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Sample records for osteosarcomas

  1. Childhood Cancer: Osteosarcoma

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Osteosarcoma KidsHealth > For Parents > Osteosarcoma Print A A A ... kids with osteosarcoma do recover. Risk for Childhood Osteosarcoma Osteosarcoma is most often seen in teenage boys. ...

  2. Telangiectatic osteosarcoma.

    PubMed

    Gomes, H; Menanteau, B; Gaillard, D; Behar, C

    1986-01-01

    Two cases of telangiectatic osteosarcoma are described. The difficulty in differentiating this tumour from aneurysmal bone cyst is emphasized both from the pathological and radiological aspects. PMID:3456553

  3. Spinal Osteosarcoma

    PubMed Central

    Katonis, P.; Datsis, G.; Karantanas, A.; Kampouroglou, A.; Lianoudakis, S.; Licoudis, S.; Papoutsopoulou, E.; Alpantaki, K.

    2013-01-01

    Although osteosarcoma represents the second most common primary bone tumor, spinal involvement is rare, accounting for 3%–5% of all osteosarcomas. The most frequent symptom of osteosarcoma is pain, which appears in almost all patients, whereas more than 70% exhibit neurologic deficit. At a molecular level, it is a tumor of great genetic complexity and several genetic disorders have been associated with its appearance. Early diagnosis and careful surgical staging are the most important factors in accomplishing sufficient management. Even though overall prognosis remains poor, en-block tumor removal combined with adjuvant radiotherapy and chemotherapy is currently the treatment of choice. This paper outlines histopathological classification, epidemiology, diagnostic procedures, and current concepts of management of spinal osteosarcoma. PMID:24179411

  4. Chondroblastic osteosarcoma

    PubMed Central

    Almeida, Etanaiara; Mascarenhas, Bruno Araújo; Cerqueira, Arlei; Medrado, Alena Ribeiro Alves Peixoto

    2014-01-01

    The purpose of this paper is to report a case of chondroblastic osteosarcoma in the region of the maxilla, with 5 months of evolution. The term osteosarcoma refers to a heterogeneous group of malignancies with bone formation or mesenchymal tissue with histopathological evidence of osteogenic differentiation. The pattern of chondroblastic osteosarcoma represents 25% of all reported cases of this neoplasm. Its histopathological diagnosis is based on the predominance of a chondroid matrix formed in the midst of neoplastic cells. A woman patient, 27-year old, melanoderm, presented on extraoral exam with facial asymmetry caused by the a swelling in the premaxillary region with upper lip protrusion. Intraoral exam showed a maxillary tumefaction with involvement of the vestibular and palatine regions. The computerized tomography (CT) analysis exhibited a radiolucent mass with dispersed areas of radiopacity, with poorly defined and indistinct peripheral edges. The patient was subjected to incisional biopsy and histopathological examination showed the presence of a malignant neoplasm of mesenchymal origin characterized by the presence of irregular bone trabeculae dispersed among mildly atypical chondroblastic cells. The World Health Organization (WHO) recognizes several variants that differ in location, clinical behavior and degree of cellular atypia. The conventional or classical osteosarcoma is the most frequent variant, which develops within the medullary bone. This report illustrates the rapid evolution of one of the histological variants of osteosarcoma. PMID:25949008

  5. Parosteal osteosarcoma.

    PubMed

    Samardziski, M; Zafiroski, G; Tolevska, C; Konstadinova-Kunovska, S; Vasilevska, V

    2009-01-01

    In this retrospective clinical study, 6 cases of osteosarcoma of the bone have been analyzed. Five patients were with parosteal osteosarcoma and one with periosteal osteosarcoma. The study was performed at the Clinic for Orthopaedic Surgery in Skopje, Macedonia, from 1995 to 2005. This tumor represents 1.5% of all primary bone tumors treated at the Clinic in the 11 year period. The age of the 6 patients (2 female and 4 male) ranged from 8 to 39 years (average 23.8). The history analysis of the patients showed misinterpreted diagnosis in 50% of the cases, with 83.3% rate of local recurrence, 33.3% of metastases and 33.3% of mortality. Follow-up varied from 11 months to 9 years (average 4.5). The clinical and histopathological findings (identical with those reviewed in the literature) confirmed occurrence of two biologically different types of parosteal osteosarcoma: predominant type is originally "benign" but has a definite malignant potential, causing metastases after long symptom-free interval. The other type is highly malignant from the beginning. More radical surgery is recommended for the latter category of tumors, followed by chemotherapy. Compartmental, radical "en bloc" resection, followed by regular review of the patients, is recommended for the former (Tab. 1, Fig. 3, Ref. 20). Full Text (Free, PDF) www.bmj.sk. PMID:19507652

  6. Purely lytic osteosarcoma

    SciTech Connect

    De Santos, L.A.; Eideken, B.

    1982-11-01

    The radiographic features of 42 purely lytic osteosarcomas are presented. Purely lytic osteosarcoma is identified as a lytic lesion of bone with no demonstrable osteoid matrix by conventional radiographic modalities. Purely lytic osteosarcoma represented 13.7% of a group of 305 osteosarcomas. The most common presentation was that of a lytic illdefined lesion with a moderate to large extraosseous mass component. Nine lesions presented with benign radiographic features. The differential diagnosis is outlined. The need for awareness of this type of presentation of osteosarcoma is stressed.

  7. Extraskeletal Osteosarcoma

    PubMed Central

    Vu, Charles C.; Sohawon, Schoeb; Van Houtte, Paul; Thariat, Juliette; Novotny, Paul J.; Miller, Robert C.; Bar-Sela, Gil

    2016-01-01

    Objectives: To report characteristics, treatment, and outcomes for an international cohort of patients with extraskeletal osteosarcoma (ESOS). Materials and Methods: Through the Rare Cancer Network, retrospective data on patients with ESOS were collected. Patient characteristics, multimodality treatment information, and survival status were analyzed. Results: Thirty-seven patients in 4 health care institutions were identified. Thirty-one (86%) patients had grade 3 or 4 tumors. Most patients (27 [73%]) had stage III disease. Fourteen (38%) received neoadjuvant chemotherapy or chemoradiation. Of 28 (85%) who underwent surgery, 21 (75%) had free margins achieved and 15 (41%) subsequently received adjuvant chemotherapy. At median follow-up of 45 months, 20 (55%) patients were alive, 13 (43%) of whom were disease free. Univariate analysis showed that poor overall survival was related to stage IV (P<0.001), no surgery (P<0.001), primary size >10 cm (P=0.002), and age (P=0.002). In multivariate analysis, primary size >10 cm (P=0.005) was prognostic for overall survival. For patients without metastases, univariate analysis showed disease-free survival (DFS) related to primary size >10 cm (P=0.003), surgery (P=0.004), local recurrence (P=0.003), and age (P<0.001). In multivariate analysis for DFS, primary size >10 cm (P=0.01) and older age (P<0.001) were significant for worse outcome. Conclusions: Multimodality treatment remains standard for localized ESOS, with indications for neoadjuvant therapy less clear. Larger tumor size and older age were prognostic of poorer DFS. PMID:24401667

  8. Postradiation multicentric osteosarcoma

    SciTech Connect

    Tillotson, C.; Rosenberg, A.; Gebhardt, M.; Rosenthal, D.I.

    1988-07-01

    The oncogenic effects of radiation are well-established. Osteosarcomas and fibrosarcomas are the two most common histologic types of secondary sarcoma. In this article a case of postradiation osteosarcoma is presented in which four discrete foci of sarcomatous transformation have occurred in the tibia and fibula after irradiation for a rhabdomyosarcoma of the calf 8 years earlier. A review of the literature reveals no similar case. Although synchronous, multifocal osteosarcoma without prior radiation has been described, this case differs in clinical, radiographic, and pathologic features; it best fits the description of postradiation multicentric osteosarcoma.

  9. Oral metastasis of chondroblastic osteosarcoma

    PubMed Central

    Dumpala, Rakesh Kumar; Guttikonda, Venkateswara Rao; Yeluri, Sivaranjani; Madala, Jayakiran

    2012-01-01

    Osteosarcoma is the most common primary malignant mesenchymal tumor, accounting for approximately 20% of sarcomas, with 5% incidence in the jaws. They present various clinical and histological aspects as well as variable disease prognosis and outcome. About 50% of all osteosarcomas are osteoblastic, 25% fibroblastic, 25% chondroblastic. Metastasis of osteosarcoma in the oral cavity is rare, and very few cases have been described so far in the literature. This article presents a metastatic case of chondroblastic osteosarcoma in the mandibular right-attached gingiva arising from 4th rib. This case report further suggests that chondroblastic osteosarcoma has poor prognosis. PMID:23293503

  10. The epidemiology of osteosarcoma.

    PubMed

    Ottaviani, Giulia; Jaffe, Norman

    2009-01-01

    Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. The incidence rates and 95% confidence intervals of osteosarcoma for all races and both sexes are 4.0 (3.5-4.6) for the range 0-14 years and 5.0 (4.6-5.6) for the range 0-19 years per year per million persons. Among childhood cancers, osteosarcoma occurs eighth in general incidence and in the following order: leukemia (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), Non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), retinoblastoma (2.8%), osteosarcoma (2.4%), and Ewing sarcoma (1.4%). The incidence rates of childhood and adolescent osteosarcoma with 95% confidence intervals areas follows: Blacks, 6.8/year/million; Hispanics, 6.5/year/million; and Caucasians, 4.6/year/million. Osteosarcoma has a bimodal age distribution, having the first peak during adolescence and the second peak in older adulthood. The first peak is in the 10-14-year-old age group, coinciding with the pubertal growth spurt. This suggests a close relationship between the adolescent growth spurt and osteosarcoma. The second osteosarcoma peak is in adults older than 65 years of age; it is more likely to represent a second malignancy, frequently related to Paget's disease. The incidence of osteosarcoma has always been considered to be higher in males than in females, occurring at a rate of 5.4 per million persons per year in males vs. 4.0 per million in females, with a higher incidence in blacks (6.8 per million persons per year) and Hispanics (6.5 per million), than in whites (4.6 per million). Osteosarcoma commonly occurs in the long bones of the extremities near the metaphyseal growth plates. The most common sites are the femur (42%, with 75% of tumors in the distal femur), the tibia (19%, with 80% of tumors in the proximal tibia), and the humerus (10%, with 90% of tumors in the proximal humerus). Other likely locations are the skull

  11. The etiology of osteosarcoma.

    PubMed

    Ottaviani, Giulia; Jaffe, Norman

    2009-01-01

    Studies to determine the etiology of osteosarcoma involve epidemiologic and environmental factors and genetic impairments. Factors related to patient characteristics include age, gender, ethnicity, growth and height, genetic and familial factors, and preexisting bone abnormalities. Rapidly proliferating cells may be particularly susceptible to oncogenic agents and mitotic errors which lead to neoplastic transformation. Genetic aberrations that accompany osteosarcoma have received increasing recognition as an important factor in its etiology. Osteosarcoma tumor cells exhibit karyotypes with a high degree of complexity which has made it difficult to determine whether any recurrent chromosomal aberrations characterize osteosarcoma. Although extremely rare, osteosarcoma has occasionally been observed in several members of the same family. No other clinical abnormalities in the proband or the affected members were reported. Pathologic examination of the tumors revealed no unusual features. Genetic testing was not available in most of these reports. The patients generally responded to conventional therapy. A genetic predisposition to osteosarcoma is found in patients with hereditary retinoblastoma, characterized by mutation of the retinoblastoma gene RB1 on chromosome 13q14. The Rothmund-Thomson syndrome is an autosomal recessive disorder with a heterogeneous clinical profile. Patients may have a few or multiple clinical features including skin rash, small stature, skeletal dysplasias, sparse or absent scalp hair, eyebrows or eyelashes, juvenile cataracts, and gastrointestinal disturbance including chronic emesis and diarrhea; its molecular basis is the mutation in the RECQL4 gene in a subset of cases. The Li-Fraumeni syndrome is an autosomal dominant disorder characterized by a high risk of developing osteosarcoma and has been found in up to 3% of children with osteosarcoma. It is associated with a germline mutation of the p53, a suppressor gene. The following three

  12. Osteosarcoma of the larynx

    PubMed Central

    Każmierczak, Wojciech; Szylberg, Łukasz; Marszałek, Andrzej

    2015-01-01

    Malignant neoplasms of the larynx are divided into epithelial and non-epithelial. Non-epithelial neoplasms include, among others, mesenchymal chondrosarcomas and osteosarcomas. Few cases of laryngeal osteosarcomas described in the literature were usually treated by surgery without the need to use adjuvant radio- or chemotherapy. Few authors propose the initial application of radiotherapy or high-dose chemotherapy. Our study presents a very rare case of a woman treated due to laryngeal osteosarcoma. We have also presented diagnostic difficulties preceding a decision to perform radical surgery. The patient had been eligible for radical surgical treatment, even though there were no features of malignancy in a histopathological examination of the biopsy material. Complete laryngectomy was carried out without the surgery of the cervical lymphatic system. Laryngeal osteosarcoma was diagnosed based on the postoperative histopathological examination using vimentin and Ki67. The patient remains under the care of the Otolaryngology and Laryngological Oncology Department and Oncology Centre in Bydgoszcz. There were no reports on local recurrence or distant metastases during regular check-ups. PMID:26557767

  13. Diagnostic imaging of osteosarcoma

    SciTech Connect

    Seeger, L.L.; Gold, R.H.; Chandnani, V.P. )

    1991-09-01

    The diagnosis, treatment planning, and follow-up evaluation of osteosarcoma rely heavily on a variety of imaging techniques. Plain roentgenography, radionuclide bone scanning, computed tomography, and magnetic resonance imaging play important roles in defining local tumor extent, detecting metastatic disease, and monitoring for recurrent tumor. Invasive studies such as angiography are now rarely necessary. In the future, newer imaging modalities, including positron emission tomography, can be expected to become important tools for evaluation of these tumors. 23 references.

  14. Osteosarcoma after bone marrow transplantation.

    PubMed

    Ueki, Hideaki; Maeda, Naoko; Sekimizu, Masahiro; Tsukushi, Satoshi; Nishida, Yoshihiro; Horibe, Keizo

    2013-03-01

    Three children treated with bone marrow transplantation for acute lymphoblastic leukemia, Diamond-Blackfan anemia, and congenital amegakaryocytic thrombocytopenia developed secondary osteosarcoma in the left tibia at the age of 13, 13, and 9 years, respectively, at 51, 117, and 106 months after transplantation, respectively. Through treatment with chemotherapy and surgery, all 3 patients are alive without disease. We surveyed the literature and reviewed 10 cases of osteosarcoma after hematopoietic stem cell transplantation (SCT), including our 3 cases. Eight of the patients had received myeloablative total body irradiation before SCT. The mean interval from SCT to the onset of osteosarcoma was 6 years and 4 months, and the mean age at the onset of osteosarcoma was 14 years and 5 months. The primary site of the post-SCT osteosarcoma was the tibia in 6 of 10 cases, in contrast to de novo osteosarcoma, in which the most common site is the femur. At least 7 of the 10 patients are alive without disease. Osteosarcoma should be one of the items for surveillance in the follow-up of patients who undergo SCT. PMID:22995925

  15. Preclinical mouse models of osteosarcoma.

    PubMed

    Uluçkan, Özge; Segaliny, Aude; Botter, Sander; Santiago, Janice M; Mutsaers, Anthony J

    2015-01-01

    Osteosarcoma is the most common form of primary bone tumors with high prevalence in children. Survival rates of osteosarcoma are low, especially in the case of metastases. Mouse models of this disease have been very valuable in investigation of mechanisms of tumorigenesis, metastasis, as well as testing possible therapeutic options. In this chapter, we summarize currently available mouse models for osteosarcoma and provide detailed methodology for the isolation of cell lines from genetically engineered mouse models (GEMMs), gene modification and tumor cell injection methods, as well as imaging techniques. PMID:25987985

  16. [Lymph node metastasis of osteosarcomas].

    PubMed

    Vasil'ev, N V

    2016-01-01

    Lymph node metastasis of osteosarcomas is a rather rare phenomenon; according to different authors, the incidence of lymph node metastasis is 4 to 11%. The detection of lymph node metastases in osteosarcoma is associated with a significant reduction in the 5-year survival of patients and allows its classification as clinical stage IV tumor. The risk factors for lymph node metastases in patients with bone sarcomas are age (≥64 years), gender (female), nosological entity (undifferentiated pleomorphic sarcoma, osteosarcoma, chondrosarcoma), tumor depth (muscle, bone), and the size of primary tumor (>5 сm). The mechanism of lymph node metastasis of osteosarcomas seems to be related to mesenchymal-to-epithelial transition. PMID:27600784

  17. Osteoblastic and fibroblastic multicentric osteosarcoma

    PubMed Central

    Cabello, Raúl Romero; Sánchez, Carlos J.; Padilla, Marco A. Duran; De la Garza Navarro, José M.; Feregrino, Raul Romero; Vázquez, Avissai Alcántara; González, Mercedes Hernández; Feregrino, Rodrigo Romero

    2011-01-01

    Bone sarcomas are uncommon tumours, of which osteosarcoma is the least rare, as well as the third most common malignant tumour in childhood, appearing usually between the 10 and 20 years of age. The case the authors present in this work is of a patient suffering from a long-standing condition encompassing skin and soft tissue lesions. After multiple medical treatments, the patient was diagnosed with squamous osteosarcoma, which required aggressive surgical management and chemotherapy. PMID:22674697

  18. Postirradiation parosteal osteosarcoma. A case report

    SciTech Connect

    Masuda, S.; Murakawa, Y.

    1984-04-01

    A 16-year-old Japanese boy received a high dose of radiation for treatment of eosinophilic granuloma in the femur at the age of two years. He presented with a parosteal osteosarcoma 14 years later. Although a number of cases of postirradiation osteosarcoma have been reported, reports of parosteal osteosarcoma following radiation therapy are rare.

  19. A porcine model of osteosarcoma

    PubMed Central

    Saalfrank, A; Janssen, K-P; Ravon, M; Flisikowski, K; Eser, S; Steiger, K; Flisikowska, T; Müller-Fliedner, P; Schulze, É; Brönner, C; Gnann, A; Kappe, E; Böhm, B; Schade, B; Certa, U; Saur, D; Esposito, I; Kind, A; Schnieke, A

    2016-01-01

    We previously produced pigs with a latent oncogenic TP53 mutation. Humans with TP53 germline mutations are predisposed to a wide spectrum of early-onset cancers, predominantly breast, brain, adrenal gland cancer, soft tissue sarcomas and osteosarcomas. Loss of p53 function has been observed in >50% of human cancers. Here we demonstrate that porcine mesenchymal stem cells (MSCs) convert to a transformed phenotype after activation of latent oncogenic TP53R167H and KRASG12D, and overexpression of MYC promotes tumorigenesis. The process mimics key molecular aspects of human sarcomagenesis. Transformed porcine MSCs exhibit genomic instability, with complex karyotypes, and develop into sarcomas on transplantation into immune-deficient mice. In pigs, heterozygous knockout of TP53 was sufficient for spontaneous osteosarcoma development in older animals, whereas homozygous TP53 knockout resulted in multiple large osteosarcomas in 7–8-month-old animals. This is the first report that engineered mutation of an endogenous tumour-suppressor gene leads to invasive cancer in pigs. Unlike in Trp53 mutant mice, osteosarcoma developed in the long bones and skull, closely recapitulating the human disease. These animals thus promise a model for juvenile osteosarcoma, a relatively uncommon but devastating disease. PMID:26974205

  20. Silencing FAT10 inhibits metastasis of osteosarcoma.

    PubMed

    Ma, Chengbin; Zhang, Zhiyu; Cui, Yan; Yuan, Hongmou; Wang, Feng

    2016-08-01

    Metastasis is the main challenge of osteosarcoma treatment. Herein, we first reveal the oncogenic role of FAT10 in metastasis of osteosarcoma. FAT10 was upregulated in osteosarcoma, especially in metastatic osteosarcoma. High level of FAT10 was associated with poorer prognosis of osteosarcoma patients. Moreover, Transwell and Matrigel assays revealed that silencing FAT10 significantly inhibited the invasive and migratory abilities of osteosarcoma cells. Metastasis assay in vivo showed that silencing FAT10 decreased the number of mice with distant metastasis. We also found that FAT10 may act its oncogenic functions through regulating HOXB9. Collectively, the results suggested that FAT10 may be a novel therapeutic target for osteosarcoma patients. PMID:27279480

  1. Osteoblastic Osteosarcoma in a Rabbit

    PubMed Central

    Ishikawa, Megumi; Kondo, Hirotaka; Onuma, Mamoru; Shibuya, Hisashi; Sato, Tsuneo

    2012-01-01

    An osteosarcoma developed in the tarsal joint region involving the distal tibia of a domestic rabbit (Oryctolagus cuniculus). Micrometastases were present in the lungs. Histologically the tumor was composed of ovoid to short-spindle cells with abundant giant cells, producing irregular islands of osteoids. The tumor cells were immunopositive with antiosteocalcin monoclonal antibody, consistent with their derivation from osteoblasts. According to review of 10 published cases, productive osteoblasic osteosarcoma is the most common bone tumor in rabbits, with half of all cases developing in the skull or facial bones. PMID:22546918

  2. Osteosarcoma in Baboons (Papio spp)

    PubMed Central

    Mezzles, Marguerite J; Dick, Edward J; Owston, Michael A; Bauer, Cassondra

    2015-01-01

    Bone neoplasms in baboons (Papio spp) are rare, with only one confirmed case of osteosarcoma previously described in the literature. Over a 12-y period, 6 baboons at a national primate research center presented with naturally occurring osteosarcoma; 3 lesions affected the appendicular skeleton, and the remaining 3 were in the head (skull and mandible). The 6 cases presented were identified in members of a large outdoor-housed breeding colony. The subjects were not genetically related or exposed to the same research conditions. Diagnoses were made based on the presentation and radiographic findings, with histologic confirmation. PMID:25926401

  3. Wnt signaling in osteosarcoma.

    PubMed

    Lin, Carol H; Ji, Tao; Chen, Cheng-Fong; Hoang, Bang H

    2014-01-01

    Osteosarcoma (OS) is the most common primary bone malignancy diagnosed in children and adolescents with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the last two decades. With current treatments, 60-70 % of patients with localized disease survive. Given a propensity of Wnt signaling to control multiple cellular processes, including proliferation, cell fate determination, and differentiation, it is a critical pathway in OS disease progression. At the same time, this pathway is extremely complex with vast arrays of cross-talk. Even though decades of research have linked the role of Wnt to tumorigenesis, there are still outstanding areas that remain poorly understood and even controversial. The canonical Wnt pathway functions to regulate the levels of the transcriptional co-activator β-catenin, which ultimately controls key developmental gene expressions. Given the central role of this mediator, inhibition of Wnt/β-catenin signaling has been investigated as a potential strategy for cancer control. In OS, several secreted protein families modulate the Wnt/β-catenin signaling, including secreted Frizzled-related proteins (sFRPs), Wnt inhibitory protein (WIF), Dickkopf proteins (DKK-1,2,3), sclerostin, and small molecules. This chapter focuses on our current understanding of Wnt/β-catenin signaling in OS, based on recent in vitro and in vivo data. Wnt activates noncanonical signaling pathways as well that are independent of β-catenin which will be discussed. In addition, stem cells and their association with Wnt/β-catenin are important factors to consider. Ultimately, the multiple canonical and noncanonical Wnt/β-catenin agonists and antagonists need to be further explored for potential targeted therapies. PMID:24924167

  4. Surface osteosarcoma: Clinical features and therapeutic implications

    PubMed Central

    Nouri, H.; Ben Maitigue, M.; Abid, L.; Nouri, N.; Abdelkader, A.; Bouaziz, M.; Mestiri, M.

    2015-01-01

    Introduction Surface osteosarcoma are rare variant of osteosarcoma that include parosteal osteosarcoma, periosteal osteosarcoma and high grade surface osteosarcoma. These lesions have different clinical presentation and biological behavior compared to conventional osteosarcoma, and hence need to be managed differently. Goal The aim of this study is to analyze the clinico-pathological features and outcome of a series of surface osteosarcoma in an attempt to define the adequate treatment of this rare entity. Patient and method It is a retrospective and bicentric study of 18 surface osteosarcoma that were seen at the KASSAB’s Institute and SAHLOUL Hospital from 2006 to 2013. The authors reviewed the clinical and radiologic features, histologic sections, treatments, and outcomes in this group of patients. Results Seven patients were male (38.9%) and 11 were female (61.1%) with mean age of 25 years (range from 16 to 55 years). Eleven lesions were in the femur and 7 in the tibia. We identified 11 parosteal osteosarcoma (six of them were dedifferentiated), 3 periosteal osteosarcoma and 4 high grade surface osteosarcoma. Six patients had neoadjuvant chemotherapy and all lesions had surgical resection. Margins were wide in 15 cases and intra lesional in 3 cases. Histological response to chemotherapy was poor in all cases. The mean follow up was 34.5 months. Six patients (33.3%) presented local recurrence and 8 patients (44.4%) presented lung metastases. Six patients (33.3%) died from the disease after a mean follow up of 12 months (6–30 months); all of them had high grade lesions. Conclusion Histological grade of malignancy is the main point to assess in surface osteosarcoma since it determines treatment and prognosis. Low grade lesions should be treated by wide resection, while high grade lesions need more aggressive surgical approach associated to post operative chemotherapy. PMID:26730360

  5. Cytotoxic Effects of Fucoidan Nanoparticles against Osteosarcoma

    PubMed Central

    Kimura, Ryuichiro; Rokkaku, Takayoshi; Takeda, Shinji; Senba, Masachika; Mori, Naoki

    2013-01-01

    In this study, we analyzed the size-dependent bioactivities of fucoidan by comparing the cytotoxic effects of native fucoidan and fucoidan lipid nanoparticles on osteosarcoma in vitro and in vivo. In vitro experiments indicated that nanoparticle fucoidan induced apoptosis of an osteosarcoma cell line more efficiently than native fucoidan. The more potent effects of nanoparticle fucoidan, relative to native fucoidan, were confirmed in vivo using a xenograft osteosarcoma model. Caco-2 cell transport studies showed that permeation of nanoparticle fucoidan was higher than native fucoidan. The higher bioactivity and superior bioavailability of nanoparticle fucoidan could potentially be utilized to develop novel therapies for osteosarcoma. PMID:24177673

  6. Osteosarcoma of the jaws: a review of literature and a case report on synchronous multicentric osteosarcomas

    PubMed Central

    2012-01-01

    Background In the head and neck region, osteosarcoma is the most common primary malignant bone tumor, representing 23% of total head and neck malignancies. Osteosarcomas of the jaws are nevertheless rare lesions, representing only 2 to 10% of all osteosarcomas. This report reviews a single-center histopathology experience with craniofacial osteosarcomas, and reports the management of unusually large synchronous mandibular and maxillary osteosarcomas in a patient. Patients and methods A search of the hospital pathology database for specimens with a histological diagnosis of osteosarcomas submitted between July 1992 and May 2011 was made. A chart review of a patient with large synchronous maxillary and mandibular osteosarcomas was performed, and is reported. Case presentation A 21-year-old African man with large maxillary and mandibular tumors under palliative care presented with increasing difficulties with eating, speech, and breathing. Surgical debulking was performed, with histology confirming synchronous osteosarcomas of the mandible and maxilla. The patient is well after one year, with no evidence of recurrence, having undergone no further treatment. Conclusion Osteosarcomas of the jaw remain enigmatic, and a number of difficulties related to their diagnosis and treatment are yet to be resolved. True synchronous multicentric osteosarcomas of the jaws are extremely rare but, like other osteosarcomas of the jaws, have a favorable outcome, and palliative resection of such lesions, though challenging, can therefore lead to an enormously improved quality of life and self-image, and may even offer the opportunity for cure. PMID:23140538

  7. Proteomic Technologies for the Study of Osteosarcoma

    PubMed Central

    Byrum, Stephanie D.; Washam, Charity L.; Montgomery, Corey O.; Tackett, Alan J.; Suva, Larry J.

    2012-01-01

    Osteosarcoma is the most common primary bone cancer of children and is established during stages of rapid bone growth. The disease is a consequence of immature osteoblast differentiation, which gives way to a rapidly synthesized incompletely mineralized and disorganized bone matrix. The mechanism of osteosarcoma tumorogenesis is poorly understood, and few proteomic studies have been used to interrogate the disease thus far. Accordingly, these studies have identified proteins that have been known to be associated with other malignancies, rather than being osteosarcoma specific. In this paper, we focus on the growing list of available state-of-the-art proteomic technologies and their specific application to the discovery of novel osteosarcoma diagnostic and therapeutic targets. The current signaling markers/pathways associated with primary and metastatic osteosarcoma that have been identified by early-stage proteomic technologies thus far are also described. PMID:22550414

  8. Computed tomography of parosteal osteosarcoma

    SciTech Connect

    Hudson, T.M.; Springfield, D.S.; Benjamin, M.; Bertoni, F.; Present, D.A.

    1985-05-01

    Twelve patients with parosteal osteosarcomas were evaluated by computed tomography (CT). CT accurately defined the extent of the tumors for purposes of surgical planning, although tumor bone often could not be distinguished from thickened host bone. Nine tumors invaded the medullary cavity, a feature that implies a poorer prognosis when the tumor also contains high-grade areas. Six CT studies accurately detected the medullary invasion, but three did not. Lucent areas within dense tumors contained either benign tissue or high- or low-grade tumor; CT did not differentiate among these different tissues. CT also did not reveal small satellite nodules of tumor beyond the main tumor mass.

  9. Current Therapeutic Strategies and Novel Approaches in Osteosarcoma

    PubMed Central

    Ando, Kosei; Heymann, Marie-Françoise; Stresing, Verena; Mori, Kanji; Rédini, Françoise; Heymann, Dominique

    2013-01-01

    Osteosarcoma is the most frequent malignant primary bone tumor and a main cause of cancer-related death in children and adolescents. Although long-term survival in localized osteosarcoma has improved to about 60% during the 1960s and 1970s, long-term survival in both localized and metastatic osteosarcoma has stagnated in the past several decades. Thus, current conventional therapy consists of multi-agent chemotherapy, surgery and radiation, which is not fully adequate for osteosarcoma treatment. Innovative drugs and approaches are needed to further improve outcome in osteosarcoma patients. This review describes the current management of osteosarcoma as well as potential new therapies. PMID:24216993

  10. Telangiectatic osteosarcoma: a review of literature

    PubMed Central

    Liu, Jun-jian; Liu, Shen; Wang, Jian-guang; Zhu, Wei; Hua, Ying-qi; Sun, Wei; Cai, Zheng-dong

    2013-01-01

    Telangiectatic osteosarcoma is a rare variant of osteosarcoma and hence its occurrence, presentation, and prognosis are poorly understood. With advancements in technology and available treatment options, the scenario of its diagnosis, management, and outcome has changed. Chemotherapy with surgery was challenged previously, but has now been proved to be beneficial. We reviewed the available literature and compared results to define the characteristics of the disease, its presentation, radiographic and pathologic features, optimal treatment, and prognosis. PMID:23745051

  11. In vivo photoacoustic imaging of osteosarcoma on animal model

    NASA Astrophysics Data System (ADS)

    Yu, Menglei; Ye, Fei; Hu, Jun

    2011-01-01

    Osteosarcoma is the commonest primary malignant tumor of bone, and the second highest cause of cancer-related death in the paediatric age group. Although there are several methods for osteosarcoma detection, e.g. X-ray, CT, MRI and bone scan, they are not satisfied methods because they can hardly detect osteosarcoma in early stage. Photoacoustic imaging (PAI) is an emerging hybrid imaging modality that is noninvasive, nonionizing, with high sensitivity, satisfactory imaging depth and good temporal and spatial resolution. In order to explore this new method to detect osteosarcoma, we established SD rat models with osteosarcoma and utilized PAI to reconstruct the osteosarcoma image in vivo. This is the first time detecting osteosarcoma in vivo using PAI, and the results suggested that PAI has potential clinical application for detecting osteosarcoma in the early stage.

  12. Osteosarcoma

    MedlinePlus

    ... risk. This gene is also associated with familial retinoblastoma . This is a cancer of the eye that ... More Bone tumor Distal Incidence Lung metastases Proximal Retinoblastoma Swelling Tumor Update Date 11/26/2014 Updated ...

  13. Radiation-induced osteosarcoma of the sphenoid bone

    SciTech Connect

    Tanaka, S.; Nishio, S.; Morioka, T.; Fukui, M.; Kitamura, K.; Hikita, K. )

    1989-10-01

    The case of a patient who developed osteosarcoma in the sphenoid bone 15 years after radiation therapy for a craniopharyngioma is reported. Radiation-induced osteosarcoma of the sphenoid bone has not been reported previously. Reported cases of radiation-induced osteosarcomas are reviewed.

  14. Periosteal osteosarcoma: a review of clinical evidence

    PubMed Central

    Liu, Xin-Wei; Zi, Ying; Xiang, Liang-Bi; Han, Tian-Yu

    2015-01-01

    Periosteal osteosarcoma (PO) is a rare primary malignant bone tumor and a variant of osteosarcoma. It is a surface lesion without evidence of medullary involvement. The radiologic appearance of periosteal osteosarcoma is a broad-based surface soft-tissue mass that causes extrinsic erosion of thickened underlying diaphyseal cortex and perpendicular periosteal reaction extending into the soft-tissue component. The tumour presents as non-homogeneous masses of speculated osteoid matrix progressively denser from the periphery to their cortical base. The average age is around 28 and the most common location is the proximal third of the femur; with all the lesions diaphyseal in location. The treatment usually indicated is amputation, but in selected cases, radical segmental resection is appropriate. Long-term disease-free survival is possible after resection of the local recurrence. Limb-salvage therapy seems to offer survival equivalent to amputation, and there does not seem to be a substantial risk of late recurrence, dedifferentiation, or disease progression. The current review also highlights on various rare occurrences of periosteal osteosarcoma including the one of calcaneum, fifth metatarsal, mandible cranium, jaws, clavicle, maxilla, sphenoid bone with extensive periosteal extension, metacarpal in a paediatric age group and bilateral metachronous periosteal osteosarcoma. Recent findings relating to genetic factors governing the pathogenesis of PO is also presented. PMID:25784972

  15. Telangiectatic osteosarcoma--a case report.

    PubMed Central

    Suh, Y. L.; Chi, J. G.

    1989-01-01

    Telangiectatic osteosarcoma is a rare and special variant of osteogenic sarcoma with distinct radiologic, gross and microscopic features. This tumor is predominantly lytic, destructive tumor without sclerosis on roentgenogram, and is soft and cystic on gross examination. Histologically aneurysmally dilated spaces lined or traversed by stromal cells producing osteoid are noted. This report concerns a case of telangiectatic osteosarcoma occurring in a 7 years old boy. He presented with pathologic fracture of the right distal tibia, followed by a purely lytic lesion on X-ray examination. This lesion recurred five times during a span of one year. Microscopic features of the biopsy specimen was difficult to differentiate from aneurysmal bone cyst because of prominant blood-filled cyst formation. It was finally identified as osteosarcoma from the below-knee amputation specimen through the close examination for anaplastic osteoid-producing stromal cells in the septa that separate the blood cysts. PMID:2597366

  16. Telangiectatic osteosarcoma--a case report.

    PubMed

    Suh, Y L; Chi, J G

    1989-06-01

    Telangiectatic osteosarcoma is a rare and special variant of osteogenic sarcoma with distinct radiologic, gross and microscopic features. This tumor is predominantly lytic, destructive tumor without sclerosis on roentgenogram, and is soft and cystic on gross examination. Histologically aneurysmally dilated spaces lined or traversed by stromal cells producing osteoid are noted. This report concerns a case of telangiectatic osteosarcoma occurring in a 7 years old boy. He presented with pathologic fracture of the right distal tibia, followed by a purely lytic lesion on X-ray examination. This lesion recurred five times during a span of one year. Microscopic features of the biopsy specimen was difficult to differentiate from aneurysmal bone cyst because of prominant blood-filled cyst formation. It was finally identified as osteosarcoma from the below-knee amputation specimen through the close examination for anaplastic osteoid-producing stromal cells in the septa that separate the blood cysts. PMID:2597366

  17. In vivo photoacoustic imaging of osteosarcoma in a rat model

    NASA Astrophysics Data System (ADS)

    Hu, Jun; Yu, Menglei; Ye, Fei; Xing, Da

    2011-02-01

    Osteosarcoma is one of the most common primary malignant tumors of the bone and the second leading cause of cancer-related deaths in the pediatric age group. Confirmed diagnosis and prompt treatment of osteosarcoma are critical for effective prognosis. In this study, we investigate the application of photoacoustic imaging (PAI) for the detection of osteosarcoma in an animal model. Cross-section images of a normal rat leg and a tumorous rat leg were successfully reconstructed in vivo. Morphological changes and the development of the implanted osteosarcoma were accurately mapped with time-dependent photoacoustic images. Furthermore, we evaluate the use of gold nanorods as contrast agents for imaging osteosarcoma with PAI. This is the first study that uses PAI to detect osteosarcoma in vivo, and the results suggest that PAI has the potential clinical application for detecting osteosarcoma in the early stage.

  18. Telangiectatic dedifferentiation of a parosteal osteosarcoma.

    PubMed

    Wines, A; Bonar, F; Lam, P; McCarthy, S; Stalley, P

    2000-10-01

    A unique case of parosteal osteosarcoma (POS) of the proximal femur, with areas of telangiectatic dedifferentiation, in a 28-year-old woman is reported. The patient had a 7-week history of pain and swelling in her right thigh. A biopsy diagnosis of POS was established. The patient was treated with two cycles of intraarterial chemotherapy, followed by limb salvage surgery. Histological examination of the resected specimen showed POS with areas of dedifferentiation composed of highgrade telangiectatic osteosarcoma with associated secondary aneurysmal bone cyst change. PMID:11127684

  19. Potential role of S-adenosylmethionine in osteosarcoma development

    PubMed Central

    Shi, Hui; Mu, Wei-dong; Zhang, Bing; Meng, Tao; Zhang, Shou-tao; Zhou, Dong-sheng

    2016-01-01

    The metastatic form of osteosarcoma is a life threatening one since it metastasizes to the lungs. The major cause of metastatic osteosarcoma is hypomethylation of numerous genes that undergo overexpression to enable the progression of the disease. In the present study, S-adenosylmethionine (SAM), a predominant methyl donor, was administered to find out its effects on osteosarcoma progression. As evidence of tumor suppression, the SAM-treated mouse tissue was analyzed histologically, which exemplifies the control that SAM has over abnormal cell proliferation, especially on primary osteosarcoma, but it lacks positive effects on metastatic osteosarcoma. At the molecular level, the successful inhibition of primary osteosarcoma was found to be associated with a lower expression of Sox2, a protein highly expressed in osteosarcoma stem cells, along with an upregulated expression of TCTP. The data suggest that the administration of SAM has a positive role in treating primary osteosarcoma, but it has no role in suppressing metastatic osteosarcoma. The decreased expression of Sox2 together with upregulation of TCTP following SAM administration indicates that SAM has a control over primary osteosarcoma. PMID:27382303

  20. Perspectives on cancer stem cells in osteosarcoma.

    PubMed

    Basu-Roy, Upal; Basilico, Claudio; Mansukhani, Alka

    2013-09-10

    Osteosarcoma is an aggressive pediatric tumor of growing bones that, despite surgery and chemotherapy, is prone to relapse. These mesenchymal tumors are derived from progenitor cells in the osteoblast lineage that have accumulated mutations to escape cell cycle checkpoints leading to excessive proliferation and defects in their ability to differentiate appropriately into mature bone-forming osteoblasts. Like other malignant tumors, osteosarcoma is often heterogeneous, consisting of phenotypically distinct cells with features of different stages of differentiation. The cancer stem cell hypothesis posits that tumors are maintained by stem cells and it is the incomplete eradication of a refractory population of tumor-initiating stem cells that accounts for drug resistance and tumor relapse. In this review we present our current knowledge about the biology of osteosarcoma stem cells from mouse and human tumors, highlighting new insights and unresolved issues in the identification of this elusive population. We focus on factors and pathways that are implicated in maintaining such cells, and differences from paradigms of epithelial cancers. Targeting of the cancer stem cells in osteosarcoma is a promising avenue to explore to develop new therapies for this devastating childhood cancer. PMID:22659734

  1. Zebrafish as a model for human osteosarcoma.

    PubMed

    Mohseny, A B; Hogendoorn, P C W

    2014-01-01

    For various reasons involving biological comparativeness, expansive technological possibilities, accelerated experimental speed, and competitive costs, zebrafish has become a comprehensive model for cancer research. Hence, zebrafish embryos and full-grown fish have been instrumental for studies of leukemia, melanoma, pancreatic cancer, bone tumors, and other malignancies. Although because of its similarities to human osteogenesis zebrafish appears to be an appealing model to investigate osteosarcoma, only a few osteosarcoma specific studies have been accomplished yet. Here, we review interesting related and unrelated reports of which the findings might be extrapolated to osteosarcoma. More importantly, rational but yet unexplored applications of zebrafish are debated to expand the window of opportunities for future establishment of osteosarcoma models. Accordingly technological advances of zebrafish based cancer research, such as robotic high-throughput multicolor injection systems and advanced imaging methods are discussed. Furthermore, various use of zebrafish embryos for screening drug regimens by combinations of chemotherapy, novel drug deliverers, and immune system modulators are suggested. Concerning the etiology, the high degree of genetic similarity between zebrafish and human cancers indicates that affected regions are evolutionarily conserved. Therefore, zebrafish as a swift model system that allows for the investigation of multiple candidate gene-defects is presented. PMID:24924177

  2. Polyostotic Chondroblastic Osteosarcoma in a Kestrel ( Falco tinnunculus ).

    PubMed

    De Luca Bossa, Luigi Maria; Mennonna, Giuseppina; Meomartino, Leonardo; Paciello, Orlando; Ciccarelli, Francesca; De Biase, Davide; Raia, Pasquale; Caputo, Vincenzo; Fioretti, Alessandro; Dipineto, Ludovico

    2015-12-01

    We report a case of polyostotic chondroblastic osteosarcoma in a kestrel ( Falco tinnunculus ) admitted to the Wildlife Rehabilitation and Rescue Center (Naples, Italy). A consolidated fracture of the left tibiotarsus bone and a deviation of the limb were evident. After radiographic, cytologic, and histopathologic examinations, a diagnosis of polyostotic chondroblastic osteosarcoma was made. To our knowledge, this is the first report on polyostotic chondroblastic osteosarcoma in a kestrel. PMID:26771323

  3. Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies.

    PubMed

    Morrow, James J; Khanna, Chand

    2015-01-01

    Osteosarcoma is the most common primary malignancy of bone, typically presenting in the first or second decade of life. Unfortunately, clinical outcomes for osteosarcoma patients have not substantially improved in over 30 years. This stagnation in therapeutic advances is perhaps explained by the genetic, epigenetic, and biological complexities of this rare tumor. In this review we provide a general background on the biology of osteosarcoma and the clinical status quo. We go on to enumerate the genetic and epigenetic defects identified in osteosarcoma. Finally, we discuss ongoing large-scale studies in the field and potential new therapies that are currently under investigation. PMID:26349415

  4. A popliteal giant synovial osteochondroma mimicking a parosteal osteosarcoma

    PubMed Central

    2013-01-01

    Both giant synovial osteochondroma and parosteal osteosarcoma are rare musculo-skeletal tumors, often localized in the vicinity of the knee. Misdiagnosis of a malignant bone tumor can entail fatal consequences. Etiology of giant synovial osteochondroma is widely unsolved but is believed to originate from synovial chondromatosis, a mostly benign metaplasia of the synovial membrane. Parosteal osteosarcoma is a low-grade surface osteosarcoma with a propensity of local recurrence and the potential of distant metastasis and therefore requiring a different therapeutical approach. We report the case of a popliteal giant osteochondroma mimicking a parosteal osteosarcoma. Relevant facts of this rare entity regarding pathogenesis, treatment, and differential diagnoses will be discussed. PMID:24066980

  5. Osteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies

    PubMed Central

    Morrow, James J.; Khanna, Chand

    2016-01-01

    Osteosarcoma is the most common primary malignancy of bone, typically presenting in the first or second decade of life. Unfortunately, clinical outcomes for osteosarcoma patients have not substantially improved in over 30 years. This stagnation in therapeutic advances is perhaps explained by the genetic, epigenetic, and biological complexities of this rare tumor. In this review we provide a general background on the biology of osteosarcoma and the clinical status quo. We go on to enumerate the genetic and epigenetic defects identified in osteosarcoma. Finally, we discuss ongoing large-scale studies in the field and potential new therapies that are currently under investigation. PMID:26349415

  6. Oncological and functional outcome of periosteal osteosarcoma

    PubMed Central

    Gulia, Ashish; Puri, Ajay; Pruthi, Manish; Desai, Saral

    2014-01-01

    Background: Periosteal osteosarcoma is an uncommon variant of osteosarcoma which constitutes less than 2% of all osteosarcomas. Whereas adequate surgical excision remains the cornerstone of treatment, the role of chemotherapy in this tumor is still unclear. Existing literature contains very few single center studies on the outcomes for periosteal osteosarcomas and any additional information will help in better understanding of these uncommon lesions. This study aims to evaluate the oncologic and functional outcomes of treatment of periosteal osteosarcoma treated at our institute. Materials and Methods: A retrospective analysis of 18 cases of periosteal osteosarcoma treated between January 2001 and December 2010 was carried out. There were 12 males and 6 females. The mean age at presentation was 16.3 years (range 5-26 years). Tibia and femur were the most common sites (n = 8). 16 of 18 patients received chemotherapy, 16 had limb sparing resection, one had an amputation and one had rotationplasty. Of the 16 patients with limb salvage, conventional wide excision was done in 11 cases. In 5 cases tumor was excised with hemicortical excision. Of the 11 cases treated with wide excisions, 4 patients underwent an osteoarticular resection and in 7 patients a joint preserving segmental intercalary resection was done. Results: All patients were available for followup. Surgical margins were free in all patients. A good response to chemotherapy was seen in 4/11 cases and poor in 6/11 cases. In one case the histological response was not discernible due to predominant chondromyxoid nature of the tumor. The median followup was 61 months (range: 18-130 months). There were two local recurrences (11%) at 9 and 18 months postsurgery. Pulmonary metastasis subsequently occurred in 4 cases (22%). Fourteen patients are currently alive and continuously disease free. Disease free survival at 5 years was 77.8% and overall survival (OVS) was 83.3%. Patients without marrow involvement had a

  7. Strategies and developments of immunotherapies in osteosarcoma

    PubMed Central

    WAN, JIA; ZHANG, XIANGHONG; LIU, TANG; ZHANG, XIANGSHENG

    2016-01-01

    Osteosarcoma (OS) is a frequently observed primary malignant tumor. Current therapy for osteosarcoma consists of comprehensive treatment. The long-term survival rate of patients exhibiting nonmetastatic OS varies between 65–70%. However, a number of OS cases have been observed to be resistant to currently used therapies, leading to disease recurrence and lung metastases, which are the primary reasons leading to patient mortality. In the present review, a number of pieces of evidence provide support for the potential uses of immunotherapy, including immunomodulation and vaccine therapy, for the eradication of tumors via upregulation of the immune response. Adoptive T-cell therapy and oncolytic virotherapy have been used to treat OS and resulted in objective responses. Immunologic checkpoint blockade and targeted therapy are also potentially promising therapeutic tools. Immunotherapy demonstrates significant promise with regard to improving the outcomes for patients exhibiting OS. PMID:26834853

  8. Improvement in High-Grade Osteosarcoma Survival

    PubMed Central

    Hung, Giun-Yi; Yen, Hsiu-Ju; Yen, Chueh-Chuan; Wu, Po-Kuei; Chen, Cheng-Fong; Chen, Paul C-H; Wu, Hung-Ta H.; Chiou, Hong-Jen; Chen, Wei-Ming

    2016-01-01

    Abstract The aim of this study was to compare survival before and after 2004 and define the prognostic factors for high-grade osteosarcomas beyond those of typical young patients with localized extremity disease. Few studies have reported the long-term treatment outcomes of high-grade osteosarcoma in Taiwan. A total of 202 patients with primary high-grade osteosarcoma who received primary chemotherapy at Taipei Veterans General Hospital between January 1995 and December 2011 were retrospectively evaluated and compared by period (1995–2003 vs 2004–2011). Patients of all ages and tumor sites and those following or not following controlled protocols were included in analysis of demographic, tumor-related, and treatment-related variables and survival. Overall survival and progression-free survival at 5 years were, respectively, 67.7% and 48% for all patients (n = 202), 77.3% and 57.1% for patients without metastasis (n = 157), and 33.9% and 14.8% for patients with metastasis (n = 45). The survival rates of patients treated after 2004 were significantly higher (by 13%–16%) compared with those of patients treated before 2004, with an accompanying 30% increase in histological good response rate (P = .002). Factors significantly contributing to inferior survival in univariate and multivariate analyses were diagnosis before 2004, metastasis at diagnosis, and being a noncandidate for a controlled treatment protocol. By comparison with the regimens used at our institution before 2004, the current results support the effectiveness of the post-2004 regimens, which consisted of substantially reduced cycles of high-dose methotrexate and a higher dosage of ifosfamide per cycle, cisplatin, and doxorubicin, for treating high-grade osteosarcoma in Asian patients. PMID:27082623

  9. Serum fluoride and sialic acid levels in osteosarcoma.

    PubMed

    Sandhu, R; Lal, H; Kundu, Z S; Kharb, S

    2011-12-01

    Osteosarcoma is a rare malignant bone tumor most commonly occurring in children and young adults presenting with painful swelling. Various etiological factors for osteosarcoma are ionizing radiation, family history of bone disorders and cancer, chemicals (fluoride, beryllium, and vinyl chloride), and viruses. Status of fluoride levels in serum of osteosarcoma is still not clear. Recent reports have indicated that there is a link between fluoride exposure and osteosarcoma. Glycoproteins and glycosaminoglycans are an integral part of bone and prolonged exposure to fluoride for long duration has been shown to cause degradation of collagen and ground substance in bones. The present study was planned to analyze serum fluoride, sialic acid, calcium, phosphorus, and alkaline phosphatase levels in 25 patients of osteosarcoma and age- and sex-matched subjects with bone-forming tumours other than osteosarcoma and musculo-skeletal pain (controls, 25 each). Fluoride levels were analyzed by ISE and sialic acid was analyzed by Warren's method. Mean serum fluoride concentration was found to be significantly higher in patients with osteosarcoma as compared to the other two groups. The mean value of flouride in patients with other bone-forming tumors was approximately 50% of the group of osteosarcoma; however, it was significantly higher when compared with patients of group I. Serum sialic acid concentration was found to be significantly raised in patients with osteosarcoma as well as in the group with other bone-forming tumors as compared to the group of controls. There was, however, no significant difference in the group of patients of osteosarcoma when compared with group of patients with other bone-forming tumors. These results showing higher level of fluoride with osteosarcoma compared to others suggesting a role of fluoride in the disease. PMID:19390788

  10. Aberrant ADAM10 expression correlates with osteosarcoma progression

    PubMed Central

    2014-01-01

    Background Osteosarcoma is the most common type of bone cancer and is notorious for its rapid progression. The Notch signaling pathway has recently been shown to be involved in osteosarcoma. As a major sheddase of Notch receptors, ADAM10 has been implicated in many types of cancers, but its role in osteosarcoma has not been investigated. Previous studies have shown that the expression of CD31 was significantly elevated in metastatic osteosarcoma; however, its expression in nonmetastatic groups is not known. In addition, the mysterious multinucleated giant cell in giant cell-rich osteosarcoma was previously regarded as an osteoclast-like cell, but its exact identity is unclear. Method Tissue chip samples from 40 cases of nonmetastatic osteosarcoma were stained for cytoplasmic ADAM10, activated Notch1 and CD31. Osteoclasts in tumor sections were also stained for tartrate-resistant acid phosphatase (TRAP). Results Immunofluorescence staining revealed that ADAM10 expression significantly increased with the progression of osteosarcoma as well as in osteoblastic osteosarcoma, whereas the expression of the Notch intracellular domain (NICD) and CD31 was not significantly altered between different pathological stages. In addition, multinucleated giant cells in giant cell-rich osteosarcoma were also found to coexpress CD31, ADAM10 and NICD, but were negative for TRAP staining. Conclusions Our results highlight the importance of ADAM10 in the progression of osteosarcoma and suggest that the protein might be a potential therapeutic target in osteosarcoma treatment. This study also demonstrates that the multinucleated giant cell is an angiogenic tumor cell, rather than an osteoclast, and involves ADAM10/Notch1 signaling activation. PMID:24548763

  11. Classification, imaging, biopsy and staging of osteosarcoma.

    PubMed

    Kundu, Zile Singh

    2014-05-01

    Osteosarcoma is the most common primary osseous malignancy excluding malignant neoplasms of marrow origin (myeloma, lymphoma and leukemia) and accounts for approximately 20% of bone cancers. It predominantly affects patients younger than 20 years and mainly occurs in the long bones of the extremities, the most common being the metaphyseal area around the knee. These are classified as primary (central or surface) and secondary osteosarcomas arising in preexisting conditions. The conventional plain radiograph is the best for probable diagnosis as it describes features like sun burst appearance, Codman's triangle, new bone formation in soft tissues along with permeative pattern of destruction of the bone and other characteristics for specific subtypes of osteosarcomas. X-ray chest can detect metastasis in the lungs, but computerized tomography (CT) scan of the thorax is more helpful. Magnetic resonance imaging (MRI) of the lesion delineates its extent into the soft tissues, the medullary canal, the joint, skip lesions and the proximity of the tumor to the neurovascular structures. Tc99 bone scan detects the osseous metastases. Positron Emission Tomography (PET) is used for metastatic workup and/or local recurrence after resection. The role of biochemical markers like alkaline phosphatase and lactate dehydrogenase is pertinent for prognosis and treatment response. The biopsy confirms the diagnosis and reveals the grade of the tumor. Enneking system for staging malignant musculoskeletal tumors and American Joint Committee on Cancer (AJCC) staging systems are most commonly used for extremity sarcomas. PMID:24932027

  12. Osteosarcoma in a sixteen-month old boy.

    PubMed

    Ibrahim, S; Sundari, M N; Masir, N

    1999-06-01

    We report a case of a sixteen-month old boy with osteosarcoma of the left humerus. To the best of our knowledge this is the youngest case reported in Malaysia. This case illustrates that osteosarcoma although rare does occur in a very young child. The child died six weeks after presentation due to disseminated disease. PMID:10972039

  13. Germline TP53 Variants and Susceptibility to Osteosarcoma

    PubMed Central

    Yeager, Meredith; Mai, Phuong L.; Gastier-Foster, Julie M.; Gorlick, Richard; Khanna, Chand; Patiño-Garcia, Ana; Sierrasesúmaga, Luis; Lecanda, Fernando; Andrulis, Irene L.; Wunder, Jay S.; Gokgoz, Nalan; Barkauskas, Donald A.; Zhang, Xijun; Vogt, Aurelie; Jones, Kristine; Boland, Joseph F.; Chanock, Stephen J.; Savage, Sharon A.

    2015-01-01

    The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ2 tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants. PMID:25896519

  14. Germline TP53 variants and susceptibility to osteosarcoma.

    PubMed

    Mirabello, Lisa; Yeager, Meredith; Mai, Phuong L; Gastier-Foster, Julie M; Gorlick, Richard; Khanna, Chand; Patiño-Garcia, Ana; Sierrasesúmaga, Luis; Lecanda, Fernando; Andrulis, Irene L; Wunder, Jay S; Gokgoz, Nalan; Barkauskas, Donald A; Zhang, Xijun; Vogt, Aurelie; Jones, Kristine; Boland, Joseph F; Chanock, Stephen J; Savage, Sharon A

    2015-07-01

    The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ(2) tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants. PMID:25896519

  15. Expression and prognostic relevance of PRAME in primary osteosarcoma

    SciTech Connect

    Tan, Pingxian; Zou, Changye; Yong, Bicheng; Han, Ju; Zhang, Longjuan; Su, Qiao; Yin, Junqiang; Wang, Jin; Huang, Gang; Peng, Tingsheng; Shen, Jingnian

    2012-03-23

    Graphical abstract: High PRAME expression was associated with osteosarcoma patients' poor prognosis and lung metastasis. Highlights: Black-Right-Pointing-Pointer We analyzed and verified the role of PRAME in primary osteosarcoma. Black-Right-Pointing-Pointer High PRAME expression in osteosarcoma correlated to poor prognosis and lung metastasis. Black-Right-Pointing-Pointer PRAME siRNA knockdown significantly suppressed the proliferation, colony formation, and G1 cell cycle arrest in U-2OS cells. -- Abstract: The preferentially expressed antigen of melanoma (PRAME), a cancer-testis antigen with unknown function, is expressed in many human malignancies and is considered an attractive potential target for tumor immunotherapy. However, studies of its expression and function in osteosarcoma have rarely been reported. In this study, we found that PRAME is expressed in five osteosarcoma cell lines and in more than 70% of osteosarcoma patient specimens. In addition, an immunohistochemical analysis showed that high PRAME expression was associated with poor prognosis and lung metastasis. Furthermore, PRAME siRNA knockdown significantly suppressed the proliferation, colony formation, and G1 cell cycle arrest in U-2OS cells. Our results suggest that PRAME plays an important role in cell proliferation and disease progression in osteosarcoma. However, the detail mechanisms of PRAME function in osteosarcoma require further investigation.

  16. Metastatic Osteosarcoma to the Breast Presenting as a Densely Calcified Mass on Mammography.

    PubMed

    Kim, Jonghyeon; Woo, Ha Young; Kim, Eun-Kyung; Kim, Min Jung; Moon, Hee Jung; Yoon, Jung Hyun

    2016-03-01

    Osteosarcoma most commonly metastasizes to the lung or the skeleton, and metastatic osteosarcoma to the breast is very rare, with only a few cases reported. Due to its rarity, little has been reported about its imaging features. In this report, we represent a 58-year-old woman with metastatic osteosarcoma to the right breast from a tibial osteosarcoma. The imaging features of the metastatic osteosarcoma to the breast by using dedicated breast imaging modalities are described. Although rare, metastatic osteosarcoma to the breast should be considered when dense calcified masses with suspicious features are seen on breast imaging in patients with a history of osteosarcoma. PMID:27064762

  17. Metastatic Osteosarcoma to the Breast Presenting as a Densely Calcified Mass on Mammography

    PubMed Central

    Kim, Jonghyeon; Woo, Ha Young; Kim, Eun-Kyung; Kim, Min Jung; Moon, Hee Jung

    2016-01-01

    Osteosarcoma most commonly metastasizes to the lung or the skeleton, and metastatic osteosarcoma to the breast is very rare, with only a few cases reported. Due to its rarity, little has been reported about its imaging features. In this report, we represent a 58-year-old woman with metastatic osteosarcoma to the right breast from a tibial osteosarcoma. The imaging features of the metastatic osteosarcoma to the breast by using dedicated breast imaging modalities are described. Although rare, metastatic osteosarcoma to the breast should be considered when dense calcified masses with suspicious features are seen on breast imaging in patients with a history of osteosarcoma. PMID:27064762

  18. 3D-printed guiding templates for improved osteosarcoma resection

    PubMed Central

    Ma, Limin; Zhou, Ye; Zhu, Ye; Lin, Zefeng; Wang, Yingjun; Zhang, Yu; Xia, Hong; Mao, Chuanbin

    2016-01-01

    Osteosarcoma resection is challenging due to the variable location of tumors and their proximity with surrounding tissues. It also carries a high risk of postoperative complications. To overcome the challenge in precise osteosarcoma resection, computer-aided design (CAD) was used to design patient-specific guiding templates for osteosarcoma resection on the basis of the computer tomography (CT) scan and magnetic resonance imaging (MRI) of the osteosarcoma of human patients. Then 3D printing technique was used to fabricate the guiding templates. The guiding templates were used to guide the osteosarcoma surgery, leading to more precise resection of the tumorous bone and the implantation of the bone implants, less blood loss, shorter operation time and reduced radiation exposure during the operation. Follow-up studies show that the patients recovered well to reach a mean Musculoskeletal Tumor Society score of 27.125. PMID:26997197

  19. 3D-printed guiding templates for improved osteosarcoma resection.

    PubMed

    Ma, Limin; Zhou, Ye; Zhu, Ye; Lin, Zefeng; Wang, Yingjun; Zhang, Yu; Xia, Hong; Mao, Chuanbin

    2016-01-01

    Osteosarcoma resection is challenging due to the variable location of tumors and their proximity with surrounding tissues. It also carries a high risk of postoperative complications. To overcome the challenge in precise osteosarcoma resection, computer-aided design (CAD) was used to design patient-specific guiding templates for osteosarcoma resection on the basis of the computer tomography (CT) scan and magnetic resonance imaging (MRI) of the osteosarcoma of human patients. Then 3D printing technique was used to fabricate the guiding templates. The guiding templates were used to guide the osteosarcoma surgery, leading to more precise resection of the tumorous bone and the implantation of the bone implants, less blood loss, shorter operation time and reduced radiation exposure during the operation. Follow-up studies show that the patients recovered well to reach a mean Musculoskeletal Tumor Society score of 27.125. PMID:26997197

  20. 3D-printed guiding templates for improved osteosarcoma resection

    NASA Astrophysics Data System (ADS)

    Ma, Limin; Zhou, Ye; Zhu, Ye; Lin, Zefeng; Wang, Yingjun; Zhang, Yu; Xia, Hong; Mao, Chuanbin

    2016-03-01

    Osteosarcoma resection is challenging due to the variable location of tumors and their proximity with surrounding tissues. It also carries a high risk of postoperative complications. To overcome the challenge in precise osteosarcoma resection, computer-aided design (CAD) was used to design patient-specific guiding templates for osteosarcoma resection on the basis of the computer tomography (CT) scan and magnetic resonance imaging (MRI) of the osteosarcoma of human patients. Then 3D printing technique was used to fabricate the guiding templates. The guiding templates were used to guide the osteosarcoma surgery, leading to more precise resection of the tumorous bone and the implantation of the bone implants, less blood loss, shorter operation time and reduced radiation exposure during the operation. Follow-up studies show that the patients recovered well to reach a mean Musculoskeletal Tumor Society score of 27.125.

  1. Actein Inhibits Cell Proliferation and Migration in Human Osteosarcoma

    PubMed Central

    Chen, Zhi; Wu, Jingdong; Guo, Qinghao

    2016-01-01

    Background Osteosarcoma is one of the most common malignant bone cancers worldwide. Although the traditional chemotherapies have made some progression in the past decades, the mortality of osteosarcoma in children and adolescent is very high. Herein, the role of actein in osteosarcoma was explored. Material/Methods Cell viability assay was performed in osteosarcoma cell lines 143B and U2OS. Colony formation analysis was included when cells were treated with different doses of actin. Cell cycle assay was conducted to further examine the role of actein. Cell apoptotic rate and the relative activities of caspase-3, caspase-8, and caspase-9 were detected in 143B and U2OS osteosarcoma cells. Moreover, transwell assays were used to explore the effects of actein on cell metastasis. Results Actein significantly inhibited osteosarcoma cell viability in a time- and dose-dependent manner. Actein also dramatically suppressed the colony formation ability in osteosarcoma143B and U2OS cells. It was revealed that osteosarcoma cells were arrested in G0/G1 phase in the cell cycle progression and induced to apoptosis by administration of actein. The activities of pro-apoptotic factors such as caspase-3 and caspase-9 were significantly increased by actein. Furthermore, administration of actein decreased cell migrated and invasive abilities in both 143B and U2OS cell lines. Conclusions Actein inhibits tumor growth by inducing cell apoptosis in osteosarcoma. The inhibitive roles of actein in cell proliferation, migration and invasion suggest that actein may serve as a potential therapeutic agent in the treatment of osteosarcoma. PMID:27173526

  2. MMP-3 gene polymorphisms and Osteosarcoma.

    PubMed

    Adiguzel, Mustafa; Horozoglu, Cem; Kilicoglu, Onder; Ozger, Harzem; Acar, Leyla; Ergen, Arzu

    2016-03-01

    Osteosarcoma (OSA) is the most common adolescence cancer among all primary bone tumors next only to multiplemyeloma. It has a substantially worse prognosis and ability to metastasize to lung. MMPs (matrix metalloproteinases) are among the major proteases that take part in regulation of ECM (extracellular matrix). MMPs play an active role in the formation of the osteoid tissue, rich in collagens and other ECM proteoglycans. They also take part in pro-osteoclast, osteoclast, osteoblast, and osteoid formation. Many members of the MMP gene family have been linked to human cancers. It has been shown that MMPs particularly play a role in the tumor's acquisition of an invasive and metastatic character. In our study, the E45K and T102T polymorphisms of MMP-3 were studied using the PCR-RFLP method in 135 Turkish subjects (54 subjects with osteosarcoma and 81 healthy controls). We found that frequencies of E45K G allele (p:0,010, χ²:6,710, OR:1,429, 95% Cl: 1,019-1,858) and AG genotype (p:0,001, χ²:14,753, OR:2,32, 95% Cl: 1,491-3,626) were elevated in patients compared to controls. Besides, there was a significant difference in.E45K AA genotype between study groups (p:0,004, χ²:8,182, OR: 2,929, 95% Cl: 1,38-6,19). There were no significant differences between any genotypes or allele in the control and patient groups for MMP-3 T102T polymorphism. Our findings indicate that the G allele and AG genotype of MMP-3 E45K polymorphism is associated with increased risk of osteosarcoma in adolescent population of Turkey. PMID:27145630

  3. Osteosarcoma With Apparent Ewing Sarcoma Gene Rearrangement.

    PubMed

    Mathias, Melissa D; Chou, Alexander J; Meyers, Paul; Shukla, Neerav; Hameed, Meera; Agaram, Narasimhan; Wang, Lu; Berger, Michael F; Walsh, Michael; Kentsis, Alex

    2016-07-01

    Poorly differentiated round cell sarcomas present diagnostic challenges because of their variable morphology and lack of specific immunophenotypic markers. We present a case of a 15-year-old female with a tibial tumor that exhibited features of Ewing-like sarcoma, including apparent rearrangement of the EWSR1 gene. Hybridization capture-based next-generation DNA sequencing showed evidence of complex genomic rearrangements, absence of known pathogenic Ewing-like chromosome translocations, and deletions RB1, PTCH1, and ATRX, supporting the diagnosis of osteosarcoma. This illustrates the potential of clinical genomic profiling to improve diagnosis and enable specifically targeted therapies for cancers with complex pathologies. PMID:27352193

  4. Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma

    PubMed Central

    Tavanti, E; Sero, V; Vella, S; Fanelli, M; Michelacci, F; Landuzzi, L; Magagnoli, G; Versteeg, R; Picci, P; Hattinger, C M; Serra, M

    2013-01-01

    Background: Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours. Methods: Biological relevance of Aurora kinase-A and -B was assessed on osteosarcoma clinical samples and by silencing these genes with specific siRNA in three human osteosarcoma cell lines. In vitro efficacy of two Aurora kinases-targeting drugs (VX-680 and ZM447439) was evaluated on a panel of four drug-sensitive and six drug-resistant human osteosarcoma cell lines. Results: Human osteosarcoma cell lines proved to be highly sensitive to both drugs. A decreased drug sensitivity was observed in doxorubicin-resistant cell lines, most probably related to ABCB1/MDR1 overexpression. Both drugs variably induced hyperploidy and apoptosis in the majority of cell lines. VX-680 also reduced in vitro cell motility and soft-agar cloning efficiency. Drug association experiments showed that VX-680 positively interacts with all conventional drugs used in osteosarcoma chemotherapy, overcoming the cross-resistance observed in the single-drug treatments. Conclusion: Aurora kinase-A and -B represent new candidate therapeutic targets for osteosarcoma. In vitro analysis of the Aurora kinases inhibitors VX-680 and ZM447439 indicated in VX-680 a new promising drug of potential clinical usefulness in association with conventional osteosarcoma chemotherapeutic agents. PMID:24129234

  5. Telangiectatic osteosarcoma of the spine: a case report

    PubMed Central

    Venkatesh, K.; Cherian, R.; Shah, A.; Sundararaj, G. D.

    2008-01-01

    Telangiectatic osteosarcoma (TOS) of the spine is rare accounting for only 0.08% of all primary osteosarcomas. Though a well described radio-pathological entity it is not often thought of as a cause of paraplegia. We describe the clinical, radiological and pathological features and discuss the treatment options of telangiectatic osteosarcoma of the dorsal spine presenting in a young man. The diagnostic pitfalls are discussed emphasising the fact that the diagnosis of TOS of the spine requires not only a multi modal approach of appropriate radiological and pathological tests but also an awareness of this condition.

  6. Minnelide reduces tumor burden in preclinical models of osteosarcoma

    PubMed Central

    Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N.; Saluja, Ashok K.; Subramanian, Subbaya

    2015-01-01

    Osteosarcoma is the most common bone cancer in children and adolescents with a five-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets NF-κB pathway. PMID:23499892

  7. Minnelide reduces tumor burden in preclinical models of osteosarcoma.

    PubMed

    Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N; Saluja, Ashok K; Subramanian, Subbaya

    2013-07-28

    Osteosarcoma is the most common bone cancer in children and adolescents with a 5-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets the NF-κB pathway. PMID:23499892

  8. Progress and opportunities for immune therapeutics in osteosarcoma.

    PubMed

    Lettieri, Christina K; Appel, Nicole; Labban, Nicole; Lussier, Danielle M; Blattman, Joseph N; Hingorani, Pooja

    2016-10-01

    Survival outcomes for osteosarcoma have plateaued since the 1980s, and patients with relapsed or refractory disease have a particularly dismal outcome. Treatment options for these patients are limited primarily due to the paucity of effective therapeutics. Immune therapies such as tumor vaccines and traditional antigen-targeted monoclonal antibodies have had limited success in solid tumors. The recent discovery of novel immune checkpoint blockade strategies and their success in adult cancers has revitalized the use of immunotherapy strategies for the treatment of solid tumors. This paper summarizes existing data supporting the use of immune therapies in osteosarcoma and the progress of this class of drugs in osteosarcoma therapy. PMID:27605071

  9. Wikipedia and osteosarcoma: a trustworthy patients' information?

    PubMed

    Leithner, Andreas; Maurer-Ertl, Werner; Glehr, Mathias; Friesenbichler, Joerg; Leithner, Katharina; Windhager, Reinhard

    2010-01-01

    The English version of the online encyclopedia, Wikipedia, has been recently reported to be the prominent source of online health information. However, there is little information concerning the quality of information found in Wikipedia. Therefore, we created a questionnaire asking for scope, completeness, and accuracy of information found on osteosarcoma. Three independent observers tested the English version of Wikipedia, as well as the patient version and the health professional version of the US National Cancer Institute (NCI) website. Answers were verified with authoritative resources and international guidelines. The results of our study demonstrate that the quality of osteosarcoma-related information found in the English Wikipedia is good but inferior to the patient information provided by the NCI. Therefore, non-peer-reviewed commonly used websites offering health information, such as Wikipedia, should include links to more definitive sources, such as those maintained by the NCI and professional international organizations on healthcare treatments. Furthermore, frequent checks should make sure such external links are to the highest quality and to the best-maintained aggregate sites on a given healthcare topic. PMID:20595302

  10. Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets.

    PubMed

    Yan, Guang-Ning; Lv, Yang-Fan; Guo, Qiao-Nan

    2016-01-28

    Osteosarcoma is the most common type of bone cancer, especially in children and young adults. The primary treatment for osteosarcoma is a combination of surgery and chemotherapy, however prognoses remain poor due to chemoresistance and early metastases. Osteosarcoma stem cells appear to play central roles in tumor recurrence, metastases and chemoresistance via self-renewal and differentiation. Targeting these cells may provide a novel strategy in the treatment of osteosarcoma. This review summarizes current knowledge of this rare phenotype and recent advances in understanding the functions OSCs (osteosarcoma stem cells) in osteosarcoma, with the aim of improving therapies in the future. PMID:26571463

  11. Intramedullary Osteosarcoma of the Mandible: A Clinicoradiologic Perspective

    PubMed Central

    Chittaranjan, Bhogisetty; Tejasvi, ML Avinash; Babu, Bangi Balaji; Geetha, Paramkusam

    2014-01-01

    Osteosarcoma is a non-hematopoietic primary malignant tumor of bone or mesenchymal tissue. Although osteosarcoma is not a common malignant bone tumor, accounting for approximately 20% of sarcomas, tumor of the jaw bone is uncommon, representing only about 4% of osteosarcomas of long bones. We report a case of a 72-year-old female with a swelling on the left side of the mandible and intra-oral swelling on the floor of the mouth. Conventional radiograph and advanced imaging modalities such as computed tomography and magnetic resonance imaging revealed an intramedullary osteosarcoma of the mandible. This report highlights importance of imaging modalities in the diagnosis of malignant tumors of the jaws. PMID:25598996

  12. Simultaneous bilateral spontaneous pneumothorax as a presenting symptom of osteosarcoma.

    PubMed

    Boersma, R S; Buijs, J

    2007-07-01

    Simultaneous bilateral spontaneous pneumothorax (SBSP) is a very rare condition that is mainly encountered in patients with underlying lung disease. We present a patient with a SBSP as a presenting symptom of a metastasized osteosarcoma. PMID:17574115

  13. General Information about Osteosarcoma and Malignant Fibrous Histiocytoma of Bone

    MedlinePlus

    ... Histiocytoma of Bone Treatment (PDQ®)–Patient Version General Information About Osteosarcoma and Malignant Fibrous Histiocytoma of Bone ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  14. Multicentric osteosarcoma presenting as retrobulbar mass: a diagnostic enigma.

    PubMed

    Wong, K F; Shu, S J; Luk, I S C; Yuen, H L; Leung, J N S; Chan, J K C

    2006-06-01

    Osteosarcoma is the most common primary malignant bone tumor of children and adolescents. It often presents as a solitary lesion; multicentric osteosarcoma with synchronous lesions occurring at multiple skeletal sites is very rare. We report a 9-year-old boy with multicentric osteosarcoma who presented with a left retrobulbar non-sclerotic mass. The multiple lesions in bone were mostly non-sclerotic on radiological examination except for a single lesion in the left tibia. Biopsy of the retrobulbar mass showed an unclassifiable poorly differentiated malignant tumor. Marrow aspiration smears showed many large, often segregated, round cells that expressed NB84a. However, trephine biopsy showed the formation of tumoral osteoid by the malignant cells, finally permitting the definitive diagnosis of osteosarcoma to be made. A hypertetraploid clone with complex structural abnormalities was demonstrated by cytogenetic study. PMID:15926165

  15. Treatment Option Overview (Osteosarcoma and Malignant Fibrous Histiocytoma of Bone)

    MedlinePlus

    ... tomography, computerized tomography, or computerized axial tomography. MRI (magnetic resonance imaging) : A procedure that uses a magnet, radio waves , ... the body. This procedure is also called nuclear magnetic resonance imaging (NMRI). A biopsy is done to diagnose osteosarcoma. ...

  16. Expression of metabotropic glutamate receptor 4 in osteosarcoma

    PubMed Central

    WANG, SHUO; WEI, XING; CHEN, BINGYAO; ZHAO, MIN; SONG, GUANGZE; ZHANG, ZENGLIANG; LI, NAN

    2016-01-01

    Metabotropic glutamate receptor 4 (mGluR4) has been associated with the pathogenesis of osteosarcoma. The aim of this study was to investigate mGluR4 expression and its clinical significance in osteosarcoma patients. mGluR4 expression was investigated using immunohistochemistry (IHC) in 58 osteosarcomas and 32 giant-cell tumors of bone. The correlations between mGluR4 expression and clinicopathological characteristics were analyzed with the Chi-squared test and survival curves were generated using the Kaplan-Meier method. The IHC results demonstrated that 20.69% (12/58) of the osteosarcomas and 43.75% (14/32) of the giant-cell tumors were mGluR4-positive. The statistical analysis revealed that mGluR4 expression was correlated with gender, age, Enneking stage and tumor volume in osteosarcomas (P<0.05). In the multivariate stepwise Cox regression analysis, Enneking stage was found to be statistically significantly associated with survival (P<0.05) and the survival analysis demonstrated that the survival probability was significantly higher in patients with higher mGluR4 expression compared with those with lower expression (P<0.05). Therefore, mGluR4 expression may be used to estimate the prognosis of osteosarcoma patients. PMID:26870360

  17. Primary Hepatic Osteosarcoma: A Rare Cause of Primary Liver Tumor

    PubMed Central

    Tamang, Tsering Gyalpo Lama; Shuster, Marina; Chandra, Abhinav B.

    2016-01-01

    INTRODUCTION Extraosseous osteosarcomas are rare, accounting for approximately 4% of all osteosarcomas. A literature review yields very few cases of osteosarcoma primarily arising from the hepatic parenchyma. CASE REPORT This report describes a case of a man in his 50s with a history of hepatitis C and cirrhosis who presented with 5 days of progressive right upper quadrant pain. Magnetic resonance imaging of the abdomen and pelvis demonstrated a 4.4 cm × 4.8 cm × 4.8 cm right hepatic lobe mass with a large area of necrosis and peripheral enhancement. The subsequent liver biopsy showed few cores of tumor composed of fibroblastic malignant cells producing lace-like osteoid matrix. Osteosarcomatous foci in other parts of the body were excluded by performing extensive physical examination, radiologic imaging, and biopsy. Hence, a primary osteosarcoma was diagnosed. The patient underwent portal vein embolization in preparation for a surgical resection of the right liver lobe. He was admitted six weeks after the embolization for dyspnea and abdominal distension and expired due to abdominal hematoma and pulmonary embolism. CONCLUSION Based on the rarity, lack of consensus in treatment, and dismal prognosis, extraosseous osteosarcoma should be considered a separate entity from osseous osteosarcoma. More data and research are needed in this rare and understudied malignancy. PMID:27081321

  18. SRCIN1 Suppressed Osteosarcoma Cell Proliferation and Invasion.

    PubMed

    Wang, Peng; Wang, Hu; Li, Xiaotao; Liu, Ying; Zhao, Chengbin; Zhu, Daling

    2016-01-01

    SRCIN1 (SRC kinase signalling inhibitor 1) is a new tumor suppressor gene. Previous studies showed that SRCIN1 played a tumor suppressor role in the development of lung cancer and breast cancer. However, the role of SRCIN1 in osteosarcoma is still unknown. In this study, we demonstrated that SRCIN1 was downregulated in osteosarcoma cell lines compared with osteoblastic cell line. Moreover, SRCIN1 was downregulated in osteosarcoma tissues compared with the adjacent tissues. Further investigation revealed that overexpression of SRCIN1 inhibited the osteosarcoma cell line MG-63 proliferation. This effect was confirmed by measuring the ki-67 and PCNA expression. SRCIN1 overexpression promoted E-cadherin expression and suppressed N-cadherin, Vimentin and Snail expression, suggesting that SRCIN1 overexpression inhibited EMT of the osteosarcoma cell. In addition, ectopic expression of SRCIN1 inhibited the MG-63 cell colony formation and invasion. These data suggested that SRCIN1 acted as a tumor suppressor gene in the development of osteosarcoma. PMID:27513473

  19. SRCIN1 Suppressed Osteosarcoma Cell Proliferation and Invasion

    PubMed Central

    Wang, Peng; Wang, Hu; Li, Xiaotao; Liu, Ying; Zhao, Chengbin; Zhu, Daling

    2016-01-01

    SRCIN1 (SRC kinase signalling inhibitor 1) is a new tumor suppressor gene. Previous studies showed that SRCIN1 played a tumor suppressor role in the development of lung cancer and breast cancer. However, the role of SRCIN1 in osteosarcoma is still unknown. In this study, we demonstrated that SRCIN1 was downregulated in osteosarcoma cell lines compared with osteoblastic cell line. Moreover, SRCIN1 was downregulated in osteosarcoma tissues compared with the adjacent tissues. Further investigation revealed that overexpression of SRCIN1 inhibited the osteosarcoma cell line MG-63 proliferation. This effect was confirmed by measuring the ki-67 and PCNA expression. SRCIN1 overexpression promoted E-cadherin expression and suppressed N-cadherin, Vimentin and Snail expression, suggesting that SRCIN1 overexpression inhibited EMT of the osteosarcoma cell. In addition, ectopic expression of SRCIN1 inhibited the MG-63 cell colony formation and invasion. These data suggested that SRCIN1 acted as a tumor suppressor gene in the development of osteosarcoma. PMID:27513473

  20. Metastatic osteosarcoma: a challenging multidisciplinary treatment.

    PubMed

    Meazza, Cristina; Scanagatta, Paolo

    2016-05-01

    Osteosarcoma is the most common malignant bone tumor, currently treated with pre-and postoperative chemotherapy in association with the surgical removal of the tumor. About 15-20% of patients have evidence of metastases at diagnosis, mostly in the lungs. Patients with metastatic disease still have a very poor prognosis, with approximately 20-30% of long-term survivors, as compared with 65-70% of patients with localized disease. The optimum management of these patients has not been standardized yet due to several patterns of metastatic disease harboring different prognosis. Complete surgical resection of all sites of disease is mandatory and predictive of survival. Patients with multiple sites of disease not amenable to complete surgery removal should be considered for innovative therapeutic approaches because of poor prognosis. PMID:26999418

  1. Computed tomography of osteosarcoma after intraarterial chemotherapy

    SciTech Connect

    Shirkhoda, A.; Jaffe, N.; Wallace, S.; Ayala, A.; Lindell, M.M.; Zornoza, J.

    1985-01-01

    The response to intraarterial cis-diamminedichloroplatinum II (CDP) chemotherapy was evaluated by computed tomography (CT) in 33 patients with pathologically proved osteosarcoma of the long or flat bones. Twenty-one of the 33 patients had a CT scan before chemotherapy was started. In the other 12 patients, a CT scan was obtained after at least two courses of treatment, and additional studies were performed during the course of therapy. In those patients responding to treatment, the posttherapy scan revealed a remarkable decrease or complete disappearance of the associated soft-tissue mass and clear reestablishment of the fat planes between the muscle bundles that had been obscured. There was sharp definition of the peripheral margins of the calcified healing neoplasm, and the calcification in the healing tumor could be differentiated easily from that of the original bone neoplasm. CT was more accurate than conventional studies in detecting healing process and diagnosis of remission.

  2. Focal adhesion kinase overexpression and its impact on human osteosarcoma

    PubMed Central

    Chen, Yong; Yang, Aizhen; Chen, Hui; Zhang, Jian; Wu, Sujia; Shi, Xin; Wang, Chen; Sun, Xiaoliang

    2015-01-01

    Focal adhesion kinase (FAK) has been implicated in tumorigenesis in various malignancies. We sought to examine the expression patterns of FAK and the activated form, phosphorylated FAK (pFAK), in human osteosarcoma and to investigate the correlation of FAK expression with clinicopathologic parameters and prognosis. In addition, the functional consequence of manipulating the FAK protein level was investigated in human osteosarcoma cell lines. Immunohistochemical staining was used to detect FAK and pFAK in pathologic archived materials from 113 patients with primary osteosarcoma. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognoses. The role of FAK in the cytological behavior of MG63 and 143B human osteosarcoma cell lines was studied via FAK protein knock down with siRNA. Cell proliferation, migration, invasiveness and apoptosis were assessed using the CCK8, Transwell and Annexin V/PI staining methods. Both FAK and pFAK were overexpressed in osteosarcoma. There were significant differences in overall survival between the FAK-/pFAK- and FAK+/pFAK- groups (P = 0.016), the FAK+/pFAK- and FAK+/pFAK+ groups (P = 0.012) and the FAK-/pFAK- and FAK+/pFAK+ groups (P < 0.001). There were similar differences in metastasis-free survival between groups. The Cox proportional hazards analysis showed that the FAK expression profile was an independent indicator of both overall and metastasis-free survival. siRNA-based knockdown of FAK not only dramatically reduced the migration and invasion of MG63 and 143B cells, but also had a distinct effect on osteosarcoma cell proliferation and apoptosis. These results collectively suggest that FAK overexpression and phosphorylation might predict more aggressive biologic behavior in osteosarcoma and may be an independent predictor of poor prognosis. PMID:26393679

  3. Establishing an osteosarcoma associated protein-protein interaction network to explore the pathogenesis of osteosarcoma

    PubMed Central

    2013-01-01

    Background The aim of this study was to establish an osteosarcoma (OS) associated protein-protein interaction network and explore the pathogenesis of osteosarcoma. Methods The gene expression profile GSE9508 was downloaded from the Gene Expression Omnibus database, including five samples of non-malignant bone (the control), seven samples for non-metastatic patients (six of which were analyzed in duplicate), and 11 samples for metastatic patients (10 of which were analyzed in duplicate). Differentially expressed genes (DEGs) between osteosarcoma and control samples were identified by packages in R with the threshold of |logFC (fold change)| > 1 and false discovery rate < 0.05. Osprey software was used to construct the interaction network of DEGs, and genes at protein-protein interaction (PPI) nodes with high degrees were identified. The Database for Annotation, Visualization and Integrated Discovery and WebGestalt software were then used to perform functional annotation and pathway enrichment analyses for PPI networks, in which P < 0.05 was considered statistically significant. Results Compared to the control samples, the expressions of 42 and 341 genes were altered in non-metastatic OS and metastatic OS samples, respectively. A total of 15 significantly enriched functions were obtained with Gene Ontology analysis (P < 0.05). The DEGs were classified and significantly enriched in three pathways, including the tricarboxylic acid cycle, lysosome and axon guidance. Genes such as HRAS, IDH3A, ATP6ap1, ATP6V0D2, SEMA3F and SEMA3A were involved in the enriched pathways. Conclusions The hub genes from metastatic OS samples are not only bio-markers of OS, but also help to improve therapies for OS. PMID:24330838

  4. Notch signaling contributes to the pathogenesis of human osteosarcomas

    PubMed Central

    Engin, Feyza; Bertin, Terry; Ma, Ou; Jiang, Ming Ming; Wang, Lisa; Sutton, Richard E.; Donehower, Lawrence A.; Lee, Brendan

    2009-01-01

    Notch signaling plays an important role in developmental processes and adult tissue homeostasis. Altered Notch signaling has been associated with various diseases including cancer. While the importance of altered Notch signaling in cancers of hematopoietic and epithelial origins has been established, its role in tumors of mesenchymal origin is less clear. Here, we report that human osteosarcoma cell lines and primary human osteosarcoma tumor samples show significant up-regulation of Notch, its target genes and Osterix. Notch inhibition by γ-secretase inhibitors or by using lentiviral mediated expression of dominant negative Mastermind-like protein (DN-MAML) decreases osteosarcoma cell proliferation in vitro. In vivo, established human tumor xenografts in nude mice show decreased tumor growth after chemical or genetic inhibition of Notch signaling. Finally, transcriptional profiling of osteosarcomas from p53 mutant mice confirmed up-regulation of Notch1 target genes Hes1, Hey1 and its ligand Dll4. Our data suggest that activation of Notch signaling contributes to the pathogenesis of human osteosarcomas and its inhibition may be a therapeutic approach for the treatment of this mesenchymal tumor. PMID:19228774

  5. Antitumor activity of dobutamine on human osteosarcoma cells

    PubMed Central

    YIN, JUN; DONG, QIRONG; ZHENG, MINQIAN; XU, XIAOZU; ZOU, GUOYOU; MA, GUOLIN; LI, KEFENG

    2016-01-01

    Dobutamine has been widely used for the treatment of heart failure and cardiogenic shock since the 1970s. Osteosarcoma is the most commonly observed malignant bone tumor in children. Currently, there are no effective drugs for the treatment of osteosarcoma. In the present study, the potential anticancer activity of dobutamine on human osteosarcoma cells was examined. Human osteosarcoma MG-63 cells were treated with dobutamine at various concentrations and for various incubation times. The inhibition of cell growth by dobutamine was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry was utilized to evaluate the effect of dobutamine on cell apoptosis and the cell cycle. Furthermore, the expression levels of caspase-3 and caspase-9 were assessed by western blot analysis. The influence of dobutamine on cancer cell migration and invasion was additionally evaluated using wound-healing assay and the Boyden Chamber migration method. Dobutamine significantly inhibited the growth of MG-63 cells at a concentration of 10 µM or higher when incubated for 12 h or longer (P=0.023). Dobutamine augmented cell apoptosis and arrested the cell cycle in the G2/M phase. Western blot analysis revealed that dobutamine induces expression of caspase-3 and caspase-9. In addition, the invasiveness and migration of MG-63 cells was inhibited by dobutamine in a concentration-dependent manner. The results of the present study may lead to novel applications for dobutamine in the treatment of osteosarcoma. PMID:27284371

  6. Osteosarcoma, seasonality, and environmental factors in Wisconsin, 1979-1989

    SciTech Connect

    Moss, M.E.; Kanarek, M.S.; Anderson, H.A.

    1995-05-01

    Proxy exposure measures and readily available data from the Wisconsin Cancer Reporting System were used to contrast 167 osteosarcoma cases with 989 frequency-matched cancer referents reported during 1979-1989. Differences in potential exposure to water-borne radiation and fluoridated drinking water, population size for the listed place of residence, and seasonality were assessed. An association was found between osteosarcoma and residence in a population of less that 9000 (odds ratio = 1.6, 95% confidence interval = 1.1-2.4). In addition, an association between month of birth (May through July versus other months of birth) and osteosarcoma among individuals who were less than 25 y of age (odds ratio = 1.9, 95% confidence interval = 1.1-3.4). Overall, no association was found between potential exposure to fluoridated drinking water and osteosarcoma (odds ratio = 1.0, 95% confidence interval = 0.6-1.5). The association between osteosarcoma and water-borne radiation was weak and was not significant statistically (odds ratio = 1.5, 95% confidence interval = 0.8-2.8). 27 refs., 5 tabs.

  7. Fluoride exposure and childhood osteosarcoma: a case-control study.

    PubMed Central

    Gelberg, K H; Fitzgerald, E F; Hwang, S A; Dubrow, R

    1995-01-01

    OBJECTIVES. This study tests the hypothesis that fluoride exposure in a nonoccupational setting is a risk factor for childhood osteosarcoma. METHODS. A population-based case-control study was conducted among residents of New York State, excluding New York City. Case subjects (n = 130) were diagnosed with osteosarcoma between 1978 and 1988, at age 24 years or younger. Control subjects were matched to case subjects on year of birth and sex. Exposure information was obtained by a telephone interview with the subject, parent, or both. RESULTS. Based on the parents' responses, total lifetime fluoride exposure was not significantly associated with osteosarcoma among all subjects combined or among females. However, a significant protective trend was observed among males. Protective trends were observed for fluoridated toothpaste, fluoride tablets, and dental fluoride treatments among all subjects and among males. Based on the subjects' responses, no significant associations between fluoride exposure and osteosarcoma were observed. CONCLUSIONS. Fluoride exposure does not increase the risk of osteosarcoma and may be protective in males. The protective effect may not be directly due to fluoride exposure but to other factors associated with good dental hygiene. There is also biologic plausibility for a protective effect. PMID:7503344

  8. Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma

    PubMed Central

    Yu, Diana; Kahen, Elliot; Cubitt, Christopher L.; McGuire, Jeremy; Kreahling, Jenny; Lee, Jae; Altiok, Soner; Lynch, Conor C.; Sullivan, Daniel M.; Reed, Damon R.

    2015-01-01

    Systemic therapy has improved osteosarcoma event-free and overall survival, but 30–50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development, and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. We found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of two-drug combinations to define synergistic combinations by Chou and Talalay analysis. We then evaluated order of addition to choose the combinations that may be best to translate to the clinic. We conclude that the repurposing of chemotherapeutics in osteosarcoma by using an in vitro system may define novel drug combinations with significant in vivo activity. In particular, combinations of proteasome inhibitors with histone deacetylase inhibitors and ixabepilone and MK1775 demonstrated excellent activity in our assays. PMID:26601688

  9. Primary osteogenic osteosarcoma of the ethmoid sinus in an adolescent: case report

    PubMed Central

    Gonzalez, Marta E.; Raghavan, Prashant; Cho, Benjamin; Muttikkal, Thomas Jose Eluvathingal; Rehm, Patrice K.

    2016-01-01

    Osteosarcomas of the craniofacial bones account for fewer than 10% of all osteosarcomas. Primary osteosarcomas of the nasal cavity and paranasal sinus are rare (0.5–8.1% of the osteosarcomas occur in this location). Because of the rarity of this presentation, we report a case of osteogenic osteosarcoma arising de novo from the ethmoid bone in a 13 year old male who presented with discharge from the right eye and headaches. We describe the imaging features of this rare tumor and provide a brief review of the literature. PMID:27200156

  10. Evolution and prognosis of breast osteosarcoma: A case report

    PubMed Central

    GUO, WANFENG; CAO, YANG; TENG, GUANGJU; LIU, JIN; SU, JIANBIN

    2016-01-01

    Breast osteosarcoma is a rare malignancy of unknown etiology, with no standard adjuvant treatment at present. The prognosis of the disease is poor, and it has a high propensity for recurrence and metastasis. The current report presents the case of a 52-year-old woman, in whom adenomyoepithelioma gradually developed into breast osteosarcoma following three separate surgeries. The patient survived for 41 months from the initial lesion occurrence and resection in the left breast; during this time, she underwent surgery and chemotherapy (liposomal doxorubicin and cisplatin) for the treatment of disease recurrence and lung metastasis, along with molecular-targeted therapy (sunitinib). However, the patient eventually succumbed to respiratory failure due to progressive disease. The present case underwent a clear pathological transformation process, and may provide a basis for an improved understanding of the clinical characteristics and treatment of breast osteosarcoma. PMID:26870284

  11. Extraskeletal osteosarcoma of the thorax in a goat: case report

    PubMed Central

    2011-01-01

    Background This report describes the results of clinical, ultrasonographic and computed tomographic examination of a 16-year-old goat with extraskeletal osteosarcoma of the thorax. Case presentation The lead clinical signs were abnormal condition and demeanour, fever, tachycardia, tachypnoea, dyspnoea and dilated jugular veins. Ultrasonographic examination of the thorax revealed a precardial mass, measuring 16.4 by 11.4 by 14.2 cm. Computed tomographic examination showed dorsocaudal displacement of the trachea, heart and lungs to the right. A tentative diagnosis of mediastinal or pleural neoplasia was made, and the goat was euthanased and necropsied. A definitive diagnosis was based on histological examination of the mass. Conclusions To our knowledge, this case report is the first description of extraskeletal osteosarcoma of the thorax in goats and serves to broaden the diagnostic spectrum of thoracic diseases in this species. Extraskeletal osteosarcoma should be part of the differential diagnosis in goats with thoracic tumours. PMID:21929794

  12. Therapeutic Implications of PPARgamma in Human Osteosarcoma.

    PubMed

    Wagner, Eric R; He, Bai-Cheng; Chen, Liang; Zuo, Guo-Wei; Zhang, Wenli; Shi, Qiong; Luo, Qing; Luo, Xiaoji; Liu, Bo; Luo, Jinyong; Rastegar, Farbod; He, Connie J; Hu, Yawen; Boody, Barrett; Luu, Hue H; He, Tong-Chuan; Deng, Zhong-Liang; Haydon, Rex C

    2010-01-01

    Osteosarcoma (OS) is the most common nonhematologic malignancy of bone in children and adults. Although dysregulation of tumor suppressor genes and oncogenes, such as Rb, p53, and the genes critical to cell cycle control, genetic stability, and apoptosis have been identified in OS, consensus genetic changes that lead to OS development are poorly understood. Disruption of the osteogenic differentiation pathway may be at least in part responsible for OS tumorigenesis. Current OS management involves chemotherapy and surgery. Peroxisome proliferator-activated receptor (PPAR) agonists and/or retinoids can inhibit OS proliferation and induce apoptosis and may inhibit OS growth by promoting osteoblastic terminal differentiation. Thus, safe and effective PPAR agonists and/or retinoid derivatives can be then used as adjuvant therapeutic drugs for OS therapy. Furthermore, these agents have the potential to be used as chemopreventive agents for the OS patients who undergo the resection of the primary bone tumors in order to prevent local recurrence and/or distal pulmonary metastasis. PMID:20182546

  13. Osteocalcin and Osteonectin Expression in Canine Osteosarcoma.

    PubMed

    Wehrle-Martinez, A S; Dittmer, K E; Aberdein, D; Thompson, K G

    2016-07-01

    Osteosarcoma (OSA) is a malignant heterogeneous primary bone tumor responsible for up to 90% of all primary bone tumors in dogs. In this study, osteocalcin (OC) and osteonectin (ON) immunoreactivity was evaluated in 23 canine OSAs, 4 chondrosarcomas, 4 fibrosarcomas, 2 hemangiosarcomas, and 4 histiocytic sarcomas. The effects of three different decalcification agents (ethylenediaminetetraetic acid [EDTA], formic acid and hydrochloric acid [HCl]) on the immunoreactivity for OC and ON was also assessed. Immunoreactivity to OC was present in 19/23 (83%) cases of OSA and all cases of chondrosarcoma. In three OSAs the extracellular matrix showed immunoreactivity to OC. None of the fibrosarcomas, histiocytic sarcomas or hemangiosarcomas showed immunoreactivity to OC. The sensitivity and specificity for OC in canine OSA in this study was 83% and 71% respectively. For ON, 100% of both OSAs (23/23) and non-OSAs (14/14) showed cytoplasmic immunoreactivity to this antibody, giving a sensitivity of 100% but a complete lack of specificity. There were no significant differences in immunoreactivity for OC and ON between the different decalcification agents used. In conclusion, OC showed high sensitivity for identifying OSA but it failed to distinguish between OSA and chondrosarcoma, and the osteoid produced by neoplastic cells in most cases did not show immunoreactivity to OC. These factors may limit the practical utility of OC in the diagnosis of OSA in dogs when chondrosarcoma is a differential diagnosis. ON showed no specificity in detecting OSA and has little practical application for the diagnosis of OSA in dogs. PMID:26926085

  14. YKL-40 protein in osteosarcoma tumor tissue.

    PubMed

    Thorn, Andrea Pohly; Daugaard, Søren; Christensen, Lise Hanne; Christensen, Ib Jarle; Petersen, Michael Mørk

    2016-06-01

    YKL-40, a cellular glycoprotein isolated from the human osteosarcoma (OS) cell line MG63, is increased in the blood of patients with various types of cancer, and is found as an independent prognostic variable for survival. YKL-40 is also present with variable intensity in the tumor cells of some cancer types, but survival results have been conflicting. The aim of this study was to investigate the tissue expression of YKL-40 and its possible role as a predictive marker in patients with OS. Forty-eight patients were included in the study. Diagnostic biopsies were analyzed by immunohistochemistry; YKL-staining scores as well as CD14 and CD163 scores were determined, and survival data were determined statistically. A universal intense immunostaining for YKL-40 was found in all tumor cells, but tumor cell/stroma ratio varied, and this ratio (%) served as staining score. Using 24% as mean score to divide the material, patients with tumors of high YKL-40 score had a better survival than patients with low score (p = 0.05). YKL-positive macrophages had no influence on the result. Unexpectedly and contrary to some other findings in cancer tissues, this study has shown a correlation between high YKL-40 tumor cell/matrix ratio and longer overall survival in OS. PMID:26988273

  15. Alveolar rhabdomyosarcoma after treatment of osteosarcoma.

    PubMed

    Kasahara, Yasushi; Iwabuchi, Haruko; Takachi, Takayuki; Hosokai, Ryosuke; Yoshida, Sakiko; Imamura, Masaru; Watanabe, Akihiro; Umezu, Hajime; Hotta, Tetsuo; Ogose, Akira; Imai, Chihaya

    2013-08-01

    Secondary rhabdomyosarcoma (RMS) after treatment of osteosarcoma (OS) is rare. Reported here is the case of a metachronous RMS in the nasal cavity, developing 12 years after successful treatment of non-metastatic OS. The patient was diagnosed as having OS of the femur at 2 years of age. Chemotherapy for OS included doxorubicin (cumulative dose, 488 mg/m(2) ). No radiotherapy was given. There was no family history suggestive of cancer predisposition syndrome. At 14 years of age, alveolar RMS was diagnosed on histopathology. PAX3-FKHR fusion transcripts were detected on reverse transcription-polymerase chain reaction. Germline TP53 mutation was not seen on standard DNA sequencing. The occurrence of secondary sarcomas, in the Children's Cancer Survivor study conducted in North America, has been associated with high cumulative doses of anthracyclines, which may also have played a role in the development of RMS in the present case. In the future, novel molecular technologies might uncover genetic cancer predisposition in patients with metachronous cancers. PMID:23910806

  16. Osteosarcoma in identical twins: A case report.

    PubMed

    Biazzo, Alessio; De Paolis, Massimiliano; Righi, Alberto; Lana, Debora; Donati, Davide Maria

    2014-12-01

    Osteosarcoma (OS) is the most frequent primary malignant bone tumor, if we exclude myeloma, a hematologic systemic disease. OS is relatively uncommon, with an estimated incidence of 600 cases per year in the United States. Among siblings is an even rarer phenomenon, with scattered reports throughout the English literature(1). We report the incidence of OS in identical twins. The first case is a low-grade OS arisen in the proximal tibia of a 25-year-old man, treated with en-bloc resection and reconstruction with allograft. The second one is a high-grade OS of the distal tibia of the 33-year-old twin, developed in a previous non-ossifying fibroma (NOF) followed over the time. The patient was treated with neo-adjuvant chemotherapy, en-bloc resection and reconstruction with allograft. Our literature review did not find any case of OS in identical twins, while 26 reports of OS in siblings are described. PMID:25983508

  17. Osteosarcoma in identical twins: A case report

    PubMed Central

    Biazzo, Alessio; De Paolis, Massimiliano; Righi, Alberto; Lana, Debora; Donati, Davide Maria

    2014-01-01

    Osteosarcoma (OS) is the most frequent primary malignant bone tumor, if we exclude myeloma, a hematologic systemic disease. OS is relatively uncommon, with an estimated incidence of 600 cases per year in the United States. Among siblings is an even rarer phenomenon, with scattered reports throughout the English literature1. We report the incidence of OS in identical twins. The first case is a low-grade OS arisen in the proximal tibia of a 25-year-old man, treated with en-bloc resection and reconstruction with allograft. The second one is a high-grade OS of the distal tibia of the 33-year-old twin, developed in a previous non-ossifying fibroma (NOF) followed over the time. The patient was treated with neo-adjuvant chemotherapy, en-bloc resection and reconstruction with allograft. Our literature review did not find any case of OS in identical twins, while 26 reports of OS in siblings are described. PMID:25983508

  18. Primary Osteosarcoma of the Rib Identified on Bone Scintigraphy.

    PubMed

    Xie, Peng; Huang, Jianmin

    2016-05-01

    Osteosarcomas generally arise in appendicular skeletons, but rarely in the ribs. We described Tc-MDP bone scan findings from a 23-year-old man with right back pain. The images demonstrated elevated activity in the region overlapping the posterior 8th to 10th ribs and in the L9-10 vertebral bodies. CT showed an 8.8 × 8.3 cm mildly peripherally calcified mass arising from the right 10th rib involving the 9th and 10th thoracic vertebrae. Pathological examination confirmed primary osteosarcoma of the rib. PMID:26704734

  19. Osteosarcoma of mandible: Detailed radiographic assessment of a case

    PubMed Central

    Arora, Piyush; Rehman, Farzan; Girish, K. L.; Kalra, Manpreet

    2013-01-01

    Osteosarcoma (OS) is a malignant connective tissue tumor originating from bone and is the most common primary bone malignancy of long bones but seldom arises in jaw bones. Osteosarcoma of jaws is frequently seen arising in the second and third decade as compared to earlier occurrences in other bones and show a slight predilection for body of mandible. It is a highly malignant tumor with varied radiographic features. We present a case with detailed radiographic assessment using intraoral radiograph, computed tomography (CT), 3-D CT, CT angiography techniques and histological evaluation. PMID:24124311

  20. MicroRNA-224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1.

    PubMed

    Geng, Shuo; Gu, Lina; Ju, Fang; Zhang, Hepeng; Wang, Yiwen; Tang, Han; Bi, ZhengGang; Yang, Chenglin

    2016-09-01

    Osteosarcoma is the most common primary bone tumour in children and adolescents. Accumulating evidence has shown that microRNAs (miRNAs) participate in the development of almost all types of cancer. Here, we investigated the role of miR-224 in the development and progression of osteosarcoma. We demonstrated that miR-224 was down-regulated in osteosarcoma cell lines and tissues. Lower miR-224 levels were correlated with shorter survivalin osteosarcoma patients. Furthermore, overexpression of miR-224 suppressed osteosarcoma cell proliferation, migration and invasion and contributed to the increased sensitivity of MG-63 cells to cisplatin. We identified Rac1 as a direct target gene of miR-224 in osteosarcoma. Rac1 expression was up-regulated in the osteosarcoma cell lines and tissues, and there was an inverse correlation between Rac1 and miR-224 expression in osteosarcoma tissues. Furthermore, rescuing Rac1 expression decreased the sensitivity of miR-224-overexpressing MG-63 cells to cisplatin. We also demonstrated that ectopic expression of Rac1 promoted the proliferation, migration and invasion of miR-224-overexpressing MG-63 cells. These data suggest that miR-224 plays a tumour suppressor role in the development of osteosarcoma and is related to the sensitivity of osteosarcoma to cisplatin. PMID:27222381

  1. Spinal osteosarcoma in a hedgehog with pedal self-mutilation.

    PubMed

    Rhody, Jeffrey L; Schiller, Chris A

    2006-09-01

    An African pygmy hedgehog (Atelerix albiventris) was diagnosed with osteosarcoma of vertebral origin with compression of the spinal cord and spinal nerves. The only presenting sign was a self-mutilation of rear feet. Additional diagnoses included a well-differentiated splenic hemangiosarcoma, an undifferentiated sarcoma of the ascending colon, and membranoproliferative glomerulonephritis. PMID:16931383

  2. Osteosarcoma: Current Treatment and a Collaborative Pathway to Success

    PubMed Central

    Isakoff, Michael S.; Bielack, Stefan S.; Meltzer, Paul; Gorlick, Richard

    2015-01-01

    Osteosarcoma is the bone tumor that most commonly affects children, adolescents, and young adults. Before 1970, treatment primarily included surgical resection. However, the introduction of chemotherapy led to a dramatic improvement in prognosis for patients with localized osteosarcoma; long-term survival rates of less than 20% improved to 65% to 70% after the advent of multiagent chemotherapy regimens. Controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. However, large cooperative group studies and international collaboration have demonstrated that the most effective regimens include the combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP). The introduction of biologic agents such as muramyl tripeptide and the use of additional cytotoxic chemotherapy such as ifosfamide have not definitively improved the survival of patients with osteosarcoma. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel agents will be critical to identify the path toward improving outcomes for patients. Once promising agents are identified, an international infrastructure exists for clinical trials. Herein, biologic, preclinical, and clinical trial efforts will be described along with future international collaborative strategies to improve outcomes for patients who develop this challenging tumor. PMID:26304877

  3. [Osteosarcoma--apoptosis and proliferation. Study of bcl-2 expression].

    PubMed

    Pösl, M; Amling, M; Werner, M; Bäsler, I; Salzer-Kuntschik, M; Winkler, K; Delling, G

    1994-12-01

    The relationship between the growth of tumors and the expression of the protooncogene Bcl-2 could be shown in epithelial tumors. A bcl-2 expression leads to a prolonged cell survival due to an inhibition of apoptosis. The potential meaning of bcl-2 expression in mesenchymal tumors remains still unknown. The fact, that the heterogenous group of osteosarcoma is not sufficiently characterized at present, suggested to investigate the bcl-2 expression in osteosarcoma. Thus, immunohistochemistry was used to analyze 47 specimens of different osteosarcomas of 36 patients. Sixteen cases (46%) showed a strong expression of bcl-2 and 13 cases (35%) were moderately positive for bcl-2. Seven cases (19%) were negative for bcl-2. The heterogenous, negative up to strong expression of bcl-2 yield clues, that the Bcl-2 controlled regulation of programmed cell death could be an important factor of cellular kinetics. Additionally the cellular proliferation rate was determined with the monoclonal antibody MIB 1, directed against the Ki-67 epitope. The data of bcl-2 expression and cellular proliferation rate lead to a classification correlating with the histological classification. To verify the importance of apoptosis in the genesis of mesenchymal tumors and whether Bcl-2 may play an important role as a predictive factor for the prognosis of osteosarcoma, further investigations will be needed. PMID:7855102

  4. Osteosarcoma: Current Treatment and a Collaborative Pathway to Success.

    PubMed

    Isakoff, Michael S; Bielack, Stefan S; Meltzer, Paul; Gorlick, Richard

    2015-09-20

    Osteosarcoma is the bone tumor that most commonly affects children, adolescents, and young adults. Before 1970, treatment primarily included surgical resection. However, the introduction of chemotherapy led to a dramatic improvement in prognosis for patients with localized osteosarcoma; long-term survival rates of less than 20% improved to 65% to 70% after the advent of multiagent chemotherapy regimens. Controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. However, large cooperative group studies and international collaboration have demonstrated that the most effective regimens include the combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP). The introduction of biologic agents such as muramyl tripeptide and the use of additional cytotoxic chemotherapy such as ifosfamide have not definitively improved the survival of patients with osteosarcoma. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel agents will be critical to identify the path toward improving outcomes for patients. Once promising agents are identified, an international infrastructure exists for clinical trials. Herein, biologic, preclinical, and clinical trial efforts will be described along with future international collaborative strategies to improve outcomes for patients who develop this challenging tumor. PMID:26304877

  5. Changing indications for bone scintigraphy in patients with osteosarcoma

    SciTech Connect

    Goldstein, H.; McNeil, B.J.; Zufall, E.; Jaffe, N.; Treves, S.

    1980-04-01

    Fifty-six patients with osteosarcoma were studied to determine the onset of pulmonary and bone metastases. While pulmonary metastases were always detected prior to bone metastases in the era before adjuvant chemotherapy, in this study of patients on adjuvant therapy 16% of patients with metastases showed osseous metastases prior to or without pulmonary metastases.

  6. MicroRNAs and Potential Targets in Osteosarcoma: Review

    PubMed Central

    Sampson, Valerie B.; Yoo, Soonmoon; Kumar, Asmita; Vetter, Nancy S.; Kolb, E. Anders

    2015-01-01

    Osteosarcoma is the most common bone cancer in children and young adults. Surgery and multi-agent chemotherapy are the standard treatment regimens for this disease. New therapies are being investigated to improve overall survival in patients. Molecular targets that actively modulate cell processes, such as cell-cycle control, cell proliferation, metabolism, and apoptosis, have been studied, but it remains a challenge to develop novel, effective-targeted therapies to treat this heterogeneous and complex disease. MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating cell processes including growth, development, and disease. miRNAs function as oncogenes or tumor suppressors to regulate gene and protein expression. Several studies have demonstrated the involvement of miRNAs in the pathogenesis of osteosarcoma with the potential for development in disease diagnostics and therapeutics. In this review, we discuss the current knowledge on the role of miRNAs and their target genes and evaluate their potential use as therapeutic agents in osteosarcoma. We also summarize the efficacy of inhibition of oncogenic miRNAs or expression of tumor suppressor miRNAs in preclinical models of osteosarcoma. Recent progress on systemic delivery as well as current applications for miRNAs as therapeutic agents has seen the advancement of miR-34a in clinical trials for adult patients with non-resectable primary liver cancer or metastatic cancer with liver involvement. We suggest a global approach to the understanding of the pathogenesis of osteosarcoma may identify candidate miRNAs as promising biomarkers for this rare disease. PMID:26380245

  7. Multimodal transfer of MDR by exosomes in human osteosarcoma.

    PubMed

    Torreggiani, Elena; Roncuzzi, Laura; Perut, Francesca; Zini, Nicoletta; Baldini, Nicola

    2016-07-01

    Exosomes are extracellular vesicles released by both normal and tumour cells which are involved in a new intercellular communication pathway by delivering cargo (e.g., proteins, microRNAs, mRNAs) to recipient cells. Tumour-derived exosomes have been shown to play critical roles in different stages of tumour growth and progression. In this study, we investigated the potential role of exosomes to transfer the multidrug resistance (MDR) phenotype in human osteosarcoma cells. Exosomes were isolated by differential centrifugation of culture media from multidrug resistant human osteosarcoma MG-63DXR30 (Exo/DXR) and MG-63 parental cells (Exo/S). Exosome purity was examined by transmission electron microscopy and confirmed by immunoblot analysis for the expression of specific exosomal markers. Our data showed that exosomes derived from doxorubicin-resistant osteosarcoma cells could be taken up into secondary cells and induce a doxorubicin-resistant phenotype. The incubation of osteosarcoma cells with Exo/DXR decreased the sensitivity of parental cells to doxorubicin, while exposure with Exo/S was ineffective. In addition, we demonstrated that Exo/DXR expressed higher levels of MDR-1 mRNA and P-glycoprotein compared to Exo/S (p=0.03). Interestingly, both MDR-1 mRNA and P-gp increased in MG-63 cells after incubation with Exo/DXR, suggesting this as the main mechanism of exosome-mediated transfer of drug resistance. Our findings suggest that multidrug resistant osteosarcoma cells are able to spread their ability to resist the effects of doxorubicin treatment on sensitive cells by transferring exosomes carrying MDR-1 mRNA and its product P-glycoprotein. PMID:27176642

  8. Diagnosis of High-Grade Osteosarcoma by Radiology and Cytology: A Retrospective Study of 52 Cases

    PubMed Central

    Skoog, Lambert; Unni, Krishnan K.; Bertoni, Franco; Brosjö, Otte; Kreicbergs, Andris

    2004-01-01

    The diagnostic value of combined radiology and fine needle aspiration cytology (FNAC) was retrospectively assessed in a consecutive series of 52 patients with high-grade osteosarcoma. The series was divided into typical and atypical osteosarcomas according to radiological features and site. Thirty-two of 33 radiologically typical osteosarcoma cases were correctly diagnosed by cytology; one lesion was diagnosed as sarcoma NOS. Nineteen osteosarcoma cases were radiographically atypical. Six of these were diagnosed as osteosarcoma and another six as sarcoma NOS. In three cases another type of sarcoma was suggested. One case was falsely classified as benign. FNAC of three cases were non-diagnostic. Overall, the diagnostic difficulties pertained to the radiologically atypical cases. Notably, four of these also posed considerable difficulties in the histopathological assessment prompting external consultation. Our study suggests that open biopsy can be obviated in high-grade osteosarcomas exhibiting typical radiological features, i.e., in two-thirds. PMID:18521391

  9. Silencing of carboxypeptidase E inhibits cell proliferation, tumorigenicity, and metastasis of osteosarcoma cells

    PubMed Central

    Fan, Shuli; Li, Xu; Li, Leiming; Wang, Liguo; Du, Zhangzhen; Yang, Yan; Zhao, Jiansong; Li, Yan

    2016-01-01

    Carboxypeptidase E (CPE), a prohormone processing enzyme, has been implicated in the progression of multiple malignancies. However, the biological role and molecular mechanisms of CPE in osteosarcoma remain elusive. In this study, we assessed the effects of CPE on cell proliferation, tumorigenicity, migration, and invasion in osteosarcoma. Our results showed that silencing of CPE significantly inhibited cell proliferation, caused cell cycle arrest at G0/G1 phase, decreased the expression levels of cell cycle protein, cyclin D1, and inhibited tumorigenicity in vivo. Additionally, CPE downregulation repressed the migratory and invasive capacities of osteosarcoma cells in vitro. Furthermore, overexpression of CPE-ΔN (a splice variant of CPE) enhanced the cell growth, migration, and invasion of osteosarcoma cells. It is possible that both CPE forms are involved in the tumorigenesis and development of osteosarcoma, and therefore CPE may provide a promising biological target for osteosarcoma therapy. PMID:27274275

  10. Distribution and activity levels of matrix metalloproteinase 2 and 9 in canine and feline osteosarcoma.

    PubMed

    Gebhard, Christiane; Fuchs-Baumgartinger, Andrea; Razzazi-Fazeli, Ebrahim; Miller, Ingrid; Walter, Ingrid

    2016-01-01

    Overexpression of matrix metalloproteinases (MMPs) has been associated with increased tumor aggressiveness and metastasis dissemination. We investigated whether the contrasting metastatic behavior of feline and canine osteosarcoma is related to levels and activities of MMP2 and MMP9. Zymography and immunohistochemistry were used to determine expression levels of MMP2 and MMP9 in canine and feline osteosarcoma. Using immunohistochemistry, increased MMP9 levels were identified in most canine osteosarcomas, whereas cat samples more often displayed moderate levels. High levels of pro-MMP9, pro-MMP2, and active MMP2 were detected by gelatin zymography in both species, with significantly higher values for active MMP2 in canine osteosarcoma. These findings indicate that MMP2 is probably involved in canine and feline osteosarcoma and their expression and activity could be associated with the different metastatic behavior of canine and feline osteosarcoma. PMID:26733734

  11. MiR-329 suppresses osteosarcoma development by downregulating Rab10.

    PubMed

    Jiang, Wenwei; Liu, Jin; Xu, Tianyang; Yu, Xiao

    2016-09-01

    MiR-329 has been proved to be a tumor suppressor gene in various malignancies, however, its role in osteosarcoma remains elusive. We found that miR-329 is remarkably downregulated in osteosarcoma tissues and relates to advanced stages. MiR-329 is able to inhibit osteosarcoma cell proliferation, promote apoptosis, and induce G0/G1 cell cycle arrest. In addition, miR-329 also suppresses wound-healing and migration ability of osteosarcoma cells and inhibits tumorigenicity in vivo. Rab10 was identified as a target of miR-329 in osteosarcoma and mediates its biofunction. These findings may shed light to the understanding of tumor development in osteosarcoma. PMID:27487475

  12. Clinical implication of long noncoding RNA 91H expression profile in osteosarcoma patients.

    PubMed

    Xia, Wen-Kai; Lin, Qing-Feng; Shen, Dong; Liu, Zhi-Li; Su, Jun; Mao, Wei-Dong

    2016-01-01

    Long noncoding RNAs have been documented as having widespread roles in carcinogenesis and cancer progression. However, roles of long noncoding RNAs in osteosarcoma remain unclear. This study is to investigate the clinical relevance and biological functions of long noncoding RNA 91H in osteosarcoma. Herein, we confirmed that 91H expression was notably increased in osteosarcoma patients and cell lines compared to healthy controls and normal human bone cell lines. High expression of 91H was significantly correlated with advanced clinical stage, chemotherapy after surgery, and tumor size >5 cm. Furthermore, 91H was an independent prognostic factor for overall survival in osteosarcoma patients after treatments. Additionally, the knockdown of 91H expression inhibited osteosarcoma cells' proliferation and promoted their apoptosis in vitro. In summary, these findings indicate that 91H may be a novel biomarker for risk prognostication and also provide a clue to the molecular etiology of osteosarcoma. PMID:27555785

  13. Distribution and activity levels of matrix metalloproteinase 2 and 9 in canine and feline osteosarcoma

    PubMed Central

    Gebhard, Christiane; Fuchs-Baumgartinger, Andrea; Razzazi-Fazeli, Ebrahim; Miller, Ingrid; Walter, Ingrid

    2016-01-01

    Overexpression of matrix metalloproteinases (MMPs) has been associated with increased tumor aggressiveness and metastasis dissemination. We investigated whether the contrasting metastatic behavior of feline and canine osteosarcoma is related to levels and activities of MMP2 and MMP9. Zymography and immunohistochemistry were used to determine expression levels of MMP2 and MMP9 in canine and feline osteosarcoma. Using immunohistochemistry, increased MMP9 levels were identified in most canine osteosarcomas, whereas cat samples more often displayed moderate levels. High levels of pro-MMP9, pro-MMP2, and active MMP2 were detected by gelatin zymography in both species, with significantly higher values for active MMP2 in canine osteosarcoma. These findings indicate that MMP2 is probably involved in canine and feline osteosarcoma and their expression and activity could be associated with the different metastatic behavior of canine and feline osteosarcoma. PMID:26733734

  14. Clinical implication of long noncoding RNA 91H expression profile in osteosarcoma patients

    PubMed Central

    Xia, Wen-Kai; Lin, Qing-Feng; Shen, Dong; Liu, Zhi-Li; Su, Jun; Mao, Wei-Dong

    2016-01-01

    Long noncoding RNAs have been documented as having widespread roles in carcinogenesis and cancer progression. However, roles of long noncoding RNAs in osteosarcoma remain unclear. This study is to investigate the clinical relevance and biological functions of long noncoding RNA 91H in osteosarcoma. Herein, we confirmed that 91H expression was notably increased in osteosarcoma patients and cell lines compared to healthy controls and normal human bone cell lines. High expression of 91H was significantly correlated with advanced clinical stage, chemotherapy after surgery, and tumor size >5 cm. Furthermore, 91H was an independent prognostic factor for overall survival in osteosarcoma patients after treatments. Additionally, the knockdown of 91H expression inhibited osteosarcoma cells’ proliferation and promoted their apoptosis in vitro. In summary, these findings indicate that 91H may be a novel biomarker for risk prognostication and also provide a clue to the molecular etiology of osteosarcoma. PMID:27555785

  15. Lysophosphatidic Acid Acyltransferase β (LPAATβ) Promotes the Tumor Growth of Human Osteosarcoma

    PubMed Central

    Rastegar, Farbod; Gao, Jian-Li; Shenaq, Deana; Luo, Qing; Shi, Qiong; Kim, Stephanie H.; Jiang, Wei; Wagner, Eric R.; Huang, Enyi; Gao, Yanhong; Shen, Jikun; Yang, Ke; He, Bai-Cheng; Chen, Liang; Zuo, Guo-Wei; Luo, Jinyong; Luo, Xiaoji; Bi, Yang; Liu, Xing; Li, Mi; Hu, Ning; Wang, Linyuan; Luther, Gaurav; Luu, Hue H.; Haydon, Rex C.; He, Tong-Chuan

    2010-01-01

    Background Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase β (LPAATβ, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAATβ can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATβ has been reported in several types of human tumors, the role of LPAATβ in osteosarcoma progression has yet to be elucidated. Methodology/Principal Findings Endogenous expression of LPAATβ in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATβ and silencing LPAATβ expression is employed to determine the effect of LPAATβ on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATβ is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATβ promotes osteosarcoma cell proliferation and migration, while silencing LPAATβ expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATβ effectively promotes tumor growth, while knockdown of LPAATβ expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma. Conclusions/Significance Our results strongly suggest that LPAATβ expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATβ may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATβ may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially

  16. Hyperoside, a flavonoid compound, inhibits proliferation and stimulates osteogenic differentiation of human osteosarcoma cells.

    PubMed

    Zhang, Ning; Ying, Mei-Dan; Wu, Yong-Ping; Zhou, Zhi-Hong; Ye, Zhao-Ming; Li, Hang; Lin, Ding-Sheng

    2014-01-01

    Osteosarcoma, one of the most common malignant bone tumours, is generally considered a differentiation disease caused by genetic and epigenetic disruptions in the terminal differentiation of osteoblasts. Novel therapies based on the non-cytotoxic induction of cell differentiation-responsive pathways could represent a significant advance in treating osteosarcoma; however, effective pharmaceuticals to induce differentiation are lacking. In the present study, we investigated the effect of hyperoside, a flavonoid compound, on the osteoblastic differentiation of U2OS and MG63 osteosarcoma cells in vitro. Our results demonstrated that hyperoside inhibits the proliferation of osteosarcoma cells by inducing G0/G1 arrest in the cell cycle, without causing obvious cell death. Cell migration assay further suggested that hyperoside could inhibit the invasion potential of osteosarcoma cells. Additionally, osteopontin and runt-related transcription factor 2 protein levels and osteocalcin activation were upregulated dramatically in hyperoside-treated osteosarcoma cells, suggesting that hyperoside may stimulates osteoblastic differentiation in osteosarcoma cells. This differentiation was accompanied by the activation of transforming growth factor (TGF)-β and bone morphogenetic protein-2, suggesting that the hyperoside-induced differentiation involves the TGF-β signalling pathway. To our knowledge, this study is the first to evaluate the differentiation effect of hyperoside in osteosarcoma cells and assess the possible potential for hyperoside treatment as a future therapeutic approach for osteosarcoma differentiation therapy. PMID:24983940

  17. Reduced expression and prognostic implication of inhibitor of growth 4 in human osteosarcoma

    PubMed Central

    ZHAO, DAHANG; LIU, XIANGJIE; ZHANG, YUNGE; DING, ZHAOMING; DONG, FENG; XU, HONGWEI; WANG, BAOXIN; WANG, WENBO

    2016-01-01

    Osteosarcoma is the most prevalent type of primary malignant bone tumor. Inhibitor of growth 4 (ING4) has been demonstrated to function as a tumor suppressor through multiple pathways, and is its expression is understood to be suppressed or reduced in various malignancies. The present study aimed to investigate the expression of ING4 and to determine its prognostic value in osteosarcoma tissue. Formalin-fixed, paraffin-embedded tissue microarrays were analyzed, and contained 41 osteosarcoma specimens and 11 normal bone tissue specimens with duplicate cores. ING4 expression was evaluated by immunohistochemical staining. The association between ING4 expression in the osteosarcoma and normal bone tissues was analyzed, in addition to the association between ING4 expression and Enneking classification of the osteosarcoma tissues. A significant statistical difference was observed in the ING4 immunohistochemical staining score between the osteosarcoma and normal bone tissues (P<0.001). Furthermore, a significant negative correlation was detected between the ING4 immunohistochemical staining scores and the Enneking classification results of the 41 osteosarcoma tissues (P=0.002). Low expression of ING4 was observed in the osteosarcoma specimens, and this reduced expression of ING4 was negatively correlated with Enneking classification. Thus, the results of the present study indicate that ING4 may serve as a promising prognostic marker in osteosarcoma. PMID:27073567

  18. Subcutaneous extraskeletal osteosarcoma of the forearm: a case report and review of the literature.

    PubMed

    Healy, Christopher; Kahn, Leonard B; Kenan, Samuel

    2016-09-01

    Extraskeletal osteosarcoma (ESOS) originating in the subcutaneous tissue is a rare occurrence, accounting for less than 10 % of ESOS cases. Osteosarcoma of extraskeletal origin accounts for approximately 2-4 % of all osteosarcomas, and 1 % of soft tissue sarcomas. We report a case of an 80-year-old female with an isolated primary subcutaneous tumor of the forearm. After imaging, surgical excision, and pathological analysis, the diagnosis of a subcutaneous osteosarcoma was made. This report documents the clinical and pathological findings of subcutaneous ESOS in this case, along with a review of previous cases of subcutaneous ESOS. PMID:27357312

  19. CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models

    PubMed Central

    Zhang, Shui-Jun; Zhao, Chen; Qiu, Bin-Song; Gu, Hai-Feng; Hong, Jian-Fei; Cao, Li; Chen, Yu; Xia, Bing; Bi, Qin; Wang, Ya-Ping

    2015-01-01

    Osteosarcoma is the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease still have a poor prognosis, illustrating the need for alternative therapies. In this study, we explored the use of antibodies that block CD47 with a tumor growth suppressive effect on osteosarcoma. We first found that up-regulation of CD47 mRNA levels in the tumorous tissues from eight patients with osteosarcoma when compared with that in adjacent non-tumorous tissues. Further western-blot (WB) and immunohistochemistry (IHC) demonstrated that CD47 protein level was highly expressed in osteosarcoma compared to normal osteoblastic cells and adjacent non-tumorous tissues. Osteosarcoma cancer stem cell markers staining shown that the majority of CD44+ cells expressed CD47 albeit with different percentages (ranging from 80% to 99%). Furthermore, high CD47 mRNA expression levels were associated with a decreased probability of progression-free and overall survival. In addition, blockade of CD47 by specific Abs suppresses the invasive ability of osteosarcoma tumor cells and further inhibits spontaneous pulmonary metastasis of KRIB osteosarcoma cells in vivo. Finally, CD47 blockade increases macrophage phagocytosis of osteosarcoma tumor cells. In conclusion, our findings demonstrate that CD47 is a critical regulator in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by anti-CD47 may be a novel immunotherapeutic approach in the management of this tumor. PMID:26093091

  20. Overexpression of KH-type splicing regulatory protein regulates proliferation, migration, and implantation ability of osteosarcoma

    PubMed Central

    Pruksakorn, Dumnoensun; Teeyakasem, Pimpisa; Klangjorhor, Jeerawan; Chaiyawat, Parunya; Settakorn, Jongkolnee; Diskul-Na-Ayudthaya, Penchatr; Chokchaichamnankit, Daranee; Pothacharoen, Peraphan; Srisomsap, Chantragan

    2016-01-01

    Osteosarcoma is a common malignant bone tumor in children and adolescents. The current 5-year survival rate is ~60% and that seems to be reaching a plateau. In order to improve treatment outcomes of osteosarcoma, a better understanding of tumorigenesis and underlying molecular mechanisms is required for searching out possible new treatment targets. This study aimed to identify the potential proteins involving the pathogenesis of osteosarcoma using a proteomics approach. Proteins extracted from primary cell culture of osteosarcoma (n=7) and osteoblasts of cancellous bone (n=7) were studied. Using 2-DE based proteomics and LC-MS/MS analysis, we successfully determined seven differentially expressed protein spots. Four upregulated proteins and three downregulated proteins were observed in this study in which KH-type splicing regulatory protein (KSRP) was selected for further exploration. KSRP was significantly upregulated in osteosarcoma cells compared to osteoblasts using western blot assay. In addition, immunohistochemistry demonstrated that KSRP was also highly expressed in osteosarcoma tissue of independent cases from the experimental group. More importantly, KSRP silencing of osteosarcoma cell lines significantly decreased cell proliferation, migration ability, as well as implantation and growth ability in chick chorioallantoic membrane assay. Taken together, these findings demonstrate, that KSRP plays important roles in regulatory controls of osteosarcoma pathogenesis and serves as a potentially therapeutic target of osteosarcoma. PMID:27573585

  1. Long noncoding RNA MALAT1 as a potential therapeutic target in osteosarcoma.

    PubMed

    Cai, Xianyi; Liu, Yunlu; Yang, Wen; Xia, Yun; Yang, Cao; Yang, Shuhua; Liu, Xianzhe

    2016-06-01

    Recent studies have revealed that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in the development of several solid tumors. However, the function of MALAT1 in the tumorigenesis of osteosarcoma remains unknown. In the present study, levels of MALAT1 in human osteosarcoma cell lines and tissues were detected by quantitative real-time polymerase chain reaction (RT-PCR). The roles of MALAT1 in osteosarcoma were investigated by using in vitro and in vivo assays. We observed that MALAT1 expression was up-regulated in human osteosarcoma cell lines and tissues. In vitro knockdown of MALAT1 by siRNA significantly inhibited cell proliferation and migration, and induced cell cycle arrest and apoptosis in osteosarcoma cells. In addition, MALAT1 knockdown markedly suppressed the formation of tubular network structures and caused breakage of stress fibers in osteosarcoma cell lines U2OS and MNNG/HOS. Furthermore, MALAT1 knockdown delayed tumor growth in an osteosarcoma xenograft model. Specifically, we found that administration of MALAT1 siRNA decreased the protein levels of RhoA and its downstream effectors Rho-associated coiled-coil containing protein kinases (ROCKs). Taken together, these findings suggest that MALAT1 plays an oncogenic role in osteosarcoma and may be a promising therapeutic target for the treatment of osteosarcoma patients. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:932-941, 2016. PMID:26575981

  2. Overexpression of KH-type splicing regulatory protein regulates proliferation, migration, and implantation ability of osteosarcoma.

    PubMed

    Pruksakorn, Dumnoensun; Teeyakasem, Pimpisa; Klangjorhor, Jeerawan; Chaiyawat, Parunya; Settakorn, Jongkolnee; Diskul-Na-Ayudthaya, Penchatr; Chokchaichamnankit, Daranee; Pothacharoen, Peraphan; Srisomsap, Chantragan

    2016-09-01

    Osteosarcoma is a common malignant bone tumor in children and adolescents. The current 5-year survival rate is ~60% and that seems to be reaching a plateau. In order to improve treatment outcomes of osteosarcoma, a better understanding of tumorigenesis and underlying molecular mechanisms is required for searching out possible new treatment targets. This study aimed to identify the potential proteins involving the pathogenesis of osteosarcoma using a proteomics approach. Proteins extracted from primary cell culture of osteosarcoma (n=7) and osteoblasts of cancellous bone (n=7) were studied. Using 2-DE based proteomics and LC-MS/MS analysis, we successfully determined seven differentially expressed protein spots. Four upregulated proteins and three downregulated proteins were observed in this study in which KH-type splicing regulatory protein (KSRP) was selected for further exploration. KSRP was significantly upregulated in osteosarcoma cells compared to osteoblasts using western blot assay. In addition, immunohistochemistry demonstrated that KSRP was also highly expressed in osteosarcoma tissue of independent cases from the experimental group. More importantly, KSRP silencing of osteosarcoma cell lines significantly decreased cell proliferation, migration ability, as well as implantation and growth ability in chick chorioallantoic membrane assay. Taken together, these findings demonstrate, that KSRP plays important roles in regulatory controls of osteosarcoma pathogenesis and serves as a potentially therapeutic target of osteosarcoma. PMID:27573585

  3. Structuring osteosarcoma knowledge: an osteosarcoma-gene association database based on literature mining and manual annotation.

    PubMed

    Poos, Kathrin; Smida, Jan; Nathrath, Michaela; Maugg, Doris; Baumhoer, Daniel; Neumann, Anna; Korsching, Eberhard

    2014-01-01

    Osteosarcoma (OS) is the most common primary bone cancer exhibiting high genomic instability. This genomic instability affects multiple genes and microRNAs to a varying extent depending on patient and tumor subtype. Massive research is ongoing to identify genes including their gene products and microRNAs that correlate with disease progression and might be used as biomarkers for OS. However, the genomic complexity hampers the identification of reliable biomarkers. Up to now, clinico-pathological factors are the key determinants to guide prognosis and therapeutic treatments. Each day, new studies about OS are published and complicate the acquisition of information to support biomarker discovery and therapeutic improvements. Thus, it is necessary to provide a structured and annotated view on the current OS knowledge that is quick and easily accessible to researchers of the field. Therefore, we developed a publicly available database and Web interface that serves as resource for OS-associated genes and microRNAs. Genes and microRNAs were collected using an automated dictionary-based gene recognition procedure followed by manual review and annotation by experts of the field. In total, 911 genes and 81 microRNAs related to 1331 PubMed abstracts were collected (last update: 29 October 2013). Users can evaluate genes and microRNAs according to their potential prognostic and therapeutic impact, the experimental procedures, the sample types, the biological contexts and microRNA target gene interactions. Additionally, a pathway enrichment analysis of the collected genes highlights different aspects of OS progression. OS requires pathways commonly deregulated in cancer but also features OS-specific alterations like deregulated osteoclast differentiation. To our knowledge, this is the first effort of an OS database containing manual reviewed and annotated up-to-date OS knowledge. It might be a useful resource especially for the bone tumor research community, as specific

  4. Extraskeletal Osteosarcoma Induced by a Foreign Body Granuloma.

    PubMed

    Slovak, Jennifer E; Kieves, Nina R; Haynes, Joseph

    2015-01-01

    An 8 yr old spayed female Italian greyhound was presented with a mass in the cranial abdomen. Preliminary evaluation of the dog revealed a large, cavitary, irregularly shaped mass with no definitive association with any abdominal organs. During an exploratory celiotomy, a 16 cm × 12 cm × 6 cm mass was removed. On subsequent histopathology, extraskeletal osteosarcoma induced by a foreign body granuloma was diagnosed. The foreign body granuloma, based on histopathological findings, was suspected to be secondary to a retained surgical sponge from her routine ovariohysterectomy performed 7 yr prior to presentation. Animals with granulomas induced by foreign bodies can remain asymptomatic for years; however, those granulomas can progress to extraskeletal osteosarcomas, which carry a poor prognosis. PMID:26355582

  5. Exomic Analysis of Myxoid Liposarcomas, Synovial Sarcomas, and Osteosarcomas

    PubMed Central

    Jiao, Yuchen; Wood, Laura D.; Kinde, Isaac; Wu, Jian; Mandahl, Nils; Luo, Jinyong; Hruban, Ralph H.; Diaz, Luis A.; He, Tong-Chuan; Vogelstein, Bert; Kinzler, Kenneth W.; Mertens, Fredrik; Papadopoulos, Nickolas

    2014-01-01

    Bone and soft tissue sarcomas are a group of histologically heterogeneous and relatively uncommon tumors. To explore their genetic origins, we sequenced the exomes of 13 osteosarcomas, eight myxoid liposarcomas (MLPS), and seven synovial sarcomas (SYN). These tumors had few genetic alterations (median of 10.8). Nevertheless, clear examples of driver gene mutations were observed, including canonical mutations in TP53, PIK3CA, SETD2, AKT1, and subclonal mutation in FBXW7. Of particular interest were mutations in H3F3A, encoding the variant histone H3.3. Mutations in this gene have only been previously observed in gliomas. Loss of heterozygosity of exomic regions was extensive in osteosarcomas but rare in SYN and MLPS. These results provide intriguing nucleotide-level information on these relatively uncommon neoplasms and highlight pathways that help explain their pathogenesis. PMID:24190505

  6. Custom facial reconstruction for osteosarcoma of the jaw.

    PubMed

    Lazarides, Alexander; Erdmann, Detlev; Powers, David; Eward, William

    2014-11-01

    Osteosarcoma accounts for most primary bone cancers in children and young adults. High-grade lesions are typically managed with a combination of chemotherapy and wide-margin surgical excision. Although this malignancy typically affects the metaphyseal region of long bones, it also can be seen in the axial skeleton. Of axial locations, tumors in the head and neck can be particularly troubling to treat. Segmental bone loss after resection of malignant mandibular tumors continues to present important challenges to the reconstructive surgeon. Recent advancements in 3-dimensional modeling have facilitated custom templates for patient-specific reconstructions. This report describes the case of a young woman with osteosarcoma of the mandible undergoing customized template composite facial reconstruction using a vascularized osteoseptocutaneous fibula flap. PMID:25438280

  7. Aberrant Hedgehog Signaling and Clinical Outcome in Osteosarcoma

    PubMed Central

    Lo, Winnie W.; Pinnaduwage, Dushanthi; Gokgoz, Nalan; Wunder, Jay S.; Andrulis, Irene L.

    2014-01-01

    Despite the importance of Hedgehog signaling in bone development, the relationship between Hedgehog pathway expression and osteosarcoma clinical characteristics and outcome has not been investigated. In this study of 43 high-grade human osteosarcoma samples, we detected high expression levels of the Hedgehog ligand gene, IHH, and target genes, PTCH1 and GLI1, in most samples. Further analysis in tumors of patients with localized disease at diagnosis identified coexpression of IHH and PTCH1 exclusively in large tumors. Higher levels of IHH were observed more frequently in males and patients with higher levels of GLI1 were more responsive to chemotherapy. Subgroup analysis by tumor size and IHH expression indicated that the well-known association between survival and tumor size was further refined when IHH levels were taken into consideration. PMID:24799831

  8. Bio-inspired cisplatin nanocarriers for osteosarcoma treatment.

    PubMed

    Zhou, Haidong; Wang, Gangxiang; Lu, Yiyun; Pan, Zhijun

    2016-08-19

    In this study, cisplatin (cis-diaminedichloroplatinum, CDDP) nanocarriers with phosphorylcholine surface tailoring were developed to enhance the anti-tumor potential of CDDP for the treatment of osteosarcoma. Poly(2-methacryloyloxyethyl phosphorylcholine)-b-poly(methacrylic acid) (PMPC-b-PMAA) was synthesized for the preparation of CDDP/PMPC-b-PMAA micelles. The synthesis, self-assembly, and in vitro drug release were well characterized. In vitro cytotoxicity showed that CDDP/PMPC-b-PMAA micelles can strongly inhibit the proliferation of Saos-2 cells. In vivo experiments indicated that CDDP/PMPC-b-PMAA micelles showed prolonged circulation time, reduced renal accumulation, and enhanced tumor accumulation compared to free CDDP. Overall, the CDDP/PMPC-b-PMAA micelles exhibited optimal anti-tumor activity with minimal side effects in the treatment of osteosarcoma. PMID:27315174

  9. Morphologic characterization of osteosarcoma growth on the chick chorioallantoic membrane

    PubMed Central

    2010-01-01

    Background The chick chorio-allantoic membrane (CAM) assay is a commonly used method for studying angiogenic or anti-angiogenic activities in vivo. The ease of access allows direct monitoring of tumour growth by biomicroscopy and the possibility to screen many samples in an inexpensive way. The CAM model provides a powerful tool to study effects of molecules, which interfere with physiological angiogenesis, or experimental tumours derived from cancer cell lines. We therefore screened eight osteosarcoma cell lines for their ability to form vascularized tumours on the CAM. Findings We implanted 3-5 million cells of human osteosarcoma lines (HOS, MG63, MNNG-HOS, OST, SAOS, SJSA1, U2OS, ZK58) on the CAM at day 10 of embryonic development. Tumour growth was monitored by in vivo biomicroscopy at different time points and tumours were fixed in paraformaldehyde seven days after cell grafting. The tissue was observed, photographed and selected cases were further analyzed using standard histology. From the eight cell lines the MNNG-HOS, U2OS and SAOS were able to form solid tumours when grafted on the CAM. The MNNG-HOS tumours showed the most reliable and consistent growth and were able to penetrate the chorionic epithelium, grow in the CAM stroma and induce a strong angiogenic response. Conclusions Our results show that the CAM assay is a useful tool for studying osteosarcoma growth. The model provides an excellent alternative to current rodent models and could serve as a preclinical screening assay for anticancer molecules. It might increase the speed and efficacy of the development of new drugs for the treatment of osteosarcoma. PMID:20202196

  10. Diagnostic assessment of osteosarcoma chemoresistance based on Virtual Clinical Trials.

    PubMed

    Rejniak, K A; Lloyd, M C; Reed, D R; Bui, M M

    2015-09-01

    Osteosarcoma is the most common primary bone tumor in pediatric and young adult patients. Successful treatment of osteosarcomas requires a combination of surgical resection and systemic chemotherapy, both neoadjuvant (prior to surgery) and adjuvant (after surgery). The degree of necrosis following neoadjuvant chemotherapy correlates with the subsequent probability of disease-free survival. Tumors with less than 10% of viable cells after treatment represent patients with a more favorable prognosis. However, being able to predict early, such as at the time of the pre-treatment tumor biopsy, how the patient will respond to the standard chemotherapy would provide an opportunity for more personalized patient care. Patients with unfavorable predictions could be studied in a protocol, rather than a standard setting, towards improving therapeutic success. The onset of necrotic cells in osteosarcomas treated with chemotherapeutic agents is a measure of tumor sensitivity to the drugs. We hypothesize that the remaining viable cells, i.e., cells that have not responded to the treatment, are chemoresistant, and that the pathological characteristics of these chemoresistant tumor cells within the osteosarcoma pre-treatment biopsy can predict tumor response to the standard-of-care chemotherapeutic treatment. This hypothesis can be tested by comparing patient histopathology samples before, as well as after treatment to identify both morphological and immunochemical cellular features that are characteristic of chemoresistant cells, i.e., cells that survived treatment. Consequently, using computational simulations of dynamic changes in tumor pathology under the simulated standard of care chemotherapeutic treatment, one can couple the pre- and post-treatment morphological and spatial patterns of chemoresistant cells, and correlate them with patient clinical diagnoses. This procedure, that we named 'Virtual Clinical Trials', can serve as a potential predictive biomarker providing a

  11. Unilateral synchronous breast tumors. Rare association of myofibroblastoma and osteosarcoma

    PubMed Central

    BARBUSCIA, M.A.; PAPARO, D.; QUERCI, A.; LEMMA, G.; FEDELE, F.; SCOLLICA, M.; CAIZZONE, A.; LENTINI, M.

    2013-01-01

    Summary: The authors describe the case of a patient with two particularly rare contiguous tumors, myofibroblastoma and osteosarcoma, in the same breast. Rare does not mean untreatable, and the chance of recovery is no less than with more common tumors. However, rare tumors do present a significant problem for pathologists due to diagnostic difficulties, and so an exact prognosis is not always possible. PMID:23660159

  12. Diagnostic Assessment of Osteosarcoma Chemoresistance Based on Virtual Clinical Trials

    PubMed Central

    Rejniak, K.A.; Lloyd, M.C.; Reed, D.R.; Bui, M.M.

    2015-01-01

    Osteosarcoma is the most common primary bone tumor in pediatric and young adult patients. Successful treatment of osteosarcomas requires a combination of surgical resection and systemic chemotherapy, both neoadjuvant (prior to surgery) and adjuvant (after surgery). The degree of necrosis following neoadjuvant chemotherapy correlates with the subsequent probability of disease-free survival. Tumors with less than 10% of viable cells after treatment represent patients with a more favorable prognosis. However, being able to predict early, such as at the time of the pre-treatment tumor biopsy, how the patient will respond to the standard chemotherapy would provide an opportunity for more personalized patient care. Patients with unfavorable predictions could be studied in a protocol, rather than a standard setting, towards improving therapeutic success. The onset of necrotic cells in osteosarcomas treated with chemotherapeutic agents is a measure of tumor sensitivity to the drugs. We hypothesize that the remaining viable cells, i.e., cells that have not responded to the treatment, are chemoresistant, and that the pathological characteristics of these chemoresistant tumor cells within the osteosarcoma pre-treatment biopsy can predict tumor response to the standard-of-care chemotherapeutic treatment. This hypothesis can be tested by comparing patient histopathology samples before, as well as after treatment to identify both morphological and immunochemical cellular features that are characteristic of chemoresistant cells, i.e., cells that survived treatment. Consequently, using computational simulations of dynamic changes in tumor pathology under the simulated standard of care chemotherapeutic treatment, one can couple the pre- and post-treatment morphological and spatial patterns of chemoresistant cells, and correlate them with patient clinical diagnoses. This procedure, that we named ‘Virtual Clinical Trials’, can serve as a potential predictive biomarker providing a

  13. Retroperitoneal Extraskeletal Osteosarcoma: Imaging Findings and Transarterial Chemoembolization

    SciTech Connect

    Zhang Huojun Yang Jijin Lu Jianping; Sheng Jin; Yuan Min; Jiang Xu; Li Yuxiao; Gupta, Sanjay

    2010-04-15

    Extraskeletal osteosarcoma (EOS) is an uncommon and usually highly aggressive mesenchymal tumor. Retroperitoneal extraskeletal osteosarma (REOS) is exceedingly rare. Due to the rare nature of the disease, both the diagnosis and the management of REOS can be challenging. We present the clinical history, CT findings, angiographic manifestations, and use of transarterial chemoembolization for treatment in a case of REOS. To our knowledge, the angiographic features of and attempt at transarterial treatment of REOS have not been reported in the literature.

  14. SERUM VALUES OF ALKALINE PHOSPHATASE AND LACTATE DEHYDROGENASE IN OSTEOSARCOMA

    PubMed Central

    ZUMÁRRAGA, JUAN PABLO; BAPTISTA, ANDRÉ MATHIAS; ROSA, LUIS PABLO DE LA; CAIERO, MARCELO TADEU; CAMARGO, OLAVO PIRES DE

    2016-01-01

    ABSTRACT Objective: To study the relationship between the pre and post chemotherapy (CT) serum levels of alkaline phosphatase (AP) and lactate dehydrogenase (LDH), and the percentage of tumor necrosis (TN) found in specimens after the pre surgical CT in patients with osteosarcoma. Methods: Series of cases with retrospective evaluation of patients diagnosed with osteosarcoma. Participants were divided into two groups according to serum values of both enzymes. The values of AP and LDH were obtained before and after preoperative CT. The percentage of tumor necrosis (TN) of surgical specimens of each patient was also included. Results: One hundred and thirty seven medical records were included from 1990 to 2013. Both the AP as LDH decreased in the patients studied, being the higher in pre CT than post CT. The average LHD decrease was 795.12U/L and AP decrease was 437.40 U/L. The average TN was 34.10 %. There was no statistically significant correlation between the serums values and the percentage of tumoral necrosis. Conclusion: The serum levels values of AP and LDH are not good predictors for the chemotherapy-induced necrosis in patients with osteosarcoma. Level of Evidence IV, Case Series. PMID:27217815

  15. Paraoxonase 1 192 and 55 polymorphisms in osteosarcoma.

    PubMed

    Ergen, Arzu; Kılıcoglu, Onder; Ozger, Harzem; Agachan, Bedia; Isbir, Turgay

    2011-08-01

    Paraoxonase is an HDL-associated enzyme that plays a preventive role against oxidative stres. Previous studies suggested that involved an amino acid substitution at position 192 gives rise to two alloenzymes with a low activity (Q allele) and a high activity (R allele) towards paraoxon. There also exists a second polymorphism of the human PON1 gene affecting amino acid 55, giving rise to a leucine (L-allele) substitution for methionine (M-allele). PON1 gene polymorphisms were studied in 50 patients with osteosarcoma and 50 healthy controls. Paraoxonase genotypes were determined by PCR-RFLP. We found a reduction in the frequency of PON1 192 R allele in patients (P=0.015). Besides, PON1 192 wild type QQ genotype (P=0.015) and PON1 55 wild type L allele (P=0.001) were higher in patients compared to healthy controls. PON1 192 QQ genotype was associated with osteosarcoma in multivariate logistic regression analysis. Our findings have suggested that PON1 192 wild type genotypes may be associated with a risk of developing osteosarcoma. PMID:21104436

  16. Contrasting epidemiology of childhood osteosarcoma, Ewing's tumor, and rhabdomyosarcoma

    SciTech Connect

    Miller, R.W.

    1981-04-01

    Marked dissimilarities in the epidemiology of osteosarcoma, Ewing's tumor, and rhabdomyosarcoma indicate differences in their origins. A major clue to the genesis of Ewing's tumor comes not from defining persons at high risk but from the observation that blacks are at unusually low risk. The neoplasm does not aggregate in families and is not part of any known syndrome. No environmental causes have been identified. By contrast, osteosarcoma may be caused by external or internal ionizing radiation, and it aggregated in families with the same tumor or with dissimilar tumors and in certain genetic disorders of bone. In man and in dogs, the frequency of the neoplasm is related to bone mass and growth. Rhabdomyosarcoma of the upper versus the lower limbs seems related to muscle mass. Age peaks in the occurrence of the tumor elsewhere vary with the anatomic site; head and neck tumors develop in early childhood and urogenital tumors both in early years and in adolescence. The sex ratio (male to female) also varies with the site affected. Rhabdomyosarcoma aggregates with certain other tumors in families and overlaps with osteosarcoma in some of these relationships but is distinguished from that tumor by its excessive occurrence in neurofibromatosis.

  17. Osteosarcomas among beagles exposed to /sup 239/Pu

    SciTech Connect

    Whittemore, A.S.; McMillan, A.

    1982-04-01

    A Weibull distribution was fit to the osteosarcoma death times of beagles given single intravenous injections of /sup 239/Pu. For injected doses in the range 0-1..mu..Ci/kg the osteosarcoma incidence rate h(t) at t days after injection can be fit by a quadratic function of injected dose d: h(t) = 2.61 X 10/sup -18/ d/sup 2/t/sup 4.91/. The best-fitting linear function was rejected by the data (P < 0.001). A different formula for h(t), derived from a multistage theory for osteosarcoma induction, was also fit to these data. For this purpose microdosimetry calculations were used to estimate the dose to the cells at risk in the endosteal layer (endosteal dose). According to the best fit, h(t) is a quadratic function of endosteal dose at low doses. A linear dose-response relationship was again rejected. The absence of a linear component at low doses might be explained by the fact that 108 of the 185 animals injected at the lowest doses (<0.02 ..mu..Ci/kg) were still alive at the time these data were collected.

  18. Fibroblastic Type Osteosarcoma of the Ulna: a Case Report of a Tumor in a Rare Location with Atypical Imaging Findings

    PubMed Central

    Joo, Ijin; Chung, Jin-Haeng; Oh, Joo Han; Hong, Sung Hwan; Kang, Heung Sik

    2009-01-01

    The ulna is a rare site of origin for osteosarcoma, and purely osteolytic osteosarcomas are uncommonly noted on conventional radiographs. We present a patient with a lytic lesion of the distal ulna for which imaging findings suggested an aneurysmal bone cyst. The lesion was histologically confirmed to be a fibroblastic osteosarcoma. PMID:19182508

  19. An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development

    PubMed Central

    Komura, Shingo; Semi, Katsunori; Itakura, Fumiaki; Shibata, Hirofumi; Ohno, Takatoshi; Hotta, Akitsu; Woltjen, Knut; Yamamoto, Takuya; Akiyama, Haruhiko; Yamada, Yasuhiro

    2016-01-01

    Summary EWS-FLI1, a multi-functional fusion oncogene, is exclusively detected in Ewing sarcomas. However, previous studies reported that rare varieties of osteosarcomas also harbor EWS-ETS family fusion. Here, using the doxycycline-inducible EWS-FLI1 system, we established an EWS-FLI1-dependent osteosarcoma model from murine bone marrow stromal cells. We revealed that the withdrawal of EWS-FLI1 expression enhances the osteogenic differentiation of sarcoma cells, leading to mature bone formation. Taking advantage of induced pluripotent stem cell (iPSC) technology, we also show that sarcoma-derived iPSCs with cancer-related genetic abnormalities exhibited an impaired differentiation program of osteogenic lineage irrespective of the EWS-FLI1 expression. Finally, we demonstrate that EWS-FLI1 contributed to secondary sarcoma development from the sarcoma iPSCs after osteogenic differentiation. These findings demonstrate that modulating cellular differentiation is a fundamental principle of EWS-FLI1-induced osteosarcoma development. This in vitro cancer model using sarcoma iPSCs should provide a unique platform for dissecting relationships between the cancer genome and cellular differentiation. PMID:26997645

  20. An EWS-FLI1-Induced Osteosarcoma Model Unveiled a Crucial Role of Impaired Osteogenic Differentiation on Osteosarcoma Development.

    PubMed

    Komura, Shingo; Semi, Katsunori; Itakura, Fumiaki; Shibata, Hirofumi; Ohno, Takatoshi; Hotta, Akitsu; Woltjen, Knut; Yamamoto, Takuya; Akiyama, Haruhiko; Yamada, Yasuhiro

    2016-04-12

    EWS-FLI1, a multi-functional fusion oncogene, is exclusively detected in Ewing sarcomas. However, previous studies reported that rare varieties of osteosarcomas also harbor EWS-ETS family fusion. Here, using the doxycycline-inducible EWS-FLI1 system, we established an EWS-FLI1-dependent osteosarcoma model from murine bone marrow stromal cells. We revealed that the withdrawal of EWS-FLI1 expression enhances the osteogenic differentiation of sarcoma cells, leading to mature bone formation. Taking advantage of induced pluripotent stem cell (iPSC) technology, we also show that sarcoma-derived iPSCs with cancer-related genetic abnormalities exhibited an impaired differentiation program of osteogenic lineage irrespective of the EWS-FLI1 expression. Finally, we demonstrate that EWS-FLI1 contributed to secondary sarcoma development from the sarcoma iPSCs after osteogenic differentiation. These findings demonstrate that modulating cellular differentiation is a fundamental principle of EWS-FLI1-induced osteosarcoma development. This in vitro cancer model using sarcoma iPSCs should provide a unique platform for dissecting relationships between the cancer genome and cellular differentiation. PMID:26997645

  1. Highly frequent allelic loss of chromosome 6q16-23 in osteosarcoma: involvement of cyclin C in osteosarcoma.

    PubMed

    Ohata, Norihide; Ito, Sachio; Yoshida, Aki; Kunisada, Toshiyuki; Numoto, Kunihiko; Jitsumori, Yoshimi; Kanzaki, Hirotaka; Ozaki, Toshifumi; Shimizu, Kenji; Ouchida, Mamoru

    2006-12-01

    The molecular pathogenesis of osteosarcoma is very complicated and associated with chaotic abnormalities on many chromosomal arms. We analyzed 12 cases of osteosarcomas with comparative genomic hybridization (CGH) to identify chromosomal imbalances, and detected highly frequent chromosomal alterations in chromosome 6q, 8p, 10p and 10q. To define the narrow rearranged region on chromosome 6 with higher resolution, loss of heterozygosity (LOH) analysis was performed with 21 microsatellite markers. Out of 31 cases, 23 cases (74%) showed allelic loss at least with one marker on chromosome 6q. We identified two distinct commonly deleted regions on chromosome 6 using markers D6S1565 located at 6q16 and 6q23MS1 at 6q23. The expression analysis of genes located at the deleted region was performed, and the decreased mRNA expression of the CCNC gene, one of the regulators of cell cycle, was detected. Growth of osteosarcoma cell line was significantly suppressed after the CCNC cDNA transfection. Fine mapping of the deleted region containing a possible tumor suppressor gene and the transfection assay suggest that the CCNC is a candidate tumor suppressor gene. PMID:17089020

  2. Expression of B7-H3 in cancer tissue during osteosarcoma progression in nude mice.

    PubMed

    Yin, S J; Wang, W J; Zhang, J Y

    2015-01-01

    Immune cells might participate in the ontogenesis of osteosarcoma. B7-H3 is a new discovered T cell co-stimulatory molecule that was found to be overexpressed in malignant tumors. We aimed to investigate the dynamic expression level of B7-H3 in nude mice with osteosarcoma. A nude mouse osteosarcoma model was successfully established. B7-H3 expression and distribution changes in the early, middle, and late phases of osteosarcoma formation after tumor implantation were observed. Reverse transcription-polymerase chain reaction and western blot analyses were applied to measure the B7-H3 mRNA and protein dynamic changes. Confocal microscopy and immunohistochemistry were used to determine B7-H3 localization and CD3+ T cell expression, respectively, in osteosarcoma tissue. B7-H3 mRNA and protein levels fluctuated during the process of osteosarcoma formation in the nude mouse model. Expression levels were lower in the early and middle phases, while B7-H3 mRNA and protein were overexpressed in the late stage. Accordingly, CD3+ T cell numbers in the early, middle, and late phases in osteosarcoma tissue were 93 ± 13, 92 ± 12, and 46 ± 15, respectively; they can be seen to have decreased significantly in the late stage (P < 0.05). Overall, our results indicated that the B7-H3 expression level is correlated with tumor volume and severity; therefore, it might serve as a tumor biomarker for osteosarcoma. PMID:26600483

  3. Systemically administered PEDF against primary and secondary tumours in a clinically relevant osteosarcoma model

    PubMed Central

    Broadhead, M L; Dass, C R; Choong, P F M

    2011-01-01

    Background: Pigment epithelium-derived factor (PEDF) is an endogenous glycoprotein with a potential role as a therapeutic for osteosarcoma. Animal studies have demonstrated the biological effects of PEDF on osteosarcoma; however, these results are difficult to extrapolate for human use due to the chosen study design and drug delivery methods. Methods: In this study we have attempted to replicate the human presentation and treatment of osteosarcoma using a murine orthotopic model of osteosarcoma. The effects of PEDF on osteosarcoma cell lines were evaluated in vitro prior to animal experimentation. Orthotopic tumours were induced by intra-tibial injection of SaOS-2 osteosarcoma cells. Treatment with PEDF was delayed until after the macroscopic appearance of primary tumours. Pigment epithelium-derived factor was administered systemically via an implanted intraperitoneal micro-osmotic pump. Results: In vitro, PEDF inhibited proliferation, induced apoptosis and inhibited cell cycling of osteosarcoma cells. Pigment epithelium-derived factor promoted adhesion to Collagen I and inhibited invasion through Collagen I. In vivo, treatment with PEDF caused a reduction in both primary tumour volume and burden of pulmonary metastases. Systemic administration of PEDF did not cause toxic effects on normal tissues. Conclusion: Systemically delivered PEDF is effective in suppressing the size of primary and secondary tumours in an orthotopic murine model of osteosarcoma. PMID:21979423

  4. B7-H3 protein expression in a murine model of osteosarcoma

    PubMed Central

    ZHAO, JIA-LI; CHEN, FENG-LI; ZHOU, QUAN; PAN, WEI; WANG, XIN-HONG; XU, JIN; ZHANG, SHAO-XIAN; NI, LI; YANG, HUI-LIN

    2016-01-01

    Osteosarcoma is an aggressive type of bone tumor that commonly occurs in pediatric age groups. The complete molecular mechanisms behind osteosarcoma formation and progression require elucidation. B7-H3 is a protein of the B7 family that acts as a co-stimulatory molecule with a significant role in adaptive immune responses. The link between B7-H3 expression and its role in different types of cancer remains unclear. B7-H3 protein exhibits different functional roles in in vivo and in vitro conditions that remain controversial. In the present study, a murine model of osteosarcoma was successfully established using a modified protocol so as to easily obtain a low grade and metastatic form of osteosarcoma tissue without complication. Histological data showed that a less organized and highly proliferative mass of cells was observed in the osteosarcoma tissue. A higher expression level of B7-H3 protein was also observed at each advanced stage of osteosarcoma, which indicated the contributory role of the protein in the development of the primary and metastatic forms of osteosarcoma. Immunohistochemistry was performed, which showed that the overexpression of B7-H3 protein in the metastatic form of osteosarcoma may be associated with its migration and invasion. PMID:27347155

  5. IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling.

    PubMed

    Lu, Jinchang; Song, Guohui; Tang, Qinglian; Zou, Changye; Han, Feng; Zhao, Zhiqiang; Yong, Bicheng; Yin, Junqiang; Xu, Huaiyuan; Xie, Xianbiao; Kang, Tiebang; Lam, YingLee; Yang, Huiling; Shen, Jingnan; Wang, Jin

    2015-05-01

    Osteosarcoma is a common malignant bone tumor with a propensity to metastasize to the lungs. Epigenetic abnormalities have been demonstrated to underlie osteosarcoma development; however, the epigenetic mechanisms that are involved in metastasis are not yet clear. Here, we analyzed 2 syngeneic primary human osteosarcoma cell lines that exhibit disparate metastatic potential for differences in epigenetic modifications and expression. Using methylated DNA immunoprecipitation (MeDIP) and microarray expression analysis to screen for metastasis-associated genes, we identified Iroquois homeobox 1 (IRX1). In both human osteosarcoma cell lines and clinical osteosarcoma tissues, IRX1 overexpression was strongly associated with hypomethylation of its own promoter. Furthermore, experimental modulation of IRX1 in osteosarcoma cell lines profoundly altered metastatic activity, including migration, invasion, and resistance to anoikis in vitro, and influenced lung metastasis in murine models. These prometastatic effects of IRX1 were mediated by upregulation of CXCL14/NF-κB signaling. In serum from osteosarcoma patients, the presence of IRX1 hypomethylation in circulating tumor DNA reduced lung metastasis-free survival. Together, these results identify IRX1 as a prometastatic gene, implicate IRX1 hypomethylation as a potential molecular marker for lung metastasis, and suggest that epigenetic reversion of IRX1 activation may be beneficial for controlling osteosarcoma metastasis. PMID:25822025

  6. The Prognostic Significance of Src and p-Src Expression in Patients with Osteosarcoma

    PubMed Central

    Hu, Chao; Deng, Zhouming; Zhang, Yi; Yan, Lei; Cai, Lin; Lei, Jun; Xie, Yuanlong

    2015-01-01

    Background The expression of Src and phospho-Src (p-Src) is closely related to tumor invasion and metastasis. The aim of the present study was to investigate the expression of these molecules in osteosarcoma and their relationship with each other, to provide a theoretical basis to understand the prognosis of osteosarcoma. Material/Methods We selected surgically resected osteosarcoma specimens from 116 patients of Zhongnan Hospital of Wuhan University and Hubei Cancer Hospital, Hubei, China, between January 2000 and January 2010 with detailed follow-up data. Twenty osteochondroma specimens from the corresponding period were used as controls. Expression of Src and p-Src was detected in osteosarcoma and osteochondroma by immunohistochemistry. We analyzed the relationship of the 2 proteins and osteosarcoma patient prognosis. Results The expression of Src and p-Src in osteosarcoma was significantly higher than the expression level in osteochondroma (P<0.05). The expression levels of the 2 proteins, clinical stage, and tumor metastasis were significantly associated with survival time (P<0.05), but there was no correlation between age or sex and survival time. The expression of Src and p-Src in osteosarcoma was positively correlated. Conclusions Src and p-Src can be used as an auxiliary indicator to determine a malignant phenotype of bone tumors, and the combined detection of Src and p-Src may indicate the prognosis of osteosarcoma. PMID:25725252

  7. Silencing of Eag1 Gene Inhibits Osteosarcoma Proliferation and Migration by Targeting STAT3-VEGF Pathway

    PubMed Central

    Wu, Xinyu; Chen, Zhida; Zeng, Wengrong; Zhong, Yuanfu; Liu, Qingjun; Wu, Jin

    2015-01-01

    So far, the role of Ether à go-go 1 (Eag1) potassium channels in migration and invasion progression of cancers remains elusive. In the present study, the effects of Eag1 knockdown on osteosarcoma cell proliferation, growth, and apoptosis were examined. Then, we evaluated the effects of Eag1 silencing on osteosarcoma cell migration and invasion. In addition, we detected the expression of vascular endothelial growth factor (VEGF) and signal transducer and activator of transcription 3 (STAT3) in osteosarcoma cell treated with Eag1 small interfering RNAs (siRNAs). Finally, STAT3 siRNA was employed to determine the influence of downregulation of STAT3 on cell proliferation and migration. The results showed that knockdown of Eag1 significantly suppressed osteosarcoma cell proliferation and osteosarcoma xenografts growth. However, Eag1 silencing had little effect on cell apoptosis. Additionally, osteosarcoma cell adhesion, migration, and invasion were also potently attenuated. Notably, the expression levels of VEGF decreased evidently upon Eag1 siRNAs treatment, paralleled with reductions in the expression levels of STAT3. Moreover, a similar pattern was observed in osteosarcoma cell proliferation and migration suppression between STAT3 siRNA and Eag1 siRNAs groups. Our data indicated that Eag1 promotes osteosarcoma proliferation and migration, at least in part, by targeting STAT3-VEGF pathway. PMID:26783521

  8. Targeting CDK11 in osteosarcoma cells using the CRISPR-Cas9 system

    PubMed Central

    Feng, Yong; Sassi, Slim; Shen, Jacson K; Yang, Xiaoqian; Gao, Yan; Osaka, Eiji; Zhang, Jianming; Yang, Shuhua; Yang, Cao; Mankin, Henry J.; Hornicek, Francis J; Duan, Zhenfeng

    2014-01-01

    Osteosarcoma is the most common type primary malignant tumor of bone. Patients with regional osteosarcoma are routinely treated with surgery and chemotherapy. In addition, many patients with metastatic or recurrent osteosarcoma show poor prognosis with current chemotherapy agents. Therefore, it is important to improve the general condition and the overall survival rate of patients with osteosarcoma by identifying novel therapeutic strategies. Recent studies have revealed that CDK11 is essential in osteosarcoma cell growth and survival by inhibiting CDK11 mRNA expression with RNAi. Here, we apply the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system, a robust and highly efficient novel genome editing tool, to determine the effect of targeting endogenous CDK11 gene at the DNA level in osteosarcoma cell lines. We show that CDK11 can be efficiently silenced by CRISPR-Cas9. Inhibition of CDK11 is associated with decreased cell proliferation and viability, and induces cell death in osteosarcoma cell lines KHOS and U-2OS. Furthermore, the migration and invasion activities are also markedly reduced by CDK11 knockout. These results demonstrate that CRISPR-Cas9 system is a useful tool for the modification of endogenous CDK11 gene expression, and CRISPR-Cas9 targeted CDK11 knockout may be a promising therapeutic regimen for the treatment of osteosarcoma. PMID:25348612

  9. A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma

    PubMed Central

    Mirabello, Lisa; Koster, Roelof; Moriarity, Branden S.; Spector, Logan G.; Meltzer, Paul S.; Gary, Joy; Machiela, Mitchell J.; Pankratz, Nathan; Panagiotou, Orestis A.; Largaespada, David; Wang, Zhaoming; Gastier-Foster, Julie M.; Gorlick, Richard; Khanna, Chand; de Toledo, Silvia Regina Caminada; Petrilli, Antonio S.; Patiño-Garcia, Ana; Sierrasesúmaga, Luis; Lecanda, Fernando; Andrulis, Irene L.; Wunder, Jay S.; Gokgoz, Nalan; Serra, Massimo; Hattinger, Claudia; Picci, Piero; Scotlandi, Katia; Flanagan, Adrienne M.; Tirabosco, Roberto; Amary, Maria Fernanda; Halai, Dina; Ballinger, Mandy L.; Thomas, David M.; Davis, Sean; Barkauskas, Donald A.; Marina, Neyssa; Helman, Lee; Otto, George M.; Becklin, Kelsie L.; Wolf, Natalie K.; Weg, Madison T.; Tucker, Margaret; Wacholder, Sholom; Fraumeni, Joseph F.; Caporaso, Neil E.; Boland, Joseph F.; Hicks, Belynda D.; Vogt, Aurelie; Burdett, Laurie; Yeager, Meredith; Hoover, Robert N.; Chanock, Stephen J.; Savage, Sharon A.

    2015-01-01

    Metastasis is the leading cause of death in osteosarcoma patients, the most common pediatric bone malignancy. We conducted a multi-stage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified a SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P=1.2×10−9, OR 2.43, 95% CI 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. Additionally, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib, and had lowered Nfib expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis, and that NFIB is an osteosarcoma metastasis susceptibility gene. PMID:26084801

  10. Emerging concepts for PI3K/mTOR inhibition as a potential treatment for osteosarcoma

    PubMed Central

    Bishop, Michael W.; Janeway, Katherine A.

    2016-01-01

    Patients with metastatic and recurrent osteosarcoma fare poorly, and new therapeutic strategies are needed to improve survival. Several recent complementary genomic and pathway analyses of both murine and human osteosarcoma have revealed common aberrations of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway in osteosarcoma. Preclinical data demonstrate that inhibition of PI3K and mTOR with either a combination of single agents or dual inhibiting compounds can decrease cell proliferation and induce cell cycle arrest and apoptosis. With a lack of available clinical agents active in osteosarcoma, PI3K/mTOR inhibition represents a potential vulnerability in osteosarcoma that warrants clinical investigation. PMID:27441088

  11. A review of primary osteosarcoma of the larynx and case report.

    PubMed

    Mosalleum, Esraa; Afrogheh, Amir; Stofberg, Sacha; Bezuidenhout, Abraham Fourie; Schneider, Johann; Hille, Jos

    2015-03-01

    Sarcomas of the larynx are exceedingly uncommon, of which primary laryngeal osteosarcomas are the rarest. To date, 25 cases of primary laryngeal osteosarcomas have been reported in the literature. Laryngeal osteosarcomas may closely simulate sarcomatoid carcinomas, since both entities share clinical, histological and immunohistochemical features. Herein, we report a case of primary laryngeal osteosarcoma in a 55 year old male, focusing on the importance of light microscopic, immunohistochemical and ultrastructural features in accurately establishing the diagnosis. In addition, the current paper provides a review of the English language literature on the subject. Laryngeal osteosarcomas usually carry a dismal prognosis with no general consensus on the most effective mode of therapy. Similarly, the current patient developed bilateral lung metastases 8 months after the initial surgery. PMID:24947052

  12. Establishment of a cell line producing bone morphogenetic protein from a human osteosarcoma.

    PubMed

    Takaoka, K; Yoshikawa, H; Masuhara, K; Sugamoto, K; Tsuda, T; Aoki, Y; Ono, K; Sakamoto, Y

    1989-07-01

    A human osteosarcoma cell line was established from a biopsy specimen from a 13-year-old girl. The osteosarcoma tissue was maintained in athymic nude mice (Balb C nu/nu) by serial transplantation for three years. The tumor was excised from a host mouse and digested with collagenase. The isolated cells were cultured by 98 passages in 14 months, and clones of osteosarcoma cells were obtained by limiting dilution. A clone named human osteosarcoma cell 6 (H-OS-6) that showed the osteoblastic phenotypes of productions of bone morphogenetic protein (BMP) and alkaline phosphatase and a response to human parathyroid hormone (h-PTH 1-34) was selected. The morphology of its chromosomes indicated its human origin. This human osteosarcoma cell line is unique in producing BMP under in vitro conditions. PMID:2545399

  13. Emerging concepts for PI3K/mTOR inhibition as a potential treatment for osteosarcoma.

    PubMed

    Bishop, Michael W; Janeway, Katherine A

    2016-01-01

    Patients with metastatic and recurrent osteosarcoma fare poorly, and new therapeutic strategies are needed to improve survival. Several recent complementary genomic and pathway analyses of both murine and human osteosarcoma have revealed common aberrations of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway in osteosarcoma. Preclinical data demonstrate that inhibition of PI3K and mTOR with either a combination of single agents or dual inhibiting compounds can decrease cell proliferation and induce cell cycle arrest and apoptosis. With a lack of available clinical agents active in osteosarcoma, PI3K/mTOR inhibition represents a potential vulnerability in osteosarcoma that warrants clinical investigation. PMID:27441088

  14. Overexpression of Long Non-Coding RNA HOTAIR Promotes Tumor Growth and Metastasis in Human Osteosarcoma

    PubMed Central

    Wang, Bo; Su, Yun; Yang, Qun; Lv, Decheng; Zhang, Weiguo; Tang, Kai; Wang, Hong; Zhang, Rui; Liu, Yang

    2015-01-01

    Human osteosarcoma usually presented a high tendency to metastatic spread and caused poor outcomes, however, the underlying mechanism was still largely unknown. In the present study, using a series of in vitro experiments and an animal model, we investigated the roles of HOX antisense intergenic RNA (HOTAIR) during the proliferation and invasion of osteosarcoma. According with our results, HOTAIR was commonly overexpressed in osteosarcoma, which significantly correlated with advanced tumor stage, highly histological grade and poor prognosis. In vitro and in vivo experiments demonstrated that knockdown of HOTAIR could notably suppress cellular proliferation, inhibit invasion and decrease the secretion of MMP2 and MMP9 in osteosarcoma. Collectively, our results suggested that HOTAIR might be a potent therapeutic target for osteosarcoma. PMID:25728753

  15. MicroRNA-200b acts as a tumor suppressor in osteosarcoma via targeting ZEB1

    PubMed Central

    Li, Yusheng; Zeng, Chao; Tu, Min; Jiang, Wei; Dai, Zixun; Hu, Yuling; Deng, Zhenhan; Xiao, Wenfeng

    2016-01-01

    Osteosarcoma is the most common type of cancer that develops in bone, mainly arising from the metaphysis of the long bones. MicroRNA (miR)-200b has been found to generally act as a tumor suppressor in multiple types of human cancers. However, the detailed role of miR-200b in osteosarcoma still remains to be fully understood. This study aimed to investigate the exact role of miR-200b in the progression of osteosarcoma and the underlying mechanism. Real-time reverse transcription-polymerase chain reaction data showed that miR-200b was significantly downregulated in osteosarcoma tissues compared to their matched adjacent nontumor tissues. Low miR-200b level was associated with the advanced clinical stage and positive distant metastasis. Besides, it was also downregulated in osteosarcoma cell lines (U2OS, Saos2, HOS, and MG63) compared to normal osteoblast cell line NHOst. In vitro study showed that restoration of miR-200b led to a significant decrease in proliferation, migration, and invasion of osteosarcoma cells. Moreover, ZEB1 was identified as a target gene of miR-200b, and its expression levels were negatively mediated by miR-200b in osteosarcoma cells. In addition, ZEB1 was significantly upregulated in osteosarcoma cells compared to the normal osteoblast cell line NHOst, and inhibition of ZEB1 expression also suppressed the proliferation, migration, and invasion in osteosarcoma cells. Finally, we showed that ZEB1 was frequently upregulated in osteosarcoma tissues compared to their matched adjacent normal tissues, and its expression was reversely correlated to the miR-200b levels in osteosarcoma tissues. Based on these findings, our study suggests that miR-200b inhibits the proliferation, migration, and invasion of osteosarcoma cells, probably via the inhibition of ZEB1 expression. Therefore, miR-200b/ZEB1 may become a potential target for the treatment of osteosarcoma. PMID:27307751

  16. Identification of CBX3 and ABCA5 as Putative Biomarkers for Tumor Stem Cells in Osteosarcoma

    PubMed Central

    Saini, Vaibhav; Hose, Curtis D.; Monks, Anne; Nagashima, Kunio; Han, Bingnan; Newton, Dianne L.; Millione, Angelena; Shah, Jalpa; Hollingshead, Melinda G.; Hite, Karen M.; Burkett, Mark W.; Delosh, Rene M.; Silvers, Thomas E.; Scudiero, Dominic A.; Shoemaker, Robert H.

    2012-01-01

    Recently, there has been renewed interest in the role of tumor stem cells (TSCs) in tumorigenesis, chemoresistance, and relapse of malignant tumors including osteosarcoma. The potential exists to improve osteosarcoma treatment through characterization of TSCs and identification of therapeutic targets. Using transcriptome, proteome, immunophenotyping for cell-surface markers, and bioinformatic analyses, heterogeneous expression of previously reported TSC or osteosarcoma markers, such as CD133, nestin, POU5F1 (OCT3/4), NANOG, SOX2, and aldehyde dehydrogenase, among others, was observed in vitro. However, consistently significantly lower CD326, CD24, CD44, and higher ABCG2 expression in TSC-enriched as compared with un-enriched osteosarcoma cultures was observed. In addition, consistently higher CBX3 expression in TSC-enriched osteosarcoma cultures was identified. ABCA5 was identified as a putative biomarker of TSCs and/or osteosarcoma. Lastly, in a high-throughput screen we identified epigenetic (5-azacytidine), anti-microtubule (vincristine), and anti-telomerase (3,11-difluoro-6,8,13-trimethyl- 8H-quino [4,3,2-kl] acridinium methosulfate; RHPS4)-targeted therapeutic agents as candidates for TSC ablation in osteosarcoma. PMID:22870217

  17. Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma.

    PubMed

    Baranski, Zuzanna; Booij, Tijmen H; Cleton-Jansen, Anne-Marie; Price, Leo S; van de Water, Bob; Bovée, Judith V M G; Hogendoorn, Pancras C W; Danen, Erik H J

    2015-07-01

    Conventional high-grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis-free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti-apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G2 cell-cycle arrest; Chk1 protein levels were attenuated and ATR-Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven-depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven-controlled ATR-Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix-embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR-Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy. PMID:25757065

  18. Clinical and histopathological profile of primary or secondary osteosarcoma of the jaws.

    PubMed

    Angiero, Francesca; Moltrasio, Francesca; Cattoretti, Giorgio; Valente, Maria Gabriella

    2011-12-01

    Osteosarcoma of the jaw is a rare disease; we report two cases, one in which the primary osteosarcoma had occurred in the sacrum and ileum, the second at the mandible. Dissemination of osteosarcoma to other organs, especially early dissemination to the lung, is common, but metastasis to the jaw has only rarely been reported. About 10% of osteosarcomas occur in the head and neck, most in the mandible or maxilla. Clinically, both patients presented swelling, and pain at the jaw in the premolar-molar region. At radiography, extensive bone erosion and soft-tissue swelling were apparent. A biopsy was taken and a diagnosis of osteosarcoma rendered in both cases. Histological examination revealed a proliferation of atypical osteoblast-like cells with hyperchromatic nuclei and formation of scattered neoplastic osteoid tissue. Immunohistochemistry for a panel of antibodies showed strong positivity for CD99, weak positivity for S-100, but was negative for desmin, vimentin, and cytokeratins. The diagnosis for both cases was of osteogenic osteosarcoma, chondroblastic subtype. Unfortunately, both patients died, one before the planned chemotherapy regime could begin, the second during the chemotherapy course. Our report aims to highlight the importance of the diagnostic profile in formulating a diagnosis of osteosarcoma, and that this tumor, although very rare, may be primary or may metastasize to the jaws. PMID:22199320

  19. Leukemia inhibitory factor promotes tumor growth and metastasis in human osteosarcoma via activating STAT3.

    PubMed

    Liu, Bin; Lu, Yi; Li, Jinzhi; Liu, Yanping; Liu, Jian; Wang, Weiguo

    2015-10-01

    The leukemia inhibitory factor (LIF) has been demonstrated to be an oncogene and participated in multiple procedures during the initiation and progression of many human malignancies. However, the role of LIF in osteosarcoma is still largely unknown. Here, we performed a series of in vitro and in vivo experiments to investigate the expression and biological functions of LIF in osteosarcoma. Compared to that in the non-cancerous tissues, LIF was significantly overexpressed in a panel of 68 osteosarcoma samples (p < 0.0001). Moreover, the overexpression of LIF was significantly correlated with advanced tumor stage, larger tumor size, and shorter overall survival. In addition, knockdown of LIF notably suppressed the proliferation and invasion of osteosarcoma via blocking the STAT3 signal pathway; in contrast, treatment with the recombinant LIF protein significantly promoted the growth and invasion of osteosarcoma through enhancing the phosphorylation of STAT3, which can be partially neutralized by the STAT3 inhibitor, HO-3867. In conclusion, we demonstrated that LIF was frequently overexpressed in osteosarcoma, which could promote the growth and invasion through activating the STAT3 pathway. Our findings proposed that LIF might be a potent therapeutic target for osteosarcoma. PMID:26271643

  20. TRIM66 overexpresssion contributes to osteosarcoma carcinogenesis and indicates poor survival outcome

    PubMed Central

    Chen, Yu; Guo, Yongfei; Yang, Haisong; Shi, Guodong; Xu, Guohua; Shi, Jiangang; Na, Yin; Chen, Deyu

    2015-01-01

    TRIM66 belongs to the family of tripartite motif (TRIM)-containing proteins. Alterations in TRIM proteins have been implicated in several malignancies. This study was aimed at elucidating the expression and biological function of TRIM66 in osteosarcoma. Here, TRIM66 expression level was higher in osteosarcoma tissues than in normal tissues. High TRIM66 expression was correlated with high rate of local recurrence and lung metastasis, and short survival time. Then, we found that knockdown of TRIM66 in two osteosarcoma cell lines, MG63 and HOS, significantly inhibited cell proliferation and induced G1-phase arrest. Moreover, inhibition of TRIM66 in osteosarcoma cells significantly induced cell apoptosis, while remarkably inhibited cell migration, invasion as well as tumorigenicity in nude mice. Gene set enrichment analysis in Gene Expression Omnibus dataset revealed that apoptosis, epithelial-mesenchymal transition (EMT) and transforming growth factor-β (TGF-β) signaling pathway-related genes were enriched in TRIM66 higher expression patients, which was confirmed by western blot analysis in osteosarcoma cells with TRIM66 silenced. In conclusion, TRIM66 may act as an oncogene through suppressing apoptosis pathway and promoting TGF-β signaling in osteosarcoma carcinogenesis. TRIM66 may be a prognostic factor and potential therapeutic target in osteosarcoma. PMID:26247633

  1. TP53 Mutations and Survival in Osteosarcoma Patients: A Meta-Analysis of Published Data

    PubMed Central

    Chen, Zhe; Guo, Jiayi; Zhang, Kun; Guo, Yanxing

    2016-01-01

    Several research groups have examined the association between TP53 mutations and prognosis in human osteosarcoma. However, the results were controversial. The purpose of this study was to evaluate the prognostic value of TP53 mutations in osteosarcoma patients. A meta-analysis was conducted with all eligible studies which quantitatively evaluated the relationship between TP53 mutations and clinical outcome of osteosarcoma patients. Eight studies with a total of 210 patients with osteosarcoma were included in this meta-analysis. The risk ratio (RR) with a 95% confidence interval (95% CI) was calculated to assess the effect of TP53 mutations on 2-year overall survival. The quantitative synthesis of 8 published studies showed that TP53 mutations were associated with 2-year overall survival in osteosarcoma patients. These data suggested that TP53 mutations had an unfavorable impact on 2-year overall survival when compared to the counterparts with wild type (WT) TP53 (RR: 1.79; 95% CI: 1.12 to 2.84; P = 0.01; I2 = 0%). There was no between-study heterogeneity. TP53 mutations are an effective prognostic marker for survival of patients with osteosarcoma. However, further large-scale prospective trials should be performed to clarify the prognostic value of TP53 mutations on 3- or 5-year survival in osteosarcoma patients. PMID:27239089

  2. p27 Is a Candidate Prognostic Biomarker and Metastatic Promoter in Osteosarcoma.

    PubMed

    Li, Yiting; Nakka, Manjula; Kelly, Aaron J; Lau, Ching C; Krailo, Mark; Barkauskas, Donald A; Hicks, John M; Man, Tsz-Kwong

    2016-07-01

    Metastatic progression is the major cause of death in osteosarcoma, the most common bone malignancy in children and young adults. However, prognostic biomarkers and efficacious targeted treatments for metastatic disease remain lacking. Using an immunoproteomic approach, we discovered that autoantibodies against the cell-cycle kinase inhibitor p27 (KIP1, CDKN1B) were elevated in plasma of high-risk osteosarcoma patients. Using a large cohort of serum samples from osteosarcoma patients (n = 233), we validated that a higher level of the p27 autoantibody significantly correlated with poor overall and event-free survival (P < 0.05). Immunohistochemical analysis also showed that p27 was mislocalized to the cytoplasm in the majority of osteosarcoma cases and in highly metastatic osteosarcoma cell lines. We demonstrated that ectopic expression of cytoplasmic p27 promoted migration and invasion of osteosarcoma cells, whereas shRNA-mediated gene silencing suppressed these effects. In addition, mutations at the p27 phosphorylation sites S10 or T198, but not T157, abolished the migratory and invasive phenotypes. Furthermore, the development of pulmonary metastases increased in mice injected with cells expressing cytoplasmic p27 compared with an empty vector control. Collectively, our findings support further investigation of p27 as a potential prognostic biomarker and therapeutic target in osteosarcoma cases exhibiting aberrant p27 subcellular localization. Cancer Res; 76(13); 4002-11. ©2016 AACR. PMID:27197201

  3. ZD6474, a new treatment strategy for human osteosarcoma, and its potential synergistic effect with celecoxib.

    PubMed

    Liu, Jiani; Wu, Jiangxue; Zhou, Ling; Pan, Changchuan; Zhou, Yi; Du, Wuying; Chen, Jie-Min; Zhu, Xiaofeng; Shen, Jingnan; Chen, Shuai; Liu, Ran-Yi; Huang, Wenlin

    2015-08-28

    ZD6474, a small molecule VEGFR and EGFR tyrosine kinase inhibitor, has been considered as a promising tumor-targeted drug in various malignancies. EGFR and cyclooxygenase-2 (COX-2) were found overexpressed in osteosarcoma in previous reports, so here we tried to explore the anti-osteosarcoma effect of ZD6474 alone or combination with celecoxib, a COX-2 inhibitor. The data demonstrated that ZD6474 inhibited the growth of osteosarcoma cells, and promoted G1-phase cell cycle arrest and apoptosis by inhibiting the activity of EGFR tyrosine kinase, and consequently suppressing its downstream PI3k/Akt and MAPK/ERK pathway. Additionally, daily administration of ZD6474 produced a dose-dependent inhibition of tumor growth in nude mice. Celecoxib also significantly inhibited the growth of osteosarcoma cells in dose-dependent manner, while combination of ZD6474 and celecoxib displayed a synergistic or additive antitumor effect on osteosarcoma in vitro and in vivo. The possible molecular mechanisms to address the synergism are likely that ZD6474 induces the down-regulation of COX-2 expression through inhibiting ERK phosphorylation, while celecoxib promotes ZD6474-directed inhibition of ERK phosphorylation. In conclusion, ZD6474 exerts direct anti-proliferative effects on osteosarcoma cells, and the synergistic antitumor effect of the combination of ZD6474 with celecoxib may indicate a new strategy of the combinative treatment of human osteosarcoma. PMID:26050198

  4. ZD6474, a new treatment strategy for human osteosarcoma, and its potential synergistic effect with celecoxib

    PubMed Central

    Pan, Changchuan; Zhou, Yi; Du, Wuying; Chen, Jie-min; Zhu, Xiaofeng; Shen, Jingnan; Chen, Shuai; Liu, Ran-yi; Huang, Wenlin

    2015-01-01

    ZD6474, a small molecule VEGFR and EGFR tyrosine kinase inhibitor, has been considered as a promising tumor-targeted drug in various malignancies. EGFR and cyclooxygenase-2 (COX-2) were found overexpressed in osteosarcoma in previous reports, so here we tried to explore the anti-osteosarcoma effect of ZD6474 alone or combination with celecoxib, a COX-2 inhibitor. The data demonstrated that ZD6474 inhibited the growth of osteosarcoma cells, and promoted G1-phase cell cycle arrest and apoptosis by inhibiting the activity of EGFR tyrosine kinase, and consequently suppressing its downstream PI3k/Akt and MAPK/ERK pathway. Additionally, daily administration of ZD6474 produced a dose-dependent inhibition of tumor growth in nude mice. Celecoxib also significantly inhibited the growth of osteosarcoma cells in dose-dependent manner, while combination of ZD6474 and celecoxib displayed a synergistic or additive antitumor effect on osteosarcoma in vitro and in vivo. The possible molecular mechanisms to address the synergism are likely that ZD6474 induces the down-regulation of COX-2 expression through inhibiting ERK phosphorylation, while celecoxib promotes ZD6474-directed inhibition of ERK phosphorylation. In conclusion, ZD6474 exerts direct anti-proliferative effects on osteosarcoma cells, and the synergistic antitumor effect of the combination of ZD6474 with celecoxib may indicate a new strategy of the combinative treatment of human osteosarcoma. PMID:26050198

  5. Gene function analysis in osteosarcoma based on microarray gene expression profiling

    PubMed Central

    Zhao, Liang; Zhang, Jinghua; Tan, Hongyu; Wang, Weidong; Liu, Yilin; Song, Ruipeng; Wang, Limin

    2015-01-01

    Osteosa rcoma is an aggressive malignant neoplasm that exhibits osteoblastic differentiation and produces malignant osteoid. The aim of this study was to find feature genes associated with osteosarcoma and correlative gene functions which can distinguish cancer tissues from non-tumor tissues. Gene expression profile GSE14359 was downloaded from Gene Expression Omnibus (GEO) database, including 10 osteosarcoma samples and 2 normal samples. The differentially expressed genes (DEGs) between osteosarcoma and normal specimens were identified using limma package of R. DAVID was applied to mine osteosarcoma associated genes and analyze the GO enrichment on gene functions and KEGG pathways. Then, corresponding protein-protein interaction (PPI) network of DEGs was constructed based on the data collected from STRING datasets. Principal component of top10 DEGs and PPI network of top 20 DEGs were further analyzed. Finally, transcription factors were predicted by uploading the two groups of DEGs to TfactS database. A total of 437 genes, including 114 up-regulated genes and 323 down-regulated genes, were filtered as DEGs, of which 46 were associated with osteosarcoma by Disease Module. GO and KEGG pathway enrichment analysis showed that genes mainly affected the process of immune response and the development of skeletal and vascular system. The PPI network analysis elucidated that hemoglobin and histocompatibility proteins and enzymes, which were associated with immune response, were closely associated with osteosarcoma. Transcription factors MYC and SP1 were predicted to be significantly related to osteosarcoma. The discovery of gene functions and transcription factors has the potential to use in clinic for diagnosis of osteosarcoma in future. In addition, it will pave the way to studying mechanism and effective therapies for osteosarcoma. PMID:26379830

  6. Alpha-CaMKII plays a critical role in determining the aggressive behavior of human osteosarcoma.

    PubMed

    Daft, Paul G; Yuan, Kaiyu; Warram, Jason M; Klein, Michael J; Siegal, Gene P; Zayzafoon, Majd

    2013-04-01

    Osteosarcoma is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. Despite improvements in osteosarcoma treatment, more specific molecular targets are needed as potential therapeutic options. One target of interest is α-Ca(2+)/calmodulin-dependent protein kinase II (α-CaMKII), a ubiquitous mediator of Ca(2+)-linked signaling, which has been shown to regulate tumor cell proliferation and differentiation. Here, we investigate the role of α-CaMKII in the growth and tumorigenicity of human osteosarcoma. We show that α-CaMKII is highly expressed in primary osteosarcoma tissue derived from 114 patients, and is expressed in varying levels in different human osteosarcoma (OS) cell lines [MG-63, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)/HOS, and 143B). To examine whether α-CaMKII regulates osteosarcoma tumorigenic properties, we genetically inhibited α-CaMKII in two osteosarcoma cell lines using two different α-CaMKII shRNAs delivered by lentiviral vectors and overexpressed α-CaMKII by retrovirus. The genetic deletion of α-CaMKII by short hairpin RNA (shRNA) in MG-63 and 143B cells resulted in decreased proliferation (50% and 41%), migration (22% and 25%), and invasion (95% and 90%), respectively. The overexpression of α-CaMKII in HOS cells resulted in increased proliferation (240%), migration (640%), and invasion (10,000%). Furthermore, α-CaMKII deletion in MG-63 cells significantly reduced tumor burden in vivo (65%), whereas α-CaMKII overexpression resulted in tumor formation in a previously nontumor forming osteosarcoma cell line (HOS). Our results suggest that α-CaMKII plays a critical role in determining the aggressive phenotype of osteosarcoma, and its inhibition could be an attractive therapeutic target to combat this devastating adolescent disease. PMID:23364534

  7. Local recurrence of a parosteal osteosarcoma 21 years after incomplete resection

    PubMed Central

    Combalia, Andrés; Muñoz-Mahamud, Ernesto; Palacín, Antonio; Pomés, Jaume; López, Vicente

    2011-01-01

    Parosteal osteosarcoma (POS) is the most common form of surface osteosarcoma. Its symptoms are insidious and its duration prior to diagnosis is considerably longer than that of other types of osteosarcoma. We report a case of POS with a growing mass but no evidence of metastasis. This tumor, which was diagnosed as calcified hematoma with benign characteristics, was incompletely resected in our hospital 21 years before the diagnosis of recurrence. The patient underwent a wide en bloc resection in our hospital and was free of symptoms, with no signs of tumor recurrence or metastasis during a 53-month follow-up. PMID:22059909

  8. 18F-NaF PET/CT Images of Cardiac Metastasis From Osteosarcoma.

    PubMed

    Chou, Yi-Hsien; Ko, Kuan-Yin; Cheng, Mei-Fang; Chen, Wei-Wu; Yen, Ruoh-Fang

    2016-09-01

    Osteosarcomas are aggressive with a high incidence of recurrence and metastasis. Cardiac osteosarcoma metastasis is rare. We described a 17-year-old boy who had right distal femoral osteosarcoma with lung metastases. During follow-up, right ventricular (RV) metastasis was noted and confirmed by histopathological examination of the surgical specimen. F-NaF PET/CT was then arranged 1 month after debulking surgery for residual tumor survey. The images showed intense F-NaF uptake at RV region, suggestive of residual cardiac metastases. PMID:27405028

  9. Induction of osteosarcomas in mouse lumbar vertebrae by repeated external beta-irradiation

    SciTech Connect

    Ootsuyama, A.; Tanooka, H.

    1989-03-15

    Besides skin tumors, osteosarcomas were induced at high frequency in the lumbar vertebrae of ICR mice by repeated local external irradiation of the back with /sup 90/Sr-/sup 90/Y beta-rays when irradiation was repeated three times a week until tumors appeared. The optimum dose range for osteosarcoma induction was 250-350 cGy per exposure at the surface of the back, or 125-175 cGy at the depth of the center of the bone. With the same irradiation schedule, the optimal dose of radiation for induction of osteosarcomas was much lower than that for induction of skin tumors.

  10. Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis

    PubMed Central

    Takagi, Satoshi; Takemoto, Ai; Takami, Miho; Oh-hara, Tomoko; Fujita, Naoya

    2014-01-01

    The interactions of tumor cells with platelets contribute to the progression of tumor malignancy, and the expression levels of platelet aggregation-inducing factors positively correlate with the metastatic potential of osteosarcoma cells. However, it is unclear how tumor-platelet interaction contributes to the proliferation of osteosarcomas. We report here that osteosarcoma-platelet interactions induce the release of platelet-derived growth factor (PDGF) from platelets, which promotes the proliferation of osteosarcomas. Co-culture of platelets with MG63 or HOS osteosarcoma cells, which could induce platelet aggregation, enhanced the proliferation of each cell line in vitro. Analysis of phospho-antibody arrays revealed that co-culture of MG63 cells with platelets induced the phosphorylation of platelet derived growth factor receptor (PDGFR) and Akt. The addition of supernatants of osteosarcoma-platelet reactants also increased the growth of MG63 and HOS cells as well as the level of phosphorylated-PDGFR and -Akt. Sunitinib or LY294002, but not erlotinib, significantly inhibited the platelet-induced proliferation of osteosarcoma cells, indicating that PDGF released from platelets plays an important role in the proliferation of osteosarcomas by activating the PDGFR and then Akt. Our results suggest that inhibitors that specifically target osteosarcoma-platelet interactions may eradicate osteosarcomas. PMID:24974736

  11. Application of eupatilin in the treatment of osteosarcoma

    PubMed Central

    LI, YAN-YAN; WU, HAO; DONG, YI-GUO; LIN, BO; XU, GANG; MA, YU-BO

    2015-01-01

    5,7-dihydroxy-3′,4′,6-trimethoxyflavone, commonly known as eupatilin, is a traditional Asian medicinal plant, which is mainly used for the treatment of gastritis, as well as its use as an anti-inflammatory agent. Eupatilin is a bioactive compound; however, its effects on osteosarcoma (OS) have remained to be elucidated. Therefore, the present study aimed to investigate the effects of eupatilin on this malignant bone tumor, using the U-2 OS cell line. The experimental results revealed that eupatilin inhibited U-2 OS cell growth in a concentration-dependent manner and induced G2/M phase cell cycle arrest and apoptosis. Additionally, western blot analysis indicated that eupatilin was able to trigger the mitochondrial apoptotic pathway, demonstrated by the enhanced Bax/B cell lymphoma-2 ratio, decrease in mitochondrial membrane potential, release of cytochrome c, caspase-3 and -9 activation and poly(ADP-ribose)polymerase cleavage detected in the U-2 OS cells. These results indicated that eupatilin was able to inhibit U-2 OS cancer cell proliferation by the induction of apoptosis via the mitochondrial intrinsic pathway. Eupatilin may therefore represent a novel anticancer drug for use in the treatment of osteosarcoma. PMID:26622880

  12. Rib osteoblastic osteosarcoma in an African hedgehog (Atelerix albiventris).

    PubMed

    Benoit-Biancamano, Marie-Odile; D'Anjou, Marc-André; Girard, Christiane; Langlois, Isabelle

    2006-07-01

    A 3-year-old African hedgehog (Atelerix albiventris) was presented to the Exotic Animal Clinic of the University of Montreal for evaluation of a mass growing on the right thoracic wall. The diagnostic workup, which included helical computed tomography, confirmed the presence of a large mass, originating from the right 7th rib, infiltrating the thoracic wall and cavity. The animal was euthanized due to the poor prognosis. At necropsy, a well-demarcated mass penetrated the thoracic wall and incorporated the 6th to 8th ribs. Cut sections of the tumor were white, glistening, firm, and gritty. Microscopically, it was composed of polyhedral to elongated cells with interspersed trabeculae of osteoid and large areas of coagulative necrosis. On the basis of histopathologic findings, a diagnosis of osteoblastic osteosarcoma was made. To the authors' knowledge, this is the first report of an osteoblastic osteosarcoma on the thoracic wall of an African hedgehog, as well as the first report of the use of helical computed tomography in that species. PMID:16921888

  13. The survivin suppressant YM155 reverses doxorubicin resistance in osteosarcoma.

    PubMed

    Zhang, Zhuo; Zhang, Yunfeng; Lv, Jiayin; Wang, Jincheng

    2015-01-01

    Doxorubicin (DOX) is one of the widely used chemotherapeutic drugs for the treatment of human osteosarcoma (OS). However, acquisition of DOX resistance is common in patients with OS, leading to local and distant failure. In this study, we demonstrate that survivin expression is significantly upregulated in OS primary tumors compared to paired normal tissue. In addition, survivin expression was further increased in DOX resistant cells (MG63/DOX) as compared to its parent cells (MG63). Thus, we hypothesize that targeting of survivin in OS could reverse the DOX resistant phenotype in tumor cells thereby enhancing the therapeutic efficacy of DOX. We test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with DOX in vitro and in vivo. We found that combination treatment of YM155 and DOX in DOX resistant cells (MG63/DOX) could significantly inhibited cell proliferation and colony formation, induce cell apoptosis and promoted caspase-3, -8, and -9 activity in vitro, and promoted tumor regression in established OS xenograft models. Taken together, the evidence presented here supports the favorable preclinical evaluation that YM155 could overcome DOX the resistance in tumor cells thereby enhancing the effectiveness of DOX in OS, suggesting that YM155 in combination with DOX has potential in the treatment of osteosarcoma. PMID:26770398

  14. The survivin suppressant YM155 reverses doxorubicin resistance in osteosarcoma

    PubMed Central

    Zhang, Zhuo; Zhang, Yunfeng; Lv, Jiayin; Wang, Jincheng

    2015-01-01

    Doxorubicin (DOX) is one of the widely used chemotherapeutic drugs for the treatment of human osteosarcoma (OS). However, acquisition of DOX resistance is common in patients with OS, leading to local and distant failure. In this study, we demonstrate that survivin expression is significantly upregulated in OS primary tumors compared to paired normal tissue. In addition, survivin expression was further increased in DOX resistant cells (MG63/DOX) as compared to its parent cells (MG63). Thus, we hypothesize that targeting of survivin in OS could reverse the DOX resistant phenotype in tumor cells thereby enhancing the therapeutic efficacy of DOX. We test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with DOX in vitro and in vivo. We found that combination treatment of YM155 and DOX in DOX resistant cells (MG63/DOX) could significantly inhibited cell proliferation and colony formation, induce cell apoptosis and promoted caspase-3, -8, and -9 activity in vitro, and promoted tumor regression in established OS xenograft models. Taken together, the evidence presented here supports the favorable preclinical evaluation that YM155 could overcome DOX the resistance in tumor cells thereby enhancing the effectiveness of DOX in OS, suggesting that YM155 in combination with DOX has potential in the treatment of osteosarcoma. PMID:26770398

  15. Genetically Modified T-Cell Therapy for Osteosarcoma

    PubMed Central

    DeRenzo, Christopher

    2015-01-01

    T-cell immunotherapy may offer an approach to improve outcomes for patients with osteosarcoma, who fail current therapies. In addition, it has the potential to reduce treatment-related complications for all patients. Generating tumor-specific T cells with conventional antigen presenting cells ex vivo is time consuming and often results in T-cell products with a low frequency of tumor-specific T cells. In addition, the generated T cells remain sensitive to the immunosuppressive tumor microenvironment. Genetic modification of T cells is one strategy to overcome these limitations. For example, T cells can be genetically modified to render them antigen specific, resistant to inhibitory factors, or increase their ability to home to tumor sites. Most genetic modification strategies have only been evaluated in preclinical models, however early phase clinical trials are in progress. In this chapter we review the current status of gene-modified T-cell therapy with special focus on osteosarcoma, highlighting potential antigenic targets, preclinical and clinical studies, and strategies to improve current T-cell therapy approaches. PMID:24924183

  16. Biological effectiveness of fast neutrons on a murine osteosarcoma

    SciTech Connect

    Ishii, T.; Ando, K.; Koike, S.

    1989-03-01

    The effect of fast neutrons and gamma rays on a murine osteosarcoma was studied. The NROS tumor, a radiation-induced osteosarcoma in a C3H mouse, was transplanted into the right hind legs of syngeneic female mice and locally irradiated with single or four daily doses of either fast neutrons or gamma rays. The NROS contained 13-30% hypoxic cells. It took approximately 7 days for the NROS tumor to show apparent reoxygenation following gamma ray irradiations. Two assays were used to determine the neutrons' relative biological effectiveness (RBE) to gamma rays: tumor growth delay time and tumor control dose. The largest RBE of 4.5 was obtained at the smallest dose of neutrons examined, followed by a gradual decrease down to 2.3. The tumor growth delay assay indicated that the RBE values of 2.6-3.1 after single doses of fast neutrons increased to 3.1-4.5 after four daily fractions. The 50% tumor control doses were 78.5 Gy and 33.0 Gy after single doses of gamma rays and fast neutrons, resulting in an RBE of 2.3. Fractionated doses increased the RBE to 2.6. Mitotic cells disappeared shortly after irradiation but reappeared 7 days after irradiation.

  17. Capsaicin induces immunogenic cell death in human osteosarcoma cells

    PubMed Central

    Jin, Tao; Wu, Hongyan; Wang, Yanlin; Peng, Hao

    2016-01-01

    Immunogenic cell death (ICD) is characterized by the early surface exposure of calreticulin (CRT). As a specific signaling molecule, CRT on the surface of apoptotic tumor cells mediates the recognition and phagocytosis of tumor cells by antigen presenting cells. To date, only a small quantity of anti-cancer chemicals have been found to induce ICD, therefore it is clinically important to identify novel chemicals that may induce ICD. The purpose of the present study is to explore the function of capsaicin in inducing ICD. In the current study, MTT assays were used to examine the growth inhibiting effects of MG-63 cells when they were treated with capsaicin or cisplatin. Mitochondrial membrane potential and western blot analysis were used to investigate capsaicin- and cisplatin-induced apoptosis. In addition, the effects of capsaicin and cisplatin were evaluated for their abilities in inducing calreticulin membrane translocation and mediating ICD in human osteosarcoma cells (MG-63). The results demonstrated that capsaicin and cisplatin can induce the apoptosis of MG-63 cells. However, only capsaicin induced a rapid translocation of CRT from the intracellular space to the cell surface. Treatment with capsaicin increased phagocytosis of MG-63 cells by dendritic cells (DCs), and these MG-63-loaded DCs could efficiently stimulate the secretion of IFN-γ by lymphocytes. These results identify capsaicin as an anti-cancer agent capable of inducing ICD in human osteosarcoma cells in vitro. PMID:27446273

  18. Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma.

    PubMed

    Shaikh, Atik Badshah; Li, Fangfei; Li, Min; He, Bing; He, Xiaojuan; Chen, Guofen; Guo, Baosheng; Li, Defang; Jiang, Feng; Dang, Lei; Zheng, Shaowei; Liang, Chao; Liu, Jin; Lu, Cheng; Liu, Biao; Lu, Jun; Wang, Luyao; Lu, Aiping; Zhang, Ge

    2016-01-01

    Osteosarcoma (OS) is a bone cancer mostly occurring in pediatric population. Current treatment regime of surgery and intensive chemotherapy could cure about 60%-75% patients with primary osteosarcoma, however only 15% to 30% can be cured when pulmonary metastasis or relapse has taken place. Hence, novel precise OS-targeting therapies are being developed with the hope of addressing this issue. This review summarizes the current development of molecular mechanisms and targets for osteosarcoma. Therapies that target these mechanisms with updated information on clinical trials are also reviewed. Meanwhile, we further discuss novel therapeutic targets and OS-targeting drug delivery systems. In conclusion, a full insight in OS pathogenesis and OS-targeting strategies would help us explore novel targeted therapies for metastatic osteosarcoma. PMID:27058531

  19. Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma

    PubMed Central

    Shaikh, Atik Badshah; Li, Fangfei; Li, Min; He, Bing; He, Xiaojuan; Chen, Guofen; Guo, Baosheng; Li, Defang; Jiang, Feng; Dang, Lei; Zheng, Shaowei; Liang, Chao; Liu, Jin; Lu, Cheng; Liu, Biao; Lu, Jun; Wang, Luyao; Lu, Aiping; Zhang, Ge

    2016-01-01

    Osteosarcoma (OS) is a bone cancer mostly occurring in pediatric population. Current treatment regime of surgery and intensive chemotherapy could cure about 60%–75% patients with primary osteosarcoma, however only 15% to 30% can be cured when pulmonary metastasis or relapse has taken place. Hence, novel precise OS-targeting therapies are being developed with the hope of addressing this issue. This review summarizes the current development of molecular mechanisms and targets for osteosarcoma. Therapies that target these mechanisms with updated information on clinical trials are also reviewed. Meanwhile, we further discuss novel therapeutic targets and OS-targeting drug delivery systems. In conclusion, a full insight in OS pathogenesis and OS-targeting strategies would help us explore novel targeted therapies for metastatic osteosarcoma. PMID:27058531

  20. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency.

    PubMed

    Kovac, Michal; Blattmann, Claudia; Ribi, Sebastian; Smida, Jan; Mueller, Nikola S; Engert, Florian; Castro-Giner, Francesc; Weischenfeldt, Joachim; Kovacova, Monika; Krieg, Andreas; Andreou, Dimosthenis; Tunn, Per-Ulf; Dürr, Hans Roland; Rechl, Hans; Schaser, Klaus-Dieter; Melcher, Ingo; Burdach, Stefan; Kulozik, Andreas; Specht, Katja; Heinimann, Karl; Fulda, Simone; Bielack, Stefan; Jundt, Gernot; Tomlinson, Ian; Korbel, Jan O; Nathrath, Michaela; Baumhoer, Daniel

    2015-01-01

    Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited. PMID:26632267

  1. Silencing of YY1 downregulates RIZ1 promoter in human osteosarcoma.

    PubMed

    Abbondanza, Ciro; de Nigris, Filomena; De Rosa, Caterina; Rossiello, Raffaele; Puca, Giovanni Alfredo; Napoli, Claudio

    2008-01-01

    RIZ1 isoform, but not RIZ2, is commonly silenced in many types of tumors. In osteosarcoma cells, RIZ1 protein is very abundant. The silencing of YY1 protein, a recent target gene in osteosarcoma cells, reduced the expression of RIZ1 protein. Here we show that RIZ1 overexpression is a transcriptional event documented by Western blot, RT-PCR, and promoter assays. YY1 protein binds and cooperates to positive regulation of the RIZ1 promoter and its presence reduced the dimethyl lysine 9 histone 3 by chromatin immunoprecipitation assays. These results indicate that overexpression of YY1 in osteosarcoma cells plays a key role in positive regulation of RIZ1. The coexpression of RIZ1/YY1 proteins suggests a tandem regulatory mechanism in human osteosarcoma cells and tissues. PMID:18488713

  2. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency

    PubMed Central

    Kovac, Michal; Blattmann, Claudia; Ribi, Sebastian; Smida, Jan; Mueller, Nikola S.; Engert, Florian; Castro-Giner, Francesc; Weischenfeldt, Joachim; Kovacova, Monika; Krieg, Andreas; Andreou, Dimosthenis; Tunn, Per-Ulf; Dürr, Hans Roland; Rechl, Hans; Schaser, Klaus-Dieter; Melcher, Ingo; Burdach, Stefan; Kulozik, Andreas; Specht, Katja; Heinimann, Karl; Fulda, Simone; Bielack, Stefan; Jundt, Gernot; Tomlinson, Ian; Korbel, Jan O.; Nathrath, Michaela; Baumhoer, Daniel

    2015-01-01

    Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited. PMID:26632267

  3. Some retinoblastomas, osteosarcomas, and soft tissue sarcomas may share a common etiology

    SciTech Connect

    Weichselbaum, R.R.; Beckett, M.; Diamond, A. )

    1988-04-01

    DNA and RNA were extracted from primary human osteosarcomas and soft tissue sarcomas obtained from patients without retinoblastoma and were analyzed by hybridization with a cDNA probe for RB mRNA; absence or alterations of the RB gene are associated with development of retinoblastoma. Most of the osteosarcomas or soft tissue sarcomas examined by the authors did not express detectable levels of RB mRNA, whereas normal cells and epithelial tumor cells did. One osteosarcoma expressed a 2.4-kilobase transcript in addition to a normal 4.7-kilobase species. The data suggest that transcriptional inactivation or post-transcriptional down-regulation of the RB gene may be important in the etiology of some osteosarcomas and soft tissue sarcomas as well as retinoblastomas.

  4. The genetic basis for inactivation of Wnt pathway in human osteosarcoma

    PubMed Central

    2014-01-01

    Background Osteosarcoma is a highly genetically unstable tumor with poor prognosis. We performed microarray-based comparative genomic hybridization (aCGH), transcriptome sequencing (RNA-seq), and pathway analysis to gain a systemic view of the pathway alterations of osteosarcoma. Methods aCGH experiments were carried out on 10 fresh osteosarcoma samples. The output data (Gene Expression Omnibus Series accession number GSE19180) were pooled with published aCGH raw data (GSE9654) to determine recurrent copy number changes. These were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to identify altered pathways in osteosarcoma. Transcriptome sequencing of six osteosarcomas was performed to detect the expression profile of Wnt signaling pathway genes. Protein expression of WNT1, β-catenin, c-myc, and cyclin D1 in the Wnt pathway was detected by immunohistochemistry (IHC) in an independent group of 46 osteosarcoma samples. Results KEGG pathway analysis identified frequent deletions of Wnt and other Wnt signaling pathway genes. At the mRNA level, transcriptome sequencing found reduced levels of mRNA expression of Wnt signaling pathway transcripts. While WNT1 protein expression was detected by IHC in 69.6% (32/46) of the osteosarcomas, no β-catenin protein was detected in the nucleus. β-catenin protein expression was, however, detected in the membrane and cytoplasm of 69.6% (32/46) of the osteosarcomas. c-myc protein expression was detected in only 47.8% (22/46) and cyclin D1 protein expression in 52.2% (24/46) of osteosarcoma samples. Kaplan-Meier survival analysis showed that WNT1-negative patients had a trend towards longer disease free survival than WNT1-positive patients. Interestingly, in WNT1-negative patients, those who were also cyclin D1-negative had significantly longer disease free survival than cyclin D1-positive patients. However, there was no significant association between any of the investigated proteins and overall

  5. Prognostic Significance of Survivin Expression in Osteosarcoma Patients: A Meta-Analysis

    PubMed Central

    Liu, Yugang; Teng, Zhaowei; Wang, Ying; Gao, Pengfei; Chen, Junli

    2015-01-01

    Background Osteosarcoma is the most common primary bone malignancy and has poor prognosis. Survivin has been identified as an independent prognostic factor for a majority of cancers. In the present study, we evaluated the effect of survivin expression on the clinical outcome of osteosarcoma patients. Material/Methods Online electronic databases were searched for related articles published between 2000 and 2015. Odds ratio (OR) and risk ratio (RR) with their 95% confidence intervals (CI) were employed to calculate the significance. Results Overall, a total of 20 relevant studies were selected, including 1030 patients. No significant heterogeneity was observed among included studies (P>0.01, I2<50%). Survivin was expressed in 68.6% of all cases. Our results show that survivin expression increased the 5-year overall survival (RR=0.48, 95% CI=0.32–0.71, P=0.0002) and rate of postoperative recurrence (RR=1.80, 95% CI=1.09–2.97, P=0.02). It was associated with the grade of osteosarcoma (Enneking clinical stage, IIb–III vs. I–IIa: OR=5.26, 95% CI=3.76–7.34, P<0.00001; Price’s grade, III vs. I+II: OR=2.04, 95% CI=1.16–3.61, P=0.01), metastasis, and soft tissue invasion of osteosarcoma (OR=6.25, 95% CI=3.74–10.45, P<0.00001; OR=6.15, 95% CI=3.74–10.11, P<0.00001). No relationship was found between survivin expression and sex, age, or tumor size in patients with osteosarcoma. Conclusions Our results suggest that survivin can function as a new diagnostic biomarker for osteosarcoma and be used as a reference index to determine pathology classification of osteosarcoma, providing new targets for gene therapy of osteosarcoma. PMID:26408642

  6. PLA2G16 promotes osteosarcoma metastasis and drug resistance via the MAPK pathway

    PubMed Central

    Li, Lin; Liang, Shoulei; Wasylishen, Amanda R.; Zhang, Yanqin; Yang, Xueli; Zhou, Bingzheng; Shan, Luling; Han, Xiuxin; Mu, Tianyang; Wang, Guowen; Xiong, Shunbin

    2016-01-01

    The prognosis of metastatic osteosarcoma is dismal and a better understanding of the mechanisms underlying disease progression is essential to improve treatment options and patient outcomes. We previously demonstrated Pla2g16 overexpression in mouse osteosarcoma contributes to metastasis phenotypes and increased expression of PLA2G16 is associated with metastasis and poor prognosis in human tumors. To further examine the mechanisms through which PLA2G16 contributes to human osteosarcoma metastasis and explore the potential of PLA2G16 as a therapeutic target in osteosarcoma, we generated a panel of human osteosarcoma cell lines expressing different levels of PLA2G16. The functional analyses of these cell lines demonstrated high levels of PLA2G16 expression increased osteosarcoma cell migration, invasion, clonogenic survival, and anchorage-independent colony formation. Importantly, this activity was dependent on the phospholipase activity of PLA2G16. Additionally, PLA2G16 overexpression decreased the sensitivity of cells to a panel of chemotherapeutic agents. Analysis of downstream pathways revealed the pro-metastasis functions of PLA2G16 were mediated through the MAPK pathway, as knockdown of PLA2G16 decreased ERK1/2 phosphorylation and pharmacological inhibition of MEK significantly repressed PLA2G16 mediated cell migration and clonogenic survival. Furthermore, PLA2G16 overexpression promoted xenograft tumor growth in vivo, and these tumors exhibit increased ERK1/2 phosphorylation. Lastly, the expression of PLA2G16 is strongly correlated with the increased ERK1/2 phosphorylation in human osteosarcoma samples, and the combined lesions are associated with reduced overall and metastasis-free survival. Collectively, these results demonstrate increased PLA2G16 expression activates the MAPK pathway to enhance osteosarcoma metastasis and may be a novel therapeutic target for these cancers. PMID:26933804

  7. The Functional Role of PMP22 Gene in the Proliferation and Invasion of Osteosarcoma

    PubMed Central

    Liu, Shuyong; Chen, Zhiping

    2015-01-01

    Background As the most common primary bone tumor, osteosarcoma has an improved survival rates with advancement of treatment methods. A higher rate of metastasis, however, leads to the aggravation of the disease. Studies have shown that some genes, namely osteosarcoma metastasis-related genes, participate in the process of tumor metastasis. The peripheral myelin protein 22 (PMP22) gene has recently been found to be abundantly expressed in the oncogenesis of osteosarcoma. Its detailed role and function in the tumor metastasis, however, remains unknown. Material/Methods The recombinant retroviral plasmid pcDNA3.1-PMP22 was constructed and used to transfect osteosarcoma cells SOSP-M, whose cell proliferation was measured by MTT method. The formation of tumor cell colony, the cell migration and invasion were also measured. The signal transduction pathway MAPK was further analyzed by Western blotting. Results The pcDNA3.1-PMP22 plasmid was confirmed to have a 305bp PMP22 fragment by EcoRI-XhoI dual digestion. Compared to the control group, osteosarcoma cell invasion was significantly facilitated by the transfection of pcDNA3.1-PMP22 plasmid (p<0.05). The recombinant plasmid also significantly potentiated the formation of tumor cell colony and increased the migration and invasion ability of tumor cells (p<0.05 in all cases). Phosphorylated p-ERK and p-P38 were also up-regulated by vector transfection (p<0.05). Conclusions Osteosarcoma metastasis-related gene PMP22 participates in the proliferation, invasion, migration and colony formation of osteosarcoma cells possibly via the MAPK signal transduction pathway, providing evidences for further investigation of metastatic mechanism of osteosarcoma. PMID:26154129

  8. Coexpression of CXCR4 and MMP9 predicts lung metastasis and poor prognosis in resected osteosarcoma.

    PubMed

    Ren, Zhiwu; Liang, Shoulei; Yang, Jilong; Han, Xiuxin; Shan, Luling; Wang, Biying; Mu, Tianyang; Zhang, Yanqin; Yang, Xueli; Xiong, Shunbin; Wang, Guowen

    2016-04-01

    Osteosarcoma is a highly aggressive bone disease with a tendency to metastasize to the lung. The 5-year survival of patients with metastatic osteosarcoma is only 20 %. Many studies have demonstrated SDF-1/CXCR4 and MMP9 play important roles in the metastasis of malignant tumors, including osteosarcoma. The aim of this study was to investigate the association of CXCR4 and MMP9 expression with clinicopathological features and pulmonary metastasis in osteosarcoma. Using tumor tissue microarrays, we analyzed the expression of CXCR4 and MMP9 among 34 primary osteosarcomas with pulmonary metastasis and 62 primary osteosarcomas without metastasis. A median time of 57.5 months (range: 6 to 171 months) follow-up was performed to evaluate tumor metastasis and the patient survival. The prognostic values were determined by univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis. The accuracy of oncologic outcome prediction was evaluated by receiver-operating characteristics (ROC) curves (AUC). The expression of CXCR4 and MMP9 was significantly correlated in tumor tissues (P = 0.026). Both CXCR4 and MMP9 were independent predictors for overall survival and metastasis-free survival by Cox multivariate analysis, and high expression for both CXCR4 and MMP9 were even more significant and better biomarkers for osteosarcoma metastasis and survival. The combination of CXCR4 and MMP9 high expression is very likely to be a valuable independent predictor of lung metastasis and survival in osteosarcoma patients. PMID:26546437

  9. MicroRNA-21 Increases Proliferation and Cisplatin Sensitivity of Osteosarcoma-Derived Cells

    PubMed Central

    Vanas, Vanita; Haigl, Barbara; Stockhammer, Verena; Sutterlüty-Fall, Hedwig

    2016-01-01

    Osteosarcoma is the most common primary bone tumor and poor prognosis for osteosarcoma patients is mainly due to chemotherapy resistance. MicroRNAs are important to maintain pathophysiological mechanisms of cancer and influence cell sensitivity to chemotherapy. In this study, we tested the functions of microRNA-21 for malignant features as well as for drug resistance of osteosarcoma. We used Northern blot to measure microRNA-21 levels in osteosarcoma-derived cell lines. MicroRNA-21 activity was modulated by either expressing a sponge to decrease its activity in an osteosarcoma-derived cell line expressing high levels of microRNA-21 or by introducing pri-microRNA-21 in a cell line with low endogenous levels. Cell migration was determined in a scratch assay and cell proliferation was measured by performing growth curve analysis. Sensitivity of the cells towards chemotherapeutics was investigated by performing cell viability assays and calculating the IC50 values. While cell migration was unaffected by modulated microRNA-21 levels, microRNA-21 inhibition slowed proliferation and exogenously expressed microRNA-21 promoted this process. Modulated microRNA-21 activity failed to effect sensitivity of osteosarcoma-derived cell lines to doxorubicin or methotrexate. Contrarily, reduction of microRNA-21 activity resulted in enhanced resistance towards cisplatin while ectopic expression of microRNA-21 showed the opposite effect. Increased microRNA-21 levels repressed the expression of Sprouty2 and ectopic expression of Sprouty2 was able to largely rescue the observed effects of microRNA-21 in osteosarcoma. In summary, our data indicate that in osteosarcoma microRNA-21 expression is an important component for regulation of cell proliferation and for determining sensitivity to cisplatin. PMID:27513462

  10. MicroRNA-603 functions as an oncogene by suppressing BRCC2 protein translation in osteosarcoma.

    PubMed

    Ma, Chengbin; Zhan, Chuan; Yuan, Hongmou; Cui, Yan; Zhang, Zhiyu

    2016-06-01

    The present study was conducted to investigate the expression of miR-603 in osteosarcoma cells, and the effect of miR-603 on the biological behavior and expression of breast cancer cell 2 (BRCC2) in osteosarcoma cells. In the present study, qRT-PCR was used to measure the levels of miRNA and mRNA. The results showed that miR-603 was significantly upregulated in human osteosarcoma tissues and cell lines. MTT and colony formation assays were employed to evaluate the role of miR-603 in the regulation of osteosarcoma cell proliferation. The results showed that overexpression of miR-603 promoted the proliferation of MG-63 and U2OS cells. Furthermore, a nude mouse subcutaneous tumor model indicated that miR-603 promoted osteosarcoma growth in vivo. Moreover, miR-603 expression levels were increased in patients with distant metastasis in comparison with levels in patients without distant metastasis. We discovered that BRCC2 may be a target of miR-603. Our results demonstrated that overexpression of miR-603 suppressed BRCC2 protein expression, and an miR-603 inhibitor enhanced BRCC2 protein expression as determined by western blot assay and immunohistochemical analysis. Luciferase reporter assays confirmed that BRCC2 is a direct target of miR-603 in osteosarcoma cells, and the results suggest that miR-603 downregulates BRCC2 expression in osteosarcoma via translational inhibition. Finally, we found that the reduction in BRCC2 expression induced by miR-603 was responsible for the enhanced colony formation and proliferative ability noted in the MG-63 and U2OS cells. In conclusion, miR-603 enhanced osteosarcoma growth by downregulation of BRCC2 expression via translational inhibition. PMID:27035098

  11. MicroRNA-124 functions as a tumor suppressor and indicates prognosis in human osteosarcoma

    PubMed Central

    HAN, GANG; WANG, YAN; BI, WENZHI; JIA, JINPENG; WANG, WEI

    2015-01-01

    MicroRNA-124 (miR-124) has been demonstrated to be downregulated in numerous human malignancies and correlated with tumor progression. However, its expression and clinical significance in osteosarcoma remains unclear. Thus, the aim of the present study was to explore the effects of miR-124 in osteosarcoma tumorigenesis and development. Using reverse transcription-quantitative polymerase chain reaction, miR-124 expression was detected in primary osteosarcoma tissues and osteosarcoma cell lines. The correlation of miR-124 expression with clinicopathological factors and prognosis was statistically analyzed. MTT, flow cytometric, and Transwell invasion and migration assays were used to test the proliferation, apoptosis, invasion and migration of osteosarcoma cells transfected with miR-124 mimic. It was found that the expression levels of miR-124 in osteosarcoma tissues were significantly lower than those in corresponding noncancerous bone tissues (P<0.001). In addition, miR-124 downregulation more frequently occurred in osteosarcoma specimens with advanced clinical stage (P<0.001), positive distant metastasis (P=0.005) and poor response to neoadjuvant chemotherapy (P=0.013). Univariate and multivariate analysis identified low miR-124 expression as an unfavorable prognostic factor for overall survival. Furthermore, transfection of miR-124 mimic into MG63 cells was able to reduce cell proliferation, invasion and migration, and promote cell apoptosis. These findings indicate that miR-124 may act not only as a novel diagnostic and prognostic marker, but also as a potential target for the molecular therapy of osteosarcoma. PMID:25667613

  12. MicroRNA-21 Increases Proliferation and Cisplatin Sensitivity of Osteosarcoma-Derived Cells.

    PubMed

    Vanas, Vanita; Haigl, Barbara; Stockhammer, Verena; Sutterlüty-Fall, Hedwig

    2016-01-01

    Osteosarcoma is the most common primary bone tumor and poor prognosis for osteosarcoma patients is mainly due to chemotherapy resistance. MicroRNAs are important to maintain pathophysiological mechanisms of cancer and influence cell sensitivity to chemotherapy. In this study, we tested the functions of microRNA-21 for malignant features as well as for drug resistance of osteosarcoma. We used Northern blot to measure microRNA-21 levels in osteosarcoma-derived cell lines. MicroRNA-21 activity was modulated by either expressing a sponge to decrease its activity in an osteosarcoma-derived cell line expressing high levels of microRNA-21 or by introducing pri-microRNA-21 in a cell line with low endogenous levels. Cell migration was determined in a scratch assay and cell proliferation was measured by performing growth curve analysis. Sensitivity of the cells towards chemotherapeutics was investigated by performing cell viability assays and calculating the IC50 values. While cell migration was unaffected by modulated microRNA-21 levels, microRNA-21 inhibition slowed proliferation and exogenously expressed microRNA-21 promoted this process. Modulated microRNA-21 activity failed to effect sensitivity of osteosarcoma-derived cell lines to doxorubicin or methotrexate. Contrarily, reduction of microRNA-21 activity resulted in enhanced resistance towards cisplatin while ectopic expression of microRNA-21 showed the opposite effect. Increased microRNA-21 levels repressed the expression of Sprouty2 and ectopic expression of Sprouty2 was able to largely rescue the observed effects of microRNA-21 in osteosarcoma. In summary, our data indicate that in osteosarcoma microRNA-21 expression is an important component for regulation of cell proliferation and for determining sensitivity to cisplatin. PMID:27513462

  13. Pilot Study of Vascular Health in Survivors of Osteosarcoma

    PubMed Central

    Mulrooney, Daniel A.; Ness, Kirsten K.; Huang, Sujuan; Solovey, Anna; Hebbel, Robert P.; Neaton, James D.; Clohisy, Denis R.; Kelly, Aaron S.; Neglia, Joseph P.

    2014-01-01

    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-β, 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/m2; range: 90–645 mg/m2), 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. PMID:23720361

  14. Establishment of reproducible osteosarcoma rat model using orthotopic implantation technique.

    PubMed

    Yu, Zhe; Sun, Honghui; Fan, Qingyu; Long, Hua; Yang, Tongtao; Ma, Bao'an

    2009-05-01

    In experimental musculoskeletal oncology, there remains a need for animal models that can be used to assess the efficacy of new and innovative treatment methodologies for bone tumors. Rat plays a very important role in the bone field especially in the evaluation of metabolic bone diseases. The objective of this study was to develop a rat osteosarcoma model for evaluation of new surgical and molecular methods of treatment for extremity sarcoma. One hundred male SD rats weighing 125.45+/-8.19 g were divided into 5 groups and anesthetized intraperitoneally with 10% chloral hydrate. Orthotopic implantation models of rat osteosarcoma were performed by injecting directly into the SD rat femur with a needle for inoculation with SD tumor cells. In the first step of the experiment, 2x10(5) to 1x10(6) UMR106 cells in 50 microl were injected intraosseously into median or distal part of the femoral shaft and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from ultrasound with findings from necropsia and determining time of survival. In the third stage, the orthotopically implanted tumors and lung nodules were resected entirely, sectioned, and then counter stained with hematoxylin and eosin for histopathologic evaluation. The tumor take rate was 100% for implants with 8x10(5) tumor cells or more, which was much less than the amount required for subcutaneous implantation, with a high lung metastasis rate of 93.0%. Ultrasound and necropsia findings matched closely (r=0.942; p<0.01), which demonstrated that Doppler ultrasonography is a convenient and reliable technique for measuring cancer at any stage. Tumor growth curve showed that orthotopically implanted tumors expanded vigorously with time-lapse, especially in the first 3 weeks. The median time of survival was 38 days and surgical mortality was 0%. The UMR106 cell line has strong carcinogenic capability and high lung metastasis frequency. The present rat

  15. MEK inhibition induces apoptosis in osteosarcoma cells with constitutive ERK1/2 phosphorylation.

    PubMed

    Baranski, Zuzanna; Booij, Tijmen H; Kuijjer, Marieke L; de Jong, Yvonne; Cleton-Jansen, Anne-Marie; Price, Leo S; van de Water, Bob; Bovée, Judith V M G; Hogendoorn, Pancras C W; Danen, Erik H J

    2015-11-01

    Conventional high-grade osteosarcoma is the most common primary bone cancer with relatively high incidence in young people. Recurrent and metastatic tumors are difficult to treat. We performed a kinase inhibitor screen in two osteosarcoma cell lines, which identified MEK1/2 inhibitors. These inhibitors were further validated in a panel of six osteosarcoma cell lines. Western blot analysis was performed to assess ERK activity and efficacy of MEK inhibition. A 3D culture system was used to validate results from 2D monolayer cultures. Gene expression analysis was performed to identify differentially expressed gene signatures in sensitive and resistant cell lines. Activation of the AKT signaling network was explored using Western blot and pharmacological inhibition. In the screen, Trametinib, AZD8330 and TAK-733 decreased cell viability by more than 50%. Validation in six osteosarcoma cell lines identified three cell lines as resistant and three as sensitive to the inhibitors. Western blot analysis of ERK activity revealed that sensitive lines had high constitutive ERK activity. Treatment with the three MEK inhibitors in a 3D culture system validated efficacy in inhibition of osteosarcoma viability. MEK1/2 inhibition represents a candidate treatment strategy for osteosarcomas displaying high MEK activity as determined by ERK phosphorylation status. PMID:26807203

  16. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

    PubMed Central

    Moriarity, Branden S; Otto, George M; Rahrmann, Eric P; Rathe, Susan K; Wolf, Natalie K; Weg, Madison T; Manlove, Luke A; LaRue, Rebecca S; Temiz, Nuri A; Molyneux, Sam D; Choi, Kwangmin; Holly, Kevin J; Sarver, Aaron L; Scott, Milcah C; Forster, Colleen L; Modiano, Jaime F; Khanna, Chand; Hewitt, Stephen M; Khokha, Rama; Yang, Yi; Gorlick, Richard; Dyer, Michael A; Largaespada, David A

    2016-01-01

    Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma. PMID:25961939

  17. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis.

    PubMed

    Moriarity, Branden S; Otto, George M; Rahrmann, Eric P; Rathe, Susan K; Wolf, Natalie K; Weg, Madison T; Manlove, Luke A; LaRue, Rebecca S; Temiz, Nuri A; Molyneux, Sam D; Choi, Kwangmin; Holly, Kevin J; Sarver, Aaron L; Scott, Milcah C; Forster, Colleen L; Modiano, Jaime F; Khanna, Chand; Hewitt, Stephen M; Khokha, Rama; Yang, Yi; Gorlick, Richard; Dyer, Michael A; Largaespada, David A

    2015-06-01

    Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma. PMID:25961939

  18. An improved intrafemoral injection with minimized leakage as an orthotopic mouse model of osteosarcoma.

    PubMed

    Sasaki, Hiromi; Iyer, Swathi V; Sasaki, Ken; Tawfik, Ossama W; Iwakuma, Tomoo

    2015-10-01

    Osteosarcoma, the most common type of primary bone cancer, is the second highest cause of cancer-related death in pediatric patients. To understand the mechanisms behind osteosarcoma progression and to discover novel therapeutic strategies for this disease, a reliable and appropriate mouse model is essential. For this purpose, osteosarcoma cells need to be injected into the bone marrow. Previously, the intratibial and intrafemoral injection methods were reported; however, the major drawback of these methods is the potential leakage of tumor cells from the injection site during or after these procedures. To overcome this, we have established an improved method to minimize leakage in an orthotopic mouse model of osteosarcoma. By taking advantage of the anatomical benefits of the femur with less bowing and larger medullary cavity than those of the tibia, osteosarcoma cells are injected directly into the femoral cavity following reaming of its intramedullary space. To prevent potential leakage of tumor cells during and after the surgery, the injection site is sealed with bone wax. This method requires a minor surgery of approximately 15min under anesthesia. Our established orthotopic osteosarcoma model could serve as a valuable and reliable tool for examining progression of various types of bone tumors. PMID:26142221

  19. Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: samarium-153-EDTMP and radium-223.

    PubMed

    Anderson, Peter M; Subbiah, Vivek; Rohren, Eric

    2014-01-01

    Osteosarcoma is a cancer characterized by formation of bone by malignant cells. Routine bone scan imaging with Tc-99m-MDP is done at diagnosis to evaluate primary tumor uptake and check for bone metastases. At time of relapse the Tc-99m-MDP bone scan also provides a specific means to assess formation of bone by malignant osteosarcoma cells and the potential for bone-seeking radiopharmaceuticals to deliver radioactivity directly into osteoblastic osteosarcoma lesions. This chapter will review and compare a bone-seeking radiopharmaceutical that emits beta-particles, samarium-153-EDTMP, with an alpha-particle emitter, radium-223. The charged alpha particles from radium-223 have far more mass and energy than beta particles (electrons) from Sm-153-EDTMP. Because radium-223 has less marrow toxicity and more radiobiological effectiveness, especially if inside the bone forming cancer cell than samarium-153-EDTMP, radium-223 may have greater potential to become widely used against osteosarcoma as a targeted therapy. Radium-223 also has more potential to be used with chemotherapy against osteosarcoma and bone metastases. Because osteosarcoma makes bone and radium-223 acts like calcium, this radiopharmaceutical could possibly become a new targeted means to achieve safe and effective reduction of tumor burden as well as facilitate better surgery and/or radiotherapy for difficult to resect large, or metastatic tumors. PMID:24924181

  20. Oncolytic vesicular stomatitis virus administered by isolated limb perfusion suppresses osteosarcoma growth.

    PubMed

    Kubo, Tadahiko; Shimose, Shoji; Matsuo, Toshihiro; Fujimori, Jun; Sakaguchi, Takemasa; Yamaki, Minoru; Shinozaki, Katsunori; Woo, Savio L C; Ochi, Mitsuo

    2011-05-01

    A significant limitation to oncolytic virotherapy in vivo is the lack of a clinically relevant means of delivering the virus. We evaluated the oncolytic activity of vesicular stomatitis virus (VSV) in human osteosarcoma cells and explored isolated limb perfusion (ILP) as a novel oncolytic virus delivery system to extremity sarcoma in immune-competent rats. Human and rat osteosarcoma cells transduced with rVSV-lacZ uniformly expressed β-gal. VSV was fully capable of replicating its RNA genome in all osteosarcoma cell lines, and efficiently killed them in time- and dose-dependent manners, whereas normal bone marrow stromal cells were refractory to the virus. VSV delivered by ILP inhibited growth of osteosarcoma xenografts more potently than that injected intravenously and intratumorally in the hind limb of immune-competent rats. Histopathological sections of tumor lesions treated by ILP-delivered VSV showed positive for VSV-G protein. There were no VSV-G expressions in perfused leg muscle, nonperfused leg muscle, brain, lung, and liver in VSV-treated rats. Our findings show efficient VSV gene expression and replication in osteosarcoma cells, suggesting that osteosarcoma may be a promising target for oncolytic virotherapy with VSV. Furthermore, we firstly showed that ILP of VSV against extremity sarcoma caused antitumor activity. PMID:21437961

  1. Craniofacial osteosarcomas: plain film, CT, and MR findings in 46 cases

    SciTech Connect

    Lee, Y.Y.; Van Tassel, P.; Nauert, C.; Raymond, A.K.; Edeiken, J.

    1988-06-01

    Forty-six osteosarcomas of the cranial and facial bones were reviewed radiographically by using the conventional parameters for long bone tumors. There were 32 de novo osteosarcomas (11 maxillary, 13 mandibular, and eight cranial) and 14 postradiation osteosarcomas. All the maxillary tumors originated from the alveolar ridge, and the majority of mandibular lesions began in the body of the mandible. The postradiation osteosarcomas occurred in portions of bones at the borders of the radiation field; the latent period ranged from 4 years, 2 months to 50 years (mean, 14 years). The majority of de novo or postradiation craniofacial osteosarcomas were osteolytic with a long transition zone and no periosteal reaction; the exception was in the mandible, where nearly half the cases were osteoblastic and periosteal reaction was occasionally present. Tumor matrix mineralization occurred in more than 75% of the cases, and osteoid matrix calcification was most frequent, even though most tumors were chondroblastic. Soft-tissue extension of tumor was present in all cases and contained calcifications in more than half. Conventional radiographs are of limited value in evaluating head and neck osteosarcomas because of the superimposed bony structures. CT provides excellent detection of tumor calcification, cortical involvement, and, in most instances, soft-tissue and intramedullary extension. MR is even more effective in demonstrating the intramedullary and extraosseous tumor components on both T1- and T2-weighted images. However, CT and plain films are superior to MR in detecting the matrix calcifications and bone destruction or reaction.

  2. TRIM59 is upregulated and promotes cell proliferation and migration in human osteosarcoma.

    PubMed

    Liang, Jinqian; Xing, Dan; Li, Zheng; Shen, Jianxiong; Zhao, Hong; Li, Shugang

    2016-06-01

    Osteosarcoma is a prevalent type of cancer and has a high metastatic ability, particularly for metastasis to the lungs. Effective treatment strategies have improved, however, the detailed molecular mechanism underlying the onset of this malignancy remains to be fully elucidated. The current study investigated the role of the tripartite motif (TRIM) family protein TRIM59 in osteosarcoma growth and metastasis. It was identified that TRIM59 was overexpressed in clinical osteosarcoma tissues and cultured osteosarcoma cell lines. In addition, the MTT assay demonstrated that in U2OS and MG63 cells, knockdown of TRIM59 by specific siRNA inhibited proliferation, whereas overexpression of TRIM59 promoted cell proliferation. Furthermore, overexpression of TRIM59 significantly increased the U2OS cell migrative and invasive abilities in a Transwell chamber assay. In addition, TRIM59 was able to negatively regulate the protein levels of P53 without significantly affecting the mRNA levels in U2OS and MG63 cells. These data suggest the oncogenic abilities of TRIM59 in osteosarcoma, which promote osteosarcoma cell proliferation, migration and invasion. PMID:27121462

  3. Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma

    PubMed Central

    2009-01-01

    Background Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy. Methods Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOSR2, U-2OS, and U-2OSR2 cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed. Results Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone. Conclusion Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma. PMID:19917123

  4. Enhancer of zeste homolog 2 silencing inhibits tumor growth and lung metastasis in osteosarcoma

    PubMed Central

    Lv, Yang-Fan; Yan, Guang-Ning; Meng, Gang; Zhang, Xi; Guo, Qiao-Nan

    2015-01-01

    The enhancer of zeste homolog 2 (EZH2) methyltransferase is the catalytic subunit of polycomb repressive complex 2 (PRC2), which acts as a transcription repressor via the trimethylation of lysine 27 of histone 3 (H3K27me3). EZH2 has been recognised as an oncogene in several types of tumors; however, its role in osteosarcoma has not been fully elucidated. Herein, we show that EZH2 silencing inhibits tumor growth and lung metastasis in osteosarcoma by facilitating re-expression of the imprinting gene tumor-suppressing STF cDNA 3 (TSSC3). Our previous study showed that TSSC3 acts as a tumor suppressor in osteosarcoma. In this study, we found that EZH2 was abnormally elevated in osteosarcoma, and its overexpression was associated with poor prognosis in osteosarcoma. Silencing of EZH2 resulted in tumor growth inhibition, apoptosis and chemosensitivity enhancement. Moreover, suppression of EZH2 markedly inhibited tumor growth and lung metastasis in vivo. Furthermore, EZH2 knockdown facilitated the re-expression of TSSC3 by reducing H3K27me3 in the promoter region. Cotransfection with siEZH2 and siTSSC3 could partially reverse the ability of siEZH2 alone. We have demonstrated that EZH2 plays a crucial role in tumor growth and distant metastasis in osteosarcoma; its oncogenic role is related to its regulation of the expression of TSSC3. PMID:26265454

  5. Contribution of the GSTP1 gene polymorphism to the development of osteosarcoma in a Chinese population.

    PubMed

    Qu, W R; Wu, J; Li, R

    2016-01-01

    We conducted a case-control study to investigate the associations between GSTT1, GSTM1, and GSTP1 gene polymorphisms and development of osteosarcoma in a Chinese population. Between January 2013 and February 2015, 153 patients diagnosed with osteosarcoma and 252 control subjects were enrolled in the current study from the Orthopedic Hospital of the Second Hospital of Jilin University. The GSTM1, GSTT1, and GSTP1 gene polymorphisms were detected by polymerase chain reaction coupled with restriction fragment length polymorphism analysis. As determined by a multiple-logistic regression analysis, the Val/Val genotype of GSTP1 was associated with a significantly increased risk of osteosarcoma compared to that of the Ile/Ile genotype, with an odds ratio (OR) = 3.39, and a 95% confidence interval (CI) = 1.45-8.13. Moreover, the Ile/Val+Val/Val genotype of GSTP1 was correlated with a marginally significant increased risk of osteosarcoma compared to that of the Ile/Ile genotype (OR = 1.65, 95%CI = 1.08-2.53). However, we did not find any significant associations between the GSTM1 and GSTT1 gene polymorphisms and osteosarcoma risk. In conclusion, our results suggest that the GSTP1 gene polymorphism is associated with an increased risk of osteosarcoma, whereas the GSTM1 and GSTT1 gene polymorphisms may not influence the development of this cancer. PMID:27525908

  6. Heterogeneous expression and biological function of ubiquitin carboxy-terminal hydrolase-L1 in osteosarcoma.

    PubMed

    Zheng, Shuier; Qiao, Guanglei; Min, Daliu; Zhang, Zhichang; Lin, Feng; Yang, Qingcheng; Feng, Tao; Tang, Lina; Sun, Yuanjue; Zhao, Hui; Li, Hongtao; Yu, Wenxi; Yang, Yumei; Shen, Zan; Yao, Yang

    2015-04-01

    Ubiquitin carboxyl terminal hydrolase 1 (UCHL1), a member of the UCH class of DUBs, has been reported as either an oncogene or a tumor suppressor. However, the molecular mechanism underlying the biological function of UCHL1 in osteosarcoma is still unclear. This study was aimed at elucidating the roles of UCHL1 in regulating the biological behavior of osteosarcoma cells. In this study, we found that UCHL1 was elevated in osteosarcoma compared with normal bone tissue. Moreover, UCHL1 expression level was correlated with tumor maximum diameter, high rate of lung metastases and short survival time. Then, we found that knockdown of UCHL1 in osteosarcoma cell MG63 inhibited cell proliferation and significantly increased cell population in the G1 phase. Several cyclins promoting G1/S phase transition were reduced after UCHL1 knockdown, including cell cycle regulator cyclin D1, cyclin E1 and CDK6. Moreover, inhibition of UCHL1 in MG63 cells dramatically induced cell apoptosis. We also found that down-regulation of UCHL1 in MG63 significantly inhibited cell invasion. Then, we found that there was a positive correlation between UCHL1 expression level and the Akt and ERK phosphorylation status. Finally, in vivo data showed that knockdown of UCHL1 inhibited osteosarcoma growth in nude mice. These results indicate that UCHL1 could work as an oncogene and may serve as a promising therapeutic strategy for osteosarcoma. PMID:25578779

  7. Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas.

    PubMed

    Osaki, Shuhei; Tazawa, Hiroshi; Hasei, Joe; Yamakawa, Yasuaki; Omori, Toshinori; Sugiu, Kazuhisa; Komatsubara, Tadashi; Fujiwara, Tomohiro; Sasaki, Tsuyoshi; Kunisada, Toshiyuki; Yoshida, Aki; Urata, Yasuo; Kagawa, Shunsuke; Ozaki, Toshifumi; Fujiwara, Toshiyoshi

    2016-01-01

    Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients. PMID:27356624

  8. Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas

    PubMed Central

    Osaki, Shuhei; Tazawa, Hiroshi; Hasei, Joe; Yamakawa, Yasuaki; Omori, Toshinori; Sugiu, Kazuhisa; Komatsubara, Tadashi; Fujiwara, Tomohiro; Sasaki, Tsuyoshi; Kunisada, Toshiyuki; Yoshida, Aki; Urata, Yasuo; Kagawa, Shunsuke; Ozaki, Toshifumi; Fujiwara, Toshiyoshi

    2016-01-01

    Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients. PMID:27356624

  9. Suppression of liver receptor homolog-1 by microRNA-451 represses the proliferation of osteosarcoma cells

    SciTech Connect

    Li, Zhiyong; Wu, Shuwen; Lv, Shouzheng; Wang, Huili; Wang, Yong; Guo, Qiang

    2015-06-05

    Liver receptor homolog-1 (LRH-1) plays an important role in the onset and progression of many cancer types. However, the role of LRH-1 in osteosarcoma has not been well investigated. In this study, the critical role of LRH-1 in osteosarcoma cells was described. Quantitative polymerase chain reaction and Western blot analysis results revealed that LRH-1 was highly overexpressed in osteosarcoma cells. LRH-1 was knocked down by small interfering RNA (siRNA), and this phenomenon significantly inhibited osteosarcoma cell proliferation. Bioinformatics analysis results showed that LRH-1 contained putative binding sites of microRNA-451 (miR-451); this result was further validated through a dual-luciferase activity reporter assay. miR-451 was overexpressed in osteosarcoma cells through transfection of miR-451 mimics; miR-451 overexpression then significantly inhibited LRH-1 expression and cell proliferation. The loss of LRH-1 by siRNA or miR-451 mimics significantly impaired Wnt/β-catenin activity, leading to G0/G1 cell cycle arrest. Results showed that LRH-1 is implicated in osteosarcoma. Therefore, miR-451-induced suppression of LRH-1 can be a novel therapy to treat osteosarcoma. - Highlights: • LRH-1 was highly overexpressed in osteosarcoma cells. • Knockdown of LRH-1 inhibited osteosarcoma cell proliferation. • miR-451 directly targeted and regulated LRH-1 expression. • Overexpression of miR-451 suppressed Wnt activity.

  10. T-ray relevant frequencies for osteosarcoma classification

    NASA Astrophysics Data System (ADS)

    Withayachumnankul, W.; Ferguson, B.; Rainsford, T.; Findlay, D.; Mickan, S. P.; Abbott, D.

    2006-01-01

    We investigate the classification of the T-ray response of normal human bone cells and human osteosarcoma cells, grown in culture. Given the magnitude and phase responses within a reliable spectral range as features for input vectors, a trained support vector machine can correctly classify the two cell types to some extent. Performance of the support vector machine is deteriorated by the curse of dimensionality, resulting from the comparatively large number of features in the input vectors. Feature subset selection methods are used to select only an optimal number of relevant features for inputs. As a result, an improvement in generalization performance is attainable, and the selected frequencies can be used for further describing different mechanisms of the cells, responding to T-rays. We demonstrate a consistent classification accuracy of 89.6%, while the only one fifth of the original features are retained in the data set.

  11. Osteocytes serve as a progenitor cell of osteosarcoma

    PubMed Central

    Sottnik, Joseph L; Campbell, Brittany; Mehra, Rohit; Behbahani-Nejad, Omid; Hall, Christopher L.; Keller, Evan T.

    2016-01-01

    Osteosarcoma (OSA) is the most common primary bone tumor in humans. However, the cell of origin of OSA is not clearly defined although there is evidence that osteoblasts may serve as OSA progenitors. The role of osteocytes, terminally differentiated osteoblasts, as OSA progenitors has yet to be described. Analysis of patient cDNA from publicly available microarray data revealed that patients with OSA have increased expression of dentin matrix phosphoprotein 1 (DMP1), a marker of osteocytes. Analysis of multiple murine, human, and canine OSA cell lines revealed DMP1 expression. To test the tumorigenic potential of osteocytes, MLO-Y4, an SV-40 immortalized murine osteocyte cell line, was injected into subcutaneous and orthotopic (intratibial) sites of mice. Tumor growth occurred in both locations. Orthotopic MLO-Y4 tumors produced mixed osteoblastic/osteolytic radiographic lesions; a hallmark of OSA. Together, these data demonstrate for the first time that osteocytes can serve as OSA progenitors. PMID:24700678

  12. Osteocytes serve as a progenitor cell of osteosarcoma.

    PubMed

    Sottnik, Joseph L; Campbell, Brittany; Mehra, Rohit; Behbahani-Nejad, Omid; Hall, Christopher L; Keller, Evan T

    2014-08-01

    Osteosarcoma (OSA) is the most common primary bone tumor in humans. However, the cell of origin of OSA is not clearly defined although there is evidence that osteoblasts may serve as OSA progenitors. The role of osteocytes, terminally differentiated osteoblasts, as OSA progenitors has yet to be described. Analysis of patient cDNA from publicly available microarray data revealed that patients with OSA have increased expression of dentin matrix phosphoprotein 1 (DMP1), a marker of osteocytes. Analysis of multiple murine, human, and canine OSA cell lines revealed DMP1 expression. To test the tumorigenic potential of osteocytes, MLO-Y4, a SV-40 immortalized murine osteocyte cell line, was injected into subcutaneous and orthotopic (intratibial) sites of mice. Tumor growth occurred in both locations. Orthotopic MLO-Y4 tumors produced mixed osteoblastic/osteolytic radiographic lesions; a hallmark of OSA. Together, these data demonstrate for the first time that osteocytes can serve as OSA progenitors. PMID:24700678

  13. [Osteosarcoma and chondrosarcoma of the pelvis and lower extremities].

    PubMed

    Guder, W K; Hardes, J; Gosheger, G; Nottrott, M; Streitbürger, A

    2015-10-01

    A wide tumor resection is essential in the therapy of primary malignant bone tumors to minimize the risk of local recurrence and ensure long-term survival. While chondrosarcoma is mainly treated surgically, osteosarcoma therapy consists of both chemotherapy and surgical resection of the tumor. While endoprosthetic replacement after hemipelvectomy tends to be associated with high infection rates and has been superseded by hip transposition and composite osteosynthetic replacements, the use of megaendoprosthetic tumor prostheses is the most common reconstruction technique when the extremities are affected. Biological reconstruction or ablative procedures are reserved for special indications. Overall, the reconstruction techniques presented in this article manage to ensure limb salvage in most patients. Functional outcome, however, greatly depends on the tumor size and site as well as postoperative residual soft tissue coverage. PMID:26385887

  14. In vitro osteosarcoma biosensing using THz time domain spectroscopy

    NASA Astrophysics Data System (ADS)

    Ferguson, Bradley S.; Liu, Haibo; Hay, Shelley; Findlay, David; Zhang, Xi-Cheng; Abbott, Derek

    2004-03-01

    Terahertz time domain spectroscopy (THz-TDS) has a wide range of applications from semiconductor diagnostics to biosensing. Recent attention has focused on bio-applications and several groups have noted the ability of THz-TDS to differentiate basal cell carcinoma tissue from healthy dermal tissue ex vivo. The contrast mechanism is unclear but has been attributed to increased interstitial water in cancerous tissue. In this work we investigate the THz response of human osteosarcoma cells and normal human bone cells grown in culture to isolate the cells' responses from other effects. A classification algorithms based on a frequency selection by genetic algorithm is used to attempt to differentiate between the cell types based on the THz spectra. Encouraging preliminary results have been obtained.

  15. Involvement and Clinical Aspects of MicroRNA in Osteosarcoma.

    PubMed

    Ram Kumar, Ram Mohan; Boro, Aleksandar; Fuchs, Bruno

    2016-01-01

    Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents, but its pathogenesis has been difficult to establish because of its well-known heterogeneous nature. OS has been associated with genetic and cytogenetic abnormalities, which include function-impairing mutations in tumor suppressors and the activation of oncogenes. OS tumorigenesis has been linked to alterations of several genes characterized by a high level of genetic instability and recurrent DNA amplifications and deletions. MicroRNAs (miRNAs), 18-25-nucleotide noncoding RNAs, are critical for various biological processes like differentiation, cell growth and cell death. Dysregulation of miRNA expression leads to phenotypic and genotypic changes in cells, which leads to cancer. Studies on miRNAs have initiated a significant effect in both diagnosis and treatment of cancer. This review focuses on the current knowledge of clinical applications of miRNAs for the better diagnosis and management of OS. PMID:27271607

  16. Survivin inhibition via EZN-3042 in canine lymphoma and osteosarcoma.

    PubMed

    Shoeneman, J K; Ehrhart, E J; Charles, J B; Thamm, D H

    2016-06-01

    Canine lymphoma (LSA) and osteosarcoma (OS) have high mortality rates and remain in need of more effective therapeutic approaches. Survivin, an inhibitor of apoptosis (IAP) family member protein that inhibits apoptosis and drives cell proliferation, is commonly elevated in human and canine cancer. Survivin expression is a negative prognostic factor in dogs with LSA and OS, and canine LSA and OS cell lines express high levels of survivin. In this study, we demonstrate that survivin downregulation in canine LSA and OS cells using a clinically applicable locked nucleic acid antisense oligonucleotide (EZN-3042, Enzon Pharmaceuticals, Piscataway Township, NJ, USA) inhibits growth, induces apoptosis and enhances chemosensitivity in vitro, and inhibits survivin transcription and protein production in orthotopic canine OS xenografts. Our findings strongly suggest that survivin-directed therapies might be effective in treatment of canine LSA and OS and support evaluation of EZN-3042 in dogs with cancer. PMID:24923332

  17. Involvement and Clinical Aspects of MicroRNA in Osteosarcoma

    PubMed Central

    Ram Kumar, Ram Mohan; Boro, Aleksandar; Fuchs, Bruno

    2016-01-01

    Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents, but its pathogenesis has been difficult to establish because of its well-known heterogeneous nature. OS has been associated with genetic and cytogenetic abnormalities, which include function-impairing mutations in tumor suppressors and the activation of oncogenes. OS tumorigenesis has been linked to alterations of several genes characterized by a high level of genetic instability and recurrent DNA amplifications and deletions. MicroRNAs (miRNAs), 18–25-nucleotide noncoding RNAs, are critical for various biological processes like differentiation, cell growth and cell death. Dysregulation of miRNA expression leads to phenotypic and genotypic changes in cells, which leads to cancer. Studies on miRNAs have initiated a significant effect in both diagnosis and treatment of cancer. This review focuses on the current knowledge of clinical applications of miRNAs for the better diagnosis and management of OS. PMID:27271607

  18. Primary extraskeletal pleural osteosarcoma: a rare pleural identity

    PubMed Central

    Copeland, Hannah; Makdisi, Peter B.; Duncan, Michael; Wozniak, Thomas C.

    2016-01-01

    A 69-year-old female with a history of a heart transplant 16 years prior, presented with a large left chest mass identified on fluoroscopy in the cardiac catheterization lab. The patient noted a 40 pound weight loss in one year. A chest X-ray (CXR) and chest computed tomography (CT) demonstrated a large complex cystic mass in the left chest. A CT guided aspiration was performed, and the cytology for the cyst fluid was negative for malignancy. The patient continued to have worsening shortness of breath, a repeat chest CT scan and magnetic resonance imaging (MRI) three months later, demonstrated a recurrence of the left pleural mass. Further, work-up was negative for tumor. A left video assisted thoracotomy exploration was performed and left thoracotomy was needed for the mass resection. The final pathology demonstrated a high grade osteosarcoma. The post-operative course was unremarkable. PMID:27386494

  19. Shikonin inhibits invasiveness of osteosarcoma through MMP13 suppression.

    PubMed

    Deng, Biyong; Qiu, Bing

    2015-12-01

    Osteosarcoma (OS) is the most common primary malignant bone tumor, notorious for its metastasis. We have recently shown that shikonin, an effective constituent extracted from Chinese medicinal herb, induces necroptosis in OS cells. Nevertheless, the effects of low-dose shikonin on the invasiveness of OS cells are unknown. Here, we showed that shikonin dose-dependently decreased OS cell invasiveness in both scratch wound healing assay and transwell cell migration assay. Moreover, the direct target of shikonin on cell invasiveness was found to be matrix metalloproteinase (MMP)-13. Further, the inhibitory effects of shikonin on cell invasiveness were completely abolished in MMP13-overexpressing OS cells. Together, these data suggest that shikonin may suppress OS invasiveness through MMP13 suppression. Thus, our data highlight a previous unappreciated role for shikonin in suppressing OS cell metastasis. PMID:26104765

  20. Radionuclide bone scanning of osteosarcoma: falsely extended uptake patterns

    SciTech Connect

    Chew, F.S.; Hudson, T.M.

    1982-07-01

    The pathologic specimens of 18 osteosarcomas of long bones were examined to correlate histologic abnormalities with abnormalities seen on preoperative /sup 99m/Tc pyrophosphate or methylene diphosphonate bone scans. Seven scans accurately represented the extent of the tumor. Eleven scans disclosed increased activity extending beyond the radiographic abnormalities. In eight of these, there was no occult tumor extension and in the other three, the scan activity did not accurately portray the skip metastases that were present. Therefore, these 11 scans demonstrated the falsely extended pattern of uptake beyond the true limits of the tumors. Pathologic slides were available for 10 of the 11 areas of bone that exhibited extended uptake. In two instances, there was no pathologic abnormality. In the other eight cases we found marrow hyperemia, medullary reactive bone, or periosteal new bone. This is the first description of these histologic abnormalities of medullary bone in areas of extended uptake on radionuclide bone scans.

  1. Primary extraskeletal pleural osteosarcoma: a rare pleural identity.

    PubMed

    Copeland, Hannah; Makdisi, Peter B; Duncan, Michael; Wozniak, Thomas C; Makdisi, George

    2016-06-01

    A 69-year-old female with a history of a heart transplant 16 years prior, presented with a large left chest mass identified on fluoroscopy in the cardiac catheterization lab. The patient noted a 40 pound weight loss in one year. A chest X-ray (CXR) and chest computed tomography (CT) demonstrated a large complex cystic mass in the left chest. A CT guided aspiration was performed, and the cytology for the cyst fluid was negative for malignancy. The patient continued to have worsening shortness of breath, a repeat chest CT scan and magnetic resonance imaging (MRI) three months later, demonstrated a recurrence of the left pleural mass. Further, work-up was negative for tumor. A left video assisted thoracotomy exploration was performed and left thoracotomy was needed for the mass resection. The final pathology demonstrated a high grade osteosarcoma. The post-operative course was unremarkable. PMID:27386494

  2. Osteosarcoma: mouse models, cell of origin and cancer stem cell

    PubMed Central

    Guijarro, Maria V.

    2016-01-01

    Osteosarcoma (OS) is the most common non-hematologic primary tumor of bone in children and adults. High-dose cytotoxic chemotherapy and surgical resection have improved prognosis, with long-term survival for non-metastatic disease approaching 70%. However, most OS tumors are high grade and tend to rapidly develop pulmonary metastases. Despite clinical advances, patients with metastatic disease or relapse have a poor prognosis. Here the cell biology of OS is reviewed with a special emphasis on mouse models as well as the roles of the cell of origin and cancer stem cells. A better understanding of the molecular pathogenesis of human OS is essential for the development of improved prognostic and diagnostic markers as well as targeted therapies for both primary and metastatic OS.

  3. Biodegradable bisphosphonate nanoparticles for imaging and therapeutic applications in osteosarcoma

    NASA Astrophysics Data System (ADS)

    Rudnick-Glick, S.; Corem-Salkmon, E.; Grinberg, I.; Gluz, E.; Margel, S.

    2015-08-01

    Osteosarcoma (OS) is amongst the most commonly diagnosed bone tumors occurring in adolescence, young adults and adults over the age of 65. Current treatment is based on a combination of surgery and chemotherapy. Chemotherapy has improved the survival rate, however it is associated with severe side effects due to the use of high dosages, nonspecific uptake and poor bone blood supply. At present bisphosphonates (BP) are widely used in the treatment of bone disorders including OS. We have engineered a unique biodegradable BP nanoparticle that possesses a dual functionality: 1) covalent attachment of a dye (e.g., NIR dye) or drug to the nanoparticles through the primary amine groups on the surface of the nanoparticle; 2) chelation to the bone mineral hydroxyapatite through the BP on the surface of the nanoparticle. Due to a high concentration of PEG in the BP nanoparticles they possess a relatively long plasma half-life time. Therefore, the nanoparticle has potential for use both in diagnosis and therapy of OS. Doxorubicin was conjugated to the free amine on the surface of the BP nanoparticles. In vitro experiments on osteosarcoma cells demonstrated that the doxorubicin-conjugated BP nanoparticles possess a higher efficacy than the free doxorubicin. Further investigation in vivo in a chicken embryo model confirmed that the doxorubicin-conjugated nanoparticle was significantly more effective in inhibiting tumor growth compared to free doxorubicin at a similar concentration. Additionally, we have shown that these BP nanoparticles preferentially target OS tumor tissue, thus increasing anti-cancer drug bioavailability at targeted site.

  4. Preoperative easily misdiagnosed telangiectatic osteosarcoma: clinical–radiologic–pathologic correlations

    PubMed Central

    Gao, Zhen-Hua; Yin, Jun-Qiang; Liu, Da-Wei; Meng, Quan-Fei

    2013-01-01

    Abstract Purpose: To describe the clinical, imaging, and pathologic characteristics and diagnostic methods of telangiectatic osteosarcoma (TOS) for improving the diagnostic level. Materials and methods: The authors retrospectively reviewed patient demographics, serum alkaline phosphatase (AKP) levels, preoperative biopsy pathologic reports, pathologic materials, imaging findings, and treatment outcomes from 26 patients with TOS. Patient images from radiography (26 cases) and magnetic resonance (MR) imaging (22 cases) were evaluated by 3 authors in consensus for intrinsic characteristics. There were 15 male and 11 female patients in the study, with an age of 9–32 years (mean age 15.9 years). Results: Eighteen of 26 patients died of lung metastases within 5 years of follow-up. The distal femur was affected more commonly (14 cases, 53.8%). Regarding serum AKP, normal (8 cases) or mildly elevated (18 cases) levels were found before preoperative chemotherapy. Radiographs showed geographic bone lysis without sclerotic margin (26 cases), cortical destruction (26 cases), periosteal new bone formation (24 cases), soft-tissue mass (23 cases), and matrix mineralization (4 cases). The aggressive radiographic features of TOS simulated the appearance of conventional high-grade intramedullary osteosarcoma, though different from aneurysmal bone cyst. MR images demonstrated multiple big (16 cases) or small (6 cases) cystic spaces, fluid-fluid levels (14 cases), soft-tissue mass (22 cases), and thick peripheral and septal enhancement (22 cases). Nine of 26 cases were misdiagnosed as aneurysmal bone cysts by preoperative core-needle biopsy, owing to the absence of viable high-grade sarcomatous cells in the small tissue samples. Conclusion: The aggressive growth pattern with occasional matrix mineralization, and multiple big or small fluid-filled cavities with thick peripheral, septal, and nodular tissue surrounding the fluid-filled cavities are characteristic imaging features of

  5. Gene expression profiling analysis of osteosarcoma cell lines

    PubMed Central

    SUN, LU; LI, JIE; YAN, BING

    2015-01-01

    Osteosarcoma (OS) is the most common type of primary bone malignancy and has a poor prognosis. To investigate the mechanisms of osteosarcoma, the present analyzed the GSE28424 microarray. GSE28424 was downloaded from the Gene Expression Omnibus, and included a collective of 19 OS cell lines and four normal bone cell lines, which were used as controls. Subsequently, the differentially expressed genes (DEGs) were screened using the Limma package in Bioconductor. Gene Ontology (GO) and pathway enrichment analysis of the DEGs was performed using the Database for Annotation, Visualization and Integrated Discovery, interactions between the proteins encoded by the DEGs were identified using STRING, and the protein-protein interaction (PPI) network was visualized using Cytoscape. In addition, modular analysis of the PPI network was performed using the Clique Percolation Method (CPM) in CFinder. A total of 1,170 DEGs were screened, including 530 upreguated and 640 downregulated genes. The enriched functions included organelle fission, immune response and response to wounding. In addition, RPL8 was observed to be involved with the ribosomal pathway in module A of the PPI network of the DEGs. PLCG1, SYK and PLCG2 were also involved in the B-cell receptor signaling pathway in module B and the Fc-epsilon RI signaling pathway in module C. In addition, AURKA (degree=39), MAD2L1 (degree=38), CDCA8 (degree=38), BUB1 (degree=37) and MELK (degree=37) exhibited higher degrees of connectivity in module F. The results of the present study suggested that the RPL8, PLCG1, PLCG2, SYK, MAD2L1, AURKA, CDCA8, BUB1 and MELK genes may be involved in OS. PMID:26096802

  6. Limited specificity of promoter constructs for gene therapy in osteosarcoma.

    PubMed

    Pollmann, Annika; Kabisch, Hartmut; Block, Andreas; Müller, Jürgen; Hellwinkel, Olaf J C

    2004-10-01

    Osteosarcoma (OS), a malignant bone neoplasia in childhood, has poor prognosis if metastases appear in the lung. A novel therapeutic approach could consist in a gene therapeutic treatment of OS metastases. However, if promiscuous viral vectors are applied for the delivery of potentially toxic transgenes, their misdelivery into normal tissues could cause severe complications. This problem could be circumvented by application of OS-specific promoters for transgene expression control. We analysed the function of promoters described to be tumour-, osteosarcoma- or osteoblast-specific. Expression rates driven by osteoblast- specific fragments from the collagen1A1-promoter, the human Osteocalcin-promoter, the bone-sialoprotein promoter and the beta-catenin promoter depending on vitamin supplementation were analysed in five OS cell lines, in normal lung fibroblasts and in a non-osteoblastic prostate cancer cell line (LNCaP) by dual luciferase assays. In addition, an unspecific but doxycyclin-repressible promoter construct (pAd.3r-luc) was examined. We found that all constructs were active in OS cell lines to varying extents. The complete human Osteocalcin promoter and the bone-sialoprotein promoter were partially induced by vitamin D3 or C respectively while the pAd.3r-luc activity could be shut down by doxycyclin. In contrast, the human Osteocalcin-promoter was not activated by vitamin D3 in LNCaP cells; its action remained relatively low. Interestingly, excepting the beta-catenin promoter, we measured strong activities of all promoters in lung fibroblast cells. Our study demonstrates that promoter activity should be evaluated not only for the target cells of the gene therapeutic approaches, but also for neighbouring normal tissues. Unspecific but repressible promoters could represent an alternative. PMID:15375610

  7. Gene expression profiling analysis of osteosarcoma cell lines.

    PubMed

    Sun, Lu; Li, Jie; Yan, Bing

    2015-09-01

    Osteosarcoma (OS) is the most common type of primary bone malignancy and has a poor prognosis. To investigate the mechanisms of osteosarcoma, the present analyzed the GSE28424 microarray. GSE28424 was downloaded from the Gene Expression Omnibus, and included a collective of 19 OS cell lines and four normal bone cell lines, which were used as controls. Subsequently, the differentially expressed genes (DEGs) were screened using the Limma package in Bioconductor. Gene Ontology (GO) and pathway enrichment analysis of the DEGs was performed using the Database for Annotation, Visualization and Integrated Discovery, interactions between the proteins encoded by the DEGs were identified using STRING, and the protein‑protein interaction (PPI) network was visualized using Cytoscape. In addition, modular analysis of the PPI network was performed using the Clique Percolation Method (CPM) in CFinder. A total of 1,170 DEGs were screened, including 530 upreguated and 640 downregulated genes. The enriched functions included organelle fission, immune response and response to wounding. In addition, RPL8 was observed to be involved with the ribosomal pathway in module A of the PPI network of the DEGs. PLCG1, SYK and PLCG2 were also involved in the B‑cell receptor signaling pathway in module B and the Fc‑epsilon RI signaling pathway in module C. In addition, AURKA (degree=39), MAD2L1 (degree=38), CDCA8 (degree=38), BUB1 (degree=37) and MELK (degree=37) exhibited higher degrees of connectivity in module F. The results of the present study suggested that the RPL8, PLCG1, PLCG2, SYK, MAD2L1, AURKA, CDCA8, BUB1 and MELK genes may be involved in OS. PMID:26096802

  8. mRNA expression profiles of primary high-grade central osteosarcoma are preserved in cell lines and xenografts

    PubMed Central

    2011-01-01

    Background Conventional high-grade osteosarcoma is a primary malignant bone tumor, which is most prevalent in adolescence. Survival rates of osteosarcoma patients have not improved significantly in the last 25 years. Aiming to increase this survival rate, a variety of model systems are used to study osteosarcomagenesis and to test new therapeutic agents. Such model systems are typically generated from an osteosarcoma primary tumor, but undergo many changes due to culturing or interactions with a different host species, which may result in differences in gene expression between primary tumor cells, and tumor cells from the model system. We aimed to investigate whether gene expression profiles of osteosarcoma cell lines and xenografts are still comparable to those of the primary tumor. Methods We performed genome-wide mRNA expression profiling on osteosarcoma biopsies (n = 76), cell lines (n = 13), and xenografts (n = 18). Osteosarcoma can be subdivided into several histological subtypes, of which osteoblastic, chondroblastic, and fibroblastic osteosarcoma are the most frequent ones. Using nearest shrunken centroids classification, we generated an expression signature that can predict the histological subtype of osteosarcoma biopsies. Results The expression signature, which consisted of 24 probes encoding for 22 genes, predicted the histological subtype of osteosarcoma biopsies with a misclassification error of 15%. Histological subtypes of the two osteosarcoma model systems, i.e. osteosarcoma cell lines and xenografts, were predicted with similar misclassification error rates (15% and 11%, respectively). Conclusions Based on the preservation of mRNA expression profiles that are characteristic for the histological subtype we propose that these model systems are representative for the primary tumor from which they are derived. PMID:21933437

  9. Hypoxia promotes drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling

    PubMed Central

    Zhao, Changfu; Zhang, Qiao; Yu, Tao; Sun, Shudong; Wang, Wenjun; Liu, Guangyao

    2016-01-01

    Purpose Drug resistance has been recognized to be a major obstacle to the chemotherapy for osteosarcoma. And the potential importance of hypoxia as a target to reverse drug resistance in osteosarcoma has been indicated, though the mechanism underlining such role is not clarified. The present study aims to investigate the role of hypoxia in the drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling. Experimental design We investigated the promotion of the resistance to doxorubicin of osteosarcoma MG-63 and U2-os cells in vitro, and then determined the role of hypoxia-inducible factor-1 (HIF-1)α and HIF-1β, the activation and regulatory role of AMPK in the osteosarcoma U2-os cells which were treated with doxorubicin under hypoxia. Results It was demonstrated that hypoxia significantly reduced the sensitivity of MG-63 and U2-os cells to doxorubicin, indicating an inhibited viability reduction and a reduced apoptosis promotion. And such reduced sensitivity was not associated with HIF-1α, though it was promoted by hypoxia in U2-os cells. Interestingly, the AMPK signaling was significantly promoted by hypoxia in the doxorubicin-treated U2-os cells, with a marked upregulation of phosphorylated AMPK (Thr 172) and phosphorylated acetyl-CoA carboxylase (ACC) (Ser 79), which were sensitive to the AMPK activator, AICAR and the AMPK inhibitor, Compound C. Moreover, the promoted AMPK activity by AICAR or the downregulated AMPK activity by Compound C significantly reduced or promoted the sensitivity of U2-os cells to doxorubicin. Conclusion The present study confirmed the AMPK signaling activation in the doxorubicin-treated osteosarcoma cells, in response to hypoxia, and the chemical upregulation or downregulation of AMPK signaling reduced or increased the chemo-sensitivity of osteosarcoma U2-os cells in vitro. Our study implies that AMPK inhibition might be a effective strategy to sensitize osteocarcoma cells to chemotherapy. PMID

  10. Regulation of osteosarcoma cell lung metastasis by the c-Fos/AP-1 target FGFR1

    PubMed Central

    Weekes, Daniel; Zandueta, Carolina; Perurena, Naiara; Thomas, David P; Sunters, Andrew; Vuillier, Céline; Bozec, Aline; El-Emir, Ethaar; Miletich, Isabelle; Patiño-Garcia, Ana; Lecanda, Fernando; Grigoriadis, Agamemnon E

    2015-01-01

    Osteosarcoma is the most common primary malignancy of the skeleton and is prevalent in children and adolescents. Survival rates are poor and have remained stagnant due to chemoresistance and the high propensity to form lung metastases. In this study, we used in vivo transgenic models of c-fos oncogene-induced osteosarcoma and chondrosarcoma in addition to c-Fos-inducible systems in vitro to investigate downstream signaling pathways that regulate osteosarcoma growth and metastasis. Fgfr1 was identified as a novel c-Fos/AP-1 regulated gene. Induction of c-Fos in vitro in osteoblasts and chondroblasts caused an increase in Fgfr1 RNA and FGFR1 protein expression levels that resulted in increased and sustained activation of MAPKs, morphological transformation and increased anchorage-independent growth in response to FGF2 ligand treatment. High levels of FGFR1 protein and activated pFRS2α signalling were observed in murine and human osteosarcomas. Pharmacological inhibition of FGFR1 signalling blocked MAPK activation and colony growth of osteosarcoma cells in vitro. Orthotopic injection in vivo of FGFR1 silenced osteosarcoma cells caused a marked 2- to 5-fold decrease in spontaneous lung metastases. Similarly, inhibition of FGFR signalling in vivo with the small molecule inhibitor AZD4547 markedly reduced the number and size of metastatic nodules. Thus, deregulated FGFR signalling plays an important role in osteoblast transformation and osteosarcoma formation and regulates the development of lung metastases. Our findings support the development of anti-FGFR inhibitors as potential antimetastatic therapy. PMID:26387545

  11. Osteosarcoma Microenvironment: Whole-Slide Imaging and Optimized Antigen Detection Overcome Major Limitations in Immunohistochemical Quantification

    PubMed Central

    Kunz, Pierre; Fellenberg, Jörg; Moskovszky, Linda; Sápi, Zoltan; Krenacs, Tibor; Poeschl, Johannes; Lehner, Burkhard; Szendrõi, Miklos; Ewerbeck, Volker; Kinscherf, Ralf; Fritzsching, Benedikt

    2014-01-01

    Background In osteosarcoma survival rates could not be improved over the last 30 years. Novel biomarkers are warranted to allow risk stratification of patients for more individual treatment following initial diagnosis. Although previous studies of the tumor microenvironment have identified promising candidates, novel biomarkers have not been translated into routine histopathology. Substantial difficulties regarding immunohistochemical detection and quantification of antigens in decalcified and heterogeneous osteosarcoma might largely explain this translational short-coming. Furthermore, we hypothesized that conventional hot spot analysis is often not representative for the whole section when applied to heterogeneous tissues like osteosarcoma. We aimed to overcome these difficulties for major biomarkers of the immunovascular microenvironment. Methods Immunohistochemistry was systematically optimized for cell surface (CD31, CD8) and intracellular antigens (FOXP3) including evaluation of 200 different antigen retrieval conditions. Distribution patterns of these antigens were analyzed in formalin-fixed and paraffin-embedded samples from 120 high-grade central osteosarcoma biopsies and computer-assisted whole-slide analysis was compared with conventional quantification methods including hot spot analysis. Results More than 96% of osteosarcoma samples were positive for all antigens after optimization of immunohistochemistry. In contrast, standard immunohistochemistry retrieved false negative results in 35–65% of decalcified osteosarcoma specimens. Standard hot spot analysis was applicable for homogeneous distributed FOXP3+ and CD8+ cells. However, heterogeneous distribution of vascular CD31 did not allow reliable quantification with hot spot analysis in 85% of all samples. Computer-assisted whole-slide analysis of total CD31- immunoreactive area proved as the most appropriate quantification method. Conclusion Standard staining and quantification procedures are not

  12. Regulation of osteosarcoma cell lung metastasis by the c-Fos/AP-1 target FGFR1.

    PubMed

    Weekes, D; Kashima, T G; Zandueta, C; Perurena, N; Thomas, D P; Sunters, A; Vuillier, C; Bozec, A; El-Emir, E; Miletich, I; Patiño-Garcia, A; Lecanda, F; Grigoriadis, A E

    2016-06-01

    Osteosarcoma is the most common primary malignancy of the skeleton and is prevalent in children and adolescents. Survival rates are poor and have remained stagnant owing to chemoresistance and the high propensity to form lung metastases. In this study, we used in vivo transgenic models of c-fos oncogene-induced osteosarcoma and chondrosarcoma in addition to c-Fos-inducible systems in vitro to investigate downstream signalling pathways that regulate osteosarcoma growth and metastasis. Fgfr1 (fibroblast growth factor receptor 1) was identified as a novel c-Fos/activator protein-1(AP-1)-regulated gene. Induction of c-Fos in vitro in osteoblasts and chondroblasts caused an increase in Fgfr1 RNA and FGFR1 protein expression levels that resulted in increased and sustained activation of mitogen-activated protein kinases (MAPKs), morphological transformation and increased anchorage-independent growth in response to FGF2 ligand treatment. High levels of FGFR1 protein and activated pFRS2α signalling were observed in murine and human osteosarcomas. Pharmacological inhibition of FGFR1 signalling blocked MAPK activation and colony growth of osteosarcoma cells in vitro. Orthotopic injection in vivo of FGFR1-silenced osteosarcoma cells caused a marked twofold to fivefold decrease in spontaneous lung metastases. Similarly, inhibition of FGFR signalling in vivo with the small-molecule inhibitor AZD4547 markedly reduced the number and size of metastatic nodules. Thus deregulated FGFR signalling has an important role in osteoblast transformation and osteosarcoma formation and regulates the development of lung metastases. Our findings support the development of anti-FGFR inhibitors as potential antimetastatic therapy. PMID:26387545

  13. Identification of CD20, ECM, and ITGA as Biomarkers for Osteosarcoma by Integrating Transcriptome Analysis

    PubMed Central

    Wang, Da-wei; Yu, Sheng-yuan; Cao, Yang; Yang, Lei; Liu, Wei; Er, Xiao-qiang; Yao, Gui-jun; Bi, Zheng-gang

    2016-01-01

    Background Osteosarcoma is the most frequent primary bone cancer derived from primitive mesenchymal cells. The aim of this study was to explore the molecular mechanism of the development and progression of osteosarcoma. Material/Methods The gene expression profiles of osteosarcoma from 17 specimens (3 normal and 14 osteosarcoma) were downloaded from the GEO database. The differentially expressed genes were identified by use of the Limma package. DAVID and Enrichment Map were used to perform GO and KEGG pathways enrichment analysis and to integrate enrichment results of differentially expressed genes (DEGs). Protein-protein interaction network was constructed and analyzed to screen out the potential regulatory proteins using the STRING online tools. Results A total of 417 DEGs were screened, including 215 up-regulated and 202 down-regulated ones, accounting for 51.56% and 48.4%, respectively. In GO term, a total of 12 up-regulated expression genes were enriched in Cellular Component. The up-regulated DEGs were enriched in 6 KEGG pathways while the down-regulated expression genes were enriched in 2 KEGG pathways. The constructed PPI network was aggregated with 1006 PPI relationships and 238 nodes, accounting for 57.07% of DEGs. We found that CD20, MCM, and CCNB1 (down-regulated) in cell cycle and ECM, ITGA, RTKin (up-regulated) in focal adhesion had important roles in the progression of osteosarcoma. Conclusions The identified DEGs and their enriched pathways provide references for the exploration of the molecular mechanism of the development and progression of osteosarcoma. Moreover, the key genes (CD20, ECM, and ITGA) may be useful in treatment and diagnosis of osteosarcoma. PMID:27314445

  14. Identification of CD20, ECM, and ITGA as Biomarkers for Osteosarcoma by Integrating Transcriptome Analysis.

    PubMed

    Wang, Da-Wei; Yu, Sheng-Yuan; Cao, Yang; Yang, Lei; Liu, Wei; Er, Xiao-Qiang; Yao, Gui-Jun; Bi, Zheng-Gang

    2016-01-01

    BACKGROUND Osteosarcoma is the most frequent primary bone cancer derived from primitive mesenchymal cells. The aim of this study was to explore the molecular mechanism of the development and progression of osteosarcoma. MATERIAL AND METHODS The gene expression profiles of osteosarcoma from 17 specimens (3 normal and 14 osteosarcoma) were downloaded from the GEO database. The differentially expressed genes were identified by use of the Limma package. DAVID and Enrichment Map were used to perform GO and KEGG pathways enrichment analysis and to integrate enrichment results of differentially expressed genes (DEGs). Protein-protein interaction network was constructed and analyzed to screen out the potential regulatory proteins using the STRING online tools. RESULTS A total of 417 DEGs were screened, including 215 up-regulated and 202 down-regulated ones, accounting for 51.56% and 48.4%, respectively. In GO term, a total of 12 up-regulated expression genes were enriched in Cellular Component. The up-regulated DEGs were enriched in 6 KEGG pathways while the down-regulated expression genes were enriched in 2 KEGG pathways. The constructed PPI network was aggregated with 1006 PPI relationships and 238 nodes, accounting for 57.07% of DEGs. We found that CD20, MCM, and CCNB1 (down-regulated) in cell cycle and ECM, ITGA, RTKin (up-regulated) in focal adhesion had important roles in the progression of osteosarcoma. CONCLUSIONS The identified DEGs and their enriched pathways provide references for the exploration of the molecular mechanism of the development and progression of osteosarcoma. Moreover, the key genes (CD20, ECM, and ITGA) may be useful in treatment and diagnosis of osteosarcoma. PMID:27314445

  15. SerpinE2 promotes multiple cell proliferation and drug resistance in osteosarcoma.

    PubMed

    Mao, Minzhi; Wang, Wanchun

    2016-07-01

    SerpinE2 is a member of the Serpins family, which could inhibit serine protease and promote tumor progression, particularly in tumor metastasis. However, at present, its role in the progression of osteosarcoma has not been determined. The present study analyzed the expression profiles of SerpinE2 in cancer tissues, including tissues from osteosarcoma of different stages. Higher expression of SerpinE2 was shown in osteosarcoma tissues, particularly in tissue from patients with metastasis and a tumor-node-metastasis stage II‑III. Following chemotherapy, the SerpinE2 expression levels were shown to be higher than those at diagnosis. Cell proliferation and colony formation were increased after transfection with SerpinE2 over‑expression vector. Additionally, drug resistance to bortezomib and doxorubicin treatment following SerpinE2 transfection was analyzed. MG‑63 and SAOS‑2 cells showed less sensitivity following transfection with SerpinE2. The cell cycle‑related genes, cyclin‑dependent kinase (CDK)4 and cyclin D1 were positively correlated with SerpinE2 expression in patient‑derived tissue and in osteosarcoma cells. Finally, the high expression of SerpinE2 contributes to poor survival rates in patients with osteosarcoma. In conclusion, high expression of SerpinE2 in osteosarcoma stimulates cell proliferation, promotes drug‑resistance, and results in poor survival by regulating CDK4 and cyclin D1. Thus, SerpinE2 could be a potential target for treatment of patients with osteosarcoma. PMID:27221371

  16. Induction of lymphoma and osteosarcoma in mice by single and protracted low alpha doses

    SciTech Connect

    Mueller, W.A.L.; Luz, A.; Murray, A.B.; Linzner, U. )

    1990-09-01

    Internal doses from the short-lived alpha-emitter 22Ra were given to 4-wk-old female mice. One group of about 300 animals received a single injection of 18.5 kBq 22Ra kg-1 body weight, corresponding to a mean skeletal alpha dose of 0.15 Gy. A second group of about 300 animals received the same total amount of 224Ra in the form of 72 fractions of 257 Bq kg-1 each, applied twice weekly during 36 wk. The fractionated group received the same final mean total skeletal dose of 0.15 Gy as the single injected group, but with a mean skeletal dose rate of 1 mGy d-1. A rather high incidence, 13.5% (40/296), of early malignant lymphomas was observed in the fractionated group during and shortly after the injection period, followed by a 7% incidence (21/296) of osteosarcomas during the second half of the animals' lifetime. The group with a single injection did not develop early lymphomas but did develop osteosarcomas later with an incidence of 5.8% (17/295). The occurrence of osteosarcomas was similar up to day 800 in the two experimental groups. Surprisingly, however, after this period no additional case of osteosarcoma was observed in the single-injected group, whereas one-third of all osteosarcomas occurred after day 800 in the protracted group. The additional later occurrence of osteosarcomas occurred after indicates a longer lasting induction effect on osteosarcomas, or a promoting effect in older age, for this kind of treatment.

  17. Overexpression of potassium channel ether à go-go in human osteosarcoma.

    PubMed

    Wu, J; Wu, X; Lian, K; Lin, B; Guo, L; Ding, Z

    2012-01-01

    Human ether à go-go (hEAG) potassium channels are primarily expressed in brain but also frequently overexpressed in solid tumors, which could indicate their potential value for cancer diagnosis and therapy. hEAG1, one member of the hEAG subfamily, has been shown to play a role in neoplastic process. Here we report the expression of hEAG1 in human osteosarcoma detected by a new polyclonal antibody. The full-length hEAG1 cDNA was cloned from human osteosarcoma cell line MG63 by RT-PCR and expressed in Escherichia coli as His tagged protein. The 6His-hEAG1F protein was purified by nickel agarose and used as the antigen to immunize rabbits following standard protocols. The obtained antiserum could detect hEAG1 exogenously expressed in HEK 293 cells. Furthermore, the polyclonal antibody was used to evaluate hEAG1 expression in 42 human osteosarcoma specimens and 19 osteochondromas specimens by immunohistochemistry. hEAG1 was expressed in 71.4% (30/42) osteosarcoma, and 15.8% (3/19) osteochondromas. Moreover, statistical analysis revealed that hEAG1 expression was not dependent on age, sex, site, histology, grade and type in the osteosarcoma specimens. Our data provide evidence that hEAG1 is overexpressed in human osteosarcoma and the hEAG1 polyclonal antibody offers a good tool for further characterization of the oncogenic function of hEAG1 in osteosarcoma. PMID:22248279

  18. 5-Aminolevulinic Acid-Based Sonodynamic Therapy Induces the Apoptosis of Osteosarcoma in Mice

    PubMed Central

    Li, Yongning; Zhou, Qi; Hu, Zheng; Yang, Bin; Li, Qingsong; Wang, Jianhua; Zheng, Jinhua; Cao, Wenwu

    2015-01-01

    Objective Sonodynamic therapy (SDT) is promising for treatment of cancer, but its effect on osteosarcoma is unclear. This study examined the effect of 5-Aminolevulinic Acid (5-ALA)-based SDT on the growth of implanted osteosarcoma and their potential mechanisms in vivo and in vitro. Methods The dose and metabolism of 5-ALA and ultrasound periods were optimized in a mouse model of induced osteosarcoma and in UMR-106 cells. The effects of ALA-SDT on the proliferation and apoptosis of UMR-106 cells and the growth of implanted osteosarcoma were examined. The levels of mitochondrial membrane potential (ΔψM), ROS production, BcL-2, Bax, p53 and caspase 3 expression in UMR-106 cells were determined. Results Treatment with 5-ALA for eight hours was optimal for ALA-SDT in the mouse tumor model and treatment with 2 mM 5-ALA for 6 hours and ultrasound (1.0 MHz 2.0 W/cm2) for 7 min were optimal for UMR-106 cells. SDT, but not 5-ALA, alone inhibited the growth of implanted osteosarcoma in mice (P<0.01) and reduced the viability of UMR-106 cells (p<0.05). ALA-SDT further reduced the tumor volumes and viability of UMR-106 cells (p<0.01 for both). Pre-treatment with 5-ALA significantly enhanced the SDT-mediated apoptosis (p<0.01) and morphological changes. Furthermore, ALA-SDT significantly reduced the levels of ΔψM, but increased levels of ROS in UMR-106 cells (p<0.05 or p<0.01 vs. the Control or the Ultrasound). Moreover, ALA-SDT inhibited the proliferation of osteosarcoma cells and BcL-2 expression, but increased levels of Bax, p53 and caspase 3 expression in the implanted osteosarcoma tissues (p<0.05 or p<0.01 vs. the Control or the Ultrasound). Conclusions The ALA-SDT significantly inhibited osteosarcoma growth in vivo and reduced UMR-106 cell survival by inducing osteosarcoma cell apoptosis through the ROS-related mitochondrial pathway. PMID:26161801

  19. The association of glutathione S-transferase polymorphisms in patients with osteosarcoma: evidence from a meta-analysis.

    PubMed

    Wang, Z; Xu, H; He, M; Wu, H; Zhu, Y; Su, Z

    2015-05-01

    Osteosarcoma is a life-threatening malignancy that often occurs in teenagers. Numerous studies have reported glutathione S-transferase polymorphisms are associated with osteosarcoma, but the results are inconclusive, partially because the sample size in each of published studies is relatively small. Therefore, we performed a meta-analysis of the published studies to estimate the association more accurately. To preciously examine the association between the glutathione S-transferase polymorphisms and osteosarcoma, we undertook a meta-analysis of six case-control studies. The association between the glutathione S-transferase polymorphisms and osteosarcoma risk was assessed by odds ratios together with their 95% confidence intervals using a fixed-effects model or random-effects model. In addition, hazard ratio was used to measure the relationship between glutathione S-transferase polymorphisms and prognosis in patients with osteosarcoma. We found that there was significant association between the polymorphisms in GSTT1 or GSTM3 (AA versus BB) and osteosarcoma risk. In addition, there is no evidence of association on GSTM1, GSTT1, GSTP1 (IIe/IIe versus IIe/Val) or GSTP1 (IIe/IIe versus Val/Val) polymorphisms with prognosis in osteosarcoma. In conclusion, the GSTT1 and GSTM3 polymorphisms might influence osteosarcoma risk. PMID:24689813

  20. Histone demethylase JMJD2B and JMJD2C induce fibroblast growth factor 2: mediated tumorigenesis of osteosarcoma.

    PubMed

    Li, Xiaojiang; Dong, Shanshan

    2015-03-01

    JMJD2B and JMJD2C, histone demethylases, play crucial roles in cancer development and are up-regulated in many cancers. However, the actions of JMJD2B and JMJD2C in osteosarcoma remain unknown. The levels of JMJD2B or JMJD2C were evaluated in osteosarcoma cells and tissues via quantitative real-time PCR and Western Blot. JMJD2B and JMJD2C were up-regulated in osteosarcoma tissues when compared to paired adjacent non-tumor tissues. A higher level of JMJD2B or JMJD2C was related with metastasis of osteosarcoma cells. Fibroblast growth factor 2 (FGF2) is an important factor to maintain immaturity of cells and contributes to osteosarcoma aggressiveness. Elevated levels of FGF2 promoted the proliferation, migration, and invasion of osteosarcoma cell, while FGF2 was up-regulated by JMJD2B or JMJD2C. GST pull-down assay showed that JMJD2B or JMJD2C interacted with FGF2. Thus, JMJD2B and JMJD2C play an important role in the pathology of osteosarcoma via the up-regulation of FGF2. JMJD2B and JMJD2C should be developed potential targets for the therapy of osteosarcoma patients. PMID:25636512

  1. MicroRNA-130a promotes the metastasis and epithelial-mesenchymal transition of osteosarcoma by targeting PTEN.

    PubMed

    Chen, Jiansong; Yan, Dingding; Wu, Weiliang; Zhu, Jian; Ye, Wensong; Shu, Qiang

    2016-06-01

    MicroRNAs, which serve as post-transcriptional modulators of numerous genes, have been found to be important regulators during the pathogenesis of osteosarcoma. This study demonstrates for the first time that microRNA-130a (miR-130a) is significantly upregulated in osteosarcoma, and associated with the metastasis of osteosarcoma. Elevated level of miR-130a was closely correlated with poor clinical features and prognosis of osteosarcoma patients. In vitro assays revealed that miR-130a could potentiate the migration, invasion and the epithelial-mesenchymal transtion (EMT) of osteosarcoma cells. Moreover, phosphatase and tensin homolog (PTEN) was confirmed as not only a direct downstream target but also a functional mediator of miR-130a. MiR-130a exerted promoting effects on metastatic behavior and EMT of osteosarcoma cells through suppressing PTEN expression. Based on these findings, we conclude that miR-130a is a promising prognostic biomarker for osteosarcoma patients, and targeting miR-130a may be a potential treatment option for osteosarcoma patients with metastasis. PMID:27035216

  2. Promotion of tumour proliferation, migration and invasion by miR-92b in targeting RECK in osteosarcoma.

    PubMed

    Zhou, Zhenhua; Wang, Zhiwei; Wei, Haifeng; Wu, Sujia; Wang, Xudong; Xiao, Jianru

    2016-06-01

    MicroRNAs play important roles in the development of cancers. Although miR-92b has been reported to promote the tumorigenesis of some cancers, its role in osteosarcoma remains unknown. In the present study, we focused on the expression, function and mechanisms of miR-92b in osteosarcoma development. The miRNA miR-92b was up-regulated in osteosarcoma cell lines and tissues; miR-92b up-regulation correlated with poor prognosis in osteosarcoma. Overexpression of miR-92b promoted osteosarcoma cell proliferation, migration and invasion, which was abrogated by miR-92b inhibition. Reversion-inducing, cysteine-rich protein with kazal motifs (RECK) was identified as the direct and functional target of miR-92b in osteosarcoma. Importantly, restoring RECK expression abrogated increases in cell growth, motility and invasiveness induced by miR-92b RECK was down-regulated in osteosarcoma tissues, and its expression level negatively correlated with miR-92b Collectively, our results indicate that miR-92b acts as an oncogenic miRNA and may be a therapeutic target in osteosarcoma. PMID:26993249

  3. Genetic and molecular characterization of the human osteosarcoma 3AB-OS cancer stem cell line: a possible model for studying osteosarcoma origin and stemness.

    PubMed

    Di Fiore, Riccardo; Fanale, Daniele; Drago-Ferrante, Rosa; Chiaradonna, Ferdinando; Giuliano, Michela; De Blasio, Anna; Amodeo, Valeria; Corsini, Lidia R; Bazan, Viviana; Tesoriere, Giovanni; Vento, Renza; Russo, Antonio

    2013-06-01

    Finding new treatments targeting cancer stem cells (CSCs) within a tumor seems to be critical to halt cancer and improve patient survival. Osteosarcoma is an aggressive tumor affecting adolescents, for which there is no second-line chemotherapy. Uncovering new molecular mechanisms underlying the development of osteosarcoma and origin of CSCs is crucial to identify new possible therapeutic strategies. Here, we aimed to characterize genetically and molecularly the human osteosarcoma 3AB-OS CSC line, previously selected from MG63 cells and which proved to have both in vitro and in vivo features of CSCs. Classic cytogenetic studies demonstrated that 3AB-OS cells have hypertriploid karyotype with 71-82 chromosomes. By comparing 3AB-OS CSCs to the parental cells, array CGH, Affymetrix microarray, and TaqMan® Human MicroRNA array analyses identified 49 copy number variations (CNV), 3,512 dysregulated genes and 189 differentially expressed miRNAs. Some of the chromosomal abnormalities and mRNA/miRNA expression profiles appeared to be congruent with those reported in human osteosarcomas. Bioinformatic analyses selected 196 genes and 46 anticorrelated miRNAs involved in carcinogenesis and stemness. For the first time, a predictive network is also described for two miRNA family (let-7/98 and miR-29a,b,c) and their anticorrelated mRNAs (MSTN, CCND2, Lin28B, MEST, HMGA2, and GHR), which may represent new biomarkers for osteosarcoma and may pave the way for the identification of new potential therapeutic targets. PMID:23129384

  4. Selecting key genes associated with osteosarcoma based on a differential expression network.

    PubMed

    Wang, Y B; Jia, N; Xu, C M; Zhao, L; Zhao, Y; Wang, X; Jia, T H

    2015-01-01

    Despite recent advances in osteosarcoma diagnosis and therapy, much remains unclear about the molecular mechanisms involved in the disorder, and the discovery of novel drug-targeted genes is essential. We explored the potential molecular mechanisms and target genes involved in the development and progression of osteosarcoma. First, we identified the differentially expressed genes in osteosarcoma patients and matching normal controls. We then constructed a differential expression network based on differential and non-differential interactions. Pathway-enrichment analysis was performed based on the nodes contained in the main differential expression network. Centrality analysis was used to select hub genes that may play vital roles in the progression of human osteosarcoma. Our research revealed a total of 176 differentially expressed genes including 82 upregulated and 94 downregulated genes. A differential expression network was constructed that included 992 gene pairs (1043 nodes). Pathway-enrichment analysis indicated that the nodes in the differential expression network were mainly enriched in several pathways such as those involved in cancer, cell cycle, ubiquitin-mediated proteolysis, DNA replication, ribosomes, T-cell receptor signaling, spliceosomes, neurotrophin signaling, oxidative phosphorylation, and tight junctions. Six hub genes (APP, UBC, CAND1, RPA, YWHAG, and NEDD8) were discovered; of these, two genes (UBC and RPA) were also found to be disease genes. Our study predicted that UBC and RPA had potential as target genes for the diagnosis and treatment of osteosarcoma. PMID:26782416

  5. Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

    SciTech Connect

    Nishida, Yoshihiro . E-mail: ynishida@med.nagoya-u.ac.jp; Knudson, Warren; Knudson, Cheryl B.; Ishiguro, Naoki

    2005-07-01

    Osteosarcoma is a common malignant bone tumor associated with childhood and adolescence. The results of numerous studies have suggested that hyaluronan plays an important role in regulating the aggressive behavior of various types of cancer cells. However, no studies have addressed hyaluronan with respect to osteosarcomas. In this investigation, the mRNA expression copy number of three mammalian hyaluronan synthases (HAS) was determined using competitive RT-PCR in the osteoblastic osteosarcoma cell line, MG-63. MG-63 are highly malignant osteosarcoma cells with an abundant hyaluronan-rich matrix. The results demonstrated that HAS-2 is the predominant HAS in MG-63. Accumulation of intracellular hyaluronan increased in association with the proliferative phase of these cells. The selective inhibition of HAS-2 mRNA in MG-63 cells by antisense phosphorothioate oligonucleotides resulted in reduced hyaluronan accumulation by these cells. As expected, the reduction in hyaluronan disrupted the assembly of cell-associated matrices. However, of most interest, coincident with the reduction in hyaluronan, there was a substantial decrease in cell proliferation, a decrease in cell motility and a decrease in cell invasiveness. These data suggest that hyaluronan synthesized by HAS-2 in MG-63 plays a crucial role in osteosarcoma cell proliferation, motility, and invasion.

  6. Establishment and characterization of a new highly metastatic human osteosarcoma cell line derived from Saos2

    PubMed Central

    Du, Lin; Fan, Qiming; Tu, Bing; Yan, Wei; Tang, Tingting

    2014-01-01

    Osteosarcoma is the most common primary malignancy of bone in adolescents and young adults. There is a shortage of tumorigenic and highly metastatic human osteosarcoma cell lines that can be used for metastasis study. Here we establish and characterize a highly metastatic human osteosarcoma cell line that is derived from Saos2 cell line based on bioluminescence. The occasional pulmonary metastatic cells developed from Saos2 were isolated, harvested, characterized and named Saos2-l. The parental Saos2 and Saos2-l cells were further characterized both in vitro and in vivo. Results showed that Saos2-l cells demonstrated increased cell adhesion, migration and invasion compared to the parental Saos2 cells. Conversely, Saos2-l cells grew at a slightly slower rate than that of the parental cells. When injected into nude mice, Saos2-l cells had a greater increase in developing pulmonary metastases compared to the parental Saos2 cells. Further transcriptional profiling analysis revealed that some gene expression were up-regulated or down-regulated in the highly metastatic Saos2-l cells, indicating possible influencing factors of metastasis. Thus, we have established and characterized a highly metastatic human osteosarcoma cell line that should serve as a valuable tool for future investigations on the pathogenesis, metastasis and potential treatments of human osteosarcoma. PMID:25031706

  7. Knockdown of TRAF4 expression suppresses osteosarcoma cell growth in vitro and in vivo.

    PubMed

    Yao, Weitao; Wang, Xin; Cai, Qiqing; Gao, Songtao; Wang, Jiaqiang; Zhang, Peng

    2014-12-01

    Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is an adapter molecule that is overexpressed in certain cancers. TRAF4 is overexpressed in osteosarcoma tissues and osteosarcoma cells. Using the technique of RNA interference, the expression of TRAF4 in the human osteosarcoma Saos-2 cell line was shown to be downregulated. The proliferation, cell cycle arrest and apoptosis ability of Saos‑2 cells were examined, as was tumor development in a xenograft mouse model. The results showed that the TRAF4 knockdown exerts inhibitory effects on the proliferation ability of Saos-2 cells and tumor development in a xenograft mouse model. Simultaneously, it was found that TRAF4 knockdown led to cell cycle arrest in the G1 phase and promoted Saos-2 cell apoptosis. Following TNF-α treatment, the expression of nuclear factor κB was significantly reduced in the TRAF4‑small interfering RNA group. These results indicate that TRAF4 regulated osteosarcoma cell growth in vitro and in vivo, and offers a candidate molecular target for osteosarcoma prevention and therapy. PMID:25270078

  8. p53 mediated apoptosis in osteosarcoma MG-63 cells by inhibition of FANCD2 gene expression

    PubMed Central

    Xia, Peng; Sun, Yifu; Zheng, Changjun; Hou, Tingting; Kang, Mingyang; Yang, Xiaoyu

    2015-01-01

    Purpose: The aim of this study was to investigate the association between osteosarcoma (OS) and Fanconi anemia (FA) related pathways and the molecular mechanisms. Methods: siRNA for Fanconi anemia complementation group D2 (FANCD2) was constructed and transfected into the osteosarcoma cell line MG-63 cells. Expression of TP53INP1, p53, p21, caspase-9, and caspase-3 mRNA in MG-63 cells were examined by real-time fluorescence quantitative PCR, and the protein levels were also determined by western blot. Results: After silence of the FANCD2 gene in MG-63 cells, cell proliferation was inhibited, cell cycle was arrested and cell apoptosis was induced. The apoptosis was mediated by the p53 signaling pathway. After FANCD2 expression was inhibited, TP53INP1 gene expression was up-regulated, phosphorylation of p53 was promoted and the p21 protein was activated, leading to cell cycle arrested in G1, finally resulted in caspase-dependent cell apoptosis. Conclusions: Inhibition of FANCD2 gene expression can induce apoptosis of osteosarcoma cells, which indicated that FANCD2 played an important role in the development of osteosarcoma and it might be a potential target for treatment of osteosarcoma. PMID:26379910

  9. Stereotactic Body Radiotherapy for Metastatic and Recurrent Ewing Sarcoma and Osteosarcoma

    PubMed Central

    Brown, Lindsay C.; Lester, Rachael A.; Grams, Michael P.; Haddock, Michael G.; Olivier, Kenneth R.; Arndt, Carola A. S.; Rose, Peter S.; Laack, Nadia N.

    2014-01-01

    Background. Radiotherapy has been utilized for metastatic and recurrent osteosarcoma and Ewing sarcoma (ES), in order to provide palliation and possibly prolong overall or progression-free survival. Stereotactic body radiotherapy (SBRT) is convenient for patients and offers the possibility of increased efficacy. We report our early institutional experience using SBRT for recurrent and metastatic osteosarcoma and Ewing sarcoma. Methods. We reviewed all cases of osteosarcoma or ES treated with SBRT between 2008 and 2012. Results. We identified 14 patients with a total of 27 lesions from osteosarcoma (n = 19) or ES (n = 8). The median total curative/definitive SBRT dose delivered was 40 Gy in 5 fractions (range, 30–60 Gy in 3–10 fractions). The median total palliative SBRT dose delivered was 40 Gy in 5 fractions (range, 16–50 Gy in 1–10 fractions). Two grade 2 and 1 grade 3 late toxicities occurred, consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy. Toxicity was seen in the settings of concurrent chemotherapy and reirradiation. Conclusions. This descriptive report suggests that SBRT may be a feasible local treatment option for patients with osteosarcoma and ES. However, significant toxicity can result, and thus systematic study is warranted to clarify efficacy and characterize long-term toxicity. PMID:25548538

  10. Low-grade central osteosarcoma of distal femur, resembling fibrous dysplasia

    PubMed Central

    Vasiliadis, Haris S; Arnaoutoglou, Christina; Plakoutsis, Sotiris; Doukas, Michalis; Batistatou, Anna; Xenakis, Theodoros A

    2013-01-01

    We report a case of a 32 year-old male, admitted for a lytic lesion of the distal femur. One month after the first X-ray, clinical and imaging deterioration was evident. Open biopsy revealed fibrous dysplasia. Three months later, the lytic lesion had spread to the whole distal third of the femur reaching the articular cartilage. The malignant clinical and imaging features necessitated excision of the lesion and reconstruction with a custom-made total knee arthroplasty. Intra-operatively, no obvious soft tissue infiltration was evident. Nevertheless, an excision of the distal 15.5 cm of the femur including 3.0 cm of the surrounding muscles was finally performed. The histological examination of the excised specimen revealed central low-grade osteosarcoma. Based on the morphological features of the excised tumor, allied to the clinical findings, the diagnosis of low-grade central osteosarcoma was finally made although characters of a fibrous dysplasia were apparent. Central low-grade osteosarcoma is a rare, well-differentiated sub-type of osteosarcoma, with clinical, imaging, and histological features similar to benign tumours. Thus, initial misdiagnosis is usual with the condition commonly mistaken for fibrous dysplasia. Central low-grade osteosarcoma is usually treated with surgery alone, with rare cases of distal metastases. However, regional recurrence is quite frequent after close margin excision. PMID:24147271