation and apoptosis of SW1353 cells. This study indicated downregulation of miR-29a-3p expression and upregulation of PTEN expression in human OA primary chondrocytes or OA tissue samples, compared with the normal cartilage cells or tissues. PTEN expression was negatively correlated with miR-29a-3p expression, and miR-29a-3p targeted PTEN mechanistically. miR-29a-3p reduced SW1353 cell activity and proliferation and promoted cell apoptosis. However, the aforementioned effects could be reversed by downregulating PTEN. miR-29a-3p can stimulate chondrocyte proliferation and inhibit apoptosis by inhibiting PTEN expression.


Subject(s)
Bone Neoplasms , Chondrosarcoma , MicroRNAs , Osteoarthritis , Humans , Apoptosis/genetics , Cell Proliferation/genetics , Chondrosarcoma/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Osteoarthritis/genetics , Tensins
5.
EBioMedicine ; 102: 105090, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38547578

ABSTRACT

BACKGROUND: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. METHODS: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FINDINGS: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. INTERPRETATION: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FUNDING: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).


Subject(s)
Aminopyridines , Bone Neoplasms , Chondrosarcoma , Sarcoma , Triazines , Humans , Animals , Mice , Precision Medicine , Chondrosarcoma/drug therapy , Chondrosarcoma/genetics , Isocitrate Dehydrogenase/genetics , Mutation , Bone Neoplasms/genetics
6.
Int J Mol Sci ; 25(6)2024 Mar 09.
Article in English | MEDLINE | ID: mdl-38542153

ABSTRACT

Chondrosarcoma, the second most common primary malignant bone tumor, originates from cartilaginous tissue and accounts for almost 20% of all primary bone tumors. The management of chondrosarcoma remains challenging due to its diverse clinical course and prognosis, which can range from benign to highly aggressive with a huge risk of metastasis. Emerging research has demonstrated the importance of microRNA (miRNA) dysregulation in the pathogenesis of chondrosarcoma. MiRNAs are small, noncoding RNA molecules that play an essential role in gene expression regulation by targeting specific messenger RNAs (mRNAs) for degradation or translational repression. This article provides an extensive review of current miRNA research in chondrosarcoma, focusing on diagnostic strategies, cell cycle regulation, drug resistance, biomarkers of progression, and stem cell phenotype. We will examine recent studies identifying differentially expressed miRNAs in chondrosarcoma compared to normal cartilage tissue, exploring their potential as diagnostic and prognostic biomarkers. Furthermore, we will discuss the role of miRNAs in regulating cell cycle progression and their potential as therapeutic targets to overcome drug resistance. We will also investigate the prospective utility of miRNAs as biomarkers of progression and their role in modulating the stem cell phenotype of chondrosarcoma cells. This article offers a comprehensive analysis of current miRNA research in chondrosarcoma, focusing on its potential as diagnostic and prognostic biomarkers, therapeutic targets, and regulators of disease progression. By integrating the latest discoveries in this field, we aim to contribute to the development of novel approaches to the prevention, diagnosis, and treatment of chondrosarcoma, ultimately enhancing patient outcomes.


Subject(s)
Bone Neoplasms , Chondrosarcoma , MicroRNAs , Neoplasms, Second Primary , Humans , MicroRNAs/metabolism , Prognosis , Gene Expression Regulation, Neoplastic , Chondrosarcoma/diagnosis , Chondrosarcoma/drug therapy , Chondrosarcoma/genetics , Bone Neoplasms/diagnosis , Bone Neoplasms/drug therapy , Bone Neoplasms/genetics , Neoplasms, Second Primary/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism
7.
Orphanet J Rare Dis ; 19(1): 63, 2024 Feb 13.
Article in English | MEDLINE | ID: mdl-38351015

ABSTRACT

BACKGROUND: Multiple osteochondromas is genetic disorder characterized by the formation of multiple benign cartilage-capped bone tumors, named osteochondromas, during skeletal development. The most feared complication is the secondary peripheral chondrosarcoma, a malignant cartilaginous neoplasm that arises from the chondroid cap of pre-existent osteochondromas. We conducted a retrospective cohort study on patients diagnosed and followed up from 1960 to 2019 to describe the clinical and pathological features of individuals affected by peripheral chondrosarcoma in multiple osteochondromas, to evaluate follow up information and individual outcome and to compare the results with literature. Data, including age, gender, site, histological grade, cartilage cap thickness, surgical treatments, surgical margins, genotype mutational status as well as treatment details were captured from the hospital electronic health records and from Registry of Multiple Osteochondromas. In addition, a complete histological review of all hematoxylin and eosin (H&E)-stained sections has been performed by expert pathologists. RESULTS: One hundred five of the screened cases were included in the present study. The age at diagnosis of SPC ranges from 13 to 63, with median age at diagnosis of 34 years. The site most frequently affected by malignant degeneration was the pelvis (46 patients, 44%) with higher incidence in male patients (32 males vs.14 females). The second one was lower limbs (including femur, fibula, or tibia), identified in 35 patients. Histological information - available for 103 patients - showed: 59 patients with grade 1; 40 patients had a grade 2 and 4 patients had a grade 3. The most common surgical treatment was the complete resection, followed by debulking, amputation and partial resection. Most of cases did not have recurrence of the disease. Outcome in disease-free survival highlights that a worse course of the disease was associated with histological grade 2 or 3, and partial resection surgery. In most of analyzed cases (94%) a pathogenic variant was identified. CONCLUSIONS: In conclusion, the present study gives an overview of the secondary peripheral chondrosarcomas, confirming that this disease represents an impacting complication for multiple osteochondromas patients and suggests that malignant transformation can occur also in younger patient, in a not irrelevant number of cases.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Exostoses, Multiple Hereditary , Osteochondroma , Female , Humans , Male , Adult , Exostoses, Multiple Hereditary/genetics , Retrospective Studies , Chondrosarcoma/genetics , Chondrosarcoma/diagnosis , Chondrosarcoma/pathology , Osteochondroma/pathology , Disease-Free Survival , Bone Neoplasms/genetics , Bone Neoplasms/diagnosis , Bone Neoplasms/pathology
8.
Int J Mol Sci ; 25(3)2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38339014

ABSTRACT

Recurrent gene fusions (GFs) in translocated sarcomas are recognized as major oncogenic drivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes, defining different entities among a broad range of mesenchymal neoplasms. Molecular testing of EWSR1 translocation traditionally relies on FISH assays with break-apart probes, which are unable to identify the fusion partner. Therefore, other ancillary molecular diagnostic modalities are being increasingly adopted for accurate classification of these neoplasms. Herein, we report three cases with rare GFs involving EWSR1 in undifferentiated mesenchymal neoplasms with uncertain differential diagnoses, using targeted RNA-seq and confirming with RT-PCR and Sanger sequencing. Two GFs involved hormone nuclear receptors as 3' partners, NR4A2 and RORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3' partner in extraskeletal myxoid chondrosarcoma. The third GF, EWSR1::BEND2, has previously been reported in a subtype of astroblastoma and other rare entities, including a single case of a soft-tissue tumor that we discuss in this work. In conclusion, our findings indicate that the catalogue of mesenchymal neoplasm-bearing EWSR1 fusions continues to grow, underscoring the value of using molecular ancillary techniques with higher diagnostic abilities in the routine clinical setting.


Subject(s)
Neoplasms, Connective and Soft Tissue , Oncogene Proteins, Fusion , RNA-Binding Protein EWS , Soft Tissue Neoplasms , Humans , Calmodulin-Binding Proteins/genetics , Chondrosarcoma/genetics , Oncogene Proteins, Fusion/genetics , RNA-Binding Protein EWS/genetics , RNA-Binding Proteins/genetics , Sarcoma/pathology , Soft Tissue Neoplasms/genetics
9.
Genes (Basel) ; 15(2)2024 Feb 14.
Article in English | MEDLINE | ID: mdl-38397231

ABSTRACT

Background: Undifferentiated pleomorphic sarcoma of bone (UPSb) is a rare primary bone sarcoma that lacks a specific line of differentiation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, is challenging due to their overlapping features. We have previously identified that UPSb tumours have elevated mRNA levels of Fibroblast Growth Factor 23 (FGF23) transcripts compared to other sarcomas including osteosarcoma. In the present study, we evaluated the specificity and practicality of FGF23 immunoreactivity as a specific diagnostic tool to differentiate UPSb tumours from osteosarcomas and dedifferentiated chondrosarcomas. Methods: A total of 10 UPSb, 10 osteosarcoma, and 10 dedifferentiated chondrosarcoma cases (all high-grade), were retrieved and immunohistochemistry for FGF23 was performed. Results: FGF23 protein was expressed at high levels in 80-90% of undifferentiated pleomorphic sarcoma of the bone cases, whereas it was expressed at significantly lower levels in dedifferentiated chondrosarcoma and osteosarcoma cases. A semiquantitative analysis, considering the intensity of immunoreactivity, confirmed significantly elevated FGF23 expression levels in UPSb tissues compared to those observed in osteosarcoma and dedifferentiated chondrosarcoma tissues. Conclusions: The results we present here suggest that FGF23 immunohistochemistry may be a useful tool to aid in differentiating UPSb from morphologically similar malignant bone sarcomas, especially in situations where sampling is restricted and there is limited clinical information available.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Fibroblast Growth Factor-23 , Osteosarcoma , Sarcoma , Humans , Bone Neoplasms/diagnosis , Bone Neoplasms/genetics , Chondrosarcoma/diagnosis , Chondrosarcoma/genetics , Chondrosarcoma/metabolism , Osteosarcoma/diagnosis , Osteosarcoma/genetics , Sarcoma/diagnosis , Sarcoma/genetics , Sarcoma/pathology , Fibroblast Growth Factor-23/metabolism
10.
Cell Rep Med ; 5(1): 101385, 2024 01 16.
Article in English | MEDLINE | ID: mdl-38232691

ABSTRACT

In this Backstory, we narrate our journey in establishing a multidisciplinary team for sarcoma research and uncovering vulnerabilities in chondrosarcoma cells associated with their NAD+ dependencies for survival.1 Our findings hold promise for exploitation, yielding a synergistic cytotoxic effect when combined with systemic therapy.


Subject(s)
Antineoplastic Agents , Bone Neoplasms , Chondrosarcoma , Humans , Antineoplastic Agents/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/genetics , Chondrosarcoma/genetics , Chondrosarcoma/drug therapy
11.
Commun Biol ; 7(1): 124, 2024 01 24.
Article in English | MEDLINE | ID: mdl-38267611

ABSTRACT

The transformation of benign lesions to malignant tumours is a crucial aspect of understanding chondrosarcomas, which are malignant cartilage tumours that could develop from benign chondroid lesions. However, the process of malignant transformation for chondroid lesions remains poorly understood, and no reliable markers are available to aid clinical decision-making. To address this issue, we conducted a study analysing 11 primary cartilage tumours and controls using single-cell RNA sequencing. By creating a single-cell atlas, we were able to identify the role of endoplasmic reticulum (ER) stress in the malignant transformation of conventional central chondrosarcomas (CCCS). Our research revealed that lower levels of ER stress promote chondrosarcoma growth in a patient-derived xenograft mouse model, while intensive ER stress reduces primary chondrosarcoma cell viability. Furthermore, we discovered that the NF-κB pathway alleviates ER stress-induced apoptosis during chondrosarcoma progression. Our single-cell signatures and large public data support the use of key ER stress regulators, such as DNA Damage Inducible Transcript 3 (DDIT3; also known as CHOP), as malignant markers for overall patient survival. Ultimately, our study highlights the significant role that ER stress plays in the malignant transformation of cartilaginous tumours and provides a valuable resource for future diagnostic markers and therapeutic strategies.


Subject(s)
Ascomycota , Chondrosarcoma , Humans , Animals , Mice , Chondrosarcoma/genetics , Apoptosis , Cell Survival , Disease Models, Animal , Endoplasmic Reticulum Stress
12.
Head Neck Pathol ; 18(1): 1, 2024 Jan 18.
Article in English | MEDLINE | ID: mdl-38236556

ABSTRACT

Somatic-type malignancy (STM) can occur infrequently within a primary or metastatic testicular germ cell tumor (TGCT) and is associated with dismal prognosis and survival. STM with chondrosarcomatous features is exceedingly rare and head and neck involvement has not been previously documented. A 39-year-old white man presented with nasal obstruction and epistaxis. Imaging disclosed a 6.9-cm expansile tumor involving the nasal cavity and skull base with intraorbital and intracranial extension. The histopathologic properties of the tumor were compatible with chondrosarcoma, grade II-III. Immunohistochemically, malignant cells were strongly and diffusely positive for S100 and epithelial markers, and showed loss of SMARCB1 expression. IDH1/2 mutations were not detected. Following whole-body PET scan, a 7.0-cm left testicular mass was discovered and diagnosed as seminoma with syncytiotrophoblastic cells, stage pT3NXM1b. Extensive retroperitoneal, mediastinal, and supraclavicular lymphadenopathy was also noticed. Histopathologic examination of the left supraclavicular lymph node revealed metastatic seminoma. By FISH, most metastatic nodal seminoma cells harbored 1 to 4 copies of isochromosome 12p, while the chondrosarcoma featured duplication of 12p. Presence of a malignant TGCT with disseminated supradiaphragmatic lymphadenopathy, the unique immunophenotypic properties of the skull-based chondrosarcoma and lack of IDH1/2 aberrations with gain of 12p strongly support the diagnosis of STM chondrosarcoma arising from metastatic TGCT. The patient did not respond to chemotherapy and succumbed three months after diagnosis. Although exceedingly uncommon, metastasis to the head and neck may occur in patients with TGCT. This case of STM chondrosarcoma demonstrated divergent immunophenotypic and molecular characteristics compared to "typical" examples of head and neck chondrosarcoma. High index of suspicion is advised regarding the diagnosis of lesions that present with otherwise typical histomorphology but unexpected immunohistochemical or molecular features.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Lymphadenopathy , Neoplasms, Germ Cell and Embryonal , Neoplasms, Second Primary , Seminoma , Testicular Neoplasms , Male , Humans , Adult , Chondrosarcoma/genetics , Skull Base , Testicular Neoplasms/genetics , Bone Neoplasms/genetics , SMARCB1 Protein
14.
Cell Rep Med ; 5(1): 101342, 2024 01 16.
Article in English | MEDLINE | ID: mdl-38128534

ABSTRACT

Chondrosarcomas represent the second most common primary bone malignancy. Despite the vulnerability of chondrosarcoma cells to nicotinamide adenine dinucleotide (NAD+) depletion, targeting the NAD+ synthesis pathway remains challenging due to broad implications in biological processes. Here, we establish SIRT1 as a central mediator reinforcing the dependency of chondrosarcoma cells on NAD+ metabolism via HIF-2α-mediated transcriptional reprogramming. SIRT1 knockdown abolishes aggressive phenotypes of chondrosarcomas in orthotopically transplanted tumors in mice. Chondrosarcoma cells thrive under glucose starvation by accumulating NAD+ and subsequently activating the SIRT1-HIF-2α axis. Decoupling this link via SIRT1 inhibition unleashes apoptosis and suppresses tumor progression in conjunction with chemotherapy. Unsupervised clustering analysis identifies a high-risk chondrosarcoma patient subgroup characterized by the upregulation of NAD+ biosynthesis genes. Finally, SIRT1 inhibition abolishes HIF-2α transcriptional activity and sensitizes chondrosarcoma cells to doxorubicin-induced cytotoxicity, irrespective of underlying pathways to accumulate intracellular NAD+. We provide system-level guidelines to develop therapeutic strategies for chondrosarcomas.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Humans , Animals , Mice , NAD/metabolism , Sirtuin 1/genetics , Sirtuin 1/metabolism , Chondrosarcoma/drug therapy , Chondrosarcoma/genetics , Chondrosarcoma/pathology , Bone Neoplasms/drug therapy , Bone Neoplasms/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/therapeutic use
15.
Int J Biol Sci ; 19(16): 5174-5186, 2023.
Article in English | MEDLINE | ID: mdl-37928274

ABSTRACT

Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting reactive oxygen species (ROS) accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Humans , Cisplatin/pharmacology , Cisplatin/therapeutic use , Amphiregulin/genetics , Glutamine , Drug Resistance, Neoplasm/genetics , Chondrosarcoma/drug therapy , Chondrosarcoma/genetics , Cell Line, Tumor , Minor Histocompatibility Antigens , Amino Acid Transport System ASC
16.
Diagn Pathol ; 18(1): 103, 2023 Sep 13.
Article in English | MEDLINE | ID: mdl-37705036

ABSTRACT

BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant tumor described in the head and neck region, especially in the gingival. We present one case arising in the gingival of right mandible, and briefly reviewed the related literature. CASE PRESENTATION: A 24-year-old male patient with a lesion of 3.5*2.0 cm in buccal gingival of right posterior mandible for 2 months. The tumor was composed of cartilaginous structures and myxoid matrix. Immunohistochemical(IHC) showed that the tumor cells to be positive for vimentin, focally positive for S-100, negative for calponin, SMA, SOX10. The Ki-67 labelling index was 80%. Fluorescent in situ Hybridization (FISH) was positive for NR4A3 rearrangement. CONCLUSIONS: Due to its unusual site and low incidence in the oral region, a combination of histological findings, immunohistochemistry, and molecular pathology as well as differential diagnosis with other diseases should be taken into consideration in the process of clinical diagnosis and treatment.


Subject(s)
Chondrosarcoma , Male , Humans , Young Adult , Adult , In Situ Hybridization, Fluorescence , Chondrosarcoma/genetics , Diagnosis, Differential , Mandible
17.
Genes Chromosomes Cancer ; 62(12): 755-760, 2023 12.
Article in English | MEDLINE | ID: mdl-37732625

ABSTRACT

Dedifferentiated chondrosarcoma is a subtype of chondrosarcoma with a biphasic histological appearance of a chondrosarcoma component transitioning to a high-grade, noncartilaginous sarcoma. It is particularly difficult to confirm the diagnosis when a sarcoma lacking cartilaginous component occurs at a distant location from the primary lesion. The patient was a 72-year-old woman with multiple lesions in the pelvis, lungs, and liver, 18 months after resection of grade 2 central chondrosarcoma of the sternum. Imaging showed no cartilage component in any location. Although a needle biopsy from the pelvic region confirmed the diagnosis as high-grade sarcoma without a cartilage component, it was difficult to distinguish between a new primary sarcoma and metachronous metastatic lesions from patient's known prior dedifferentiated chondrosarcoma. We therefore performed a comparative molecular analysis by whole-exome sequencing of the biopsy sample and the resected sternal central chondrosarcoma. Both lesions had no IDH1/2 mutations but shared 19 somatic mutations and wide-range chromosomal losses, indicating similar origin. This case illustrates the challenge is coupling a diagnosis of metastatic dedifferentiated chondrosarcoma when no chondroid component is evident. Our study also highlights the benefit of genomic analysis in this differential diagnosis, especially in the context of dedifferentiated chondrosarcoma lacking IDH1/2 mutations.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Female , Humans , Aged , Chondrosarcoma/diagnosis , Chondrosarcoma/genetics , Chondrosarcoma/pathology , Mutation , Chromosome Aberrations , Bone Neoplasms/diagnosis , Bone Neoplasms/genetics , Bone Neoplasms/pathology
18.
BMC Cancer ; 23(1): 907, 2023 Sep 26.
Article in English | MEDLINE | ID: mdl-37752419

ABSTRACT

BACKGROUND: Heterozygous isocitrate dehydrogenase (IDH) mutations occur in about half of conventional central bone chondrosarcomas (CCBC). Aim of this study was to assess the frequency and prognostic impact of IDH mutations in high grade CCBC patients. METHODS: 64 patients with G2 and G3 CCBC were included. DNA extraction, PCR amplification of IDH1/2 exon 4s, and sequencing analysis with Sanger were performed. RESULTS: IDH mutations were detected in 24/54 patients (44%): IDH1 in 18, IDH2 in 4, and both IDH1/2 in 2 patients. The frequency of mutations was 37% in G2 vs. 69% in G3 (p = 0.039), and 100% in three Ollier disease associated chondrosarcoma. 5-year overall survival (OS) at 124 months (range 1-166) was 51%, with no significant difference based on the IDH mutational status: 61% in IDHmut vs. 44% in IDH wild type (IDHwt). The 5-year relapse free survival (RFS) was 33% (95% CI:10-57) for IDHmut vs. 57% (95%CI: 30-77) for IDHwt. Progression free survival (PFS) was 25% (95%CI:1-65) IDHmut vs. 16% (95%CI: 0.7-52) IDHwt. 55% (5/9) of IDHmut G2 became higher grade at the recurrence, as compared with 25% (3/12) of G2 IDHwt. CONCLUSIONS: This study shows a higher frequency of IDH mutations in G3 CCBC as compared with G2. No significant differences in OS, RFS, and PFS by mutational status were detected. After relapse, a higher rate of G3 for IDH mutated CCBC was observed.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Humans , Isocitrate Dehydrogenase/genetics , Mutation , Chondrosarcoma/genetics , Exons , Bone Neoplasms/genetics
19.
BMC Cancer ; 23(1): 862, 2023 Sep 12.
Article in English | MEDLINE | ID: mdl-37700272

ABSTRACT

BACKGROUND: Cancer cells are characterized by changes in cell cytoskeletal architecture and stiffness. Despite advances in understanding the molecular mechanisms of musculoskeletal cancers, the corresponding cellular mechanical properties remain largely unexplored. The aim of this study was to investigate the changes in cellular stiffness and the associated cytoskeleton configuration alterations in various musculoskeletal cancer cells. METHODS: Cell lines from five main sarcoma types of the musculoskeletal system (chondrosarcoma, osteosarcoma, Ewing sarcoma, fibrosarcoma and rhabdomyosarcoma) as well as their healthy cell counterparts (chondrocytes, osteoblasts, mesenchymal stem cells, fibroblasts, skeletal muscle cells) were subjected to cell stiffness measurements via atomic force microscopy (AFM). Biochemical and structural changes of the cytoskeleton (F-actin, ß-tubulin and actin-related protein 2/3) were assessed by means of fluorescence labelling, ELISA and qPCR. RESULTS: While AFM stiffness measurements showed that the majority of cancer cells (osteosarcoma, Ewing sarcoma, fibrosarcoma and rhabdomyosarcoma) were significantly less stiff than their corresponding non-malignant counterparts (p < 0.001), the chondrosarcoma cells were significant stiffer than the chondrocytes (p < 0.001). Microscopically, the distribution of F-actin differed between malignant entities and healthy counterparts: the organisation in well aligned stress fibers was disrupted in cancer cell lines and the proteins was mainly concentrated at the periphery of the cell, whereas ß-tubulin had a predominantly perinuclear localization. While the F-actin content was lower in cancer cells, particularly Ewing sarcoma (p = 0.018) and Fibrosarcoma (p = 0.023), this effect was even more pronounced in the case of ß-tubulin for all cancer-healthy cell duos. Interestingly, chondrosarcoma cells were characterized by a significant upregulation of ß-tubulin gene expression (p = 0.005) and protein amount (p = 0.032). CONCLUSION: Modifications in cellular stiffness, along with structural and compositional cytoskeleton rearrangement, constitute typical features of sarcomas cells, when compared to their healthy counterpart. Notably, whereas a decrease in stiffness is typically a feature of malignant entities, chondrosarcoma cells were stiffer than chondrocytes, with chondrosarcoma cells exhibiting a significantly upregulated ß-tubulin expression. Each Sarcoma entity may have his own cellular-stiffness and cytoskeleton organisation/composition fingerprint, which in turn may be exploited for diagnostic or therapeutic purposes.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Fibrosarcoma , Osteosarcoma , Rhabdomyosarcoma , Sarcoma, Ewing , Sarcoma , Soft Tissue Neoplasms , Humans , Sarcoma, Ewing/genetics , Tubulin , Actins , Osteosarcoma/genetics , Rhabdomyosarcoma/genetics , Chondrosarcoma/genetics , Biomarkers , Bone Neoplasms/genetics
20.
Acta Biochim Pol ; 70(3): 685-692, 2023 Sep 18.
Article in English | MEDLINE | ID: mdl-37722070

ABSTRACT

Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is an enzyme that regulates reactive oxygen species (ROS) generation, and its function in the development of chondrosarcoma remains unclear. In the present study, we studied NOX4 expression in chondrosarcoma by immunochemical examination, and analyzed the role of NOX4 in viability and apoptosis of human chondrosarcoma cell line SW1353 using NOX4 siRNA or NOX4 inhibitor GKT137831. NOX4 level significantly increased in tumor compared to that in para-carcinoma sample. The levels of NOX4 were positively correlated with histological grade and Musculoskeletal Tumor Society stage of the patients. NOX4 level was significantly increased in SW1353 compared with that in chondrocytes CHON-001. Knockdown of NOX4 or inhibition of NOX4 by GKT137831 both decreased generation of ROS, and induced growth inhibition and apoptosis in SW1353, accompanied with the activation of caspases (caspase-3, caspase-8 and caspses-9), upregulation of Bax, cytochrome C(cyt-c), cleaved-PARP and down-regulation of Bcl-2. Moreover, NOX4 siRNA and GKT137831 decreased the expression of p-Akt, p-ERK and p-p65 in SW1353 cells. In an in vivo study, NOX4 shRNA transfected SW1353 have shown impaired growth ability compared to the SW1353 when they were injected into the nude mice. Meanwhile, GKT137831 induced growth inhibition and apoptosis in SW1353 xenograft animals, together with increased expression of Bax, cyt-c, cleaved-PARP, and decreased expression of Bcl-2, p-Akt, p-ERK and p-p65. NOX4 plays a positive role in the development of chondrosarcoma and could serve as a promising target against chondrosarcoma clinically.


Subject(s)
Bone Neoplasms , Chondrosarcoma , Animals , Humans , Mice , bcl-2-Associated X Protein/genetics , Chondrosarcoma/genetics , Mice, Nude , NADPH Oxidase 4/genetics , Poly(ADP-ribose) Polymerase Inhibitors , Proto-Oncogene Proteins c-akt , Reactive Oxygen Species
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