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Osteogenic Sarcoma (osteosarcoma) is a bone forming cancer. It is the most frequent type of bone tumour and is most common between the ages of 15 to 25. Over 90% of tumours are located in the metaphysis (the growing ends of the bone), the most common sites are the bones around the knee which account for 80% of cases. Osteosarcomas vary greatly in radiological and pathological features and therefore needs careful diagnosis to differentiate this from other bone tumours. Most are high grade intramedullary osteosarcomas, about 5% are low grade lesions, some are secondary osteosarcomas (for example those caused by radiation therapy).

Figure 1. Radiograph showing an osteolytic and osteoblastic intra-medullary tumor characteristic of osteosarcoma. From Layfield J et al. Clin Med Pathol. 2008; 1: 55-59. Available under a Creative Commons CC-BY-3.0 license.

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See also: Genetic features of Osteosarcoma

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Oshiro H, Tome Y, Miyake K, et al.
A Novel Orthotopic Mouse Model of Lung Metastasis Using Fluorescent Patient-derived Osteosarcoma Cells.
Anticancer Res. 2021; 41(2):635-640 [PubMed] Related Publications
BACKGROUND: A mouse model of metastatic osteosarcoma is imperative to identify effective agents for metastatic osteosarcoma, which is a recalcitrant disease. In the present study, we established osteosarcoma patient-derived cells (OS-PDCs) and transfected them with green fluorescent protein (GFP).
MATERIALS AND METHODS: The OS-PDCs were transfected with GFP-lentivirus. GFP-expressing OS-PDCs (2.0×10
RESULTS: Primary orthotopic tumors were established in two out of three mice. The GFP-expressing OS-PDCs in the PDOC model were visualized. Multiple GFP-expressing lung metastases were detected in one of the two mice with primary tumor.
CONCLUSION: The present study proves the concept that a GFP-expressing PDOC model can mimic clinical lung-metastatic osteosarcoma. This model can serve as a paradigm to screen for effective drugs for osteosarcoma lung metastasis.

Araki Y, Hayashi K, Yamamoto N, et al.
Reconstruction using a frozen autograft for a skull and humeral lesion of synchronous multicentric osteosarcoma after undergoing successful neoadjuvant chemotherapy: a case report and review of the literature.
BMC Surg. 2021; 21(1):56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Synchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously.
CASE PRESENTATION: We report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free.
CONCLUSIONS: An early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.

Tu Y, Cai Q, Zhu X, Xu M
Down-regulation of HCP5 inhibits cell proliferation, migration, and invasion through regulating EPHA7 by competitively binding miR-101 in osteosarcoma.
Braz J Med Biol Res. 2021; 54(2):e9161 [PubMed] Free Access to Full Article Related Publications
Patients with osteosarcoma (OS) usually have poor overall survival because of frequent metastasis. Long non-coding RNAs (lncRNAs) have been reported to be associated with tumorigenesis and metastasis. In this study, we investigated the expression and roles of lncRNA human histocompatibility leukocyte antigen (HLA) complex P5 (HCP5) in OS, aiming to provide a novel molecular mechanism for OS. HCP5 was up-regulated both in OS tissues and cell lines and high expression of HCP5 was associated to low survival in OS patients. Down-regulation of HCP5 inhibited cell proliferation, migration, and invasion, suggesting its carcinogenic role in OS. miR-101 was targeted by HCP5 and its expression was decreased in OS. The inhibitor of miR-101 reversed the impact of HCP5 down-regulation on cell proliferation, apoptosis, and metastasis in OS. Ephrin receptor 7 (EPHA7) was proved to be a target of miR-101 and had ability to recover the effects of miR-101 inhibitor in OS. In conclusion, lncRNA HCP5 knockdown suppressed cell proliferation, migration, and invasion, and induced apoptosis through depleting the expression of EPHA7 by binding to miR-101, providing a potential therapeutic strategy of HCP5 in OS.

Liu Y, Liao S, Bennett S, et al.
STAT3 and its targeting inhibitors in osteosarcoma.
Cell Prolif. 2021; 54(2):e12974 [PubMed] Free Access to Full Article Related Publications
Signal transducer and activator of transcription 3 (STAT3) is one of seven STAT family members involved with the regulation of cellular growth, differentiation and survival. STAT proteins are conserved among eukaryotes and are important for biological functions of embryogenesis, immunity, haematopoiesis and cell migration. STAT3 is widely expressed and located in the cytoplasm in an inactive form. STAT3 is rapidly and transiently activated by tyrosine phosphorylation by a range of signalling pathways, including cytokines from the IL-6 family and growth factors, such as EGF and PDGF. STAT3 activation and subsequent dimer formation initiates nuclear translocation of STAT3 for the regulation of target gene transcription. Four STAT3 isoforms have been identified, which have distinct biological functions. STAT3 is considered a proto-oncogene and constitutive activation of STAT3 is implicated in the development of various cancers, including multiple myeloma, leukaemia and lymphomas. In this review, we focus on recent progress on STAT3 and osteosarcoma (OS). Notably, STAT3 is overexpressed and associated with the poor prognosis of OS. Constitutive activation of STAT3 in OS appears to upregulate the expression of target oncogenes, leading to OS cell transformation, proliferation, tumour formation, invasion, metastasis, immune evasion and drug resistance. Taken together, STAT3 is a target for cancer therapy, and STAT3 inhibitors represent potential therapeutic candidates for the treatment of OS.

Shi J, Huang D, Zhang G, et al.
A DNA methylation-associated nomogram predicts the overall survival of osteosarcoma.
Medicine (Baltimore). 2020; 99(51):e23772 [PubMed] Free Access to Full Article Related Publications
ABSTRACT: Numerous reports have demonstrated that DNA methylation may be underlying prognostic biomarkers of cancer. However, few studies indicated that DNA methylation was independent biomarker for osteosarcoma prognosis. We aimed to discover and validate a novel DNA methylation signature for prediction of osteosarcoma patients' overall survival (OS).The DNA methylation data of osteosarcoma patients was researched from The Cancer Genome Atlas (TCGA) database. Overall, 80 samples with 485,577 DNA methylation sites were enrolled in our study. The 80 samples were randomly allocated into training dataset (first two-thirds) and validation dataset (remaining one-third). Initially, the univariate Cox proportional hazard analysis was performed in the training dataset to determine methylation sites significantly (P < .05) relevant to osteosarcoma patients' OS as underlying indicators. Subsequently, the underlying indicators were employed to carry out the least absolute shrinkage and selection operator (LASSO) Cox regression analysis for further selecting the candidate methylation sites. Then, the selected candidate methylation sites were employed as covariates to perform multivariate Cox proportional hazard model for identifying the predictor of OS in osteosarcoma patients. The validation dataset was used to validate the predictive accuracy by receiver operating characteristic (ROC) analysis and Kaplan-Meier survival analysis.We discovered a 7-DNA methylation signature closely relevant to OS of osteosarcoma patients. AUC at 1, 3, 5 years in training dataset (0.951, 0.922, 0.925, respectively), testing dataset (0.952, 0.918, 0.925, respectively), and entire dataset (0.952, 0.968, 0.968, respectively). Suggesting high predictive values for OS of osteosarcoma patients. In addition, a methylation-associated nomogram suggested good predictive value and clinical application.We discovered and validated a novel 7-DNA methylation-associated nomogram for predicting OS of osteosarcoma patients.

Zhou D, Gopinath SCB, Mohamed Saheed MS, et al.
MXene Surface on Multiple Junction Triangles for Determining Osteosarcoma Cancer Biomarker by Dielectrode Microgap Sensor.
Int J Nanomedicine. 2020; 15:10171-10181 [PubMed] Free Access to Full Article Related Publications
Background: In recent years, nanomaterials have justified their dissemination for biosensor application towards the sensitive and selective detections of clinical biomarkers at the lower levels. MXene is a two-dimensional layered transition metal, attractive for biosensing due to its chemical, physical and electrical properties along with the biocompatibility.
Materials and Methods: This work was focused on diagnosing osteosarcoma (OS), a common bone cancer, on MXene-modified multiple junction triangles by dielectrode sensing. Survivin protein gene is highly correlated with OS, identified on this sensing surface. Capture DNA was immobilized on MXene by using 3-glycidoxypropyltrimethoxysilane as an amine linker and duplexed by the target DNA sequence.
Results: The limitation and sensitivity of detection were found as 1 fM with the acceptable regression co-efficient value (y=1.0037⨰ + 0.525; R
Conclusion: This microgap device with Mxene-modified multiple junction triangles dielectrode surface is beneficial to quantify the survivin gene at its lower level and diagnosing OS complication levels.

Zhou Y, Yang D, Yang Q, et al.
Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma.
Nat Commun. 2020; 11(1):6322 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4

Kushlinskii NE, Alferov AA, Boulytcheva IV, et al.
Comparative analysis of the levels of soluble forms of receptor and ligand of the immunity control point PD-1/PD-L1 in the blood serum of patients with typical bone osteosarcoma and chondrosarcoma.
Klin Lab Diagn. 2020; 65(11):669-675 [PubMed] Related Publications
Results of ELISA investigation of the pretreatment sPD-1 and sPD-L1 content in blood serum of 133 bone neoplasms patients aged 6-70 years and 57 practically healthy control persons aged 12-70 years are described. In 14 patients the neoplasms were of a benign character, in 16 - borderline giant-cell bone tumor was diagnosed, and in 103 - malignant bone lesions including 39 osteosarcomas and 42 chondrosarcomas were revealed. The sPD-1 receptor concentrations in blood serum did not differ between control healthy persons and primary bone tumor patients, while serum sPD-L1 level in bone tumor patients was statistically significantly increased (p<0.0000001). By means of ROC curve construction a cut-off sPD-L1 level of 16.5 pg/ml was found that imposed 75,9% sensitivity and 75,4% specificity in relation to healthy control. However, the frequency of sPD-L1 levels exceeding 16.5 pg/ml was approximately similar in benign, borderline and malignant bone tumor patients. Analysis of the pattern of sPD-1 and sPD-L1 circulation in the peripheral blood of patients with the most prevalent malignant bone tumors - osteosarcoma and chondrosarcoma - demonstrated that in both sarcoma types sPD-L1 level was significantly higher than in control, but in patients with chondrogenic tumors the soluble ligand sPD-L1 dominates in the circulation, while in those with osteogenic tumors - sPD-1 receptor prevails. In particular, sPD-1 level is statistically significantly higher in patients with typical osteosarcoma than in those with typical chondrosarcoma (p=0.002437), and sPD-L1/sPD-1 concentration ratio in chondrosarcoma is highly significantly more than 2-fold higher than in osteosarcoma (0.81 and 0.35 respectively; p=0.000284). The sensitivity of sPD-L1 ≥16.5 pg/ml test in typical osteosarcoma patients' group comprised only 70.2%, and in those with typical chondrosarcoma - 84.6%. Serum sPD-1 and sPD-L1 concentrations in osteosarcoma and chondrosarcoma patients were not associated with the indices of tumor advancement, its histological grade, localization in the osseous system, and type of affected bone. Thus, it can be concluded that the ratio between circulating soluble forms of the receptor and the ligand of PD-1/PD-L signaling pathway differs between patients with chondrogenic and those with osteogenic tumors, sPD-L1 being diagnostically valuable mostly for chondrogenic bone neoplasms.

Song Y
Mechanism of the Notch signaling pathway in enhancing the efficacy of chemotherapy drugs in osteosarcoma.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2020; 45(10):1234-1240 [PubMed] Related Publications
Osteosarcoma is the most common malignant tumors of bone. Since 1970s, researchers had used chemotherapy drugs to treat osteosarcoma. However, multidrug resistance is a major adverse reaction that affects the efficacy of chemotherapy drugs, leading to the reduced survival rate of osteosarcoma patients. The Notch signaling pathway plays an important role in osteosarcoma proliferation, which affects tumor resistance by reducing intracellular drug accumulation, regulating epithelial-mesenchymal transition, dysregulating microRNA, disrupting the expression of apoptosis genes, and regulating tumor stem cells.

Mardanpour K, Rahbar M, Mardanpour S, et al.
Co-expression of Epstein-Barr virus-encoded RNA1 and viral latent membrane protein 1 in osteosarcoma: A novel insight of predictive markers.
Tumour Biol. 2020; 42(11):1010428320974247 [PubMed] Related Publications
Epstein-Barr virus is an etiologic agent of several malignancies. In this study, we explored the association of Epstein-Barr virus-encoded RNA1 and Epstein-Barr virus latent membrane protein 1 co-expression with osteosarcoma. Epstein-Barr virus-encoded RNA1 expression in tumor cells was quantified using reverse transcriptase polymerase chain reaction and in situ hybridization and Epstein-Barr virus latent membrane protein 1 expression was measured using immunohistochemistry staining. There was a statistically significant association between Epstein-Barr virus latent membrane protein 1 and Epstein-Barr virus-encoded RNA1 co-expression and characteristics of osteosarcoma such as nodal stage (p < 0.04), metastasis (p < 0.04), Ki67 index (p < 0.03), and tumor stage (p < 0.05). Co-expression of Epstein-Barr virus-encoded RNA1 and Epstein-Barr virus latent membrane protein 1 in tumors correlated with advanced osteosarcoma and indicated the aggressiveness of bone sarcoma.

Chao CC, Lee WF, Yang WH, et al.
IGFBP-3 stimulates human osteosarcoma cell migration by upregulating VCAM-1 expression.
Life Sci. 2021; 265:118758 [PubMed] Related Publications
AIMS: Insulin-like growth factor (IGF) signaling has been documented in several human malignancies and is thought to contribute to cellular differentiation and migration, as well as malignant progression. A major binding molecule of IGF, IGF-binding protein 3 (IGFBP-3), regulates multiple IGF effects. Here, we focused on the effect of IGFBP-3 in the motility of osteosarcoma cells and examined signaling regulation.
MATERIALS AND METHODS: Using a human osteosarcoma tissue array, immunohistochemical staining determined levels of IGFBP-3 expression in osteosarcoma tissue and in normal tissue. The wound healing migration assay, Transwell migration assay, luciferase reporter assay, immunofluorescence staining, Western blot and real-time quantitative PCR were performed to examine whether IGFBP-3 facilitates VCAM-1-dependent migration of osteosarcoma cells.
KEY FINDINGS: In this study, we found significantly higher IGFBP-3 levels in osteosarcoma tissue compared with normal healthy tissue. IGFBP-3 treatment of two human osteosarcoma cell lines promoted cell migration and upregulated levels of VCAM-1 expression via PI3K/Akt and AP-1 signaling.
SIGNIFICANCE: IGFBP-3 appears to be a novel therapeutic target in metastatic osteosarcoma.

Zhang Z, Liu C, Liang T, et al.
Establishment of immune prognostic signature and analysis of prospective molecular mechanisms in childhood osteosarcoma patients.
Medicine (Baltimore). 2020; 99(46):e23251 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In pediatric tumors, immunotherapy exhibits less toxicity than chemotherapy and radiation. The current study aims to identify potential immune targets in immune-related genes of C-C motif chemokine ligand genes (CCLs) and C-C motif chemokine receptors (CCRs) in childhood osteosarcoma (OS) and to explore the underlying molecular mechanisms of childhood OS.
METHODS: Firstly, we identified immune-related genes in CCLs and CCRs, these genes were used for functional annotation and interaction analysis. Then, the prognostic value of these genes was evaluated using Kaplan-Meier analysis and multivariate COX regression model. And the potential relationship between risk score and immune infiltrating cells was identified. Finally, gene set enrichment analysis was used to determine the underlying molecular mechanism of OS. Immune-related genes in CCLs and CCRs are inextricably linked.
RESULTS: The results of survival analysis of these genes show that CCL5, CCL8, CCR4, and CCR5 are significantly associated with the prognosis of childhood OS. The combined effect survival analysis shows that the co-high expression of these 4 genes has a good prognosis for childhood OS. A prognostic signature model was constructed based on the 4 genes mentioned above, and the result of time-dependent receiver operating characteristic curves showed that this model was a good predictor of childhood OS 3- and 5-year prognosis. In addition, the risk score of the constructed prognostic signature model was closely related to immune infiltration. We also found that CCL5, CCL8, and CCR5 may affect the prognosis of OS through complex regulation among Toll-like receptor signaling pathway, mitogen-activated protein kinase (MAPK) family signaling cascade, and nuclear factor-kappaB pathway, whereas CCR4 affects the prognosis of OS by regulating eukaryotic translation.
CONCLUSION: CCL5, CCL8, CCR4, and CCR5 are potential prognostic markers for the prognosis of childhood OS, and the underlying molecular mechanisms of childhood OS have been identified.

Wang X, Bian Z, Hou C, et al.
Neuropilin and tolloid-like 2 regulates the progression of osteosarcoma.
Gene. 2021; 768:145292 [PubMed] Related Publications
Neuropilin and tolloid-like 2 (NETO2) is aberrantly expressed in various malignancies. However, its role in osteosarcoma (OS) remains to be elucidated. This study aimed to identify the function of NETO2 in OS cells. The expression of NETO2 in sarcoma tissues was determined using the GEPIA database, and the mRNA and protein expression of NETO2 in OS cells and OS tissue was also assessed. The biological effects of NETO2 on OS cells were determined by overexpressing and downregulating NETO2. Cell proliferation, invasion, migration, colony formation, and epithelial-mesenchymal transition in OS cells were evaluated. Consistent with the GEPIA database, expression of NETO2 was upregulated in human OS samples and cell lines. NETO2 overexpression not only promoted the proliferation, colony formation, invasion, and epithelial-mesenchymal transition of OS cells, but also activated the PI3K/AKT signaling. NETO2 downregulation resulted in opposite effects. Furthermore, after using an AKT inhibitor, the effects of NETO2 on OS cells were attenuated. In conclusion, this study showed that NETO2 functions as an oncogene of osteosarcomas by activating the PI3K/AKT pathway.

Lee TH, Chu LS, Chang CY, Huang WS
Different Pattern of Bone Scintigraphy in Mandibular Osteosarcoma Arising From Fibrous Dysplasia in a Patient With McCune-Albright Syndrome.
Clin Nucl Med. 2021; 46(1):e11-e12 [PubMed] Related Publications
McCune-Albright syndrome is a rare condition consisting of triad of fibrous dysplasia, hyperfunctioning endocrinopathy, and café au lait macules of skin. A 31-year-old man was diagnosed with fibrous dysplasia 18 years before presenting with pathologic fracture. No workup for polyostotic fibrous dysplasia was performed at that time. He now presented with left facial swelling and skeletal features of acromegaly. MRI revealed a 15-cm enhancing tumor diagnosed histopathologically as high-grade osteosarcoma. Tc-methylene diphosphonate bone scintigraphy revealed decreased uptake at the tumor site contrary to the usual finding of avid uptake by the neoplastic bone forming tumor.

Wang XZ, Zhang SF, Yang ZH, et al.
Punicalagin suppresses osteosarcoma growth and metastasis by regulating NF-κB signaling.
J Biol Regul Homeost Agents. 2020 Sep-Oct; 34(5):1699-1708 [PubMed] Related Publications
Osteosarcoma is the most prevailing malignant bone tumor among adolescents. Punicalagin, a polyphenolic compound extracted from pomegranate, possesses many functions such as anti-oxidation, anti-bacterial, anti-virus, and immunosuppression, which can counter the aggressiveness of a variety of cancers such cervical, ovarian and prostate. This study aimed to investigate the inhibitory effect of punicalagin on the proliferation and metastasis of osteosarcoma cells and its potential regulatory mechanisms. Osteosarcoma cell lines (HOS cells, U2OS cells and MG63 cells) were treated with different doses of punicalagin, and the effects on osteosarcoma cell activity were examined in vitro using cell counting kit-8 (CCK-8), colony formation and apoptosis assays. The mobility, migration and invasion abilities of osteosarcoma cells were detected by wound healing and Transwell assays. NF-κB activity was explored by the NF-κB p65 luciferase reporter assay. Western blot was used to investigate the expressions of downstream proteins. We found that punicalagin inhibited the viability of osteosarcoma cells in vitro in dose-dependent and time-dependent manners and promoted apoptosis. In addition, punicalagin could significantly impede the mobility, migration and invasion abilities of osteosarcoma cells. In terms of mechanism, punicalagin down-regulated the expressions of p65, survivin, XIAP, CIAP2 and other proteins, and suppressed the proliferation and metastasis of osteosarcoma cells by repressing NF-κB signaling pathway. In conclusion, it is concluded that punicalagin restrains the growth and metastasis of osteosarcoma by obstructing the NF-κB signal transduction pathway.

Bertin H, Gomez-Brouchet A, Rédini F
Osteosarcoma of the jaws: An overview of the pathophysiological mechanisms.
Crit Rev Oncol Hematol. 2020; 156:103126 [PubMed] Related Publications
Osteosarcoma (OS) is the most common cancer of bone. Jaw osteosarcoma (JOS) is rare and it differs from long-bone OS (LBOS) in terms of the time of onset (two decades later), lower metastatic spread, and better survival. OS is characterized by the proliferation of osteoblastic precursor cells and the production of osteoid or immature bone. OS arises from a combination of genetic aberrations and a favourable microenvironment. This local microenvironment includes bone cells, blood vessels, stromal cells, and immune infiltrates, all of which may constitute potential targets for anti-cancer drugs. Differences in the clinical and biological behaviour of JOS versus LBOS are likely to at least in part be due to differences in the microenvironment between the two sites. The present review provides a brief overview of the known pathophysiological parameters involved in JOS.

Li Z, Li X, Xu D, et al.
An update on the roles of circular RNAs in osteosarcoma.
Cell Prolif. 2021; 54(1):e12936 [PubMed] Free Access to Full Article Related Publications
Osteosarcoma is the most common primary bone malignancy and is a neoplasm thought to be derived from the bone-forming mesenchymal stem cells. Aberrant activation of oncogenes and inactivation of tumour suppressor genes by somatic mutations and epigenetic mechanisms play a pivotal pathogenic role in osteosarcoma. Aside from alterations in these protein-coding genes, it has now been realized that dysregulation of non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and the recently discovered circular RNAs (circRNAs), is crucial to the initiation and progression of osteosarcoma. CircRNAs are single-stranded RNAs that form covalently closed loops and function as an important regulatory element of the genome through multiple machineries. Recently, an increasing number of studies suggested that circRNAs also played critical roles in osteosarcoma. This review summarizes recent development and progression in circRNA transcriptome analysis and their functions in the modulation of osteosarcoma progression.

Jiang Y, Hou J, Zhang X, et al.
Circ-XPO1 upregulates XPO1 expression by sponging multiple miRNAs to facilitate osteosarcoma cell progression.
Exp Mol Pathol. 2020; 117:104553 [PubMed] Related Publications
Circular RNAs (circRNAs) act as a key role in mediating carcinogenesis. Nevertheless, the functions and mechanisms of circRNAs in osteosarcoma (OS) are still not fully understood. In the present study, we aim to investigate the functions of circ-XPO1 in OS and its potential mechanism underlying OS progression. CircRNA microarray indicated elevation of circ-XPO1 in OS specimens relative to normal samples. Elevation of circ-XPO1 and XPO1 mRNA was identified in OS tissue specimens and cells by qRT-PCR. In addition, enhanced expression of circ-XPO1 and XPO1 mRNA both correlated with poor prognosis for the patients with OS, as estimated by Kaplan-Meier analysis. Functionally, circ-XPO1 and XPO1 both facilitated the growth and invasion and decreased the apoptosis of OS cells. Moreover, we constructed the circ-XPO1-miRNAs-XPO1 3'-UTR interaction network and verified that circ-XPO1 could sponge miR-23a-3p, miR-23b-3p, miR-23c, and miR-130a-5p to regulate XPO1 expression. Furthermore, rescue assay indicated that the effect of circ-XPO1 on cell progression was partly relying on these miRNAs. Taken together, we found that circ-XPO1 regulated the expression of XPO1 through sponging miRNAs as a competing endogenous (ceRNA), providing the possibility that circ-XPO1 might play as a new therapeutic target for OS.

Wang X, Li C, Yao W, et al.
MicroRNA-761 suppresses tumor progression in osteosarcoma via negatively regulating ALDH1B1.
Life Sci. 2020; 262:118544 [PubMed] Related Publications
AIMS: Our previous study has demonstrated that high expression of ALDH1B1 promoted osteosarcoma tumor progression and was correlated with unfavorable prognosis in osteosarcoma patients. In the current study, we investigated the underlying mechanism and regulation of ALDH1B1 in osteosarcoma.
MATERIALS AND METHODS: qRT-PCR assay was applied to detect miR-761 expression. CCK-8, colony formation and EdU assays were conducted to explore the functional role of miR-761/ALDH1B1 axis in osteosarcoma. Bioinformatics analysis and luciferase reporter assay was utilized to assess the regulation between miR-761 and ALDH1B1. Mechanism experiments were implemented to investigate the underlying molecular mechanism of miR-761/ALDH1B1 axis.
KEY FINDINGS: ALDH1B1 was negatively regulated by microRNA-761 (miR-761). Functionally, miR-761 suppressed cell growth, migration, and invasion in osteosarcoma via targeting ALDH1B1 in vitro. Xenograft tumor model demonstrated that miR-761 inhibited osteosarcoma tumor development in vivo through regulating ALDH1B1. Consistently, we showed that miR-761 expression was decreased in osteosarcoma patients and low expression of miR-761 was correlated with worse prognosis in osteosarcoma patients. Mechanistically, we revealed that high expression of ALDH1B1 was significantly associated with enhanced TGF-β signaling, epithelial-mesenchymal transition (EMT), and cell adhesion. Furthermore, miR-761 regulated TGF-β and EMT/cell adhesion in osteosarcoma via targeting ALDH1B1.
SIGNIFICANCE: Taken together, our findings suggest that the oncogenic ALDH1B1 is regulated by miR-761 during osteosarcoma development and progression, which might provide a novel prognostic biomarker and therapeutic strategy for osteosarcoma treatment.

Alge O, Lu L, Li Z, et al.
Automated Classification of Osteosarcoma and Benign Tumors using RNA-seq and Plain X-ray.
Annu Int Conf IEEE Eng Med Biol Soc. 2020; 2020:1165-1168 [PubMed] Related Publications
Osteosarcoma is a prominent bone cancer that typically affects adolescents or people in late adulthood. Early recognition of this disease relies on imaging technologies such as x-ray radiography to detect tumor size and location. This paper aims to differentiate osteosarcoma from benign tumors by analyzing both imaging and RNA-seq data through a combination of image processing and machine learning. In experimental results, the proposed method achieved an Area Under the Receiver Operator Characteristic Curve (AUC) of 0.7272 in three-fold cross-validation, and an AUC of 0.9015 using leave-one-out cross-validation.

Zhang G, Jin C, Zhu Y, et al.
Sulforaphene inhibits the progression of osteosarcoma via regulating FSTL1/NF-κB pathway.
Life Sci. 2020; 263:118485 [PubMed] Related Publications
AIMS: Sulforaphene (SFE), a naturally occurring isothiocyanate found in cruciferous vegetables, has attracted increasing attention for its anti-cancer effect in many cancers.
MAIN METHODS: We explored the therapeutic effects of SFE in modulating the progression of osteosarcoma. CCK8 assay, colony formation assay, western blot, wounding healing assay and transwell assay were conducted to detect the proliferation, apoptosis, migration and invasion of osteosarcoma cells (U2OS and Saos2) treated with different concentrations of SFE. In addition, tumor xenograft in nude mice is performed to test the effects of SFE in tumorigenesis in vivo. Moreover, the levels of FSTL1 and NF-κB were determined by western blot, and loss of functions of FATL1 and NF-κB were further conducted to evaluate the underlying mechanisms of SFE on osteosarcoma development.
KEY FINDINGS: The results revealed that SFE inhibited the growth while promoted apoptosis of U2OS and Saos2 cells in a dose-dependent manner. Mechanistically, SFE significantly inhibited the expression of NF-κB and FSTL1. However, the genetic intervention of FSTL1 or pharmacologically inhibiting NF-κB weakened the anti-tumor role of SFE.
SIGNIFICANCE: This study suggested that SFE alleviates the progression of osteosarcoma through modulating the FSTL1/NF-κB pathway.

Feng W, Wang Z, Feng D, et al.
The effects of common variants in MDM2 and GNRH2 genes on the risk and survival of osteosarcoma in Han populations from Northwest China.
Sci Rep. 2020; 10(1):15939 [PubMed] Free Access to Full Article Related Publications
Accumulating evidence has shown that both MDM2 and GNRH2 might be related to Osteosarcoma (OS) susceptibility. The study aimed to evaluate the effects of common variants in MDM2 and GNRH2 genes on the risk and survival of osteosarcoma in Han populations from Northwest China. In the study, we recruited 2292 subjects including 596 OS patients and 1696 healthy controls and genotyped 16 selected tag SNPs (6 from GNRH2 and 10 from MDM2). Genetic association analyses were performed at the genotypic and allelic levels. Survival curves were made for OS patients with different genotypes. Two SNPs, rs1690916 (MDM2, P = 0.0002) and rs3761243 (GNRH2, P = 0.0004), were identified to be significantly associated with OS risk. Moreover, SNP rs3761243 was strongly associated with pathological fracture (P = 2.61 × 10

Kharb S, Halder M, Kundu ZS
Heme oxygenase-1 in osteosarcoma.
J Cancer Res Ther. 2020 Jul-Sep; 16(4):874-877 [PubMed] Related Publications
Aim of Study: The present study was planned to analyze serum heme oxygenase-1 levels in osteosarcoma patients.
Materials and Methods: Twenty five histopathologically confirmed cases of osteosarcoma localized without metastasis of all the ages attending the Orthopedic Clinics were included in the study group and twenty five patients having musculoskeletal pain (age and sex matched) served as control. Five ml of venous blood was collected aseptically from antecubital vein and serum was be separated by centrifugation and analyzed the same day. Routine biochemistry investigations were performed as per standard enzymatic methods by autoanalyzer. Serum Heme oxygenase-1 was analyzed by enzyme-linked immunosorbent assay.
Results: In osteosarcoma patients, serum HO-1 levels were increased as compared to patients having musculoskeletal pain (P < 0.05). Workers have found that HO-1 induction in prostate cancer cell lines (PC3) cells restored the proliferation of osteoblasts, which was inhibited during co-culture with parental prostate cancer cell line PC3 cells. However, no concrete data are available on blood levels of HO in osteosarcoma. Major role of HO-1 is the protection against oxidative injury, additionally, it regulates cell proliferation, modulates inflammatory response and facilitates angiogenesis.
Conclusion: Findings of the present study suggests that pharmacological agents that regulate HO activity or HO-1 gene silencing may become powerful tools for preventing the onset or progression of various cancers and sensitize them to anticancer therapies.

Feder AL, Pion E, Troebs J, et al.
Extended analysis of intratumoral heterogeneity of primary osteosarcoma tissue using 3D-in-vivo-tumor-model.
Clin Hemorheol Microcirc. 2020; 76(2):133-141 [PubMed] Related Publications
BACKGROUND: Osteosarcomas are a rare, heterogeneous and malignant group of bone tumors that have a high potential for metastasis and aggressive growth patterns. Treatment of metastasized osteosarcoma is often insufficient and research is compromised by problems encountered when culturing cells or analyzing genetic alterations due to the high level of intratumoral and intertumoral heterogeneity. The chick chorioallantoic membrane (CAM) model, a 3D-in-vivo-tumor-model, could potentially facilitate the investigation of osteosarcoma heterogeneity at an individual and highly specified level.
OBJECTIVE: Objective was to establish the grafting and transplantation of different primary osteosarcoma tissue parts onto several consecutive CAMs for tumor profiling and investigation of osteosarcoma heterogeneity.
METHODS: Various parts of primary osteosarcoma tissue were grafted onto CAMs and were transplanted onto another CAM for five to seven consecutive times, enabling further experimental analyzes.
RESULTS: Primary osteosarcoma tissue parts exhibited satisfactory growth patterns and displayed angiogenic development on the CAM. It was possible to graft and transplant different tumor parts several times while the tissue viability was still high and tumor profiling was performed.
CONCLUSIONS: Primary osteosarcoma tissue grew on several different CAMs for an extended time period and neovascularization of serial transplanted tumor parts was observed, improving the versatility of the 3D-in-vivo-tumor-model.

Cui J, Dean D, Wei R, et al.
Expression and clinical implications of leucine-rich repeat containing 15 (LRRC15) in osteosarcoma.
J Orthop Res. 2020; 38(11):2362-2372 [PubMed] Related Publications
Leucine-rich repeat containing 15 (LRRC15) is a member of the leucine-rich repeat superfamily that is overexpressed in various cancers and associated with higher tumor grade and aggression. Despite its known tumorigenicity, its roles within osteosarcoma are unknown, prompting us to evaluate its expression and clinical significance within this rare yet aggressive cancer. Western blots showed differential expression of LRRC15 in the osteosarcoma cell lines MNNG/HOS, KHOS, 143B, MG63, Saos-2, and U2OS. We additionally validated this positive expression, as well as sublocalization to the cell membrane, with immunofluorescence. A tissue microarray constructed from 69 osteosarcoma patient tissues was immunohistochemically stained for LRRC15 expression, stratified, and used for clinicopathological analysis. Publicly available databases on LRRC15 expression, including RNA sequencing data from the Therapeutically Applicable Research to Generate Effective Treatments on Osteosarcoma (TARGET-OS) and the Gene Expression database of Normal and Tumor tissues 2 (GENT2) were also analyzed. We found 63 of the 69 (91.3%) patient tissues exhibited some degree of LRRC15 immunostaining, including no staining (6 of 69, 8.7%), 1+ staining (12 of 69, 17.4%), 2+ staining (25 of 69, 36.2%), and 3+ staining (26 of 69, 37.7%). The patients with osteosarcomas having elevated LRRC15 expression demonstrated comparatively increased metastasis, chemoresistance, and shorter 5-year survival rates. Our analysis of the TARGET-OS and GENT2 databases also showed increased LRRC15 gene expression in osteosarcoma. Taken together, our study supports LRRC15 as a prognostic biomarker and emerging therapeutic target in osteosarcoma.

Wu F, Jiang X, Wang Q, et al.
The impact of miR-9 in osteosarcoma: A study based on meta-analysis, TCGA data, and bioinformatics analysis.
Medicine (Baltimore). 2020; 99(35):e21902 [PubMed] Free Access to Full Article Related Publications
The function of miR-9 in osteosarcoma is not well-investigated and controversial. Therefore, we conducted meta-analysis to explore the role of miR-9 in osteosarcoma, and collected relevant TCGA data to further testify the result. In addition, bioinformatics analysis was conducted to investigate the mechanism and related pathways of miR-9-3p in osteosarcoma.Literature search was operated on databases up to February 19, 2020, including PubMed, Web of Science, Science Direct, Cochrane Central Register of Controlled Trials, and Wiley Online Library, China National Knowledge Infrastructure, China Biology Medicine disc, Chongqing VIP, and Wan Fang Data. The relation of miR-9 expression with survival outcome was estimated by hazard ratio (HRs) and 95% CIs. Meta-analysis was conducted on the Stata 12.0 (Stata Corporation, TX). To further assess the function of miR-9 in osteosarcoma, relevant data from the TCGA database was collected. Three databases, miRDB, miRPathDB 2.0, and Targetscan 7.2, were used for prediction of target genes. Genes present in these 3 databases were considered as predicted target genes of miR-9-3p. Venny 2.1 were used for intersection analysis. Subsequently, GO, KEGG, and PPI network analysis were conducted based on the overlapping target genes of miR-9-3p to explore the possible molecular mechanism in osteosarcoma.Meta-analysis shown that overexpression of miR-9 was associated with worse overall survival (OS) (HR = 4.180, 95% CI: 2.880-6.066, P < .001, I = 23.5%). Based on TCGA data, osteosarcoma patients with overexpression of miR-9-3p (HR = 1.603, 95% CI: 1.028-2.499, P = .037) and miR-9-5p (HR = 1.698, 95% CI: 1.133-2.545, P = .01) also suffered poor OS. In bioinformatics analysis, 2 significant and important pathways were enriched: Wnt signaling pathway from gene ontology analysis (gene ontology:0016055, P-adjust = .008); hippo signaling pathway from Kyoto Encyclopedia of Genes and Genomes analysis (P-adjust = .007). Moreover, network analysis relevant protein-protein interaction was visualized, revealing 117 nodes and 161 edges.High miR-9 expression was associated with poor prognosis. Based on bioinformatics analysis, this study enhanced the understanding of the mechanism and related pathways of miR-9 in osteosarcoma.

Hayakawa K, Matsumoto S, Ae K, et al.
Definitive surgery of primary lesion should be prioritized over preoperative chemotherapy to treat high-grade osteosarcoma in patients aged 41-65 years.
J Orthop Traumatol. 2020; 21(1):13 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recently, the number of osteosarcomas in middle-aged and older patients has demonstrated an increasing trend; moreover, their results are comparatively worse than those of young patients. In Europe and the USA, the prognosis for osteosarcoma in middle-aged and older patients has improved with adjuvant chemotherapy. In Japan, however, the prognosis has remained poor.
MATERIALS AND METHODS: We retrospectively analyzed the outcomes of osteosarcoma, especially in regards to preoperative chemotherapy, from January 1980 to July 2014. A total of 29 patients with high-grade osteosarcoma between the age of 40 and 65 years were included. We included patients without distant metastasis and with primary lesions that were deemed resectable. The mean age was 52.8 years (range 41-65 years), and the mean follow-up period was 103.2 months (range 5-314 months).
RESULTS: Adjuvant chemotherapy was administered to 27 of 29 patients (93%), and 8 of 15 cases (53%) were able to undergo preoperative chemotherapy as planned, including CDDP. A major complication of chemotherapy was acute kidney injury due to CDDP (26%). The 5-year OS and 5-year EFS were 64.9% and 57.1%, respectively. After 2006, a policy to prioritize the resection of the primary lesion was implemented, and if the primary lesion was deemed resectable, preoperative chemotherapy was either not administered or administered for only a short duration. The 5-year OS after 2006 improved to 78.8%.
CONCLUSIONS: This study shows that administration of high-dose intensity preoperative chemotherapy was difficult in middle-aged and older patients due to their high rate of acute kidney injury by CDDP. For cases of osteosarcoma in middle-aged and older patients, if the primary lesion is resectable, preoperative chemotherapy should be minimized to prioritize the resection of the primary lesion. It was considered that, with appropriate measures to prevent complications, adjuvant chemotherapy may lead to improved prognosis.

Xiong J, Li T
Exploring the association mechanism between metastatic osteosarcoma and non-metastatic osteosarcoma based on dysfunctionality module.
J BUON. 2020 May-Jun; 25(3):1569-1578 [PubMed] Related Publications
PURPOSE: Osteosarcoma (OS) is the primary malignant tumor which is common in children and adolescents. The treatment effect is still poor, though the treatment strategy has been dramatically improved.
METHODS: Differentially expressed genes in metastatic osteosarcoma and non-metastatic osteosarcoma were obtained first. Secondly, co-expression analysis has been processed for differentially expressed genes, and it is necessary to figure the gene drive of each module. Furthermore, both GO function and KEGG pathway enrichment analysis were performed on the module genes. Comprehensively, the module gene set which was predicted according to hypergeometric testing was importantly regulated by both transcription factors (TFs) and non-coding RNAs (ncRNAs).
RESULTS: Conclusively, 16 co-expression modules were obtained. ACAT1 and ATBF1 would actively regulate in dysfunction modules, and thus they are identified as osteosarcoma-driven genes. Enrichment results showed that the module genes were significantly involved in transcription factor activity, specific DNA binding of the RNA polymerase II proximal promoter sequence, DNA-binding transcriptional activator activity, ubiquitin-like protein transferase activity, and another biological process. Moreover, module genes significantly regulates FcγR-mediated phagocytosis, MAPK signaling pathway, phagocytosis, PI3K-Akt signaling pathway and others. Finally, we identified pivot ncRNAs (including CRNDE, miR-106a-5p, miR-181a-5p, etc) and pivot TFs (including NFKB1, STAT6, PPARG, RELA, etc) that significantly regulate dysfunction modules.
CONCLUSION: Overall, this work deciphered a co-expression network of common core pathogenic genes including metastatic osteosarcoma and non-metastatic osteosarcoma. It helps to identify core dysfunction modules and potential regulatory factors of the disease and improves understanding the underlying molecular association mechanisms between the two diseases.

Yao J, Tan W, Wu W, et al.
Effects of miR-432 and miR-548c-3p on the proliferation and invasion of osteosarcoma cells.
J BUON. 2020 May-Jun; 25(3):1562-1568 [PubMed] Related Publications
PURPOSE: To investigate the effects of miR-432 and miR-548c-3p on the proliferation and invasion of osteosarcoma cells.
METHODS: A total of 67 cases of patients with osteosarcoma who came to the third Affiliated Hospital of Southern Medical University from April 2015 to May 2018 formed the experimental group, and 63 healthy individuals who came to this hospital for physical examination during the same period formed the control group. The expressions of miR-432 and miR-548c-3p in sera of each group were detected by RT-PCR to observe the changes of the expression levels of these miRs in the sera of the experimental and the control group, and the relationship between the expression levels of these miRs in the sera of patients with osteosarcoma and the grade of tumor differentiation and different pathological classification. GM-63 cells were selected as the target for in vitro experiments which were cultured and transfected. Before transfection, cells were divided into blank group (without transfection), negative control group (transfected with miR NC) and experimental group (transfected with miR-432 mimics/miR-548c-3p mimics). Cell proliferation was detected by CCK-8 method, cell apoptosis was detected by flow cytometry, and cell invasion by transwell invasion experiment.
RESULTS: miR-423 and miR-548c-3p showed low expression in osteosarcoma, and the overexpression of miR-432 and miR-548c-3p in osteosarcoma cells could inhibit the proliferation of tumor cells and promote their apoptosis. miR-432 and miR-548c-3p might be tumor suppressors of osteosarcoma, and their expression levels could be used as important reference indexes to evaluate the benign and malignant levels of osteosarcoma.
CONCLUSION: These results suggested that the abnormal expressions of miR-432 and miR-548c-3p may be key factors of the occurrence and development of osteosarcoma.

Cao Y, Jiang F, Zhang S, et al.
MEX3C promotes osteosarcoma malignant progression through negatively regulating FGF14.
J BUON. 2020 May-Jun; 25(3):1554-1561 [PubMed] Related Publications
PURPOSE: Previous studies have shown that MEX3C is an oncogene; however, its role in osteosarcoma (OS) development has not been reported. We aimed at investigating whether MEX3C could be engaged in the malignant progression of OS through regulating FGF14.
METHODS: MEX3C levels in tumor tissues and adjacent ones of 52 OS patients were studied by quantitative real-time polymerase chain reaction (qRT-PCR), and the relationship between MEX3C expression and clinicopathological characteristics of OS patients was analyzed. At the same time, qRT-PCR further verified the MEX3C level in OS cell lines, and HOS and MG63 OS cell lines were selected to construct MEX3C overexpression and knockdown cell model, respectively. The impact of MEX3C on OS cell functions were determined by cell wound healing and transwell assay. In addition, the interaction between MEX3C and FGF14 was further determined by luciferase assay, western blot and recovery experiments.
RESULTS: MEX3C had increased expression both in OS tissue samples and in OS cell lines. High expression of MEX3C was predictive of high incidence of nodal involvement or distant metastasis. Silencing MEX3C remarkably attenuated the migration ability of OS cells, while, conversely, overexpression enhanced that. Bioinformatics analysis and luciferase assay confirmed that MEX3C bind to FGF14 directly, and the expression of FGF14 was significantly reduced in OS tumor tissue specimens, and was negatively correlated with MEX3C. Overexpression of FGF14 was able to reverse the promoting effect of MEX3C on the crawling ability and invasiveness of OS cells.
CONCLUSIONS: MEX3C was remarkably increased in OS tissues and was remarkably correlated with the incidence of metastasis of OS patients. In addition, MEX3C accelerated the malignant progression of OS through negatively modulating FGF14.

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