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.
NHS Choices NHS Choices information is quality assured by experts and content is reviewed at least every 2 years. Further info. Overview of promary bone cancers in general, though does include some specific information about Osteosarcoma, Ewing's Sarcoma, Chondrosarcoma and Spindle cell sarcoma. Ewing's SarcomaEwing's Sarcoma
Information is reviewed by a panel of scientific and clinical experts, patients, parents/ carers, Further info. BCRT became a registered the charity in 2006 and raises funds for research into primary bone cancer, and provides information and support for patients and their families. The Website includes information booklets, personal stories and a section for teenagers. Bone CancersEwing's SarcomaEwing's Sarcoma
Bone Cancer Research Trust Information is reviewed by a panel of scientific and clinical experts, patients, parents/ carers, Further info. Overview of Osteosarcoma and the different types of the disease.
Mayo Clinic Dr. Carola Arndt discusses osteosarcoma which is one of the most common malignant tumors of bone in teenagers and young adults. She discusses diagnosis, evaluation, and treatment of osteosarcoma. Also mentions the Children's Oncology group and EURAMOS study. Mentions the multi-disciplinary approach at Mayo Clinic.
Founded in 2003 the initiative aims improve the quality of life for people dealing with sarcomas around the world, raising awareness and research funds. It has an international panel of medical experts. Ewing's SarcomaSoft Tissue SarcomasEwing's Sarcoma
PubMed Central search for free-access publications about Osteosarcoma MeSH term: Osteosarcoma US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
A website by orthopedic surgeon Dr. Henry DeGroot, with contributions from numerous clinical colleagues. It includes numerous case studies, including radiology and pathology images, and information covering a comprehensive range of bone tumours. Bone CancersEwing's SarcomaEwing's Sarcoma
This list of publications is regularly updated (Source: PubMed).
Liu T, Liu ZY, Zhang Q, Zhang XS Hemicortical resection and reconstruction using pasteurised autograft for parosteal osteosarcoma of the distal femur. Bone Joint J. 2013; 95-B(9):1275-9 [PubMed] Related Publications
The aim of this study was to assess a specific protocol for the treatment of patients with a parosteal osteosarcoma of the distal femur with limb salvage involving hemicortical resection and reconstruction using recycled pasteurised autograft and internal fixation. Between January 2000 and January 2010, 13 patients with a mean age of 26.5 years (17 to 39) underwent this procedure. All the tumours were staged according to Enneking's criteria: there were eight stage IA tumours and five stage IB tumours. The mean follow-up was 101.6 months (58 to 142), and mean post-operative Musculoskeletal Tumour Society functional score was 88.6% (80% to 100%) at the final follow-up. All the patients had achieved bony union; the mean time to union was 11.2 months (6 to 18). Local recurrence occurred in one patient 27 months post-operatively. No patient had a pulmonary metastasis. A hemicortical procedure for the treatment of a parosteal osteosarcoma is safe and effective. Precise pre-operative planning using MRI is essential in order to define the margins of resection. Although it is a technically demanding procedure, gratifying results make it worthwhile for selected patients.
Wang J, Nong L, Wei Y, et al. Association of interleukin-12 polymorphisms and serum IL-12p40 levels with osteosarcoma risk. DNA Cell Biol. 2013; 32(10):605-10 [PubMed] Related Publications
No previous studies reported the association of IL-12 polymorphisms with osteosarcoma. We aimed to investigate the association in a Chinese population. IL-12A rs568408, rs2243115, and IL-12B rs3212227 polymorphisms were evaluated in a case-control study of 106 osteosarcoma patients and 210 health controls by using polymerase chain reaction-restriction fragment length polymorphism. Serum IL-12p40 levels were measured by enzyme-linked immunosorbent assay. The serum IL-12p40 levels were significantly higher in controls than those in osteosarcoma patients (p<0.01). Genotypes of rs568408 GA and GA/AA, and rs3212227 CC and AC/CC were associated with the risk of osteosarcoma (rs568408 GA: odds ratios [OR]=1.86, 95% confidence intervals [CI]=1.11-3.12; GA/AA: OR=1.75, 95% CI=1.06-2.89, and rs3212227 CC: OR=2.70, 95% CI=1.38-5.28; CC/AC: OR=1.73, 95% CI=1.03-2.90). Moreover, rs3212227 CC/AC genotypes were significantly associated with decreased serum IL-12p40 levels in osteosarcoma patients compared to AA genotypes (p=0.035). Stratification analysis showed no associations between rs3212227 variant and the patients' gender, tumor location, and metastasis. Our data suggest that the serum IL-12p40 levels associate with the risk of osteosarcoma and are regulated by IL-12B rs3212227 polymorphism. The IL-12A rs568408 and IL-12B rs3212227 may confer the susceptibility to osteosarcoma risk.
Byun BH, Kong CB, Park J, et al. Initial metabolic tumor volume measured by 18F-FDG PET/CT can predict the outcome of osteosarcoma of the extremities. J Nucl Med. 2013; 54(10):1725-32 [PubMed] Related Publications
UNLABELLED: We evaluated the ability of metabolic and volumetric parameters measured by pretreatment (18)F-FDG PET/CT to predict the survival of patients with osteosarcoma of the extremities. METHODS: The records of 83 patients with American Joint Committee on Cancer stage II extremity osteosarcoma treated with surgery and chemotherapy were retrospectively reviewed. Imaging parameters (maximum standardized uptake value, metabolic tumor volume [MTV], total lesion glycolysis, and tumor volume based on MR images) were measured before treatment, and histologic responses to neoadjuvant chemotherapy were assessed by examination of postsurgical specimens. Receiver-operating-characteristic curve analyses and the Cox proportional hazards model were used to analyze whether imaging and clinicopathologic parameters could predict metastasis-free survival. RESULTS: Of the imaging parameters, MTV at the fixed standardized uptake value threshold of 2.0 (MTV(2.0)) most accurately predicted metastasis by receiver-operating-characteristic curve analysis (area under the curve = 0.679, P = 0.011). By multivariate analysis, MTV(2.0) > 105 mL (relative risk, 3.93; 95% confidence interval, 1.55-9.92) and poor response to neoadjuvant chemotherapy (relative risk, 4.83; 95% confidence interval, 1.64-14.21) independently shortened metastasis-free survival (P = 0.004 for both parameters). The stratification of patients by the combined criteria of MTV(2.0) and histologic response predicted outcome in more detail. CONCLUSION: MTV is an independent predictor of metastasis in patients with osteosarcoma of the extremities. The combination of MTV and histologic response predicts survival more accurately than the chemotherapeutic response alone.
Tome Y, Sugimoto N, Yano S, et al. Real-time imaging of αv integrin molecular dynamics in osteosarcoma cells in vitro and in vivo. Anticancer Res. 2013; 33(8):3021-5 [PubMed] Related Publications
αv Integrin is involved in various steps of cancer metastasis. In this report, we describe real-time imaging of αv integrin molecular dynamics in human 143B osteosarcoma cells in vitro and in vivo. We first generated osteosarcoma cells expressing αv integrin green fluorescent protein (GFP) by transfection of an αv integrin GFP fusion vector (pCMV6-AC-ITGAV-GFP) into 143B cells. Confocal laser-scanning microscopy demonstrated that αv integrin immunofluorescence staining co-localized with αv integrin-GFP fluorescence in 143B cells. When αv integrin-GFP-expressing 143B osteosarcoma cells were seeded on a dish coated with fibronectin, which is bound by αv integrin, punctate αv integrin-GFP was observed by confocal laser-scanning microscopy. When the 143B αv integrin-GFP cells were seeded onto uncoated plastic, αv integrin-GFP was diffuse within the cells. When αv integrin-GFP 143B osteosarcoma cells (1×10(6)) were orthotopically transplanted into the tibia of nude mice, the cells aligned along the collagen fibers within the tumor and had punctuate expression of αv integrin-GFP. In the orthotopic model, the invading osteosarcoma cells had punctate αv integrin-GFP in the muscle tissue at the primary tumor margin. These results show that αv integrin-GFP enables the imaging of the molecular dynamics of αv integrin in osteosarcoma cells in vitro and in vivo.
Zhou X, Wei M, Wang W MicroRNA-340 suppresses osteosarcoma tumor growth and metastasis by directly targeting ROCK1. Biochem Biophys Res Commun. 2013; 437(4):653-8 [PubMed] Related Publications
MicroRNAs (miRNAs) play key roles in cancer development and progression. In the present study, we investigated the role of miR-340 in the progression and metastasis of osteosarcoma (OS). Our results showed that miR-340 was frequently downregulated in OS tumors and cell lines. Overexpression of miR-340 in OS cell lines significantly inhibited cell proliferation, migration, and invasion in vitro, and tumor growth and metastasis in a xenograft mouse model. ROCK1 was identified as a target of miR-340, and ectopic expression of miR-340 downregulated ROCK1 by direct binding to its 3' untranslated region. siRNA-mediated silencing of ROCK1 phenocopied the effects of miR-340 overexpression, whereas restoration of ROCK1 in miR-340-overexpressing OS cells reversed the suppressive effects of miR-340. Together, these findings indicate that miR-340 acts as a tumor suppressor and its downregulation in tumor tissues may contribute to the progression and metastasis of OS through a mechanism involving ROCK1, suggesting miR-340 as a potential new diagnostic and therapeutic target for the treatment of OS.
Zhang Y, Hu H, Song L, et al. Epirubicin-mediated expression of miR-302b is involved in osteosarcoma apoptosis and cell cycle regulation. Toxicol Lett. 2013; 222(1):1-9 [PubMed] Related Publications
Epirubicin is widely used in osteosarcoma chemotherapy. Growing evidence indicates that the microRNA (miRNA) expression levels which are induced by chemotherapeutic agents play an important role in osteosarcoma development and progression. In this study we investigate the alterations of miRNA expression in the osteosarcoma cells after epirubicin treatment and whether miRNAs can enhance its anti-osteosarcoma effect. After epirubicin exposure, microarray shows 40 miRNAs are differentially expressed in osteosarcoma cells including 24 down-regulated miRNAs. Notably, miR-302b, which is stably low-expressed in osteosarcoma, could be induced by the epirubicin. Furthermore, we find that miR-302b can inhibit the osteosarcoma cell proliferation, promote cell apoptosis and cell cycle arrest MiR-302b can activate caspase-3 and regulate the Akt/pAkt, Bcl-2, Bim expression to increase the cell apoptosis. Meanwhile, miR-302b also attenuates cyclin D1 and CDKs expression to induce cell cycle arrest. Therefore, our results suggest miR-302b can play an essential role in osteosarcoma treatment as a potential tumor suppressor.
Le Guellec S, Moyal EC, Filleron T, et al. The β5/focal adhesion kinase/glycogen synthase kinase 3β integrin pathway in high-grade osteosarcoma: a protein expression profile predictive of response to neoadjuvant chemotherapy. Hum Pathol. 2013; 44(10):2149-58 [PubMed] Related Publications
To date, chemosensitivity to neoadjuvant chemotherapy of patients with high-grade osteosarcoma is evaluated on surgical resection by evaluation of the percentage of necrotic cells. As yet, no predictive profile of response to chemotherapy has been used in clinical practice. Because we have previously shown that the integrin pathway controls genotoxic-induced cell death and hypoxia, we hypothesized that in primary biopsies, expression of proteins involved in this pathway could be associated with sensitivity to neoadjuvant chemotherapy in high-grade osteosarcoma. We studied β1, β3, and β5 integrin expression and integrin-linked kinase, focal adhesion kinase (FAK), glycogen synthase kinase 3β (GSK3β), Rho B, angiopoietin-2, β-catenin, and ezrin expression by immunohistochemistry in 36 biopsies of osteosarcomas obtained before treatment. All patients received a chemotherapy regimen in the neoadjuvant setting. An immunoreactive score was assessed, combining the percentage of positive tumor cells and staining intensity. We evaluated the correlation of the biomarkers with response to chemotherapy, metastasis-free survival, and overall survival. A combination of 3 biomarkers (β5 integrin, FAK, and GSK3β) discriminated good and poor responders to chemotherapy, with the highest area under the curve (89.9%; 95% confidence interval, 77.4-1.00) and a diagnostic accuracy of 90.3%. Moreover, high expression of ezrin was associated with an increased risk of metastasis (hazard ratio, 3.93; 95% confidence interval, 1.19-12.9; P = .024). We report a protein expression profile in high-grade osteosarcoma associating β5 integrin, FAK, and GSK3β that significantly correlates with poor response to neoadjuvant chemotherapy. This biomarker profile could help select patients for whom an alternative protocol using inhibitors of this pathway can be proposed.
Salinas-Souza C, De Oliveira R, Alves MT, et al. The metastatic behavior of osteosarcoma by gene expression and cytogenetic analyses. Hum Pathol. 2013; 44(10):2188-98 [PubMed] Related Publications
Osteosarcoma is a malignant bone tumor with high metastatic potential. Metastasis at diagnosis is the most significant prognostic factor in predicting the clinical outcome of osteosarcoma. We compared the gene expression of metastases that were present at the time of initial diagnosis to those developed later in the course of the disease. We used quantitative real-time polymerase chain reaction to evaluate the gene expression of MDM2, CXCR4, RANKL, RB1, and OSTERIX in 98 samples of osteosarcoma taken from 47 patients (74 metastases and 24 primary tumors) and 30 nonmalignant lung tissues surrounding osteosarcoma metastases. In addition, we investigated the copy number changes of RB1 and MDM2 genes in 12 primary cultures of pulmonary metastases of osteosarcoma, using interphase fluorescence in situ hybridization. Metastases from metastatic patients at diagnosis were characterized by low expression of RB1 and RANKL (P = .0009 and P = .0109, respectively) and overexpression of CXCR4 and MDM2 (P = .0389 and P = .0325, respectively). The loss of RANKL and gain of CXCR4 could also be detected in the primary tumors of metastatic patients at diagnosis (P = .0121 and P = .0264, respectively). Thus, some early genetic events such as the loss of RANKL and the gain of CXCR4 expressions probably facilitate the metastatic progression concomitant with the primary tumor establishment, supporting the role of the CXCR4 receptor in directing osteosarcoma metastases to the lung. On the other hand, late events such as the loss of RB1 and gain of MDM2, crucial regulators of cell cycle, appear to be related to the final mechanisms contributing to the metastatic establishment of osteosarcoma.
Rathmanner N, Haigl B, Vanas V, et al. Sprouty2 but not Sprouty4 is a potent inhibitor of cell proliferation and migration of osteosarcoma cells. FEBS Lett. 2013; 587(16):2597-605 [PubMed] Related Publications
As negative regulators of receptor tyrosine kinase-mediated signalling, Sprouty proteins fulfil important roles during carcinogenesis. In this report, we demonstrate that Sprouty2 protein expression inhibits cell proliferation and migration in osteosarcoma-derived cells. Although earlier reports describe a tumour-promoting function, these results indicate that Sprouty proteins also have the potential to function as tumour suppressors in sarcoma. In contrast to Sprouty2, Sprouty4 expression failed to interfere with proliferation and migration of the osteosarcoma-derived cells, possibly due to a less pronounced interference with mitogen-activated protein kinase activity. Sequences within the NH2-terminus are responsible for the specific inhibitory function of Sprouty2 protein.
Miller BJ, Cram P, Lynch CF, Buckwalter JA Risk factors for metastatic disease at presentation with osteosarcoma: an analysis of the SEER database. J Bone Joint Surg Am. 2013; 95(13):e89 [PubMed] Article available free on PMC after 03/07/2014 Related Publications
BACKGROUND: Osteosarcoma is the most common primary bone sarcoma and affects all ages. There are substantial differences in management and outcomes for patients who have localized disease compared with distant spread at the time of diagnosis. Our goal was to examine potential risk factors predictive of metastatic disease at presentation. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify all patients diagnosed with osteosarcoma from 2000 to 2008 and to classify each patient as having metastatic or localized disease at the time of diagnosis. Patient-based characteristics, tumor characteristics, and county-level socioeconomic measures were analyzed to determine which factors were predictive of an increased rate of distant metastatic disease at presentation. These factors were analyzed as univariate characteristics as well as in a multivariate logistic regression model. RESULTS: We identified 2017 cases of high-grade osteosarcoma, and 464 (23.0%) of the patients presented with metastatic disease. In the unadjusted logistic regression analysis, patients had increased odds of metastatic disease at presentation if they had an age of sixty years or more (odds ratio [OR] = 2.22; 95% confidence interval [CI], 1.71 to 2.89), had a tumor located in the axial skeleton (OR = 2.47; 95% CI, 1.88 to 3.26), and lived in a county with low socioeconomic status (OR = 1.59; 95% CI, 1.08 to 2.35). These factors remained significant when combined in multivariate models controlling for age, location, and socioeconomic status. For patients with recorded tumor size information (n = 1398), the odds of metastasis at presentation increased by 10% with each additional centimeter of tumor size (OR = 1.10; 95% CI, 1.08 to 1.13). When the patients with missing tumor size information were excluded, socioeconomic status was no longer a significant risk factor for metastasis at presentation in the multivariate model. CONCLUSIONS: Osteosarcoma patients with advanced age, a tumor in the axial skeleton, a larger tumor size, and a residence in a less affluent county were more likely to have metastatic disease at presentation.
Yuan D, Liu B, Liu K, et al. Overexpression of fibroblast activation protein and its clinical implications in patients with osteosarcoma. J Surg Oncol. 2013; 108(3):157-62 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Fibroblast activation protein (FAP) expression has been detected in fibroblastic component of osteosarcomas. The aim of this study was to analyze the correlation of FAP expression with the clinicopathological features of osteosarcoma. METHODS: FAP mRNA and protein expression levels in human osteosarcoma tissues were, respectively detected by RT-PCR, Western blot, and immunohistochemistry assays. RESULTS: FAP mRNA and protein expression were both higher in osteosarcoma than in corresponding noncancerous bone tissues (both P < 0.001). In addition, the immunohistochemistry assay found that all patients showed positive FAP expression. Higher FAP expression was significantly correlated with advanced clinical stage (P = 0.006), high histological grade (P = 0.02), positive metastatic status (P = 0.01), shorter overall (P < 0.001), and disease-free (P < 0.001) survival in osteosarcoma patients. Furthermore, Cox multivariate analysis showed that FAP overexpression was an independent prognostic factor for predicting both overall and disease-free survival of osteosarcoma patients. CONCLUSION: Expression of FAP in osteosarcoma could be adopted as a candidate biomarker for the diagnosis of clinical stage, histological grade and metastasis, and for assessing prognosis, indicating for the first time that FAP may play an important role in tumor development and progression in osteosarcoma. FAP might be considered as a novel therapeutic target against this cancer.
Shelekhova KV, Kazakov DV, Michal M Extraosseous osteosarcoma arising in recurrent ossifying fibromyxoid tumor of soft tissue: a case report. Arkh Patol. 2013 Jan-Feb; 75(1):24-8 [PubMed] Related Publications
We present a case of an osteosarcoma arising in ossifying fibromyxoid tumor. The patient was a 50-year-old man when an initial tumor was identified. It was a soft tissue mass in the left popliteal area, measuring 14x9 cm. The tumor was surgically removed. Histologically, the primary tumor had the appearance of a conventional ossifying fibromyxoid tumor, although there were cellular areas with pleomorphism and high mitotic rate. The neoplasm recurred 4 times over the next 8 years, involving underlying tissues, including skeletal muscle and bone. The recurrent lesions features areas of osteoid, which increased with each recurrence and in the fourth recurrence the tumor had an appearance of extraskeletal osteosarcoma lacking the ossifying fibromyxoid tumor. The tumor generalized that killed the patient with widespread metastatic disease.
Campanile C, Arlt MJ, Krämer SD, et al. Characterization of different osteosarcoma phenotypes by PET imaging in preclinical animal models. J Nucl Med. 2013; 54(8):1362-8 [PubMed] Related Publications
UNLABELLED: The aim of this study was to characterize the different phenotypes of osteosarcoma by PET, comparing the uptake of 3 tracers ((18)F-FDG, (18)F-fluoromisonidazole [(18)F-FMISO], and (18)F-fluoride) in preclinical mouse models that reflect the heterogeneity of the human disease. METHODS: Mouse LM8 osteosarcoma, human 143B, and Caprin-1 stably overexpressing SaOS-2 cells were injected intratibially in C3H and severe-combined immunodeficient mice. PET imaging with (18)F-FDG, (18)F-FMISO, and (18)F-fluoride was performed in these mouse models, and a ratio between the standardized uptake value of the primary tumor and a control area of bone was calculated and compared among the models. Histology and immunohistochemistry were performed to confirm the PET findings. RESULTS: The pattern of tracer uptake differed among the primary tumors of the 3 models in accordance with the histology and immunohistochemistry on primary tumor sections. The osteolytic tumors in the 143B model showed the highest uptake of (18)F-FDG, an indicator of glucose metabolism, which was significantly higher (P < 0.05) than in the SaOS-2/Caprin-1 model and correlated with the percentage of Ki67-positive cells in the primary tumors. Hypoxia, indicated by (18)F-FMISO accumulation, was higher in the SaOS-2/Caprin-1 and 143B cell line-derived tumors (P < 0.01). Finally (18)F-fluoride, a marker of bone remodeling, correlated with the osteoblastic phenotype. The SaOS-2/Caprin-1 cell-derived tumors showed a significantly higher uptake than the moderately osteoblastic LM8 (P < 0.05) and the osteolytic 143B (P < 0.01) cell line-derived tumors. CONCLUSION: Differential PET imaging with tracers indicating metabolic activity, hypoxia, or bone remodeling will be helpful for the characterization of different osteosarcoma phenotypes and subsequent evaluation of more specific treatment modalities targeting the processes that are predominant in each specific tumor type or subtype.
Miao J, Wu S, Peng Z, et al. MicroRNAs in osteosarcoma: diagnostic and therapeutic aspects. Tumour Biol. 2013; 34(4):2093-8 [PubMed] Related Publications
MicroRNAs (miRNAs) are small RNA molecules, which can interfere with the expression of several genes and act as gene regulator. miRNAs have been proved as a successful diagnostic and therapeutic tool in several cancers. In this review, the differential expression of miRNAs in osteosarcoma and their possibility to be used as diagnostic and therapeutic tools have been discussed. Osteosarcoma is the most common primary bone tumor that mainly affects children and adolescents. The current treatment of osteosarcoma remains difficult, and osteosarcoma causes many deaths because of its complex pathogenesis and resistance to conventional treatments. Several studies demonstrated that the differential expression patterns of miRNAs are a promising tool for the diagnosis and treatment of osteosarcoma. Although some aspect of the mechanism of action of miRNAs in controlling osteosarcoma has been identified (e.g., targeting the Notch signaling pathway), it is far beyond to the clear understanding of miRNA targets in osteosarcoma. Identification of the specific target of miRNAs may aid molecular targets for drug development and future relief of osteosarcoma.
Rhee SH, Han I, Lee MR, et al. Role of integrin-linked kinase in osteosarcoma progression. J Orthop Res. 2013; 31(10):1668-75 [PubMed] Related Publications
Although integrin-linked kinase (ILK) has been suggested to play a role in the tumorigenesis of a number of human epithelial carcinomas, little is known of its role in musculoskeletal sarcoma. The authors studied ILK expression by immunohistochemistry using osteosarcoma prechemotherapy specimens from 56 patients, and investigated the prognostic implications of the findings obtained. It was found that ILK overexpression was significantly correlated with the presence of distant metastasis (p = 0.008) and that it was an independent prognostic factor for both poor overall survival and poor event-free survival (p = 0.015 and 0.010, respectively). During a transfection experiment conducted by transfecting osteosarcoma cells with ILK siRNA, VEGF concentrations were measured using an ELISA kit, and then compared with those of untransfected controls to evaluate its angiogenic effects. In addition, apoptotic percentages were measured by Annexin-V flow cytometry, and invasive properties were evaluated by measuring the numbers of non-migrating cells in a Boyden chamber. It was found that ILK downregulation significantly decreased angiogenesis, increased apoptosis, and decreased invasiveness of osteosarcoma cells. These results show that ILK is a promising prognostic factor in osteosarcoma and a novel potential therapeutic target for the treatment of osteosarcoma.
Bhadage CJ, Vaishampayan S, Kolhe S, Umarji H Osteosarcoma of the mandible mimicking an odontogenic abscess: a case report and review of the literature. Dent Update. 2013; 40(3):216-8, 221 [PubMed] Related Publications
UNLABELLED: Inflammatory lesions, like periapical/odontogenic abscesses, are by far the most common pathologic condition of the jaws. Radiographically, these lesions commonly manifest as widening of periodontal ligament space, discontinuity of lamina dura and ill-defined periapical radiolucency. There are some rare disorders which could cause similar radiographic changes in the jaw bone. With careful scrutiny of periapical radiolucency, regular periodic follow-up radiographs and histo-pathologic examination, the periapical abscess or infection can be differentiated from rare fatal disorders. CLINICAL RELEVANCE: This paper highlights the need for vigilant examination of even the commonest, innocuous-appearing periapical changes which sometimes are produced by some rare fatal disorders.
Ji T, Lin C, Krill LS, et al. Flavokawain B, a kava chalcone, inhibits growth of human osteosarcoma cells through G2/M cell cycle arrest and apoptosis. Mol Cancer. 2013; 12:55 [PubMed] Article available free on PMC after 03/07/2014 Related Publications
BACKGROUND: Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Limited by the severe toxicity of conventional agents, the therapeutic bottleneck of osteosarcoma still remains unconquered. Flavokawain B (FKB), a kava extract, has been reported to have significant anti-tumor effects on several carcinoma cell lines both in vitro and in vivo. Its efficacy and low toxicity profile make FKB a promising agent for use as a novel chemotherapeutic agent. RESULTS: In the current study, we investigated the anti-proliferative and apoptotic effects of FKB against human osteosarcomas. Exposure of OS cells to FKB resulted in apoptosis, evidenced by loss of cell viability, morphological changes and the externalization of phosphatidylserine. Apoptosis induced by FKB resulted in activation of Caspase-3/7, -8 and -9 in OS cell lines, 143B and Saos-2. FKB also down-regulated inhibitory apoptotic markers, including Bcl-2 and Survivin and led to concomitant increases in apoptotic proteins, Bax, Puma and Fas. Therefore, the induction of apoptosis by FKB involved both extrinsic and intrinsic pathways. FKB also caused G2/M phase cell cycle arrest, which was observed through reductions in the levels of cyclin B1, cdc2 and cdc25c and increases in Myt1 levels. Furthermore, migration and invasion ability was decreased by FKB in a dose-dependent manner. The cytotoxicity profile showed FKB had significant lower side effects on bone marrow cells and small intestinal epithelial cells compared with Adriamycin. CONCLUSIONS: Taken together, our evidence of apoptosis and cell cycle arrest by FKB treatment with less toxicity than the standard treatments provides an innovative argument for the use of FKB as a chemotherapeutic and chemopreventive compound. In vivo experiments utilizing FKB to reduce tumorigenesis and metastatic potential will be crucial to further justify clinical application.
Leon IE, Di Virgilio AL, Porro V, et al. Antitumor properties of a vanadyl(IV) complex with the flavonoid chrysin [VO(chrysin)2EtOH]2 in a human osteosarcoma model: the role of oxidative stress and apoptosis. Dalton Trans. 2013; 42(33):11868-80 [PubMed] Related Publications
Flavonoids, a polyphenolic compound family, and the vanadium compounds have interesting biological, pharmacological, and medicinal properties. We report herein the antitumor actions of the complex [VO(chrysin)2EtOH]2 (VOchrys) on the MG-63 human osteosarcoma cell line. Oxovanadium(IV), chrysin and VOchrys caused a concentration-dependent inhibition of cell viability. The complex was the strongest antiproliferative agent (p < 0.05). Cytotoxicity and genotoxicity studies also showed a concentration effect. Reactive oxygen species (ROS) and the alterations in the GSH/GSSG ratio underlie the main mechanisms of action of VOchrys. Additions of ROS scavengers (vitamin C plus vitamin E) or GSH to the viability experiments demonstrated beneficial effects (p < 0.01). Besides, the complex triggered apoptosis, disruption of the mitochondria membrane potential (MMP), increased levels of caspase 3 and DNA fragmentation measured by the sub-G1 peak in cell cycle arrest experiments (p < 0.01). Collectively, VOchrys is a cell death modulator and a promissory complex to be used in cancer treatments.
Ma JF, Von Kalle M, Plautz Q, et al. Relaxin promotes in vitro tumour growth, invasion and angiogenesis of human Saos-2 osteosarcoma cells by AKT/VEGF pathway. Eur Rev Med Pharmacol Sci. 2013; 17(10):1345-50 [PubMed] Related Publications
OBJECTIVES: In the present study, we determine the role of relaxin on cellular growth, invasion and angiogenesis of osteosarcoma Saos-2 cells in vitro, and discuss the molecular mechanisms of this action. MATERIALS AND METHODS: Saos-2 cells were transfected with Akt1/2 siRNA or VEGF siRNA for 24 hours then treated with 10-100 ng/mL recombinant human relaxin-2 (rh-RLN) for 48 h. MTT, matrigel and bone marrow-derived endothelial cells (BMDECs) was used for cell proliferation, invasion and angiogenesis assay. Western blot was used for relaxin-2, pAKT and VEGF protein assay. RESULTS: The results showed treatment with 10-100 ng/mL rh-RLN resulted in 18%, 48%, 107%, 212% increase in cell proliferation, respectively (vs control, *p < 0.05;**p < 0.01), the relative invasive cells was 1.4;1.9;2.6;4.8 (control was defined to 1) (vs control, #p < 0.01; ##p < 0.001) and the relative anglogenic branch points in Saos-2 cells was 1.04;1.36;1.69;2.10 (control was defined to 1.00) (vs control, *p < 0.05; **p < 0.01). Furthermore, treatment with rh-RLN exhibited a significant increase in the expression level of pAKT and VEGF proterin in dose-dependent manner. Saos-2 cells were transfected with AKT1/2 siRNA for 24 h. No significant increase of VEGF protein expression was shown after rh-RLN treatment. CONCLUSIONS: These results suggested that rh-RLN could promoted proliferation, invasion and angiogenesis by upregulation pAKT-dependent VEGF expression.
Savage SA, Mirabello L, Wang Z, et al. Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet. 2013; 45(7):799-803 [PubMed] Related Publications
Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10⁻⁹) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10⁻⁸ and 2.9 × 10⁻⁷, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.
Schofield AV, Gamell C, Bernard O Tubulin polymerization promoting protein 1 (TPPP1) increases β-catenin expression through inhibition of HDAC6 activity in U2OS osteosarcoma cells. Biochem Biophys Res Commun. 2013; 436(4):571-7 [PubMed] Related Publications
The Rho-associated coiled-coil kinase (ROCK) family of proteins, including ROCK1 and ROCK2, are key regulators of actin and intermediate filament morphology. The newly discovered ROCK substrate Tubulin polymerization promoting protein 1 (TPPP1) promotes microtubule polymerization and inhibits the activity of Histone deacetylase 6 (HDAC6). The effect of TPPP1 on HDAC6 activity is inhibited by ROCK signaling. Moreover, it was recently demonstrated that ROCK activity increases the cellular expression of the oncogene β-catenin, which is a HDAC6 substrate. In this study, we investigated the interplay between ROCK-TPPP1-HDAC6 signaling and β-catenin expression. We demonstrate that β-catenin expression is increased with ROCK signaling activation and is reduced with increased TPPP1 expression in U2OS cells. Further investigation revealed that ROCK-mediated TPPP1 phosphorylation, which prevents its binding to HDAC6, negates TPPP1-mediated reduction in β-catenin expression. We also show that increased HDAC6 activity resulting from ROCK signaling activation reduced β-catenin acetylation at Lys-49, which was also accompanied by its decreased phosphorylation by Caesin kinase 1 (CK1) and Glycogen synthase kinase 3β (GSK3β), thus preventing its proteasomal degradation. Overall, our results suggest that ROCK regulates β-catenin stability in cells via preventing TPPP1-mediated inhibition of HDAC6 activity, to reduce its acetylation and degradation via phosphorylation by CK1 and GSK3β.
Harada R, Kawamoto T, Ueha T, et al. Reoxygenation using a novel CO2 therapy decreases the metastatic potential of osteosarcoma cells. Exp Cell Res. 2013; 319(13):1988-97 [PubMed] Related Publications
Osteosarcoma is the most common primary solid malignant bone tumor. Despite substantial improvements in surgery and chemotherapy, metastasis remains a major cause of fatal outcomes, and the molecular mechanisms of metastasis are still poorly understood. Hypoxia, which is common in malignant tumors including osteosarcoma, increases expressions of hypoxia inducible factor (HIF)-1α, matrix metalloproteinase (MMP)-2 and MMP-9, and can induce invasiveness. As we previously showed a novel transcutaneous CO2 application to decrease HIF-1α expression and induce apoptosis in malignant fibrous histiocytoma, we hypothesize that transcutaneous CO2 application could suppress metastatic potential of osteosarcoma by improving hypoxic conditions. Here, we examined the effects of transcutaneous CO2 application on apoptosis, and development of pulmonary metastasis using a highly metastatic osteosarcoma cell line, LM8. Transcutaneous CO2 application significantly decreased tumor growth and pulmonary metastasis in LM8 cells. Apoptotic activity increased, and intratumoral hypoxia was improved with decreased expressions of HIF-1α, MMP-2 and MMP-9, significantly, in the CO2-treated tumors. In conclusion, we found that transcutaneous CO2 application can induce tumor cell apoptosis and might suppress pulmonary metastasis by improvement of hypoxic conditions with decreased expressions of HIF-1α and MMPs in highly metastatic osteosarcoma cell. These findings strongly indicate that this novel transcutaneous CO2 therapy could be a therapeutic breakthrough for osteosarcoma patients.
Zhang Q, Geng PL, Yin P, et al. Down-regulation of long non-coding RNA TUG1 inhibits osteosarcoma cell proliferation and promotes apoptosis. Asian Pac J Cancer Prev. 2013; 14(4):2311-5 [PubMed] Related Publications
OBJECTIVE: To investigate the expression level of TUG1 and one of its transcript variants (n377360) in osteosarcoma cells and assess the role of TUG1 in proliferation and apoptosis in the U2OS cell line. METHODS: TUG1 and n377360 expression levels in patients with osteosarcomas and the U2OS human osteosarcoma cell line were evaluated using real-time quantitative PCR. U2OS cells were transected with TUG1 and n377360 siRNA or non-targeting siRNA. MTS was performed to assess the cell proliferation and flow cytometry was applied to analyze apoptosis. RESULTS: We found significantly higher TUG1 and n377360 expression levels in osteosarcoma tissues compared with matched non-tumorous tissues. In line with this, suppression of TUG1 and n377360 expression by siRNA significantly impaired the cell proliferation potential of osteosarcoma cells. Furthermore, inhibition of TUG1 expression significantly promoted osteosarcoma cell apoptosis. CONCLUSIONS: The overexpression of TUG1 and n377360 in osteosarcoma specimens and the functional role of TUG1 and n377360 regarding cell proliferation and apoptosis in an osteosarcoma cell line provided evidence that the use of TUG1 or n377360 may be a viable but an as yet unexplored therapeutic strategy in tumors that over express these factors.
Mulrooney DA, Ness KK, Huang S, et al. Pilot study of vascular health in survivors of osteosarcoma. Pediatr Blood Cancer. 2013; 60(10):1703-8 [PubMed] Related Publications
BACKGROUND: Cardiovascular-related toxicities have been reported among survivors of osteosarcoma. METHODS: Fasting blood samples from 24 osteosarcoma survivors were analyzed for high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein (HDL), apolipoprotein-ß, lipoprotein (a), fibrinogen, circulating endothelial cells (CECs), and surface expression of vascular cell adhesion molecule-1 (VCAM-1). Values were compared to subjects in the natural history Coronary Artery Risk Development in Young Adults (CARDIA) cohort study except for CECs and VCAM-1 expression, which were compared to controls studied at the University of Minnesota Lillehei clinical trials unit. PROCEDURE: Survivors (54.2% male), median age 18 years (9-32) at diagnosis, 36.5 years (20-56) at evaluation were treated with a variety of chemotherapeutic exposures, all but one were exposed to doxorubicin (median dose 450 mg/m(2) ; range: 90-645 mg/m(2)), 14 (58.3%) received cisplatin, and 3 (12.5%) were exposed to carboplatin. Two survivors (8.3%) received radiation therapy for disease relapse. Compared to CARDIA subjects, mean hsCRP (3.0 mg/L ± 2.0 vs. 1.6 ± 2.3), triglycerides (151 mg/dl ± 81.7 vs. 95.4 ± 101.3), lipoprotein (a) (34.9 mg/dl ± 17.7 vs. 13.8 ± 22.0), and fibrinogen (315.0 mg/dl ± 49.3 vs. 252.4 ± 61.7) were significantly elevated. The number of CECs (0.47 cells/ml ± 2.5 vs. 0.92 ± 2.5) did not differ while surface expression of VCAM-1 (86.4% ± 34.0 vs. 42.1 ± 33.8) was significantly elevated compared to controls. CONCLUSIONS: Among survivors of osteosarcoma, assessed a median of 14 years from diagnosis, there is evidence of vascular inflammation, dyslipidemia, and early atherogenesis.
Buderi S, Theologou T, Gosney J, Shackcloth M Pulmonary artery tumor embolism in a patient with previous fibroblastic osteosarcoma. Ann Thorac Surg. 2013; 95(6):2155-7 [PubMed] Related Publications
A 48-year-old man was referred for left pulmonary metastasis and a left pulmonary artery embolus. The patient had T-cell acute lymphoblastic leukemia and fibroblastic osteosarcoma. A left pneumonectomy was performed successfully and the histologic report concluded that an embolic deposit of osteosarcoma was present. Pulmonary artery tumor embolism is a rare presentation in patients with previous fibroblastic osteosarcoma. It is important to suspect this diagnosis in a patient with cancer who presents with a pulmonary artery embolus.
Sangsin A, Pattamapaspong N, Settakorn J, et al. Extraosseous osteosarcoma: a case report and review of the literature. J Med Assoc Thai. 2013; 96(4):491-5 [PubMed] Related Publications
Extraosseous osteosarcoma (EOO) is a rare soft tissue sarcoma that produces osteoid and bone. It is sometimes accompanied by cartilage. It is located in soft tissue without skeletal attachment. A previous study revealed that extraosseous osteosarcoma is a chemoresistant tumor with a poor prognosis and should be distinct from osseous osteosarcoma. Out of more than a hundred of osteosarcoma recorded during 1992 to 2012 in Chiang Mai Hospital, only one was EOO. This is a case report of a 44-year-old Asian man who first noticed a small right thigh soft tissue mass associated with pain. MRI reveals a heterogeneous mass in the quadriceps muscle without continuity with the bone. Wide resection of the tumor was performed. Microscopically, the tumors composed of large size spindle shape and bizarre malignant cell with osteoid production. After the resection, adjuvant radiation by brachytherapy technique, and chemotherapy was performed. At postoperative 24-months follow-up, the patient was free from local recurrence and distant metastasis, compared to seven months of median survival time for patients treated with resection alone in previous case reports.
Han J, Tian R, Yong B, et al. Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients. Biochem Biophys Res Commun. 2013; 435(3):493-500 [PubMed] Related Publications
Dysregulation of the receptor tyrosine kinase Axl and its ligand Gas6 has been shown to promote multiple tumorigenic processes, as well as to correlate with worse prognosis in many different tumor types. However, studies of Axl expression and function in osteosarcoma have rarely been reported. In this study, we report that activated Axl is highly expressed in osteosarcoma cells, and this expression is significantly correlated with the recurrence and lung metastasis of osteosarcoma patients. High expression of activated Axl was an independent predictor for worse prognosis in osteosarcoma. Additionally, we confirmed a strong positive correlation between P-Axl and MMP-9 expression in those osteosarcoma patients. In osteosarcoma cell lines MG63 and U2OS, 200 ng/ml rhGas6 could cause obvious increase of P-Axl expression within 30 min, consistent with the expression of P-AKT. In both of the cell lines, Axl activated by rhGas6 could protect the tumor cells from apoptosis caused by serum starvation, and promote tumor cells' migration and invasion in vitro. Together with previous data, these studies suggest that activated Axl participate in the progression of osteosarcoma by resisting tumor cells apoptosis and promoting their migration and invasion, which may be linked to the expression of MMP-9. In the mechanism, AKT signaling pathway may contribute to the function of P-Axl in osteosarcoma rather than ERK pathway.
Machado I, López Guerrero JA, Navarro S, et al. Galectin-1 (GAL-1) expression is a useful tool to differentiate between small cell osteosarcoma and Ewing sarcoma. Virchows Arch. 2013; 462(6):665-71 [PubMed] Related Publications
Galectin-1 (GAL-1) is frequently expressed in osteosarcomas. Although a valuable diagnostic marker to differentiate between chondroblastic osteosarcomas and conventional chondrosarcomas, it has not been tested in the Ewing sarcoma family of tumors (ESFTs). We studied by immunohistochemistry GAL-1 expression in 43 osteosarcomas, 23 chondrosarcomas, and 217 genetically confirmed ESFTs using a tissue microarray. GAL-1 was expressed in 78 % of osteosarcomas, 33 % of chondrosarcomas, and 8 % of ESFTs. Osteoblastic and small cell osteosarcoma subtypes expressed GAL-1 in a high percentage of cells when compared with the other histological subtypes, whereas two chondroblastic osteosarcomas were negative. GAL-1 was mainly expressed in high-grade chondrosarcomas (grade III). ESFTs were rarely positive (8 %), and this was not related to the histological subtype nor to the clinical outcome. Although GAL-1 expression distinguishes chondroblastic osteosarcomas from conventional chondrosarcomas and is usually negative in conventional chondrosarcomas, the final diagnosis needs to incorporate histopathology since some chondroblastic osteosarcomas fail to express GAL-1, while high-grade chondrosarcomas are GAL-1 positive. Since GAL-1 is frequently expressed in osteogenic tumors, including small cell osteosarcoma, but rarely positive in ESFTs, its expression seems a valuable tool for distinguishing between these lesions. GAL-1 immunoexpression is not indicative of prognosis in ESFT.
Byun BH, Kong CB, Lim I, et al. Combination of 18F-FDG PET/CT and diffusion-weighted MR imaging as a predictor of histologic response to neoadjuvant chemotherapy: preliminary results in osteosarcoma. J Nucl Med. 2013; 54(7):1053-9 [PubMed] Related Publications
UNLABELLED: We evaluated the potential of (18)F-FDG PET/CT and diffusion-weighted imaging (DWI) to monitor the histologic response in patients with extremity osteosarcoma receiving neoadjuvant chemotherapy, using sequential PET/CT and MR imaging. METHODS: We prospectively registered 28 patients with high-grade osteosarcoma treated with 2 cycles of neoadjuvant chemotherapy and surgery. All patients underwent sequential (18)F-FDG PET/CT and MR imaging before (PET/MR1) and after neoadjuvant chemotherapy (PET/MR2). Maximum standardized uptake value (SUV), tumor volume based on MR imaging (MRV), and the mean apparent diffusion coefficient (ADC) values were measured on PET/MR1 (SUV1, MRV1, and ADC1) and PET/MR2 (SUV2, MRV2, and ADC2). The percentage changes in maximum SUV (ΔSUV), MRV (ΔMRV), and ADC (ΔADC) were calculated, and the correlations among these parameters were evaluated. After surgery, the effects of neoadjuvant chemotherapy were graded histopathologically: grades III and IV (necrosis of ≥ 90%) indicated a good response, and grades I and II (necrosis of < 90%) indicated a poor response. The optimum cutoff values of ΔSUV, ΔMRV, ΔADC, and their combination for predicting histologic response were assessed by single- and multi-receiver-operating-characteristic curve analysis. RESULTS: Twenty-seven patients were enrolled in the present study after 1 patient with inadequate acquisition of MR imaging was excluded. ΔSUV and ΔADC negatively correlated with each other (ρ = -0.593, P = 0.001), and ΔMRV did not correlate with ΔSUV or ΔADC. The cutoff value, sensitivity, specificity, and accuracy for predicting good histologic response were ≤ -52%, 67%, 87%, and 78%, respectively, for ΔSUV and > 13%, 83%, 73%, and 78%, respectively, for ΔADC. However, ΔMRV did not predict histologic response. Sensitivity, specificity, and accuracy were 83%, 87%, and 85%, respectively, using the combined criterion of ΔSUV ≤ -31% and ΔADC > 13%. CONCLUSION: In the current preliminary study, both PET/CT and DWI are useful for predicting histologic response after neoadjuvant chemotherapy in osteosarcoma. Combining PET/CT and DWI may be an effective method to predict the histologic response of patients to neoadjuvant chemotherapy.
Collins M, Wilhelm M, Conyers R, et al. Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. J Clin Oncol. 2013; 31(18):2303-12 [PubMed] Related Publications
PURPOSE: The LIVESTRONG Young Adult Alliance has conducted a meta-analysis of individual patient data from prospective neoadjuvant chemotherapy osteosarcoma studies and registries to examine the relationships of sex, age, and toxicity on survival. PATIENTS AND METHODS: Suitable data sets were identified by a survey of published data reported in PubMed. The final pooled data set comprised 4,838 patients from five international cooperative groups. RESULTS: After accounting for important variables known at study entry such as tumor location and histology, females experienced higher overall survival rates than males (P = .005) and children fared better than adolescents and adults (P = .002). Multivariate landmark analysis following surgery indicated that a higher rate of chemotherapy-induced tumor necrosis was associated with longer survival (P < .001), as was female sex (P = .004) and the incidence of grade 3 or 4 mucositis (P = .03). Age group was not statistically significant in this landmark analysis (P = .12). Females reported higher rates of grade 3 or 4 thrombocytopenia relative to males (P < .001). Children reported the highest rates of grade 3 or 4 neutropenia (P < .001) and thrombocytopenia (P < .001). The achievement of good tumor necrosis was higher for females than for males (P = .002) and for children than for adults (P < .001). CONCLUSION: These results suggest fundamental differences in the way chemotherapy is handled by females compared with males and by children compared with older populations. These differences may influence survival in a disease in which chemotherapy is critical to overall outcomes.