Role In Pathogenesis Of Osteosarcoma Research Articles

Integrating artificial intelligence in osteosarcoma prognosis: the prognostic significance of SERPINE2 and CPT1B biomarkers.

The principal aim of this investigation is to identify pivotal biomarkers linked to the prognosis of osteosarcoma (OS) through the application of artificial intelligence (AI), with an ultimate goal to enhance prognostic prediction. Expression profiles from 88 OS cases and 396 normal samples were procured from accessible public databases. Prognostic models were established using univariate COX regression analysis and an array of AI methodologies including the XGB method, RF method, GLM method, SVM method, and LASSO regression analysis. Multivariate COX regression analysis was also employed. Immune cell variations in OS were examined using the CIBERSORT software, and a differential analysis was conducted. Routine blood data from 20,679 normal samples and 437 OS cases were analyzed to validate lymphocyte disparity. Histological assessments of the study's postulates were performed through immunohistochemistry and hematoxylin and eosin (HE) staining. AI facilitated the identification of differentially expressed genes, which were utilized to construct a prognostic model. This model discerned that the survival rate in the high-risk category was significantly inferior compared to the low-risk cohort (p < 0.05). SERPINE2 was found to be positively associated with memory B cells, while CPT1B correlated positively with CD8 T cells. Immunohistochemical assessments indicated that SERPINE2 was more prominently expressed in OS tissues relative to adjacent non-tumorous tissues. Conversely, CPT1B expression was elevated in the adjacent non-tumorous tissues compared to OS tissues. Lymphocyte counts from routine blood evaluations exhibited marked differences between normal and OS groups (p < 0.001). The study highlights SERPINE2 and CPT1B as crucial biomarkers for OS prognosis and suggests that dysregulation of lymphocytes plays a significant role in OS pathogenesis. Both SERPINE2 and CPT1B have potential utility as prognostic biomarkers for OS.

Mesenchymal Stem Cells and Extracellular Vesicles in Osteosarcoma Pathogenesis and Therapy.

Osteosarcoma (OS) is an aggressive bone tumor that mainly affects children and adolescents. OS has a strong tendency to relapse and metastasize, resulting in poor prognosis and survival. The high heterogeneity and genetic complexity of OS make it challenging to identify new therapeutic targets. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into adipocytes, osteoblasts, or chondroblasts. OS is thought to originate at some stage in the differentiation process of MSC to pre-osteoblast or from osteoblast precursors. MSCs contribute to OS progression by interacting with tumor cells via paracrine signaling and affect tumor cell proliferation, invasion, angiogenesis, immune response, and metastasis. Extracellular vesicles (EVs), secreted by OS cells and MSCs in the tumor microenvironment, are crucial mediators of intercellular communication, driving OS progression by transferring miRNAs/RNA and proteins to other cells. MSC-derived EVs have both pro-tumor and anti-tumor effects on OS progression. MSC-EVs can be also engineered to deliver anti-tumor cargo to the tumor site, which offers potential applications in MSC-EV-based OS treatment. In this review, we highlight the role of MSCs in OS, with a focus on EV-mediated communication between OS cells and MSCs and their role in OS pathogenesis and therapy.

Expression of neurotrophins and their receptors in primary osteosarcoma.

to determine the expression of neurotrophins and their tyrosine-kinase receptors in patients with osteosarcoma (OS) and their correlation with clinical outcomes. we applied immunohistochemistry to biopsy specimens of patients consecutively treated for primary OS at a single institution between 2002 and 2015, analyzing them for expression receptors of tyrosine kinase A and B (TrKA and TrKB), neural growth factor (NGF) and brain derived neurotrophic factor (BDNF). Independently, two pathologists classified the immunohistochemical markers as negative (negative or weak focal) or positive (moderate focal/diffuse or strong focal/diffuse). we analyzed data from 19 patients (10 females and 9 males), with median age of 12 years (5 to 17.3). Tumors' location were 83.3% in the lower limbs, and 63.2% of patients had metastases at diagnosis. Five-year overall survival was 55.3%. BDNF was positive in 16 patients (84%) and NGF in 14 (73%). TrKA and TrKB presented positive staining in four (21,1%) and eight (42,1%) patients, respectively. Survival analysis showed no significant difference between TrK receptors and neurotrophins. primary OS samples express neurotrophins and TrK receptors by immunohistochemistry. Future studies should explore their role in OS pathogenesis and determine their prognostic significance in larger cohorts.

Hsa-let-7g promotes osteosarcoma by reducing HOXB1 to activate NF-kB pathway

MicroRNA (miRNA) is known to be involved in regulating the proliferation, migration and apoptosis of cancer cells in osteosarcoma. In this study, We aim to explore the expression of hsa-let-7 g and its role in pathogenesis of osteosarcoma. By analyzing clinical data. We found high expression of hsa-let-7 g in patients with osteosarcoma. The patients with higher expression of hsa-let-7 g showed poorer prognosis and lower survival rate. After downregulation of hsa-let-7 g in cell model and animal model, we found that with downregulation of hsa-let-7 g, the proliferation of osteosarcoma cells was significantly reduced, the level of migration and invasion was down-regulated, the cell cycle was inhibited, and cell apoptosis was increased. Through Dual Luciferase Reporter, immunohistochemistry, western blot and other experiments, it was found that hsa-let-7 g down-regulated HOXB1 gene and activated NF-kB pathway to promote the development of osteosarcoma. In conclusion, hsa-let-7 g is highly expressed in osteosarcoma tissues, and high expression of hsa-let-7 g can promote the occurrence of osteosarcoma by down-regulating HOXB1 and activating NF-kB pathway.

Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells

BackgroundOsteosarcoma is the most common bone cancer. Despite advances, molecular mechanisms associated with osteosarcoma have not been fully understood. Hence, an effective treatment for osteosarcoma has yet to be developed. Even though signal transducer and activator of transcription3 (STAT3) has been implicated, its role in pathogenesis of osteosarcoma is not fully determined. In this study, we investigated the antitumor effect of napabucasin (NP) (BBI608), an inhibitor of STAT3 on osteosarcoma in vitro and in vivo and studied the underlying molecular mechanism.MethodsCell viability, colony formation, apoptosis, tumor growth and metastasis assays were performed to examine the effect of NP on osteosarcoma in vitro and in vivo. Real-time RT-PCR, western analysis, immunofluorescence and reporter assays were used to monitor the expression and activity of proteins and underlying molecular pathways. Protein synthesis, co-immunoprecipitation and CAP binding assays were carried out to understand NP-mediated mechanism of actions in osteosarcoma cells.ResultsOur results show that NP treatment decreases cell viability and induces apoptosis in several osteosarcoma cell lines. NP treatment suppresses both expression and phosphorylation of STAT3 in addition to blocking STAT3-mediated transcription and downstream target proteins in osteosarcoma cells. Furthermore, NP inhibits protein synthesis through regulation of the eukaryotic initiation factor 4E (eIF4E) and eIF4E-binding protein 1 (4E-BP1). NP also inhibits the progression of osteosarcoma tumors and metastasis in vivo in an orthotopic tibial model of osteosarcoma.ConclusionsTaken together, our investigation reveals that NP acts through a novel mechanism and inhibits osteosarcoma growth and metastasis, and could be investigated clinically for treating osteosarcoma patients alone or in combination with other drugs.

MicroRNA-155 targets MAP3K10 and regulates osteosarcoma cell growth

Osteosarcoma is the most common type of bone cancer prevalent in young adults. Recent studies suggested that aberrant microRNA expression plays an essential role in osteosarcoma pathogenesis. In this study, we found miR-155 up-regulation in different osteosarcoma cell lines U2OS, Saos-2 and MG-63. Through bioinformatic prediction and analysis, we identified its target MAP3K10 that involved in cell proliferation and apoptosis. This work demonstrates novel interaction between microRNA, intercellular MAPK signaling and apoptosis in osteosarcoma, which will provide targets for therapeutic development.

CORR Insights(®): Transcriptional Profiling Identifies the Signaling Axes of IGF and Transforming Growth Factor-β as Involved in the Pathogenesis of Osteosarcoma.

T argeted therapeutics are needed to improve the prognosis of patients with osteosarcoma. Since the introduction of chemotherapy in the 1980s, 5-year survival for the often young patients with osteosarcoma has plateaued at about 50% to 60%. For patients with metastases, the outcomes remains particularly poor. By performing a serial analysis of a gene expression experiment comparing osteosarcomas with normal osteoblasts and mesenchymal stem cells, the authors identified the insulin-like growth factor (IGF) pathway and the transforming growth factor-b (TGF-b) pathway as possible targets for therapy. Since the effects of stimulation or inhibition of the TGF-b pathway on osteosarcoma cell proliferation is debatable [9], and the developed TGFb pathway inhibiting agents elicit unwanted effects [13], we will focus on the possibility of targeting the IGF pathway in osteosarcoma. The current paper emphasizes that the IGF pathway plays an important role in osteosarcoma pathogenesis, which is supported by other preclinical studies showing reduced proliferation in the majority of osteosarcoma cell lines [7] and xenografts [6] upon IGF 1 receptor (IGF-1R) inhibition. In addition, the peak incidence of osteosarcoma correlates with the increased levels of growth hormone and IGF ligands in puberty, and it has been described that the expression of several IGF pathway members (IGF1R, IGF-1, growth arrest-specific 6, and IGF binding proteins 4 [IGFBP4]) correlates with osteosarcoma prognosis [4, 7]. However, clinical trials demonstrate that only a small subset of osteosarcoma patients respond to IGF1R antibodies [3]. This illustrates the general trend with IGF-1R inhibitors. Although preclinical models have shown promising results, evidence for their efficacy in large-scale randomized controlled trials is lacking. As a This CORR Insights is a commentary on the article ‘‘Transcriptional Profiling Identifies the Signaling Axes of IGF and Transforming Growth Factor-b as Involved in the Pathogenesis of Osteosarcoma’’ by Yang and colleagues available at: DOI: 10.1007/ s11999-015-4578-1. The authors certify that they, or any members of their immediate families, have no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writers, and do not reflect the opinion or policy of CORR or The Association of Bone and Joint Surgeons. This CORR Insights comment refers to the article available at DOI: 10.1007/s11999-0154578-1. E. F. P. Peterse MSc, J. V. M. G. Bovee MD, PhD (&) Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands e-mail: J.V.M.G.bovee@lumc.nl CORR Insights Published online: 12 November 2015 The Author(s) 2015. This article is published with open access at Springerlink.com

Mitochondrial DNA depletion may also have a role in pathogenesis of osteosarcoma

We read the article by Yu et al. (2013a) entitled ‘Somatic mitochondrial DNA mutations in Chinese patients with Osteosarcoma’ with great interest. In this study, the aim of the authors was to investigate somatic mutations in mitochondrial DNA (mtDNA) and to explore their role in the pathogenesis and progression of osteosarcoma. With this aim the authors screened somatic mutations over the full-length mitochondrial genome of 31 osteosarcoma tumour tissue samples and corresponding peripheral blood samples from the same cohort of patients. They detected eleven somatic mutations in the mtDNA coding regions in their series. They indicated that nine of mtDNA mutations were missense or frameshift mutations that have the potential to hamper mitochondrial respiratory function. They concluded from their study that some missense and frameshift mutations are potentially harmful to proper mitochondrial activity and might play a vital role in osteosarcoma carcinogenesis. We share the authors' scientific view and think that this study is well constructed and scientific. However, we would like to express some constructive criticism. Osteosarcoma is a bone producing malignancy which mostly affects young adults. If there is early diagnosis, then it can be resectable, but it can also metastasise, usually to the lung (Caylak et al. 2006). There are previous studies investigating the presence and importance of mtDNA mutations in osteosarcoma (Guo et al. 2013). But, there are three major known alterations of mtDNA: (i) point mutations, (ii) large-scale deletions and (iii) mtDNA depletions (DiMauro & Bonilla 2004). Any one of these can be the cause of severe mitochondrial respiratory dysfunction, production of reactive oxygen species that are known to contribute in cancer development, and in turn may injure DNA further. For example, mitochondrial encephalomyopathy, lactic acidosis and stroke-like syndrome (MELAS) occur in association with a point mutation. On the other hand, Kearn–Sayre syndrome is caused by large-scale deletions. MtDNA depletion may also manifest as Alpers' syndrome. We understand that the authors have focused on point mutations in mtDNA only, but we feel that they should also cite studies in the literature which investigated mtDNA copy number in osteosarcoma (Yu et al. 2013b) and showed that changes in mtDNA copy number also occur in osteosarcoma. Thus, we feel that this well-written article would have benefited from mention that mtDNA variations other than point mutations may also have a role in the patho-carcinogenesis of osteosarcoma.

Roles of microRNA-206 in Osteosarcoma Pathogenesis and Progression

MicroRNA-206 has proven to be down-regulated in many human malignancies in correlation with tumour progression. Our study aimed to characterize miR-206 contributions to initiation and malignant progression of human osteosarcoma. MiR-206 expression was detected in human osteosarcoma cell line MG63, human normal osteoblastic cell line hFOB 1.19, and paired osteosarcoma and normal adjacent tissues from 65 patients using quantitative RT-PCR. Relationships of miR-206 levels to clinicopathological characteristics were also investigated. Moreover, miR-206 mimics and negative control siRNA were transfected into MG63 cells to observe effects on cell viability, apoptosis, invasion and migration. We found that miR-206 was down-regulated in the osteosarcoma cell line MG63 and primary tumor samples, and decreased miR-206 expression was significantly associated with advanced clinical stage, T classification, metastasis and poor histological differentiation. Additionally, transfection of miR-206 mimics could reduce MG- 63 cell viability, promote cell apoptosis, and inhibit cell invasion and migration. These findings indicate that miR-206 may have a key role in osteosarcoma pathogenesis and development. It could serve as a useful biomarker for prediction of osteosarcoma progression, and provide a potential target for gene therapy.

The microRNA-29 plays a central role in osteosarcoma pathogenesis and progression

Osteosarcoma is the most common type of bone cancer, with a peak incidence in the early childhood. The relationship between microRNAs (miRNAs) and cancer development attracted more and more attention over the last few years. Members of the miRNA-29 family, including miRNA-29a, miRNA-29b, and miRNA-29c were shown to participate in the development of rhabdomyosarcoma and hepatocarcinogenesis. Here, it has been demonstrated miRNA-29a and miRNA-29b expression levels to be downregulated in most of the osteosarcoma tissues (23 from 30). Besides, miRNA-29a displayed ability to induce apoptosis in both U2OS and SAOS-2 osteoblastic cells. While miRNA-29 members induced apoptosis through p53 gene activation, the effect of miRNA-29a on osteoblastic cells was independent on p53 expression level. Moreover, Bcl-2 and Mcl-1 were earlier demonstrated to be the direct targets of miRNA-29 in many types of cancer tissues and cancers. In both U2OS and SAOS-2 osteoblastic cell types, overexpression of miRNA-29a also downregulated Bcl-2 and Mcl-1, while silencing of miRNA-29a increased their expression. In addition, enhanced expression of miRNA-29a increased the expression of two tumor suppressor genes, E2F1 and E2F3. In summary, data obtained highlight the role of miRNA-29a in the regulation of osteoblastic cell apoptosis by silencing Bcl-2 and Mcl-1 and inducing E2F1 and E2F3 expression.

Biology of Osteogenic Sarcoma

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Despite significant clinical improvements over the past several decades through the use of combination chemotherapy and surgery, patients with metastatic or recurrent disease continue to have a very poor prognosis. Therefore, there is a continued need to study and understand the basic biology of osteosarcoma in order to devise more targeted and rational therapeutic strategies and ultimately to improve survival for these patients. This article reviews several aspects of osteosarcoma biology where data exist to suggest that specific pathways may play a role in the pathogenesis of this tumor. These areas include host genetic predispositions, tumor cytogenetics, molecular genetics (including the Rb, p53, RECQ helicase, and telomere pathways), and metastatic factors (ezrin, annexin 2, chemokine receptor 4, Fas/FasL pathways) that may contribute to both the initiation and the progression of tumor formation. Understanding the mechanisms of and interactions between the various molecular pathways that play a role in osteosarcoma pathogenesis may eventually lead to a more rational strategy for devising therapies targeted specifically toward these pathways.

Osteosarcoma

Findings from molecular genetic and cytogenetic investigations suggest that mutations in suppressor genes play a key role in osteosarcoma pathogenesis. RB and p53 are frequently involved and are speculated to be indispensable components. Alterations in putative suppressor genes on chromosomes 18q and 3q additionally may be involved in various patterns. The high resolution of magnetic resonance imaging in osteosarcoma imaging is confirmed, and the validity of dynamic gadolinium-enhanced imaging for estimation of tumor response is stated. The efficacy of single-drug high-dose methotrexate convincingly is shown to be 19%. Phase II trials with nonspecific immunostimulation using a synthetic liposomal mycobacterium-derived antigen (liposomal muramyl tripeptide phosphatidylethanolamine) do not yet allow us to draw conclusions on eventual efficacy. A novel and promising approach may be intervention in the endocrine or orthocrine and paracrine tumor growth regulation. Hypophysectomy in mice dramatically reduced plasma or insulin-like growth factor and local as well as systemic growth of transplanted osteosarcoma. The close interrelation between tumor response, surgical margins, and local control is demonstrated, as well as the fatal prognosis after local failure. Also, the validity of known risk factors in patients undergoing intensive chemotherapy has been confirmed. Interestingly, dose intensity was not found to influence prognosis.