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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. 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

  4. 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

  5. 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

  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. 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

  10. 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

  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. 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

  13. 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

  14. 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

  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 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

  17. 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

  18. 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

  19. 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

  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. 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

  6. 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

  7. 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.

  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. 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 ...

  12. 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

  13. 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

  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. 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.

  1. 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

  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. 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

  5. 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

  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. 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

  8. 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

  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. 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

  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. 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

  17. 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

  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. 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

  10. 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

  11. 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

  12. 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

  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. 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

  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. 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

  17. 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

  18. 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

  19. 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

  20. 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

  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. 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

  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. 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

  5. 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

  6. 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

  7. 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

  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 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

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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

  17. 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

  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. 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

  3. 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

  4. 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

  5. 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

  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. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  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. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  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. 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

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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

  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 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

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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

  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. 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

  6. 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

  7. 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

  8. 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

  9. 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

  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 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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

  10. [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

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  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. 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

  10. 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

  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. 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.

  13. 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

  14. 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

  15. 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

  16. 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

  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. 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

  20. 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

  1. 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

  2. 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

  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. 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

  5. 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

  6. 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

  7. KLF8 knockdown suppresses proliferation and invasion in human osteosarcoma cells

    PubMed Central

    LIN, FENG; SHEN, ZAN; TANG, LI-NA; ZHENG, SHUI-ER; SUN, YUAN-JUE; MIN, DA-LIU; YAO, YANG

    2014-01-01

    Krüppel-like factor 8 (KLF8) is a transcription factor that is important in the regulation of the cell cycle and has a critical role in oncogenic transformation and epithelial to mesenchymal transition (EMT). EMT is a key process in tumor metastasis. Although overexpression of KLF8 has been observed in a variety of human tumor types, the role of KLF8 in human osteosarcoma is yet to be elucidated. The present study aimed to investigate the biological impact of KLF8 on Saos-2 osteosarcoma cells. KLF8 gene expression was knocked down in vitro using a lentivirus-mediated small interfering (si)RNA method. Cell proliferation and cell cycle distribution were evaluated using 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide and colony formation assays, and flow cytometry, respectively. Cell invasion was analyzed using a Transwell® invasion assay. Knockdown of KLF8 was found to significantly inhibit proliferation and invasion in osteosarcoma cells. These data suggest that KLF8 may exhibit an important role in osteosarcoma tumorigenesis and that KLF8 may be a potential therapeutic target for the treatment of osteosarcoma. PMID:24604387

  8. mTORC1 Maintains the Tumorigenicity of SSEA-4+ High-Grade Osteosarcoma

    PubMed Central

    Zhang, Wu; Ding, Meng-Lei; Zhang, Jia-Nian; Qiu, Jian-Ru; Shen, Yu-Hui; Ding, Xiao-Yi; Deng, Lian-Fu; Zhang, Wei-Bin; Zhu, Jiang

    2015-01-01

    Inactivation of p53 and/or Rb pathways restrains osteoblasts from cell-cycle exit and terminal differentiation, which underpins osteosarcoma formation coupled with dedifferentiation. Recently, the level of p-S6K was shown to independently predict the prognosis for osteosarcomas, while the reason behind this is not understood. Here we show that in certain high-grade osteosarcomas, immature SSEA-4+ tumor cells represent a subset of tumor-initiating cells (TICs) whose pool size is maintained by mTORC1 activity. mTORC1 supports not only SSEA-4+ cell self-renewal through S6K but also the regeneration of SSEA-4+ TICs by SSEA-4− osteosarcoma cell dedifferentiation. Mechanistically, active mTORC1 is required to prevent a likely upregulation of the cell-cycle inhibitor p27 independently of p53 or Rb activation, which otherwise effectively drives the terminal differentiation of SSEA-4− osteosarcoma cells at the expense of dedifferentiation. Thus, mTORC1 is shown to critically regulate the retention of tumorigenicity versus differentiation in discrete differentiation phases in SSEA-4+ TICs and their progeny. PMID:25853231

  9. 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

  10. 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.

  11. 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

  12. 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

  13. AgeStandardized Incidence Rates and Survival of Osteosarcoma in Northern Thailand.

    PubMed

    Pruksakorn, Dumnoensun; Phanphaisarn, Areerak; Pongnikorn, Donsuk; Daoprasert, Karnchana; Teeyakasem, Pimpisa; Chaiyawat, Parunya; Katruang, Narisara; Settakorn, Jongkolnee

    2016-01-01

    Osteosarcoma is a common primary malignant bone tumor in children and adolescents. Recent worldwide average incidences of osteosarcoma in people aged 0 to 24 years were 4.3 and 3.4 per million, respectively, with a ratio of 1.4:1. However, data on the incidence of osteosarcoma in Thailand are limited. This study analyzed the incidence of osteosarcoma in the upper northern region of Thailand, with a population of 5.85 million people (8.9% of the total Thai population), using data for the years 1998 to 2012, obtained from the Chiang Mai Cancer Registry (CMCR) at Chiang Mai University Hospital and the Lampang Cancer Registry (LCR) at the Lampang Cancer Hospital, a total of 144 cases. The overall annual incidence of osteosarcoma was 1.67 per million with a male:female ratio of 1.36:1. Incidences by age group (male and female) at 0 to 24, 25 to 59 and over 60 years were 3.5 (3.9 and 3.0), 0.8 (0.9 and 0.6), and 0.7 (0.8 and 0.5), respectively. The peak incidence occurred at 15 to 19 years for males and at 10 to 14 years for females. The median survival time was 18 months with a 5year survival rate of 43%. Neither the age group nor the 5year interval period of treatment was significantly correlated with survival during the 15year period studied. PMID:27509991

  14. Triptolide induces the cell apoptosis of osteosarcoma cells through the TRAIL pathway.

    PubMed

    Zhao, Xingwei; Zhang, Qiang; Chen, Liang

    2016-09-01

    Research on triptolide, a diterpenoid epoxide found in the Thunder God Vine Tripterygium wilfordii, has increased our knowledge of the pharmacology, pharmacokinetics, toxicology and clinical application of this agent. In the present study, we aimed to identify the effects of triptolide on the apoptosis of osteosarcoma cells and to evaluate the anti-proliferative action of this agent. MG-63 cells were treated either with various doses of triptolide (50, 100 or 200 nM) or DMSO for 6, 12 and 24 h. Treatment with triptolide effectively suppressed the cell viability and induced the apoptosis of osteosarcoma MG-63 cells as detected by MTT assay and flow cytometry, respectively. In addition, by using caspase-3, caspase-8 and caspase-9 activity assays and western blot analysis, the anticancer effects of triptolide against osteosarcoma growth were found to involve activation of the DR-5/p53/Bax/caspase-9/ caspase-3 signaling pathway and the DR-5/FADD/caspase-8/lysosomal/cathepsin B/caspase-3 signaling pathway in the MG-63 cells. An important factor in the anticancer effects of triptolide against osteosarcoma was TRAIL-DR-5. The data suggest that triptolide may be a potential novel chemotherapeutic agent for osteosarcoma and acts through the TRAIL-DR-5 signaling pathway. PMID:27461934

  15. Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs.

    PubMed

    Pradelli, Emmanuelle; Karimdjee-Soilihi, Babou; Michiels, Jean-François; Ricci, Jean-Ehrland; Millet, Marie-Ange; Vandenbos, Fanny; Sullivan, Timothy J; Collins, Tassie L; Johnson, Michael G; Medina, Julio C; Kleinerman, Eugenie S; Schmid-Alliana, Annie; Schmid-Antomarchi, Heidy

    2009-12-01

    Metastasis continues to be the leading cause of mortality for patients with cancer. Several years ago, it became clear that chemokines and their receptors could control the tumor progress. CXCR3 has now been identified in many cancers including osteosarcoma and CXCR3 ligands were expressed by lungs that are the primary sites to which this tumor metastasize. This study tested the hypothesis that disruption of the CXCR3/CXCR3 ligands complexes could lead to a decrease in lungs metastasis. The experimental design involved the use of the CXCR3 antagonist, AMG487 and 2 murine models of osteosarcoma lung metastases. After tail vein injection of osteosarcoma cells, mice that were systematically treated with AMG487 according to preventive or curative protocols had a significant reduction in metastatic disease. Treatment of osteosarcoma cells in vitro with AMG487 led to decreased migration, decreased matrix metalloproteinase activity, decreased proliferation/survival and increased caspase-independent death. Taken together, our results support the hypothesis that CXCR3 and their ligands intervene in the initial dissemination of the osteosarcoma cells to the lungs and stimulate the growth and expansion of the metastatic foci in later stages. Moreover, these studies indicate that targeting CXCR3 may specifically inhibit tumor metastasis without adversely affecting antitumoral host response. PMID:19544560

  16. Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs

    PubMed Central

    Pradelli, Emmanuelle; Karimdjee-Soilihi, Babou; Michiels, Jean-François; Ricci, Jean-Ehrland; Millet, Marie-Ange; Vandenbos, Fanny; Sullivan, Timothy J.; Collins, Tassie L.; Johnson, Michael G.; Medina, Julio C.; Kleinerman, Eugenie S.; Schmid-Alliana, Annie; Schmid-Antomarchi, Heidy

    2009-01-01

    Metastasis continues to be the leading cause of mortality for patients with cancer. Several years ago, it became clear that chemokines and their receptors could control the tumor progress. CXCR3 has now been identified in many cancers including osteosarcoma and CXCR3 ligands were expressed by lungs that are the primary sites to which this tumor metastasize. This study tested the hypothesis that disruption of the CXCR3/CXCR3 ligands complexes could lead to a decrease in lungs metastasis. The experimental design involved the use of the CXCR3 antagonist, AMG487 and 2 murine models of osteosarcoma lung metastases. After tail vein injection of osteosarcoma cells, mice that were systematically treated with AMG487 according to preventive or curative protocols had a significant reduction in metastatic disease. Treatment of osteosarcoma cells in vitro with AMG487 led to decreased migration, decreased matrix metalloproteinase activity, decreased proliferation/survival and increased caspase-independent death. Taken together, our results support the hypothesis that CXCR3 and their ligands intervene in the initial dissemination of the osteosarcoma cells to the lungs and stimulate the growth and expansion of the metastatic foci in later stages. Moreover, these studies indicate that targeting CXCR3 may specifically inhibit tumor metastasis without adversely affecting antitumoral host response. PMID:19544560

  17. Liposomal nanoparticles as a drug delivery vehicle against osteosarcoma

    NASA Astrophysics Data System (ADS)

    Dhule, Santosh Subhashrao

    The delivery of curcumin, a broad-spectrum anticancer drug, has been explored in the form of liposomal nanoparticles to treat osteosarcoma (OS). Curcumin is water insoluble and an effective delivery route is through encapsulation in cyclodextrins followed by a second encapsulation in liposomes. Liposomal curcumin's potential was evaluated against cancer models of mesenchymal (OS) and epithelial origin (breast cancer). The resulting 2-Hydroxypropyl-gamma-cyclodextrin/curcumin - liposome complex shows promising anticancer potential both in vitro and in vivo against KHOS OS cell line and MCF-7 breast cancer cell line. An interesting aspect is that liposomal curcumin initiates the caspase cascade that leads to apoptotic cell death in vitro in comparison with DMSO-curcumin induced autophagic cell death. In addition, the efficiency of the liposomal curcumin formulation was confirmed in vivo using a xenograft OS model. Curcumin-loaded gamma-cyclodextrin liposomes indicate significant potential as delivery vehicles for the treatment of cancers of different tissue origin. The second part of this study examines the anti-tumor potential of curcumin and C6 ceramide (C6) against osteosarcoma cell lines when both are encapsulated in the bilayer of liposomal nanoparticles. Curcumin in combination with C6 showed 1.5 times enhanced cytotoxic effect in the case of MG-63 and KHOS OS cell lines, in comparison with systems with curcumin alone. Interestingly, C6-curcumin liposomes were found to be less toxic on untransformed human cells in comparison to OS cell lines. In addition, cell cycle assays on a KHOS cell line after treatment revealed that curcumin only liposomes induced G 2/M arrest by upregulation of cyclin B1, while C6 only liposomes induced G1 arrest by downregulation of cyclin D1. C6-curcumin liposomes induced G2/M arrest and showed a combined effect in the expression levels of cyclin D1 and cyclin B1. Using pegylated liposomes to increase the plasma half-life and tagging

  18. Osteosarcoma After Hematopoietic Stem Cell Transplantation in Children and Adolescents: Case Report and Review of the Literature.

    PubMed

    Kebudi, Rejin; Ozger, Harzem; Kızılocak, Hande; Bay, Sema Buyukkapu; Bilgiç, Bilge

    2016-09-01

    Osteosarcoma as a secondary malignancy after hematopoietic stem cell transplantation (HSCT) is very rare. We present a case and review of 18 other cases reported to date. Our patient underwent HSCT for myelodysplastic syndrome at the age of 4 years. She developed osteosarcoma 13 years later. She underwent surgery after three courses of neoadjuvant chemotherapy followed by chemotherapy and mifamurtide. She has no evidence of disease 28 months after termination of chemotherapy. In 18 other cases of secondary osteosarcoma in the literature, 15 had received total body irradiation, eight had received alkylating agents, and six had received etoposide. The median interval from HSCT to the onset of osteosarcoma was 6.5 years (range 2.5-15.3), which confirms that children undergoing HSCT should be followed up for many years. In conclusion, osteosarcoma must be included in the differential diagnosis among solid tumors that may develop following HSCT. PMID:27187839

  19. Down-regulation of microRNA152 is associated with the diagnosis and prognosis of patients with osteosarcoma

    PubMed Central

    Wang, Nai-Guo; Wang, Da-Chuan; Tan, Bing-Yi; Wang, Feng; Yuan, Ze-Nong

    2015-01-01

    Potential values of microRNA152 (miR-152) as a serum diagnostic and prognostic biomarker have not been determined in human osteosarcoma. By detecting the expression of miR-152 among 80 osteosarcoma patients, 20 periostitis patients and 20 healthy individuals using qRT-PCR, we aimed to explore the clinical significance of miR-152 in osteosarcoma patients. The expression of miR-152 was significantly decreased in patients with osteosarcoma compared to patients with periostitis (P<0.01) and healthy controls (P<0.01). The relationship between clinicopathologic characteristics and miR-152 was analyzed by chi-square test. The outcome indicated that miR-152 might be linked with the development of osteosarcoma. Moreover, the receiver operating characteristic (ROC) curve was performed to estimate the diagnostic value of miR-152. The result demonstrated that miR-152 might be a promising diagnostic marker of osteosarcoma with an AUC of 0.956, combing with 92.5% specificity and 96.2% sensitivity. The relationship between miR-152 and overall survival of osteosarcoma patients was analyzed by Kaplan-Meier curve and log rank test. As a result, the survival time of patients with low miR-152 expression was significantly shorter than those with high miR-152 expression (P<0.001). Then Cox regression analysis was used to estimate the prognostic value of miR-152 in osteosarcoma. The outcomes showed that low miR-152 expression (P=0.004) might be a potential independent prognostic marker for osteosarcoma patients. These findings suggested that down-regulation of miR-152 could be considered as a predictor for diagnosis and prognosis of osteosarcoma patients. PMID:26464682

  20. Down-regulation of microRNA152 is associated with the diagnosis and prognosis of patients with osteosarcoma.

    PubMed

    Wang, Nai-Guo; Wang, Da-Chuan; Tan, Bing-Yi; Wang, Feng; Yuan, Ze-Nong

    2015-01-01

    Potential values of microRNA152 (miR-152) as a serum diagnostic and prognostic biomarker have not been determined in human osteosarcoma. By detecting the expression of miR-152 among 80 osteosarcoma patients, 20 periostitis patients and 20 healthy individuals using qRT-PCR, we aimed to explore the clinical significance of miR-152 in osteosarcoma patients. The expression of miR-152 was significantly decreased in patients with osteosarcoma compared to patients with periostitis (P<0.01) and healthy controls (P<0.01). The relationship between clinicopathologic characteristics and miR-152 was analyzed by chi-square test. The outcome indicated that miR-152 might be linked with the development of osteosarcoma. Moreover, the receiver operating characteristic (ROC) curve was performed to estimate the diagnostic value of miR-152. The result demonstrated that miR-152 might be a promising diagnostic marker of osteosarcoma with an AUC of 0.956, combing with 92.5% specificity and 96.2% sensitivity. The relationship between miR-152 and overall survival of osteosarcoma patients was analyzed by Kaplan-Meier curve and log rank test. As a result, the survival time of patients with low miR-152 expression was significantly shorter than those with high miR-152 expression (P<0.001). Then Cox regression analysis was used to estimate the prognostic value of miR-152 in osteosarcoma. The outcomes showed that low miR-152 expression (P=0.004) might be a potential independent prognostic marker for osteosarcoma patients. These findings suggested that down-regulation of miR-152 could be considered as a predictor for diagnosis and prognosis of osteosarcoma patients. PMID:26464682

  1. MiR-29b suppresses the proliferation and migration of osteosarcoma cells by targeting CDK6.

    PubMed

    Zhu, Kegan; Liu, Lei; Zhang, Junliang; Wang, Yanbo; Liang, Hongwei; Fan, Gentao; Jiang, Zhenhuan; Zhang, Chen-Yu; Chen, Xi; Zhou, Guangxin

    2016-06-01

    Osteosarcoma is the most common primary sarcoma of bone, and it is a leading cause of cancer death among adolescents and young adults. However, the molecular mechanism underlying osteosarcoma carcinogenesis remains poorly understood. Recently, cyclin-dependent kinase 6 (CDK6) was identified as an important oncogene. We found that CDK6 protein level, rather than CDK6 mRNA level, is much higher in osteosarcoma tissues than in normal adjacent tissues, which indicates a post-transcriptional mechanism involved in CDK6 regulation in osteosarcoma. MiRNAs are small non-coding RNAs that repress gene expression at the post-transcriptional level and have widely been shown to play important roles in many human cancers. In this study, we investigated the role of miR-29b as a novel regulator of CDK6 using bioinformatics methods. We demonstrated that CDK6 can be downregulated by miR-29b via binding to the 3'-UTR region in osteosarcoma cells. Furthermore, we identified an inverse correlation between miR-29b and CDK6 protein levels in osteosarcoma tissues. Finally, we examined the function of miR-29b-driven repression of CDK6 expression in osteosarcoma cells. The results revealed that miR-29b acts as a tumor suppressor of osteosarcoma by targeting CDK6 in the proliferation and migration processes. Taken together, our results highlight an important role for miR-29b in the regulation of CDK6 in osteosarcoma and may open new avenues for future osteosarcoma therapies. PMID:27230400

  2. Spontaneous extraskeletal osteosarcoma with various histological growth patterns in the abdominal wall of an ICR mouse

    PubMed Central

    Ito, Tsuyoshi; Katoh, Yoshitaka; Shimada, Yuko; Ohnuma-Koyama, Aya; Takahashi, Naofumi; Kuwahara, Maki; Harada, Takanori

    2015-01-01

    Extraskeletal osteosarcoma is extremely rare in mice. This case report demonstrates a spontaneous murine extraskeletal osteosarcoma that exhibited various histological growth patterns in an ICR mouse. At necropsy, the tumor mass was located in the abdominal wall and was 45 × 30 × 25 mm in size. Histopathologically, the tumor showed the following four growth patterns: a solid pattern of polygonal cells embedded in an osteoid eosinophilic matrix with calcification, an irregular sheet pattern of short spindle cells accompanying some eosinophilic multinucleated cells, a fascicular pattern of spindle cells and a cystic pattern lined by short spindle cells. Immunohistochemically, most of the tumor cells were positive for vimentin, proliferating cell nuclear antigen and osterix. The multinucleated cells mentioned above were desmin positive and were regarded as regenerative striated muscles but not tumor cells. Since no clear continuity with normal bone tissues was observed, the tumor was diagnosed as an “extraskeletal osteosarcoma.” PMID:26989300

  3. The flavonoid luteolin enhances doxorubicin-induced autophagy in human osteosarcoma U2OS cells

    PubMed Central

    Zhang, Baoliang; Yu, Xin; Xia, Hong

    2015-01-01

    Luteolin (LUT), a flavone, which is universally present as constituent of medicinal plants as well as some vegetables and spices, has been demonstrated display specific anti-carcinogenic effects. However, the mechanisms by which LUT inhibits human osteosarcoma growth remain unknown. The effects of LUT on cell growth in human osteosarcoma U2OS cells were measured by MTT assay and flowcytometry. The effects of LUT on morphological markers of autophagy in U2OS were analyzed by fluorescence microscopy and electron microscopy. Autophagic markers, beclin1 and LC3 were detected by western blotting. Here, we found that LUT induced autophagy in U2OS and acted as an enhancer to sensitize doxorubicin (DOX)-mediated autophagy signaling. The combined treatment of LUT and DOX greatly decreases the growth of U2OS, showing synergistic cytotoxicity. Our results indicate that LUT in combination with DOX maybe a novel strategy for the treatment of human osteosarcoma. PMID:26629003

  4. Effect and mechanism of dihydroartemisinin on proliferation, metastasis and apoptosis of human osteosarcoma cells.

    PubMed

    Tang, C; Ao, P Y; Zhao, Y Q; Huang, S Z; Jin, Y; Liu, J J; Luo, J P; Zheng, J; Shi, D P

    2015-01-01

    Osteosarcoma represents an aggressive type of bone malignancy that poses a significant health threat. The objective of the current study was to analyze the effect and mechanism of dihydroartemisinin (DHA) on the proliferation, metastasis and apoptosis of human osteosarcoma cells. A gradient concentration of DHA (15, 25 and 35 μmol.L-1) was used to stimulate the cells, along with control and Dimethyl sulfoxide (DMSO). The phenotypic outcomes were characterized using MTT assay, clone formation assay, Hoechst 33258 staining assay, luciferase reporter plasmid assay, Western blot and wound healing assay. In addition, IBM SPSS Statistics 18.0 software was applied for statistical analysis and all experimental data were expressed as mean ± s.d. Analysis of variance (ANOVA) was applied to compare the differences among multiple groups. Our results demonstrated that DHA inhibited the proliferation and metastasis of osteosarcoma cells and promoted the apoptosis in the cytomorphosis. PMID:26753652

  5. Safety Concern between Autologous Fat Graft, Mesenchymal Stem Cell and Osteosarcoma Recurrence

    PubMed Central

    Perrot, Pierre; Rousseau, Julie; Bouffaut, Anne-Laure; Rédini, Françoise; Cassagnau, Elisabeth; Deschaseaux, Frédéric; Heymann, Marie-Françoise; Heymann, Dominique; Duteille, Franck; Trichet, Valérie; Gouin, François

    2010-01-01

    Background Osteosarcoma is the most common malignant primary bone tumour in young adult treated by neo adjuvant chemotherapy, surgical tumor removal and adjuvant multidrug chemotherapy. For correction of soft tissue defect consecutive to surgery and/or tumor treatment, autologous fat graft has been proposed in plastic and reconstructive surgery. Principal Findings We report here a case of a late local recurrence of osteosarcoma which occurred 13 years after the initial pathology and 18 months after a lipofilling procedure. Because such recurrence was highly unexpected, we investigated the possible relationship of tumor growth with fat injections and with mesenchymal stem/stromal cell like cells which are largely found in fatty tissue. Results obtained in osteosarcoma pre-clinical models show that fat grafts or progenitor cells promoted tumor growth. Significance These observations and results raise the question of whether autologous fat grafting is a safe reconstructive procedure in a known post neoplasic context. PMID:20544017

  6. Molecular pathogenesis and therapeutic strategies of human osteosarcoma

    PubMed Central

    Denduluri, Sahitya K; Wang, Zhongliang; Yan, Zhengjian; Wang, Jing; Wei, Qiang; Mohammed, Maryam K; Haydon, Rex C; Luu, Hue H; He, Tong-Chuan

    2016-01-01

    Abstract Osteosarcoma (OS) is a devastating illness with rapid rates of dissemination and a poor overall prognosis, despite aggressive standard-of-care surgical techniques and combination chemotherapy regimens. Identifying the molecular mechanisms involved in disease pathogenesis and progression may offer insight into new therapeutic targets. Defects in mesenchymal stem cell differentiation, abnormal expression of oncogenes and tumor suppressors, and dysregulation within various important signaling pathways have all been implicated in development of various disease phenotypes. As such, a variety of basic science and translational studies have shown promise in identifying novel markers and modulators of these disease-specific aberrancies. Born out of these and similar investigations, a variety of emerging therapies are now undergoing various phases of OS clinical testing. They broadly include angiogenesis inhibitors, drugs that act on the bone microenvironment, receptor tyrosine kinase inhibitors, immune system modulators, and other radio- or chemo-sensitizing agents. As new forms of drug delivery are being developed simultaneously, the possibility of targeting tumors locally while minimizing systemic toxicityis is seemingly more achievable now than ever. In this review, we not only summarize our current understanding of OS disease processes, but also shed light on the multitude of potential therapeutic strategies the scientific community can use to make long-term improvements in patient prognosis.

  7. Morphological and Immunohistochemical Characterization of Canine Osteosarcoma Spheroid Cell Cultures.

    PubMed

    Gebhard, C; Gabriel, C; Walter, I

    2016-06-01

    Spheroid cell culture emerges as powerful in vitro tool for experimental tumour research. In this study, we established a scaffold-free three-dimensional spheroid system built from canine osteosarcoma (OS) cells (D17). Spheroids (7, 14 and 19 days of cultivation) and monolayer cultures (2 and 7 days of cultivation) were evaluated and compared on light and electron microscopy. Monolayer and spheroid cultures were tested for vimentin, cytokeratin, alkaline phosphatase, osteocalcin and collagen I by means of immunohistochemistry. The spheroid cell culture exhibited a distinct network of collagen I in particular after 19-day cultivation, whereas in monolayer cultures, collagen I was arranged as a lamellar basal structure. Necrotic centres of large spheroids, as observed in 14- and 19-day cultures, were characterized by significant amounts of osteocalcin. Proliferative activity as determined by Ki-67 immunoreactivity showed an even distribution in two-dimensional cultures. In spheroids, proliferation was predominating in the peripheral areas. Metastasis-associated markers ezrin and S100A4 were shown to be continuously expressed in monolayer and spheroid cultures. We conclude that the scaffold-free spheroid system from canine OS cells has the ability to mimic the architecture of the in vivo tumour, in particular cell-cell and cell-matrix interactions. PMID:26287450

  8. Osteosarcoma in Adult Patients Living with HIV/AIDS

    PubMed Central

    Marais, Leonard C.; Ferreira, Nando

    2013-01-01

    Background. HIV infection has reached epidemic proportions in South Africa, with an estimated prevalence of 21.5% in adults living in the province of KwaZulu-Natal. Several malignancies have been identified as part of the spectrum of immunosuppression-related manifestations of HIV infection. Very few reports, however, exist regarding the occurrence of non-AIDS-defining sarcomas in the extremities or limb girdles. Methods. A retrospective review was performed on all adult patients, between the ages of 30 and 60 years, with histologically confirmed osteosarcomas of the appendicular skeleton referred to a tertiary-level orthopaedic oncology unit. Results. Five out of the nine patients (62.5%) included in the study were found to be HIV positive. The average CD4 count of these patients was 278 (237–301) cells/mm3, indicating advanced immunological compromise. Three of the malignancies in HIV-positive patients occurred in preexisting benign or low-grade tumours. Conclusion. A heightened index of suspicion is required in HIV patients presenting with unexplained bone and joint pain or swelling. Judicious use of appropriate radiological investigation, including magnetic resonance imaging of suspicious lesions and timely referral to an appropriate specialized orthopaedic oncology unit, is recommended. PMID:23762607

  9. Extraskeletal osteosarcoma of the larynx: an extremely unusual tumour.

    PubMed

    Bhatt, Nikita R; Kakked, Gaurav A; Merchant, Rajiv; Bhatt, Rajiv

    2014-01-01

    Osteosarcoma of the larynx is probably the rarest mesenchymal tumour of the larynx, with only 16 cases reported so far. The majority of them occur in males between the sixth and eighth decades of life. Patients usually present with non-specific symptoms such as dysphonia and upper airway compromise. The most common site of distant metastasis is the lung. Clinically, the tumour follows an aggressive course and is associated with high mortality. The case we present is unusual as it occurred at a young age (38 years) as compared with the norm and it did not arise from the endolarynx, unlike many of the other cases. This was the only known case where a Pearson near-total laryngectomy was performed whereby the patient's natural speech mechanism was preserved. This surgery was possible because the contralateral half of the larynx was clearly disease free and the interarytenoid region was uninvolved. The patient underwent postoperative adjuvant external beam radiotherapy beginning 4 weeks after surgery. The patient is doing well after 15 months of follow-up and shows no signs of recurrence. PMID:25323286

  10. Clinicopathologic Features and Results of Transcatheter Arterial Chemoembolization for Osteosarcoma

    SciTech Connect

    Chu Jianping; Chen Wei; Li Jiaping; Zhuang Wenquan; Huang Yonghui; Huang Zhaomin; Yang Jianyong

    2007-04-15

    Purpose. To evaluate the effect of transcatheter arterial chemoembolization (TACE) for osteosarcoma and to describe the clinicopathologic features produced by TACE as well as the effect of different embolic materials. Methods. From January 1998 to December 2003, preoperative TACE was carried out in 32 patients. The preoperative and postoperative clinical response, levels of alkaline phosphatase (AKP), leukocyte count, and clinicopathologic features were recorded. We also compared the effect of different embolic materials: adriblastine gelatin microspheres, anhydrous alcohol, common bletilla tuber, and gelatin sponge particles. Results. The levels of AKP were significantly decreased after treatment (p < 0.05), but there was no significant difference in the leukocyte count. Large areas of necrosis were found histologically within 85.5% tumors after TACE. Embolic agents such as adriblastine microspheres, anhydrous alcohol, and common bletilla tuber have better clinical effects than gelatin sponge particles, but there was no significant difference among the first three embolic materials. After treatment, no serious complications were noted. During successful follow-up for 86 months, the survival rate after TACE at 1, 2, and 5 years was 95.5%, 72%, and 42% respectively. Conclusion. TACE accelerated tumor necrosis and shrank the tumor volume, thus making adequate tumor resection possible. The optimal time to operate is 10-14 days after TACE. TACE in combination with limb salvage surgery and postoperative periodical chemotherapy may be beneficial for increasing local control rates.

  11. Characterizing light propagation in bone for photodynamic therapy of osteosarcoma

    NASA Astrophysics Data System (ADS)

    Rossi, Vincent M.; Gustafson, Scott B.; Jacques, Steven L.

    2009-02-01

    This work aims at characterizing how light propagates through bone in order to efficiently guide treatment of osteosarcoma with photodynamic therapy (PDT). Optical properties of various bone tissues need to be characterized in order to have a working model of light propagation in bone. Bone tissues of particular interest include cortical bone, red and yellow marrow, cancellous bone, and bone cancers themselves. With adequate knowledge of optical properties of osseous tissues, light dosimetry can determine how best to deliver adequate light to achieve phototoxic effects within bone. An optical fiber source-collector pair is used for diffuse reflectance spectroscopic measurements in order to determine the scattering and absorption properties of bone tissues. Native absorbers of interest at visible and near-IR wavelengths include water and oxygenated and deoxygenated hemoglobin. A cylindrically symmetric Monte Carlo model is then used, incorporating these results, in order to predict and guide the delivery of light within bone in order to achieve the desired phototoxic effect in PDT.

  12. TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances.

    PubMed

    Han, Xiu-Guo; Li, Yan; Mo, Hui-Min; Li, Kang; Lin, Du; Zhao, Chang-Qing; Zhao, Jie; Tang, Ting-Ting

    2016-07-01

    Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs) to limit degradation of the extracellular matrix. Low levels of TIMP3 have been demonstrated in cancer tissues at advanced clinical stages, with positive distant metastasis and chemotherapeutic resistance. We examined the role of TIMP3 in osteosarcoma (OS) cell invasiveness and chemoresistance. TIMP3 was overexpressed or knocked down in the human OS cell lines Saos2 and MG63. Cell migration and invasion capacities were then evaluated using Transwell assays, and resistance to cisplatin was assessed by CCK-8 assay and flow cytometry. Real-time PCR and western blotting were used to investigate activation of signaling pathways downstream of TIMP3. Overexpression of TIMP3 inhibited the migration and invasion of Saos2 and MG63 cells, while knockdown of TIMP3 had the opposite effect. Cell survival after exposure to cisplatin was inhibited by TIMP3 overexpression in both Saos2 and MG63 cells. Consistently, downregulation of TIMP3 gene expression significantly decreased the sensitivity of OS cells to cisplatin treatment. MMP1, MMP2, Bcl-2, and Akt1 were all downregulated following TIMP3 overexpression, while Bax and cleaved caspase-3 were upregulated. TIMP3 knockdown had opposite effects on the regulation of these genes. Taken together, our findings suggest TIMP3 as a new target for inhibition of OS progression and chemotherapeutic resistance. PMID:26749283

  13. Triptolide reduces the viability of osteosarcoma cells by reducing MKP-1 and Hsp70 expression

    PubMed Central

    ZHAO, LEI; JIANG, BO; WANG, DONG; LIU, WEI; ZHANG, HUAWU; LIU, WEISHENG; QIU, ZHEN

    2016-01-01

    Osteosarcoma is the most common type of malignant bone tumor found in adolescents and young adults. The aim of the present study was to determine whether triptolide, a diterpene epoxide extracted from the Tripterygium plant, was able effectively decrease the viability of osteosarcoma cells. The underlying molecular mechanisms are also investigated. The human osteosarcoma cell lines U-2 OS and MG-63 were used in this study. The U-2 OS and MG-63 cells were treated with 0, 5, 10, 25 or 50 nM triptolide. Cells treated with dimethyl sulfoxide only were used as the no drug treatment control. A commercial MTT kit was used to determine the effects of triptolide on cells. Mitogen-activated protein kinase phosphatase-1 (MKP-1) is frequently overexpressed in tumor tissues, possibly related to the failure of a number of chemotherapeutics. Heat shock protein 70 (Hsp70) is a chaperone molecule that is able to increase drug resistance. The protein expression levels of MKP-1 and Hsp70 were determined using western blot analysis. The results indicate that triptolide effectively reduced the viability of the osteosarcoma cells. Furthermore, triptolide was found to effectively reduce MKP-1 expression and Hsp70 levels. Further analysis showed that triptolide reduced MKP-1 mRNA expression in the U-2 OS and MG-63 cells. Triptolide reduced Hsp70 mRNA expression levels in U-2 OS and MG-63 cells. These results suggest that triptolide effectively decreases the viability of osteosarcoma cells. These effects may be associated with the decreased expression of MKP-1 and Hsp70 levels. These results suggest that triptolide may be used in the treatments of osteosarcoma. PMID:27168842

  14. Tissue factor associates with survival and regulates tumour progression in osteosarcoma.

    PubMed

    Tieken, Chris; Verboom, Michiel C; Ruf, Wolfram; Gelderblom, Hans; Bovée, Judith V M G; Reitsma, Pieter H; Cleton-Jansen, Anne-Marie; Versteeg, Henri H

    2016-05-01

    Osteosarcoma is the most common primary malignant bone tumour. Patients often develop lung metastasis and have a poor prognosis despite extensive chemotherapy and surgical resections. Tissue Factor is associated with poor clinical outcome in a wide range of cancer types, and promotes angiogenesis and metastasis. The role of Tissue Factor in OS tumourigenesis is unknown. Fifty-three osteosarcoma pre-treatment biopsies and four osteosarcoma cell lines were evaluated for Tissue Factor expression, and a possible association with clinical parameters was investigated. Tissue Factor function was inhibited in an osteosarcoma cell line (143B) by shRNA knockdown or specific antibodies, and pro-tumourigenic gene expression, proliferation, matrigel invasion and transwell migration was examined. 143B cells were implanted in mice in the presence of Tissue Factor-blocking antibodies, and tumour volume, micro-vessel density and metastases in the lung were evaluated. Tissue Factor was highly expressed in 73.6 % of osteosarcoma biopsies, and expression associated significantly with disease-free survival. Tissue Factor was expressed in all four investigated cell lines. Tissue Factor was knocked down in 143B cells, which led to reduced expression of IL-8, CXCL-1, SNAIL and MMP2, but not MMP9. Tissue Factor knockdown or inhibition with antibodies reduced matrigel invasion. Tissue Factor antibodies limited 143B tumour growth in vivo, and resulted in decreased intra-tumoural micro-vessel density. Furthermore, lung metastasis from the primary tumour was significantly reduced. Thus, Tissue Factor expression in osteosarcoma reduces metastasis-free survival in patients, and increases pro-tumourigenic behaviour both in vitro and in vivo. PMID:26763081

  15. The tumor suppressive role of RASSF1A in osteosarcoma through the Wnt signaling pathway.

    PubMed

    Wang, Wei-Guo; Chen, Shi-Jie; He, Jin-Shen; Li, Jing-Song; Zang, Xiao-Fang

    2016-07-01

    Ras-association domain family 1 isoform A (RASSF1A) is a tumor suppressor gene and its expression is lost in numerous types of cancer cells, including primary osteosarcoma cells. However, its functional significance in osteosarcoma has not been well defined. The messenger RNA (mRNA) expression of RASSF1A in osteosarcoma tissues and corresponding non-tumoral tissues was measured by real-time PCR. Overexpression of RASSF1A was established by an adenoviral vector expressing RASSF1A. Cell migration and invasion were analyzed in transwells. Apoptosis and cell cycle were analyzed using flow cytometry. Wnt/β-catenin activity was measured by TCF reporter dual-luciferase assay. Cell viability was measured by MTT assay. Protein expression was detected by Western blot. RASSF1A mRNA expression was significantly lower in osteosarcoma tissues than that in the corresponding non-tumoral tissues. The lowered RASSF1A expression correlated with the clinical severity of osteosarcoma. rAd-RASSF1A injection significantly inhibited the growth of xenograft MNNG/HOS tumors in mice. Overexpression of RASSF1A resulted in significant inhibition of the proliferation, migration, and invasion; induced apoptosis; and arrested cell cycle at G0/G1 phase in both the MNNG/HOS and SaOS2 cells. Overexpression of RASSF1A inhibited the Wnt/β-catenin activity, decreased phosphorylation of Akt/glycogen synthase kinase-3-β (GSK3-β), and increased phosphorylation of mammalian sterile 20-like kinase 1 (MST1). Overexpression of RASSF1A downregulated the cyclin D1, c-Myc, and matrix metalloproteinase-7 (MMP-7) protein levels. RASSF1A functions as a tumor suppressor in osteosarcoma and exerts anti-cancer roles through regulating Akt/GSK-3-Wnt/β-catenin signaling. PMID:26750098

  16. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma.

    PubMed

    Koirala, Pratistha; Roth, Michael E; Gill, Jonathan; Piperdi, Sajida; Chinai, Jordan M; Geller, David S; Hoang, Bang H; Park, Amy; Fremed, Michael A; Zang, Xingxing; Gorlick, Richard

    2016-01-01

    Osteosarcoma patient survival has remained stagnant for 30 years. Novel therapeutic approaches are needed to improve outcomes. We examined the expression of Programmed Death Ligand 1 (PD-L1) and defined the tumor immune microenvironment to assess the prognostic utility in osteosarcoma. PD-L1 expression in osteosarcoma was examined in two patient cohorts using immunohistochemistry (IHC) (n = 48, n = 59) and expression was validated using quantitative real time PCR (n = 21) and western blotting (n = 9). IHC was used to determine the presence of tumor infiltrating lymphocytes and antigen-presenting cells (APCs) in the tumor. Expression of PD-L1 was correlated with immune cell infiltration and event-free-survival (EFS). The 25% of primary osteosarcoma tumors that express PD-L1 were more likely to contain cells that express PD-1 than PD-L1 negative tumors (91.7% vs 47.2%, p = 0.002). Expression of PD-L1 was significantly associated with the presence of T cells, dendritic cells, and natural killer cells. Although all immune cell types examined were present in osteosarcoma samples, only infiltration by dendritic cells (28.3% vs. 83.9%, p = 0.001) and macrophages (45.5% vs. 84.4%, p = 0.031) were associated with worse five-year-EFS. PD-L1 expression was significantly associated with poorer five-year-EFS (25.0%. vs. 69.4%, p = 0.014). Further studies in osteosarcoma are needed to determine if targeting the PD-L1:PD-1 axis improves survival. PMID:27456063

  17. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma

    PubMed Central

    Koirala, Pratistha; Roth, Michael E.; Gill, Jonathan; Piperdi, Sajida; Chinai, Jordan M.; Geller, David S.; Hoang, Bang H.; Park, Amy; Fremed, Michael A.; Zang, Xingxing; Gorlick, Richard

    2016-01-01

    Osteosarcoma patient survival has remained stagnant for 30 years. Novel therapeutic approaches are needed to improve outcomes. We examined the expression of Programmed Death Ligand 1 (PD-L1) and defined the tumor immune microenvironment to assess the prognostic utility in osteosarcoma. PD-L1 expression in osteosarcoma was examined in two patient cohorts using immunohistochemistry (IHC) (n = 48, n = 59) and expression was validated using quantitative real time PCR (n = 21) and western blotting (n = 9). IHC was used to determine the presence of tumor infiltrating lymphocytes and antigen-presenting cells (APCs) in the tumor. Expression of PD-L1 was correlated with immune cell infiltration and event-free-survival (EFS). The 25% of primary osteosarcoma tumors that express PD-L1 were more likely to contain cells that express PD-1 than PD-L1 negative tumors (91.7% vs 47.2%, p = 0.002). Expression of PD-L1 was significantly associated with the presence of T cells, dendritic cells, and natural killer cells. Although all immune cell types examined were present in osteosarcoma samples, only infiltration by dendritic cells (28.3% vs. 83.9%, p = 0.001) and macrophages (45.5% vs. 84.4%, p = 0.031) were associated with worse five-year-EFS. PD-L1 expression was significantly associated with poorer five-year-EFS (25.0%. vs. 69.4%, p = 0.014). Further studies in osteosarcoma are needed to determine if targeting the PD-L1:PD-1 axis improves survival. PMID:27456063

  18. Osteosarcoma of the Mandible Masquerading as a Dental Abscess: Report of a Case

    PubMed Central

    Anil, Sukumaran; Krishnan, Anitha P.; Rajendran, R.

    2012-01-01

    An aggressive and fatal case of osteosarcoma of the mandible in a 19-year-old female is reported. Six weeks after the clinical appearance of the swelling, the patient died. This paper is unique in that the age of occurrence and the biologic behavior of the tumor were not consistent with the reported literature. The case report is followed by a brief review of osteosarcoma of the jaw with a note on its clinical presentation, diverse radiologic appearance, varied histopathologic picture, and prognosis. PMID:23243522

  19. Pulmonary toxocariasis masquerading as metastatic tumor nodules in a child with osteosarcoma.

    PubMed

    Lim, Yeon-Jung; Kim, Ji-Hye; Oh, Sung Hee; Jeon, Seok Chul; Koh, Hyun Chul; Lee, Young-Ho

    2009-12-15

    A 14-year-old male, who completed chemotherapy following limb salvage surgery for osteosarcoma approximately 2 years ago, was seen for routine follow-up. A CT scan revealed new scattered multifocal nodular lesions. An ultrasonography-guided percutaneous needle biopsy was done to confirm pulmonary metastasis of the underlying osteosarcoma. The lung biopsy showed findings of eosinophilic pneumonia with no evidence of malignancy. Peripheral eosinophilia was also noted. When a more thorough history revealed frequent intake of raw cow liver, we diagnosed pulmonary toxocariasis by ELISA for specific serum IgG antibody. PMID:19637318

  20. Serum CEACAM1 Level Is Associated with Diagnosis and Prognosis in Patients with Osteosarcoma

    PubMed Central

    Ren, Yanjun; Yang, Yun; Xiao, Xing

    2016-01-01

    Carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1) is a trans-membrane multifunctional cell adhesion molecule associated with tumor cell proliferation, apoptosis, angiogenesis, invasion, and migration during tumor development. In the present study, we evaluated serum CEACAM1 level in osteosarcoma patients to explore its diagnostic and prognostic value for this particular malignancy. Sera from 113 patients with primary osteosarcoma, 98 patients with benign bone tumors and 126 healthy controls were obtained. Serum CEACAM1 level was measured with ELISA and correlation with clinicopathological characteristics was further analyzed. Receiver operating curves (ROC), Kaplan-Meier curves, and log-rank analyses as well as Cox proportional hazard models were used to evaluate diagnostic and prognostic significance. The results revealed that serum CEACAM1 level was significantly higher in osteosarcoma patients compared to benign bone tumors and healthy controls (455.2 ± 179.9 vs 287.4 ± 103.2, 260.8 ± 109.7 pg/ml, respectively). Osteosarcoma patients with larger tumors, later-tumor stages, low tumor grades, and distant metastases had much higher CEACAM1 compared to those with smaller tumors, earlier tumor stages, high tumor grades and non-distant metastases (P < 0.05 for all). Multivariate logistic regression analysis confirmed that high serum CEACAM1 level was an independent risk factor for distant metastases (OR = 3.02, 95%CI 1.65–4.17). To distinguish osteosarcoma patients from those with benign bone tumor and healthy controls, ROC/AUC analysis indicated an AUC of 0.81 (sensitivity 0.61; specificity 0.89) and an AUC of 0.77 (sensitivity 0.57; specificity 0.92), respectively. Osteosarcoma patients with higher CEACAM1 had relatively lower survival compared to those with low CEACAM1 (P < 0.01), and multivariate analyses for overall survival revealed that high serum CEACAM1 level was an independent prognostic factor for osteosarcoma (HR = 1.56, 95%CI 1.23

  1. Pulmonary evaluation of patients with osteosarcoma: roles of standard radiography, tomography, CT, scintigraphy, and tomoscintigraphy

    SciTech Connect

    Vanel, D.; Henry-Amar, M.; Lumbroso, J.; Lemalet, E.; Couanet, D.; Piekarski, J.D.; Masselot, J.; Boddaert, A.; Kalifa, C.; Le Chevalier, T.

    1984-09-01

    Sixty-one radiologic evaluations were performed on 32 patients with possible pulmonary metastases from osteosarcoma. CT scanning was performed 61 times; standard chest radiography, 58; tomography, 36; scintigraphy, 40; and tomoscintigraphy, 33. Using CT as a reference, the sensitivities of the other examinations were 57% (32% of total metastases) for standard radiography, 88% (48%) for tomography, 21% (5%) for scintigraphy, and 41% (8%) for tomoscintigraphy. Of the 193 metastases, 98 were subpleural and 95 were parenchymatous. The authors' current evaluation of patients with metastases from osteosarcoma includes chest radiography and CT; the other three examinations are performed only before surgery.

  2. A Pediatric Case of Metastatic Conventional Parosteal Osteosarcoma Treated With Multidrug Chemotherapy.

    PubMed

    Nodomi, Seishiro; Umeda, Katsutsugu; Okamoto, Takeshi; Saida, Satoshi; Hiramatsu, Hidefumi; Watanabe, Ken-Ichiro; Adachi, Souichi; Heike, Toshio

    2016-08-01

    Parosteal osteosarcoma (POS) is conventionally a low-grade sarcoma with limited metastatic potential; however, the tumor occasionally transforms into a high-grade dedifferentiated POS, which commonly metastasizes to distant organs. The present report describes a rare pediatric case of conventional POS with no dedifferentiated component yet had multiple pulmonary metastases at initial diagnosis. Following limb-sparing surgery and osteosarcoma-oriented neoadjuvant chemotherapy, the patient received total resection of pulmonary metastases. Despite no treatment for pulmonary recurrence 1 year after adjuvant chemotherapy, the patient is alive with stable disease 4 years and 6 months after the initial diagnosis. PMID:27149276

  3. Major surgery in an osteosarcoma patient refusing blood transfusion: case report

    PubMed Central

    2010-01-01

    We describe an unusual case of osteosarcoma in a Jehovah's Witness patient who underwent chemotherapy and major surgery without the need for blood transfusion. This 16-year-old girl presented with osteosarcoma of the right proximal tibia requiring proximal tibia resection, followed by endoprosthesis replacement. She was successfully treated with neoadjuvant chemotherapy and surgery with the support of haematinics, granulocyte colony-stimulating factor, recombinant erythropoietin and intraoperative normovolaemic haemodilution. This case illustrates the importance of maintaining effective, open communication and exploring acceptable therapeutic alternative in the management of these patients, whilst still respecting their beliefs. PMID:21059231

  4. Osteosarcoma Associated With Diamond-Blackfan Anaemia: A Case of a Child Receiving Growth Hormone Therapy

    PubMed Central

    Higgs, Deborah; Haddo, Omar; Pringle, Jean

    2004-01-01

    Purpose: Diamond–Blackfan anaemia (DBA) is a rare pure congenital red cell aplasia, usually presenting in infancy or early childhood. The literature suggests a predisposition to haemopoietic malignancy but in addition solid tumours have been reported, with five cases of osteosarcoma described. Patient: A sixth case of a 12-year-old girl with DBA who developed an osteosarcoma of the distal femur is presented. Results: She was treated with methotrexate followed by tumour excision and distal femoral replacement. The patient is currently alive with multiple pulmonary metastases. Discussion: We discuss the association between the administration of growth hormone and future development of malignancy in patients with DBA. PMID:18521394

  5. A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model

    PubMed Central

    Goldstein, Seth D.; Trucco, Matteo; Guzman, Wendy Bautista; Hayashi, Masanori; Loeb, David M.

    2016-01-01

    The outcome of patients with metastatic osteosarcoma has not improved since the introduction of chemotherapy in the 1970s. Development of therapies targeting the metastatic cascade is a tremendous unmet medical need. The Wnt signaling pathway has been the focus of intense investigation in osteosarcoma because of its role in normal bone development. Although the role of Wnt signaling in the pathogenesis of osteosarcoma is controversial, there are several reports of dickkopf-1 (DKK-1), a Wnt signaling antagonist, possibly playing a pro-tumorigenic role. In this work we investigated the effect of anti-DKK-1 antibodies on the growth and metastasis of patient-derived osteosarcoma xenografts. We were able to detect human DKK-1 in the blood of tumor-bearing mice and found a correlation between DKK-1 level and tumor proliferation. Treatment with the anti-DKK-1 antibody, BHQ880, slowed the growth of orthotopically implanted patient-derived osteosarcoma xenografts and inhibited metastasis. This effect was correlated with increased nuclear beta-catenin staining and increased expression of the bone differentiation marker osteopontin. These findings suggest that Wnt signaling is anti-tumorigenic in osteosarcoma, and support the targeting of DKK-1 as an anti-metastatic strategy for patients with osteosarcoma. PMID:27049730

  6. SPRY4 Intronic Transcript 1 Promotes Epithelial-Mesenchymal Transition Through Association with Snail1 in Osteosarcoma.

    PubMed

    Ru, Neng; Liang, Jie; Zhang, Fan; Wu, Weifei; Wang, Feifan; Liu, Xinzong; Du, Yuanli

    2016-06-01

    Osteosarcoma is an aggressive tumor and the most common malignancy of the skeleton. Due to pulmonary metastasis, the 5-year survival rate is still unsatisfactory. It has been reported that SPRY4 intronic transcript 1 (SPRY4-IT1) promotes cell growth, invasion, and inhibits apoptosis in several cancers. However, the role of SPRY4-IT1 in osteosarcoma remains unclear. In the present study, we investigated the role of SPRY4-IT1 in osteosarcoma cells. Loss- and gain-of-function assays demonstrated that SPRY4-IT1 promoted cell proliferation, migration, and invasion in osteosarcoma. Moreover, SPRY4-IT1 induced epithelial-mesenchymal transition phenotype in osteosarcoma cells. Subsequent investigations revealed that SPRY4-IT1 promoted migration and invasion through association with Snail1 and regulating its stability. Based on these findings, the SPRY4-IT1/Snail1/E-cadherin pathway may play a crucial role in promoting osteosarcoma metastasis. Thus, SPRY4-IT1 may be a potential target for new therapies of osteosarcoma. PMID:26982001

  7. Hydrogel-PLGA delivery system prolongs 2-methoxyestradiol-mediated anti-tumor effects in osteosarcoma cells.

    PubMed

    Maran, Avudaiappan; Dadsetan, Mahrokh; Buenz, Colleen M; Shogren, Kristen L; Lu, Lichun; Yaszemski, Michael J

    2013-09-01

    Osteosarcoma is a bone tumor that affects children and young adults. 2-Methoxyestradiol (2-ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2-ME, we have encapsulated 2-ME in a composite of oligo-(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic-co-glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2-ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2-ME can be released in a controlled manner over 21-days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2-ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2-ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2-ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer-mediated delivery produces anti-tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2-ME and could be further explored in the treatment of osteosarcoma. PMID:23355512

  8. Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma.

    PubMed

    Shu, Jingmin; Li, Lihua; Sarver, Anne E; Pope, Emily A; Varshney, Jyotika; Thayanithy, Venugopal; Spector, Logan; Largaespada, David A; Steer, Clifford J; Subramanian, Subbaya

    2016-04-19

    Osteosarcoma is the most common primary bone malignancy affecting children and adolescents. Although several genetic predisposing conditions have been associated with osteosarcoma, our understanding of its pathobiology is rather limited. Here we show that, first, an imprinting defect at human 14q32-locus is highly prevalent (87%) and specifically associated with osteosarcoma patients < 30 years of age. Second, the average demethylation at differentially methylated regions (DMRs) in the 14q32-locus varied significantly compared to genome-wide demethylation. Third, the 14q32-locus was enriched in both H3K4-me3 and H3K27-me3 histone modifications that affected expression of all imprinted genes and miRNAs in this region. Fourth, imprinting defects at 14q32 - DMRs are present in triad DNA samples from affected children and their biological parents. Finally, imprinting defects at 14q32-DMRs were also observed at higher frequencies in an Rb1/Trp53 mutation-induced osteosarcoma mouse model. Further analysis of normal and tumor tissues from a Sleeping Beauty mouse model of spontaneous osteosarcoma supported the notion that these imprinting defects may be a key factor in osteosarcoma pathobiology. In conclusion, we demonstrate that imprinting defects at the 14q32 locus significantly alter gene expression, may contribute to the pathogenesis of osteosarcoma, and could be predictive of survival outcomes. PMID:26802029

  9. The HIF-1α/CXCR4 pathway supports hypoxia-induced metastasis of human osteosarcoma cells.

    PubMed

    Guan, Guofeng; Zhang, Yinglong; Lu, Yao; Liu, Lijuan; Shi, Doufei; Wen, Yanhua; Yang, Lianjia; Ma, Qiong; Liu, Tao; Zhu, Xiaodong; Qiu, Xiuchun; Zhou, Yong

    2015-02-01

    HIF-1α mediates hypoxia-induced expression of the chemokine receptor CXCR4 and contributes to metastasis in many different cancers. We have previously shown that hypoxia promotes migration of human osteosarcoma cells by activating the HIF-1α/CXCR4 pathway. Here, immunohistochemical analysis showed that unlike control osteochondroma samples, osteosarcoma specimens were characterized by elevated expression levels of HIF-1α and CXCR4. Moreover, we found that hypoxia-induced invasiveness was more pronounced in high metastatic potential F5M2 osteosarcoma cells than in low metastatic potential F4 cells, and that this induction was sensitive to treatment with the CXCR4 antagonist AMD3100 and the HIF-1α inhibitor KC7F2. Interestingly, hypoxia-induced CXCR4 expression persisted after cultured osteosarcoma cells were returned to normoxic conditions. These observations were confirmed by experiments in a mouse model of osteosarcoma lung metastasis showing that hypoxia stimulation of pulmonary metastasis was greater in F5M2 than in F4 cells, and was sensitive to treatment with AMD3100. Our study provides further evidence of the contributions of hypoxia and the HIF-1α/CXCR4 pathway to the progression of osteosarcoma, and suggests that this axis might be efficiently leveraged in the development of novel osteosarcoma therapeutics. PMID:25444927

  10. MicroRNA-409-3p inhibits osteosarcoma cell migration and invasion by targeting catenin-δ1.

    PubMed

    Wu, Shifeng; Du, Xinjie; Wu, Manwu; Du, Hechun; Shi, Xiaoliang; Zhang, Tao

    2016-06-10

    Osteosarcoma is the most common primary bone cancer which is associated with early metastatic potential and poor prognosis. However, the molecular mechanisms underlying osteosarcoma progression are not well characterized. Here, we investigated the role of miR-409-3p in osteosarcoma metastasis. Osteosarcoma tissue showed decreased expression of miR-409-3p compared to adjacent non-tumorous tissue. The expression level of miR-409-3p was negatively correlated with osteosarcoma metastasis. Overexpression of miR-409-3p in osteosarcoma cells (U2OS) inhibited cell migration and invasion. Bioinformatics analysis showed that catenin-δ1 (CTNND1, p120-catenin) is a direct target of miR-409-3p. Overexpression of miR-409-3p repressed the expression of catenin-δ1 in U2OS cells at both mRNA and protein levels. Meanwhile, miR-409-3p repressed the activity of luciferase reporter containing the 3'-untranslated region (3'UTR) of CTNND1 gene. Furthermore, expression of catenin-δ1 rescued the inhibitory effect of miR-409-3p on cell migration and invasion. Altogether, these results indicated that miR-409-3p targets catenin-δ1 to repress osteosarcoma metastasis. PMID:26992637

  11. Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma

    PubMed Central

    Shu, Jingmin; Li, Lihua; Sarver, Anne E.; Pope, Emily A.; Varshney, Jyotika; Thayanithy, Venugopal; Spector, Logan; Largaespada, David A.; Steer, Clifford J.; Subramanian, Subbaya

    2016-01-01

    Osteosarcoma is the most common primary bone malignancy affecting children and adolescents. Although several genetic predisposing conditions have been associated with osteosarcoma, our understanding of its pathobiology is rather limited. Here we show that, first, an imprinting defect at human 14q32-locus is highly prevalent (87%) and specifically associated with osteosarcoma patients < 30 years of age. Second, the average demethylation at differentially methylated regions (DMRs) in the 14q32-locus varied significantly compared to genome-wide demethylation. Third, the 14q32-locus was enriched in both H3K4-me3 and H3K27-me3 histone modifications that affected expression of all imprinted genes and miRNAs in this region. Fourth, imprinting defects at 14q32 - DMRs are present in triad DNA samples from affected children and their biological parents. Finally, imprinting defects at 14q32-DMRs were also observed at higher frequencies in an Rb1/Trp53 mutation-induced osteosarcoma mouse model. Further analysis of normal and tumor tissues from a Sleeping Beauty mouse model of spontaneous osteosarcoma supported the notion that these imprinting defects may be a key factor in osteosarcoma pathobiology. In conclusion, we demonstrate that imprinting defects at the 14q32 locus significantly alter gene expression, may contribute to the pathogenesis of osteosarcoma, and could be predictive of survival outcomes. PMID:26802029

  12. Focal Chromosomal Copy Number Aberrations Identify CMTM8 and GPR177 as New Candidate Driver Genes in Osteosarcoma

    PubMed Central

    Bras, Johannes; Schaap, Gerard R.; Baas, Frank; Ylstra, Bauke; Hulsebos, Theo J. M.

    2014-01-01

    Osteosarcoma is an aggressive bone tumor that preferentially develops in adolescents. The tumor is characterized by an abundance of genomic aberrations, which hampers the identification of the driver genes involved in osteosarcoma tumorigenesis. Our study aims to identify these genes by the investigation of focal copy number aberrations (CNAs, <3 Mb). For this purpose, we subjected 26 primary tumors of osteosarcoma patients to high-resolution single nucleotide polymorphism array analyses and identified 139 somatic focal CNAs. Of these, 72 had at least one gene located within or overlapping the focal CNA, with a total of 94 genes. For 84 of these genes, the expression status in 31 osteosarcoma samples was determined by expression microarray analysis. This enabled us to identify the genes of which the over- or underexpression was in more than 35% of cases in accordance to their copy number status (gain or loss). These candidate genes were subsequently validated in an independent set and furthermore corroborated as driver genes by verifying their role in other tumor types. We identified CMTM8 as a new candidate tumor suppressor gene and GPR177 as a new candidate oncogene in osteosarcoma. In osteosarcoma, CMTM8 has been shown to suppress EGFR signaling. In other tumor types, CMTM8 is known to suppress the activity of the oncogenic protein c-Met and GPR177 is known as an overexpressed upstream regulator of the Wnt-pathway. Further studies are needed to determine whether these proteins also exert the latter functions in osteosarcoma tumorigenesis. PMID:25551557

  13. CCL5/CCR5 axis induces vascular endothelial growth factor-mediated tumor angiogenesis in human osteosarcoma microenvironment.

    PubMed

    Wang, Shih-Wei; Liu, Shih-Chia; Sun, Hui-Lung; Huang, Te-Yang; Chan, Chia-Han; Yang, Chen-Yu; Yeh, Hung-I; Huang, Yuan-Li; Chou, Wen-Yi; Lin, Yu-Min; Tang, Chih-Hsin

    2015-01-01

    Chemokines modulate angiogenesis and metastasis that dictate cancer development in tumor microenvironment. Osteosarcoma is the most frequent bone tumor and is characterized by a high metastatic potential. Chemokine CCL5 (previously called RANTES) has been reported to facilitate tumor progression and metastasis. However, the crosstalk between chemokine CCL5 and vascular endothelial growth factor (VEGF) as well as tumor angiogenesis in human osteosarcoma microenvironment has not been well explored. In this study, we found that CCL5 increased VEGF expression and production in human osteosarcoma cells. The conditioned medium (CM) from CCL5-treated osteosarcoma cells significantly induced tube formation and migration of human endothelial progenitor cells. Pretreatment of cells with CCR5 antibody or transfection with CCR5 specific siRNA blocked CCL5-induced VEGF expression and angiogenesis. CCL5/CCR5 axis demonstrably activated protein kinase Cδ (PKCδ), c-Src and hypoxia-inducible factor-1 alpha (HIF-1α) signaling cascades to induce VEGF-dependent angiogenesis. Furthermore, knockdown of CCL5 suppressed VEGF expression and attenuated osteosarcoma CM-induced angiogenesis in vitro and in vivo. CCL5 knockdown dramatically abolished tumor growth and angiogenesis in the osteosarcoma xenograft animal model. Importantly, we demonstrated that the expression of CCL5 and VEGF were correlated with tumor stage according the immunohistochemistry analysis of human osteosarcoma tissues. Taken together, our findings provide evidence that CCL5/CCR5 axis promotes VEGF-dependent tumor angiogenesis in human osteosarcoma microenvironment through PKCδ/c-Src/HIF-1α signaling pathway. CCL5 may represent a potential therapeutic target against human osteosarcoma. PMID:25330803

  14. The Current and Future Therapies for Human Osteosarcoma

    PubMed Central

    Lamplot, Joseph D.; Denduluri, Sahitya; Qin, Jiaqiang; Li, Ruidong; Liu, Xing; Zhang, Hongyu; Chen, Xiang; Wang, Ning; Pratt, Abdullah; Shui, Wei; Luo, Xiaoji; Nan, Guoxin; Deng, Zhong-Liang; Luo, Jinyong; Haydon, Rex C; He, Tong-Chuan; Luu, Hue H.

    2015-01-01

    Osteosarcoma (OS) is the most common non-hematologic malignant tumor of bone in adults and children. As sarcomas are more common in adolescents and young adults than most other forms of cancer, there are a significant number of years of life lost secondary to these malignancies. OS is associated with a poor prognosis secondary to a high grade at presentation, resistance to chemotherapy and a propensity to metastasize to the lungs. Current OS management involves both chemotherapy and surgery. The incorporation of cytotoxic chemotherapy into therapeutic regimens escalated cure rates from <20% to current levels of 65-75%. Furthermore, limb-salvage surgery is now offered to the majority of OS patients. Despite advances in chemotherapy and surgical techniques over the past three decades, there has been stagnation in patient survival outcome improvement, especially in patients with metastatic OS. Thus, there is a critical need to identify novel and directed therapy for OS. Several Phase I trials for sarcoma therapies currently ongoing or recently completed have shown objective responses in OS. Novel drug delivery mechanisms are currently under phase II and III clinical trials. Furthermore, there is an abundance of preclinical research which holds great promise in the development of future OS-directed therapeutics. Our continuously improving knowledge of the molecular and cell-signaling pathways involved in OS will translate into more effective therapies for OS and ultimately improved patient survival. The present review will provide an overview of current therapies, ongoing clinical trials and therapeutic targets under investigation for OS. PMID:26834515

  15. Anemone altaica Induces Apoptosis in Human Osteosarcoma Cells.

    PubMed

    Chang, I-Chang; Chiang, Tsay-I; Lo, Chun; Lai, Yi-Hua; Yue, Chia-Herng; Liu, Jer-Yuh; Hsu, Li-Sung; Lee, Chia-Jen

    2015-01-01

    In the past decade, no significant improvement has been made in chemotherapy for osteosarcoma (OS). To develop improved agents against OS, we screened 70 species of medicinal plants and treated two human OS cell lines with different agent concentrations. We then examined cell viability using the MTT assay. Results showed that a candidate plant, particularly the rhizomes of Anemone altaica Fisch. ex C. A. Mey aqueous extract (AAE), suppressed the viability of HOS and U2OS cells in a concentration-dependent manner. Flow cytometry analysis revealed that AAE significantly increased the amount of cell shrinkage (Sub-G1 fragments) in HOS and U2OS cells. Moreover, AAE increased cytosolic cytochrome c and Bax, but decreased Bcl-2. The amount of cleaved caspase-3 and poly-(ADP-ribose) polymerase-1 (PARP-1) were significantly increased. AAE suppressed the growth of HOS and U2OS through the intrinsic apoptotic pathway. Data suggest that AAE is cytotoxic to HOS and U2OS cells and has no significant influence on human osteoblast hFOB cells. The high mRNA levels of apoptosis-related factors (PPP1R15A, SQSTM1, HSPA1B, and DDIT4) and cellular proliferation markers (SKA2 and BUB1B) were significantly altered by the AAE treatment of HOS and U2OS cells. Results show that the anticancer activity of AAE could up-regulate the expression of a cluster of genes, especially those in the apoptosis-related factor family and caspase family. Thus, AAE has great potential as a useful therapeutic drug for human OS. PMID:26224029

  16. RANK and RANK ligand expression in primary human osteosarcoma.

    PubMed

    Branstetter, Daniel; Rohrbach, Kathy; Huang, Li-Ya; Soriano, Rosalia; Tometsko, Mark; Blake, Michelle; Jacob, Allison P; Dougall, William C

    2015-09-01

    Receptor activator of nuclear factor kappa-B ligand (RANKL) is an essential mediator of osteoclast formation, function and survival. In patients with solid tumor metastasis to the bone, targeting the bone microenvironment by inhibition of RANKL using denosumab, a fully human monoclonal antibody (mAb) specific to RANKL, has been demonstrated to prevent tumor-induced osteolysis and subsequent skeletal complications. Recently, a prominent functional role for the RANKL pathway has emerged in the primary bone tumor giant cell tumor of bone (GCTB). Expression of both RANKL and RANK is extremely high in GCTB tumors and denosumab treatment was associated with tumor regression and reduced tumor-associated bone lysis in GCTB patients. In order to address the potential role of the RANKL pathway in another primary bone tumor, this study assessed human RANKL and RANK expression in human primary osteosarcoma (OS) using specific mAbs, validated and optimized for immunohistochemistry (IHC) or flow cytometry. Our results demonstrate RANKL expression was observed in the tumor element in 68% of human OS using IHC. However, the staining intensity was relatively low and only 37% (29/79) of samples exhibited≥10% RANKL positive tumor cells. RANK expression was not observed in OS tumor cells. In contrast, RANK expression was clearly observed in other cells within OS samples, including the myeloid osteoclast precursor compartment, osteoclasts and in giant osteoclast cells. The intensity and frequency of RANKL and RANK staining in OS samples were substantially less than that observed in GCTB samples. The observation that RANKL is expressed in OS cells themselves suggests that these tumors may mediate an osteoclastic response, and anti-RANKL therapy may potentially be protective against bone pathologies in OS. However, the absence of RANK expression in primary human OS cells suggests that any autocrine RANKL/RANK signaling in human OS tumor cells is not operative, and anti-RANKL therapy

  17. Auranofin is a potent suppressor of osteosarcoma metastasis

    PubMed Central

    Topkas, Eleni; Cai, Na; Cumming, Andrew; Hazar-Rethinam, Mehlika; Gannon, Orla Margaret; Burgess, Melinda; Saunders, Nicholas Andrew; Endo-Munoz, Liliana

    2016-01-01

    Osteosarcoma (OS) accounts for 56% of malignant bone cancers in children and adolescents. Patients with localized disease rarely develop metastasis; however, pulmonary metastasis occurs in approximately 50% of patients and leads to a 5-year survival rate of only 10–20%. Therefore, identifying the genes and pathways involved in metastasis, as new therapeutic targets, is crucial to improve long-term survival of OS patients. Novel markers that define metastatic OS were identified using comparative transcriptomic analyses of two highly metastatic (C1 and C6) and two poorly metastatic clonal variants (C4 and C5) isolated from the metastatic OS cell line, KHOS. Using this approach, we determined that the metastatic phenotype correlated with overexpression of thioredoxin reductase 2 (TXNRD2) or vascular endothelial growth factor (VEGF). Validation in patient biopsies confirmed TXNRD2 and VEGF targets were highly expressed in 29–42% of metastatic OS patient biopsies, with no detectable expression in non-malignant bone or samples from OS patients with localised disease. Auranofin (AF) was used to selectively target and inhibit thioredoxin reductase (TrxR). At low doses, AF was able to inhibit TrxR activity without a significant effect on cell viability whereas at higher doses, AF could induce ROS-dependent apoptosis. AF treatment, in vivo, significantly reduced the development of pulmonary metastasis and we provide evidence that this effect may be due to an AF-dependent increase in cellular ROS. Thus, TXNRD2 may represent a novel druggable target that could be deployed to reduce the development of fatal pulmonary metastases in patients with OS. PMID:26573231

  18. Aberrant tropoelastin secretion in MG-63 human osteosarcoma cells

    SciTech Connect

    Curtiss, S.W.

    1989-01-01

    The secretion of newly synthesized tropoelastin, the soluble precursor of the extracellular matrix protein elastin, is not well understood. MG-63 human osteosarcoma cells were found by immunoblot analysis to synthesize 62 kD and 64 kD tropoelastins. Media from 63 cells labelled for five hours with ({sup 3}H)-valine contain no detectable tropoelastin, unlike media from other tropoelastin-synthesizing cells. Immunoblots of conditioned media and 1Ox-concentrated conditioned media left on the cells for six days also show an absence of tropoelastin from the cell media. No insoluble elastin is associated with the cell layer, as determined by amino acid analysis and electron microscopy of 18-21 day cell cultures. The absence of tropoelastin from the cell medium and elastin from the extracellular matrix indicates that MG63 cells do not secrete tropoelastin as expected, but accumulate it intracellularly. This accumulation is transient: immunoblots and immunofluorescence microscopy show that cells three days after passage have the highest steady-state levels of tropoelastin per cell, that day 8 cells contain lower but still significant amounts of tropoelastin, and that by day 22 tropoelastin is no longer present in the cell cultures. Cell density is a critical factor in the observed pattern of tropoelastin expression. Cells seeded at ten fold their usual initial density have high tropoelastin levels at one day after passage, sooner than cells seeded normally. Tropoelastin also disappears from high density-seeded cells more quickly and is no longer detectable at day 10. Lysosome-like vesicles containing membranous structures appear by immunoelectron microscopy to be the primary site of intracellular tropoelastin localization.

  19. Oncogenic roles of carbonic anhydrase 8 in human osteosarcoma cells.

    PubMed

    Wang, Tze-Kai; Lin, Yu-Ming; Lo, Che-Min; Tang, Chih-Hsin; Teng, Chieh-Lin Jerry; Chao, Wei-Ting; Wu, Min Huan; Liu, Chin-San; Hsieh, Mingli

    2016-06-01

    Carbonic anhydrase 8 (CA8), a member of the carbonic anhydrase family, is one of the three isozymes that do not catalyze the reversible hydration of carbon dioxide due to the lack of one important histidine. In the present study, we observed increased expression of CA8 in more aggressive types of human osteosarcoma (OS) cells and found that CA8 expression is correlated with disease stages, such that more intense expression occurs in the disease late stage. We also demonstrated that overexpression of CA8 in human OS (HOS) cells significantly increased cell proliferation both in vitro and in vivo. Downregulated CA8 sensitized cells to apoptotic stress induced by staurosporine and cisplatin, suggesting a specific role of CA8 to protect cells from stresses. In addition, downregulation of CA8 in HOS cells reduced cell invasion and colony formation ability in soft agar and further decreased matrix metalloproteinase 9 and focal adhesion kinase expression, indicating that CA8 might facilitate cancer cell invasion via the activation of FAK-MMP9 signaling. Interestingly, HOS cells with CA8 knockdown showed a significant decrease in glycolytic activity and cell death under glucose withdrawal, further indicating that CA8 may be involved in regulating aerobic glycolysis and enhancing cell viability. Knockdown of CA8 significantly decreased phosphorylated Akt expression suggesting that the oncogenic role of CA8 may be mediated by the regulation of Akt activation through p-Akt induction. Importantly, the inhibition of glycolysis by 2-deoxyglucose sensitized CA8 HOS-CA8-myc cells to cisplatin treatment under low glucose condition, highlighting a new therapeutic option for OS cancer. PMID:26711783

  20. Genomic instability and telomere fusion of canine osteosarcoma cells.

    PubMed

    Maeda, Junko; Yurkon, Charles R; Fujisawa, Hiroshi; Kaneko, Masami; Genet, Stefan C; Roybal, Erica J; Rota, Garrett W; Saffer, Ethan R; Rose, Barbara J; Hanneman, William H; Thamm, Douglas H; Kato, Takamitsu A

    2012-01-01

    Canine osteosarcoma (OSA) is known to present with highly variable and chaotic karyotypes, including hypodiploidy, hyperdiploidy, and increased numbers of metacentric chromosomes. The spectrum of genomic instabilities in canine OSA has significantly augmented the difficulty in clearly defining the biological and clinical significance of the observed cytogenetic abnormalities. In this study, eight canine OSA cell lines were used to investigate telomere fusions by fluorescence in situ hybridization (FISH) using a peptide nucleotide acid probe. We characterized each cell line by classical cytogenetic studies and cellular phenotypes including telomere associated factors and then evaluated correlations from this data. All eight canine OSA cell lines displayed increased abnormal metacentric chromosomes and exhibited numerous telomere fusions and interstitial telomeric signals. Also, as evidence of unstable telomeres, colocalization of γ-H2AX and telomere signals in interphase cells was observed. Each cell line was characterized by a combination of data representing cellular doubling time, DNA content, chromosome number, metacentric chromosome frequency, telomere signal level, cellular radiosensitivity, and DNA-PKcs protein expression level. We have also studied primary cultures from 10 spontaneous canine OSAs. Based on the observation of telomere aberrations in those primary cell cultures, we are reasonably certain that our observations in cell lines are not an artifact of prolonged culture. A correlation between telomere fusions and the other characteristics analyzed in our study could not be identified. However, it is important to note that all of the canine OSA samples exhibiting telomere fusion utilized in our study were telomerase positive. Pending further research regarding telomerase negative canine OSA cell lines, our findings may suggest telomere fusions can potentially serve as a novel marker for canine OSA. PMID:22916246

  1. Unusual Finding of a Tumor Thrombus Arising From Osteosarcoma Detected on 18F-NaF PET/CT.

    PubMed

    Verma, Priyanka; Purandare, Nilendu; Agrawal, Archi; Shah, Sneha; Rangarajan, Venkatesh

    2016-06-01

    Osteosarcoma is the most common bone sarcoma in adolescents and children. Tumor thrombus arising from osteosarcoma is rare. We describe the case of a 13-year-old girl with osteosarcoma of the right femur, in whom the F-NaF PET/CT was done for initial staging to look for skeletal metastases. The scan showed abnormal increased tracer uptake in the primary tumor and the right common femoral and external iliac vein representing a tumor thrombus. Our case emphasizes the importance of extraosseous findings on F-NaF PET/CT, which may result in important management changes. PMID:26909709

  2. Acquisition of anoikis resistance in human osteosarcoma cells does not alter sensitivity to chemotherapeutic agents

    PubMed Central

    Díaz-Montero, C Marcela; McIntyre, Bradley W

    2005-01-01

    Background Chemotherapy-induced cell death can involve the induction of apoptosis. Thus, aberrant function of the pathways involved might result in chemoresistance. Since cell adhesion to the extracellular matrix acts as a survival factor that homeostatically maintains normal tissue architecture, it was tested whether acquisition of resistance to deadhesion-induced apoptosis (anoikis) in human osteosarcoma would result in resistance to chemotherapy. Methods Osteosarcoma cell lines (SAOS-2 and TE-85) obtained from ATCC and were maintained in complete Eagle's MEM medium. Suspension culture was established by placing cells in tissue culture wells coated with poly-HEMA. Cell cytotoxicity was determined using a live/dead cytotoxicity assay. Cell cycle/apoptosis analyses were performed using propidium iodide (PI) staining with subsequent FACS analysis. Apoptosis was also assayed by Annexin-FITC/PI staining. Results Etoposide, adriamycin, vinblastine, cisplatin and paclitaxel were able to induce apoptosis in human osteosarcoma cells SAOS-2 regardless of their anoikis resistance phenotype or the culture conditions (adhered vs. suspended). Moreover, suspended anoikis resistant TE-85 cells (TE-85ar) retained their sensitivity to chemotherapy as well. Conclusion Acquisition of anoikis resistance in human osteosarcoma cells does not result in a generalized resistance to all apoptotic stimuli, including chemotherapy. Moreover, our results suggest that the pathways regulating anoikis resistance and chemotherapy resistance might involve the action of different mediators. PMID:15829011

  3. Heterogeneity of osteosarcoma cell lines led to variable responses in reprogramming.

    PubMed

    Choong, Pei Feng; Teh, Hui Xin; Teoh, Hoon Koon; Ong, Han Kiat; Choo, Kong Bung; Sugii, Shigeki; Cheong, Soon Keng; Kamarul, Tunku

    2014-01-01

    Four osteosarcoma cell lines, Saos-2, MG-63, G-292 and U-2 OS, were reprogrammed to pluripotent state using Yamanaka factors retroviral transduction method. Embryonic stem cell (ESC)-like clusters started to appear between 15 to 20 days post transduction. Morphology of the colonies resembled that of ESC colonies with defined border and tightly-packed cells. The reprogrammed sarcomas expressed alkaline phosphatase and pluripotency markers, OCT4, SSEA4, TRA-1-60 and TRA-1-81, as in ESC up to Passage 15. All reprogrammed sarcomas could form embryoid body-like spheres when cultured in suspension in a low attachment dish for up to 10 days. Further testing on the directed differentiation capacity of the reprogrammed sarcomas showed all four reprogrammed sarcoma lines could differentiate into adipocytes while reprogrammed Saos-2-REP, MG-63-REP and G-292-REP could differentiate into osteocytes. Among the 4 osteosarcoma cell lines, U-2 OS reported the highest transduction efficiency but recorded the lowest reprogramming stability under long term culture. Thus, there may be intrinsic differences governing the variable responses of osteosarcoma cell lines towards reprogramming and long term culture effect of the reprogrammed cells. This is a first report to associate intrinsic factors in different osteosarcoma cell lines with variable reprogramming responses and effects on the reprogrammed cells after prolonged culture. PMID:25170299

  4. A case of polyostotic osteosarcoma with kidney metastases in a dog: histopathology and microcomputed tomographic analysis.

    PubMed

    Aguado, E; Goyenvalle, E; Guintard, C

    2014-12-01

    A 7-year- old sexually intact female Leonberg dog was evaluated for chronic lameness of the right forelimb. The bitch showed mild hyperthermia (39.3°C), a decrease in its activity, a capricious appetite, a high weight loss (4 kg in 15 days) and a right foreleg lameness. A careful clinical examination revealed a deformation of the right proximal humerus and right tibia. Radiographic examination of the right tibia, right humerus showed osteolysis of both cortical and trabecular bone with a periosteal bone proliferation in the vicinal soft tissues. The owner having refused a bone biopsy, a treatment with NSAIDs and antibiotics was prescribed. After a marked improvement during the first two weeks, an increase in lameness and activity was observed. At that time, the owner accepted the bone biopsy. Histopathologic examination evidenced an osteosarcoma but the amount of available tissue was limited. Due to the poor prognosis, he declined treatment and decided to euthanize the dog. An osteosarcoma with a large chondroid component was observed at autopsy together with ossifying kidney metastases. Histological findings revealed a grade III osteosarcoma. Conventional and undecalcified histology and X-ray microcomputed tomography findings evidenced a large and partially mineralized osteoid part with a sunburst extension in the soft tissues. This is the first time that microCT and undecalcified analyses of an osteosarcoma are presented. The osteolytic and metaplastic bone foci were easily demonstrated by this method. PMID:24993506

  5. Niclosamide inhibits the proliferation of human osteosarcoma cell lines by inducing apoptosis and cell cycle arrest.

    PubMed

    Li, Zonghuan; Yu, Yifeng; Sun, Shaoxing; Qi, Baiwen; Wang, Weiyang; Yu, Aixi

    2015-04-01

    Niclosamide, used as an antihelminthic, has demonstrated some properties of anticancer effects. However, its role in osteosarcoma remains to be determined. The aim of this study was to determine the effect of niclosamide on human osteosarcoma cell lines. The human MG-63 and U2OS osteosarcoma cell lines were treated with different concentrations of niclosamide. The cell inhibitory rate was calculated by CCK-8 assay. Cell cycle was detected by flow cytometry. Cell apoptosis was determined by Hoechst 33324 staining, flow cytometry and fluorescence microscope, respectively. The expression of bcl-2, bax and pro-caspase-3 were measured by western blotting. Niclosamide exerted an inhibitory effect on the two cell lines in a time- and dose-dependent manner. Niclosamide was found to induce the arrest of S and G2/M phase in U2OS cells and G2/M in MG-63 cells. Moreover, niclosamide induced apoptosis in MG-63 and U2OS cells. The bax/bcl-2 ratio increased while the expression of pro‑caspase-3 decreased significantly in the two cell lines. The results indicated that niclosamide inhibits proliferation, and induces apoptosis and cell cycle arrest in human osteosarcoma cell lines. PMID:25634333

  6. Antitumoral-Lipid-Based Nanoparticles: a Platform for Future Application in Osteosarcoma therapy.

    PubMed

    González-Fernández, Yolanda; Imbuluzqueta, Edurne; Patiño-García, Ana; Blanco-Prieto, María J

    2015-01-01

    Osteosarcoma is the most frequent primary bone tumor in the pediatric age group. Its aggressive local growth pattern and its high propensity to metastasize, mainly to the lungs, give the disease an unfavorable prognosis that has situated this disease as one of the leading causes of pediatric cancer death. Current protocols for osteosarcoma treatment are based on neo-adjuvant (pre-operatory) chemotherapy followed by surgical resection of the tumor and a new phase of adjuvant chemotherapy. Despite the progress that these protocols have made in improving the outcome of the disease, the limited access of drugs to bone tumor and metastases, their indiscriminate distribution in the organism, the high required doses that cause intolerable toxicity and the development of multidrug resistance, still represent a major challenge. Nanotechnology has emerged as a new strategy to successfully address these problems by the development of nanoscaled drug carriers that present the ability to target the drug to the tumor cells, achieving high drug concentrations in the tumor area, while decreasing its presence in healthy tissues and therefore its potential systemic toxicity. This review summarizes the different lipid nanocarriers developed to deliver first and second-line anti-osteosarcoma drugs as well as emerging agents in the treatment of this disease. Moreover, it also discusses the potential of these nanocarriers for the treatment of osteosarcoma. PMID:26503148

  7. The radiological appearances of telangiectatic osteosarcoma. A study of 14 cases.

    PubMed

    Vanel, D; Tcheng, S; Contesso, G; Zafrani, B; Kalifa, C; Dubousset, J; Kron, P

    1987-01-01

    Fourteen telangiectatic osteosarcomas are reported. They are rare, clinically and radiologically aggressive lesions, involving mainly the femurs of young patients, often misdiagnosed as aneurysmal bone cysts. An explanation for a characteristic early radiological appearance consisting of regular parallel striations of the shaft is suggested. PMID:3473690

  8. Synergistic antitumor efficacy by combining adriamycin with recombinant human endostatin in an osteosarcoma model.

    PubMed

    Xu, Hairong; Niu, Xiaohui; Zhang, Qing; Hao, Lin; Ding, Yi; Liu, Weifeng; Yao, Lu

    2011-09-01

    In the last 15 years, chemotherapy-based therapeutic regimens for the treatment of osteosarcoma have failed to demonstrate improved survival rates. Novel approaches, including targeted therapy and antiangiogenic therapy, may provide new methods for the treatment of osteosarcoma, one of the most deadly malignant diseases. In the present study, the therapeutic efficacy of an endogenous angiogenesis inhibitor, endostatin, was tested in combination with the chemotherapeutic agent, adriamycin. BALB/c mice, aged 4-6 weeks were fed animal chow and had access to water ad libitum. The mice were divided into groups and injected with tumor cells. Immunohistochemical staining was performed to identify the microvessel density. The TUNEL technique was also used to determine the apoptotic index. The combination of endostatin and adriamycin produced marked synergistic antitumor activity in a mouse osteosarcoma model. These findings provide new guidelines for designing future clinical trials and for the application of currently available clinical drugs (endostatin has been approved for clinical use) in the treatment of osteosarcoma. PMID:22866125

  9. Lymphatic spread of osteosarcoma shown by Tc-99m-MDP scintigraphy

    SciTech Connect

    Heyman, S.

    1980-12-01

    Osteosarcoma usually spreads via the blood stream, resulting in pulmonary and skeletal metastases. The value of bone imaging in the management of these patients is widely accepted. Less commonly, the disease spreads via the lymphatics. Such a case is reported to show that bone imaging will detect progressive involvement of the lymph nodes.

  10. Localization of /sup 99m/Tc methylene disphosphonate within synovial fluid in osteosarcoma

    SciTech Connect

    Sandler, M.S.; Heyman, S.; Watts, H.

    1984-08-01

    Extraosseous uptake of /sup 99m/Tc phosphate bone scanning agents has been reported in a wide variety of lesions, including malignant effusions. A case of uptake of bone scanning agent within synovial fluid in a joint involved with osteosarcoma is reported.

  11. Treatment of extraskeletal osteosarcoma at a previous injection site resulting in prolonged survival in 1 dog.

    PubMed

    Selmic, Laura E; Griffin, Lynn R; Rector, Megan H; Lafferty, Mary; Pool, Roy; Ehrhart, Nicole P

    2016-09-01

    A rare presentation of an extraskeletal osteosarcoma at a previous interscapular injection site in a dog is described. Treatment included surgical excision of the tumor followed by 6 rounds of intravenous carboplatin, oral toceranib, and cyclophosphamide. The dog survived for 20.5 months after diagnosis despite early development of pulmonary metastases. PMID:27587886

  12. Hepatic extraskeletal chondroblastic osteosarcoma with unusual angioinvasion of the caudal vena cava in a dog.

    PubMed

    Wiersma, L; Kuiper, R V; Gröne, A

    2010-12-15

    Extraskeletal osteosarcomas are rare malignant mesenchymal neoplasms that are able to directly produce osteoid, without requiring a cartilage template. The extraskeletal localization indicates that these neoplasms are not associated with pre-existing skeletal elements or periosteum. We describe the gross and histological findings of a 4-year-old male Rottweiler that presented with an extraskeletal chondroblastic osteosarcoma (also known as osteosarcoma of the chondroblastic subtype) originating from the liver and extending into the lumen of the caudal vena cava, passing through the right atrium and terminating in the right ventricle of the heart immediately below the pulmonary valve. In the liver, predominantly fusiform cells grew in loosely packed streams and whorls. In the vena cava, the neoplasm was multilobular with polygonal neoplastic cells scattered within lacunae in a chondroid matrix. In the cardiac lumen, neoplastic cells produced osteoid that showed multifocal mineralization. Immunohistochemical staining showed no cytokeratin and variable S-100 protein and vimentin immunoreactivity. To the best of our knowledge, this is the first report of a chondroblastic osteosarcoma arising in the liver and showing such extensive and unusual extension into the vasculature. PMID:21284251

  13. Waardenburg-like features with cataracts, small head size, joint abnormalities, hypogonadism, and osteosarcoma.

    PubMed Central

    Parry, D M; Safyer, A W; Mulvihill, J J

    1978-01-01

    A 32-year-old black man was observed with osteosarcoma and multiple anomalies including deafness, hypopigmentation, cataracts, small head size, hypogonadism, and restricted joint mobility. The birth defects may comprise a new syndrome or combination of syndromes, of which the malignancy may be a part. Images PMID:273099

  14. hTERT promoter activity identifies osteosarcoma cells with increased EMT characteristics

    PubMed Central

    YU, LING; LIU, SHIQING; GUO, WEICHUN; ZHANG, CHUN; ZHANG, BO; YAN, HUICHAO; WU, ZHENG

    2014-01-01

    Epithelial-mesenchymal transition (EMT) is a critical step in order for epithelial-derived malignancies to metastasize, however, its role in mesenchymal-derived tumors, i.e., osteosarcoma, remains unclear. Cancer stem cells (CSCs) are enriched with cells that undergo EMT. The activity of telomerase is maintained in normal stem cells and a number of malignant tumors. The current study observed the heterogeneity of telomerase activity among individual osteosarcoma cells. We hypothesized that telomerase-positive (TELpos) cells are enriched for stem cell-like and EMT properties. A human telomerase reverse transcriptase (hTERT) promoter-reporter was applied to assess the telomerase activity of individual MG63 osteosarcoma cells and sort them into TELpos and telomerase-negative (TELneg) subpopulations. It was found that the TELpos cells exhibited an enhanced ability to form sarcospheres in vitro. In addition, TELpos cells exhibited a higher expression of vimentin, accompanied by an increased long/short axis ratio. A panel of EMT-related genes was evaluated by quantitative PCR and western blot analysis, and were found to be significantly upregulated in TELpos cells. Next, the in vitro migration capacity was examined by Transwell assay, which confirmed that TELpos cells are more prone to migration (2.6 fold). The results of the present study support the concept that EMT also applies to mesenchymal-derived osteosarcoma and draws a connection between telomerase and EMT characteristics. PMID:24348856

  15. The Cancer-Related Transcription Factor Runx2 Modulates Cell Proliferation in Human Osteosarcoma Cell Lines

    PubMed Central

    Lucero, Claudia M.J.; Vega, Oscar A.; Osorio, Mariana M.; Tapia, Julio C.; Antonelli, Marcelo; Stein, Gary S.; Van Wijnen, Andre J.; Galindo, Mario A.

    2013-01-01

    Runx2 regulates osteogenic differentiation and bone formation, but also suppresses pre-osteoblast proliferation by affecting cell cycle progression in the G1 phase. The growth suppressive potential of Runx2 is normally inactivated in part by protein destabilization, which permits cell cycle progression beyond the G1/S phase transition, and Runx2 is again up-regulated after mitosis. Runx2 expression also correlates with metastasis and poor chemotherapy response in osteosarcoma. Here we show that six human osteosarcoma cell lines (SaOS, MG63, U2OS, HOS, G292, and 143B) have different growth rates, which is consistent with differences in the lengths of the cell cycle. Runx2 protein levels are cell cycle-regulated with respect to the G1/S phase transition in U2OS, HOS, G292, and 143B cells. In contrast, Runx2 protein levels are constitutively expressed during the cell cycle in SaOS and MG63 cells. Forced expression of Runx2 suppresses growth in all cell lines indicating that accumulation of Runx2 in excess of its pre-established levels in a given cell type triggers one or more anti-proliferative pathways in osteosarcoma cells. Thus, regulatory mechanisms controlling Runx2 expression in osteosarcoma cells must balance Runx2 protein levels to promote its putative oncogenic functions, while avoiding suppression of bone tumor growth. PMID:22949168

  16. The Treatment and Outcomes of Extraskeletal Osteosarcoma: Institutional Experience and Review of The Literature

    PubMed Central

    Nystrom, Lukas M.; Reimer, Nickolas B.; Reith, John D.; Scarborough, Mark T.; Gibbs, C. Parker

    2016-01-01

    Background Extraskeletal osteosarcoma is a rare tumor with a poor prognosis. The purpose of this study is to examine the oncologic outcomes of this disease as they relate to surgical treatment and use of adjuvant therapies. Methods We retrospectively analyzed all patients treated at our institution for high-grade extraskeletal osteosarcoma of the limb or chest wall. We recorded demographic data, presenting stage, surgical margin, use of adjuvant chemotherapy or radiation, incidence of local recurrence, metastases, and death. Overall and event-free survival were calculated using Kaplan-Meier survival methods. Results There were 12 patients treated with primary wide resection or re-excision of a previously operated tumor bed. Four patients presented with metastases. Seven patients received chemotherapy and four patients received radiation therapy. There were two local recurrences, six patients developed new metastases, and nine patients died. There was no difference in overall survival in patients who received chemotherapy. There was, however, a trend towards increased length of survival in patients who received chemotherapy compared to those who did not (16.4 months vs. 9.3 months, p=0.16). Conclusions Despite no difference in overall survival, patients treated with adjuvant chemotherapy have a trend towards increased length of survival. We suggest that extraskeletal osteosarcoma be treated with standard osteosarcoma chemotherapy regimens in addition to wide resection.

  17. Resveratrol inhibits canonical Wnt signaling in human MG-63 osteosarcoma cells.

    PubMed

    Zou, Yonggen; Yang, Jiexiang; Jiang, Dianming

    2015-11-01

    In the last 30 years, the 5-year-survival rate of patients with osteosarcoma has not improved as a result of the low prevalence and large tumor heterogeneity. Therefore, the development of novel drugs for the treatment of osteosarcoma is urgently required. The present study aimed to identify potential novel drugs for the treatment of osteosarcoma, thus used β‑catenin as a target and performed high content screening. In a total of 14 botanical extracts assessed, resveratrol markedly downregulated the expression of β‑catenin and significantly inhibited MG‑63 cell proliferation. CCK‑8 assay was used to confirm the anti‑osteosarcoma effect of resveratrol and flow cytometry and western blotting were performed to analyze the underlying mechanisms of the proapoptotic effects of resveratrol. β‑catenin is a vital member of the canonical Wnt signaling pathway and, therefore, the target genes of this pathway were further analyzed. The results of this analysis demonstrated that resveratrol suppressed the MG‑63 cells by inhibiting the canonical Wnt signaling pathway. PMID:26398440

  18. HER-2 expression in biopsy and surgical specimen on prognosis of osteosarcoma

    PubMed Central

    Zhang, Qingyu; Liu, Fanxiao; Wang, Bomin; Li, Zhenfeng; Zhou, Dongsheng; Yang, Qiang; Dong, Jinlei; Li, Jianmin

    2016-01-01

    Abstract Numerous original clinical studies have attempted to investigate the prognostic value of HER-2 overexpression in osteosarcoma, but the results of these studies are not consistent. This meta-analysis and systematic review was performed to further assess the correlation between HER-2 expression and prognosis in patients with osteosarcoma. A detailed search of relevant publications was conducted using 7 electronic databases: PubMed, Embase, the Cochrane library, the Wanfang database, the China National Knowledge Internet (CNKI) database, the Chinese VIP database, and the Chinese Biological Medical (CBM) Database for publications through August 1, 2015, using the following keywords (HER-2 OR ErbB-2 OR C-erbB-2 OR neu) AND (osteosarcoma OR osteogenic tumor). The bibliographies of potentially relevant articles and identified articles were then searched by hand. Eligible studies were those that enrolled participants with osteosarcoma and provided survival outcome in HER-2 positive and negative groups. The hazard ratio (HR) and 95% confidence interval (CI) for each individual study was calculated and pooled to obtain integrated estimates, using random effects modeling. Sixteen studies involving 934 participants with osteosarcoma met our inclusion criteria. HER-2 overexpression was documented in 42.2% of patients with osteosarcoma. Compared with patients without HER-2 overexpression, those overexpressing HER-2 had decreased overall survival (HR = 2.03, 95% CI: 1.36–3.03, P < 0.001). Statistical associations between HER-2 overexpression and unfavorable overall survival (OS) were observed for both biopsy and surgical removal specimens (HR = 2.07, 95%CI: 1.16–3.72, P = 0.014; and HR = 2.02, 95%CI: 1.10–3.71, P = 0.024). Results for disease-free survival (DFS) were similar. Overexpression of HER-2 is significantly associated with poor outcome for patients with osteosarcoma and should be assessed at diagnosis and after surgery as a prognostic factor. However

  19. The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma

    PubMed Central

    Hu, Yafang; Bobb, Daniel; He, Jianping; Hill, D Ashley; Dome, Jeffrey S

    2015-01-01

    The unsatisfactory outcomes for osteosarcoma necessitate novel therapeutic strategies. This study evaluated the effect of the telomerase inhibitor imetelstat in pre-clinical models of human osteosarcoma. Because the chaperone molecule HSP90 facilitates the assembly of telomerase protein, the ability of the HSP90 inhibitor alvespimycin to potentiate the effect of the telomerase inhibitor was assessed. The effect of single or combined treatment with imetelstat and alvespimycin on long-term growth was assessed in osteosarcoma cell lines (143B, HOS and MG-63) and xenografts derived from 143B cells. Results indicated that imetelstat as a single agent inhibited telomerase activity, induced telomere shortening, and inhibited growth in all 3 osteosarcoma cell lines, though the bulk cell cultures did not undergo growth arrest. Combined treatment with imetelstat and alvespimycin resulted in diminished telomerase activity and shorter telomeres compared to either agent alone as well as higher levels of γH2AX and cleaved caspase-3, indicative of increased DNA damage and apoptosis. With dual telomerase and HSP90 inhibition, complete growth arrest of bulk cell cultures was achieved. In xenograft models, all 3 treatment groups significantly inhibited tumor growth compared with the placebo-treated control group, with the greatest effect seen in the combined treatment group (imetelstat, p = 0.045, alvespimycin, p = 0.034; combined treatment, p = 0.004). In conclusion, HSP90 inhibition enhanced the effect of telomerase inhibition in pre-clinical models of osteosarcoma. Dual targeting of telomerase and HSP90 warrants further investigation as a therapeutic strategy. PMID:25920748

  20. Prognostic value and in vitro biological relevance of Neuropilin 1 and Neuropilin 2 in osteosarcoma.

    PubMed

    Boro, Aleksandar; Arlt, Matthias Je; Lengnick, Harald; Robl, Bernhard; Husmann, Maren; Bertz, Josefine; Born, Walter; Fuchs, Bruno

    2015-01-01

    Neoadjuvant chemotherapy in osteosarcoma increased the long-term survival of patients with localized disease considerably but metastasizing osteosarcoma remained largely treatment resistant. Neuropilins, transmembrane glycoproteins, are important receptors for VEGF dependent hyper-vascularization in tumor angiogenesis and their aberrant expression promotes tumorigenesis and metastasis in many solid tumors. Our analysis of Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2) immunostaining in a tissue microarray of 66 osteosarcoma patients identified NRP2 as an indicator of poor overall, metastasis-free and progression free survival while NRP1 had no predictive value. Patients with tumors that expressed NRP2 in the absence of NRP1 had a significantly worse prognosis than NRP1(-)/NRP2(-), NRP1(+) or NRP1(+)/NRP2(+) tumors. Moreover, patients with overt metastases and with NRP2-positive primary tumors had a significantly shorter survival rate than patients with metastases but NRP2-negative tumors. Furthermore, the expression of both NRP1 and NRP2 in osteosarcoma cell lines correlated to a variable degree with the metastatic potential of the respective cell line. To address the functional relevance of Neuropilins for VEGF signaling we used shRNA mediated down-regulation and blocking antibodies of NRP1 and NRP2 in the metastatic 143B and HuO9-M132 cell lines. In 143B cells, VEGFA signaling monitored by AKT phosphorylation was more inhibited by blocking of NRP1, whereas in HuO9-M132 cells NRP2 blocking was more effective indicating that NRP1 and NRP2 can substitute each other in the functional interaction with VEGFR1. Altogether, these data point to NRP2 as a powerful prognostic marker in osteosarcoma and together with NRP1 as a novel target for tumor-suppressive therapy. PMID:26045903

  1. In vitro generation of cytotoxic T lymphocyte response using dendritic cell immunotherapy in osteosarcoma

    PubMed Central

    He, Ye-Teng; Zhang, Qing-Min; Kou, Quan-Chun; Tang, Bo

    2016-01-01

    Immunotherapy with tumor lysate-pulsed dendritic cells (DCs) is one of the breakthrough strategies used in the treatment of cancer. However, DC-based immunotherapies for osteosarcoma are limited. In the present study, preclinical studies of a C3H osteosarcoma mouse model (produced by subcutaneous injection of LM8 murine osteosarcoma cells) validated the concept that LM8 cell lysate-pulsed bone marrow-derived DCs may evoke a more potent immune response compared with DCs that have been matured using polyinosinic:polycytidylic acid (poly I:C). A cytotoxic T lymphocyte (CTL) response was established using two groups of C3H mice (n=9) with osteosarcoma; the treatment group consisted of LM8 cell lysate-pulsed DCs and the control group consisted of DCs matured using poly I:C. Each group was immunized with doses of 1×106 cells twice per week for 3 weeks. No difference in the expression of cluster of differentiation markers was identified in the two groups. DCs pulsed with LM8 cell lysate were associated with the increased induction of CTL activity. Serum interferon-γ levels were increased in mice that received DCs pulsed with LM8 cell lysate compared with that in the poly I:C-matured DC group (P<0.041). Serum interleukin-4 was decreased in the treatment group vs. the control group (P<0.033). A mixed lymphocyte reaction assay confirmed that LM8-DC immunotherapy may evoke a significant antigen-specific immune response in a mouse model. The present study reveals promising data on efficacy of a DC-based immunotherapy in the treatment of osteosarcoma; however, further clinical studies are warranted. PMID:27446401

  2. Effectiveness evaluation of dendritic cell immunotherapy for osteosarcoma on survival rate and in vitro immune response.

    PubMed

    Fang, X; Jiang, C; Xia, Q

    2015-01-01

    The aim of this study was to investigate the effects of dendritic cell (DC) therapy in osteosarcoma. Bone marrow DCs from Wistar (allograft group) and Sprague Dawley (SD) (homograft group) rats were electrically fused with the SD-derived osteosarcoma cell line UMR106 to generate a DC-osteosarcoma fusion (DOF) tumor vaccine, which was co-incubated with SD T lymphocytes to stimulate T cell proliferation. CD8+ and CD4+ cell percentages were measured by flow cytometry; tumor-cytotoxic effects of cytotoxic T lymphocytes (CTLs) were measured by the MTT assay. Active immunotherapy was applied to SD osteosarcoma model rats via subcutaneous injection of the tumor vaccine. Significant potentiation of T lymphocyte proliferation was observed in both groups. In the homograft group, the CD8+/CD4+ ratio was elevated to 78.2 from 55.1% after stimulation (P < 0.05) whereas the CD4+ cell percentage was reduced from 61.3 to 21.2% (P < 0.05). Similarly, in the allograft group the CD8+ and CD4+ cell percentages significantly increased (33.8 to 69.6%) or decreased (61.3 to 28.1%) after stimulation, respectively (P < 0.05). The preferential homograft group response was not significant (P > 0.05). Induced UMR106- specific CTLs showed a significantly higher tumor-cytotoxic effect after stimulation (P < 0.05). After DOF active immunotherapy, tumor bodies displayed atrophy or disappearance, leading to higher survival times and rates (60 and 70% in the allograft and homograft groups) (P < 0.05). This study demonstrated that osteosarcoma immunotherapy using a DC-fused tumor vaccine can effectively stimulate T lymphocyte proliferation and induce the tumor-cytotoxic activity of CTLs. PMID:26436501

  3. Ampelopsin suppresses TNF-α-induced migration and invasion of U2OS osteosarcoma cells.

    PubMed

    Liu, Changying; Zhao, Pengfei; Yang, Yubao; Xu, Xiaodong; Wang, Liang; Li, Bo

    2016-06-01

    Ampelopsin has been suggested as a novel anticancer agent, however, there is no evidence regarding its direct effect on the migration and invasion of osteosarcoma cells. The aims of the present study were to investigate the influence of ampelopsin on the migration and invasion of osteosarcoma cells and to clarify the underlying mechanisms. Scratch wound healing and Transwell assays were used to measure the migratory and invasive activities of the cells, respectively. The protein and RNA levels of matrix metalloproteinase-2 (MMP-2) were detected with western blot and RT-qPCR, respectively, following stimulation with tumor necrosis factor‑α (TNF-α) and ampelopsin. The expression levels of phospho‑ and total-p38MAPK were detected using western blot analysis. Additionally, SB203580, an inhibitor of p38MAPK, was used to investigate the effect of TNF‑α and ampelopsin. The results demonstrated that TNF‑α upregulated the expression level of MMP‑2 and promoted the migration and invasion of osteosarcoma cells. TNF‑α also activated the p38MAPK pathway, and SB203580 significantly inhibited the effect of TNF‑α on MMP‑2 expression. The application of ampelopsin abolished the effects of TNF‑α on the activation of the p38MAPK pathway and the expression of MMP‑2, and downregulated the migration and invasion of the osteosarcoma cells. These results demonstrated that ampelopsin inhibits the TNF‑α‑induced migration and invasion of osteosarcoma cells, and that the effect of ampelopsin was mediated by p38MAPK/MMP‑2 signaling. PMID:27082056

  4. Osteosarcoma of the spine: prognostic variables for local recurrence and overall survival, a multicenter ambispective study.

    PubMed

    Dekutoski, Mark B; Clarke, Michelle J; Rose, Peter; Luzzati, Alessandro; Rhines, Laurence D; Varga, Peter P; Fisher, Charles G; Chou, Dean; Fehlings, Michael G; Reynolds, Jeremy J; Williams, Richard; Quraishi, Nasir A; Germscheid, Niccole M; Sciubba, Daniel M; Gokaslan, Ziya L; Boriani, Stefano

    2016-07-01

    OBJECTIVE Primary spinal osteosarcomas are rare and aggressive neoplasms. Poor outcomes can occur, as obtaining marginal margins is technically demanding; further Enneking-appropriate en bloc resection can have significant morbidity. The goal of this study is to identify prognostic variables for local recurrence and mortality in surgically treated patients diagnosed with a primary osteosarcoma of the spine. METHODS A multicenter ambispective database of surgically treated patients with primary spine osteosarcomas was developed by AOSpine Knowledge Forum Tumor. Patient demographic, diagnosis, treatment, perioperative morbidity, local recurrence, and cross-sectional survival data were collected. Tumors were classified in 2 cohorts: Enneking appropriate (EA) and Enneking inappropriate (EI), as defined by pathology margin matching Enneking-recommended surgical margins. Prognostic variables were analyzed in reference to local recurrence and survival. RESULTS Between 1987 and 2012, 58 patients (32 female patients) underwent surgical treatment for primary spinal osteosarcoma. Patients were followed for a mean period of 3.5 ± 3.5 years (range 0.5 days to 14.3 years). The median survival for the entire cohort was 6.7 years postoperative. Twenty-four (41%) patients died, and 17 (30%) patients suffered a local recurrence, 10 (59%) of whom died. Twenty-nine (53%) patients underwent EA resection while 26 (47%) patients underwent EI resection with a postoperative median survival of 6.8 and 3.7 years, respectively (p = 0.048). EI patients had a higher rate of local recurrence than EA patients (p = 0.001). Patient age, previous surgery, biopsy type, tumor size, spine level, and chemotherapy timing did not significantly influence recurrence and survival. CONCLUSIONS Osteosarcoma of the spine presents a significant challenge, and most patients die in spite of aggressive surgery. There is a significant decrease in recurrence and an increase in survival with en bloc resection (EA

  5. Phyllostachys edulis extract induces apoptosis signaling in osteosarcoma cells, associated with AMPK activation

    PubMed Central

    Chou, Chi-Wen; Cheng, Ya-Wen; Tsai, Chung-Hung

    2014-01-01

    Objective Bamboo is distributed worldwide, and its different parts are used as foods or as a traditional herb. Recently, antitumoral effects of bamboo extracts on several tumors have been increasingly reported; however, antitumoral activity of bamboo extracts on osteosarcoma remains unclear. In the present study, we investigated effects of an aqueous Phyllostachys edulis leaf extract (PEE) on osteosarcoma cells and the underlying mechanism of inhibition. Methods The growth of human osteosarcoma cell lines 143B and MG-63 and lung fibroblast MRC-5 cells was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Apoptosis was demonstrated using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay and flow cytometric analysis. Phosphorylation and protein levels were determined by immunoblotting. Results After treatment with PEE, viability of 143B and MG-63 cells was dose-dependently reduced to 36.3%±1.6% of control values, which were similar to AICAR (5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside) treatments. In parallel, ratios of apoptotic cells and cells in the sub-G1 phase were significantly increased. Further investigation showed that PEE treatments led to activation of caspase cascades and changes of apoptotic mediators Bcl2, Bax, and p53. Consistently, our results revealed that PEE activated adenosine monophosphate-activated protein kinase (AMPK) signaling, and the AMPK activation was associated with the induction of apoptotic signaling. Conclusion Our results indicated that PEE suppressed the growth of 143B and MG-63 cells but moderately affected MRC-5 cells. PEE-induced apoptosis may attribute to AMPK activation and the following activation of apoptotic signaling cascades. These findings revealed that PEE possesses antitumoral activity on human osteosarcoma cells by manipulating AMPK signaling, suggesting that PEE alone or combined with regular antitumor drugs may be beneficial as osteosarcoma

  6. Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity: The Rizzoli experience in 20 cases

    SciTech Connect

    Bacci, Gaetano . E-mail: gaetano.bacci@ior.it; Longhi, Alessandra; Forni, Cristiana R.N.; Fabbri, Nicola; Briccoli, Antonio; Barbieri, Enza; Mercuri, Mario; Balladelli, Alba B.A.; Ferrari, Stefano; Picci, Piero

    2007-02-01

    Purpose: Evaluate treatment and outcome of 20 patients with radioinduced osteosarcoma (RIO). Because of previous primary tumor treatment, RIO protocols were different from others we used for non-RIO. Patients and Methods: Between 1983 and 1998, we treated 20 RIO patients, ages 4-36 years (mean 16 years), with chemotherapy (two cycles before surgery, three postoperatively). The first preoperative cycle consisted of high-dose Methotrexate (HDMTX)/Cisplatinum (CDP)/Adriamycin (ADM) and the second of HDMTX/CDP/Ifosfamide (IFO). The three postoperative treatments were performed with cycles of MTX/CDP; IFO was used as single agent per cycle repeated three times. Results: Two patients received palliative treatment because their osteosarcoma remained unresectable after preoperative chemotherapy. The remaining 18 patients had surgery (7 amputations, 11 resections); histologic response to preoperative chemotherapy was good in 8 patients, poor in 10. At a mean follow-up of 11 years (range, 7-22 years), 9 patients remained continuously disease-free, 10 died from osteosarcoma and 1 died from a third neoplasm (myeloid acute leukemia). These results are not significantly different from those achieved in 754 patients with conventional osteosarcoma treated in the same period with protocols used for conventional treatment. However, this later group had an 18% 3-year event-free survival after treatment of relapse vs. 0% in the RIO group. Conclusion: Treated with neoadjuvant chemotherapy RIO seem to have an outcome that is not significantly different from that of comparable patients with conventional primary high grade osteosarcoma (5-year event-free survival: 40% vs. 60%, p = NS; 5-year overall survival 40% vs. 67%, p < 0.00008.

  7. Coexistence of HER2, Ki67, and p53 in Osteosarcoma: A Strong Prognostic Factor

    PubMed Central

    Mardanpour, Keykhosro; Rahbar, Mahtab; Mardanpour, Sourena

    2016-01-01

    Background: Many laboratories are currently evaluating the usefulness of the determination of human epidermal growth factor receptor 2 (HER2), p53, and Ki67 proliferation indices using immunohistochemical techniques in cancer. Although the available studies suggest that these factors might indeed be helpful in making treatment decisions in osteosarcoma patients, their clinical usefulness is still controversial. Aims: We proposed to introduce the value of the coexistence of HER2 overexpression, p53 protein accumulation, and Ki67 in osteosarcoma, which could be a prognostic factor in osteosarcoma. Material and Methods: Expression of HER2, p53, and Ki67 was examined by immunohistochemistry in samples of resected bone tumor tissue from 56 patients with osteosarcoma, obtained between 2009 and 2014 (median follow-up period of 48 months), and their significance for prognosis was analyzed. Results: Of the 56 osteogenic sarcoma tissue samples, 80, 89, and 96.5% were positive for HER2 overexpression, p53 protein accumulation, and Ki67 expression, respectively. Overexpression of HER2 and accumulation of p53 protein significantly correlated with reduced disease-free (P < 0.01) and overall survival (P < 0.003). HER2 and Ki67 co-overexpression significantly correlated with decreased disease-free (P < 0.03) and overall survival (P < 0.02). HER2, accumulation of p53 protein, and Ki67 co-overexpression significantly correlated with reduced disease-free (P < 0.01) and overall survival (P < 0.005) as did patients with larger tumor size, high grade of tumor, positive lymph node, and metastasis status within the specified period of follow up. Conclusions: We found evidence that coexistence of HER2 and Ki67 overexpression and p53 protein accumulation predict the development of lymph node involvement and metastases in patients with high-grade osteosarcoma and were significantly associated with reduced survival. PMID:27298815

  8. Towards a Drug Development Path that Targets Metastatic Progression in Osteosarcoma

    PubMed Central

    Khanna, Chand; Fan, Timothy M.; Gorlick, Richard; Helman, Lee J; Kleinerman, Eugenie S.; Adamson, Peter C.; Houghton, Peter J.; Tap, William D.; Welch, Danny R.; Steeg, Patricia S.; Merlino, Glenn; Sorensen, Poul HB; Kirsch, David G.; Janeway, Katherine A.; Weigel, Brenda; Randall, R. Lor; Meltzer, Paul; Withrow, Stephen J; Paoloni, Melissa; Kaplan, Rosandra N.; Teicher, Beverly A.; Seibel, Nita L.; Üren, Aykut; Patel, Shreyaskumar R.; Trent, Jeffrey; Savage, Sharon A.; Mirabello, Lisa; Reinke, Denise; Barkauskas, Donald A.; Krailo, Mark; Smith, Malcolm A.; Bernstein, Mark

    2014-01-01

    Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in osteosarcoma patients. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for osteosarcoma patients in over 30 years. Based on our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda Maryland. The goal of this meeting was to provide a “Perspective” that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: That the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data is needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micro-metastatic disease setting. PMID:24803583

  9. Relationship Between P15 Gene Mutation and Formation and Metastasis of Malignant Osteosarcoma

    PubMed Central

    Yu, ChangShui; Wang, WenBo

    2016-01-01

    Background As a type of primary malignant bone tumor, osteosarcoma has high incidence and poor prognosis, and is predisposed for pulmonary metastasis. The abnormal expression of P15 gene directly participates in the invasion of various cancers. Therefore, this study investigated the gene mutation of P15 in both primary lesion and pulmonary metastasis lesion of osteosarcoma in a rat model, in an attempt to elucidate the value of P15 gene as a biological marker. Material/Methods A total of 60 SD rats were randomly divided into 2 groups. Model rats had injection of osteosarcoma UMR-106 cells (5×106) inoculated underneath the right forelimb skin, while control rats received saline injection instead. Six rats were sacrificed after 0, 1, 2, 4, and 6 weeks of the inoculation. Tissue samples from inoculation sites and lungs were extracted for measuring the tumor size. SP immunohistochemical (IHC) staining was used to detect the positive expression rate, while P15 gene mutation was detected by PCR method. Results With the elongation of inoculation time, tumor size was significantly increased (p<0.05). The positive expression rates in both primary and pulmonary metastasis lesions were also significantly elevated (p<0.05). The occurrence rate of P15 gene mutation in model rats was significantly elevated and showed a correlation with the tumor formation (r=0.998, p<0.05). Conclusions The P15 gene mutation was significantly correlated with osteosarcoma formation and metastasis towards the pulmonary tissue, suggesting its potency as a novel biological marker for early diagnosis of osteosarcoma. PMID:26921270

  10. The HSP90 inhibitor alvespimycin enhances the potency of telomerase inhibition by imetelstat in human osteosarcoma.

    PubMed

    Hu, Yafang; Bobb, Daniel; He, Jianping; Hill, D Ashley; Dome, Jeffrey S

    2015-01-01

    The unsatisfactory outcomes for osteosarcoma necessitate novel therapeutic strategies. This study evaluated the effect of the telomerase inhibitor imetelstat in pre-clinical models of human osteosarcoma. Because the chaperone molecule HSP90 facilitates the assembly of telomerase protein, the ability of the HSP90 inhibitor alvespimycin to potentiate the effect of the telomerase inhibitor was assessed. The effect of single or combined treatment with imetelstat and alvespimycin on long-term growth was assessed in osteosarcoma cell lines (143B, HOS and MG-63) and xenografts derived from 143B cells. Results indicated that imetelstat as a single agent inhibited telomerase activity, induced telomere shortening, and inhibited growth in all 3 osteosarcoma cell lines, though the bulk cell cultures did not undergo growth arrest. Combined treatment with imetelstat and alvespimycin resulted in diminished telomerase activity and shorter telomeres compared to either agent alone as well as higher levels of γH2AX and cleaved caspase-3, indicative of increased DNA damage and apoptosis. With dual telomerase and HSP90 inhibition, complete growth arrest of bulk cell cultures was achieved. In xenograft models, all 3 treatment groups significantly inhibited tumor growth compared with the placebo-treated control group, with the greatest effect seen in the combined treatment group (imetelstat, p = 0.045, alvespimycin, p = 0.034; combined treatment, p = 0.004). In conclusion, HSP90 inhibition enhanced the effect of telomerase inhibition in pre-clinical models of osteosarcoma. Dual targeting of telomerase and HSP90 warrants further investigation as a therapeutic strategy. PMID:25920748

  11. Up-regulated isocitrate dehydrogenase 1 suppresses proliferation, migration and invasion in osteosarcoma: In vitro and in vivo

    PubMed Central

    Hu, Xiang; Liu, Yang; Qin, Chunxia; Pan, Zhenyu; Luo, Jun; Yu, Aixi; Cheng, Zhen

    2015-01-01

    Very few studies have been reported the function of wild type IDH1 in tumor progress. Previously, we reported that IDH1 correlated with pathological grade and metastatic potential inversely in human osteosarcoma. Here, IDH1 was found lower expressed in osteosarcoma tissues than that of adjacent normal bone tissues. In addition, we observed in vitro anti-proliferation and pro-apoptosis effects of up-regulated IDH1 on osteosarcoma cell lines. The migration and invasion activity was also markedly reduced by IDH1 up-regulation. Unexpectedly, IDH1 up-regulation also suppressed tumor growth and metastasis in vivo. Therefore, IDH1 may represent a potential novel treatment and preventive strategy for osteosarcoma. PMID:24368190

  12. Radiation-induced osteosarcomas in the pediatric population

    SciTech Connect

    Koshy, Matthew; Paulino, Arnold C. . E-mail: apaulino@tmh.tmc.edu; Mai, Wei Y.; Teh, Bin S.

    2005-11-15

    Purpose: Radiation-induced osteosarcomas (R-OS) have historically been high-grade, locally invasive tumors with a poor prognosis. The purpose of this study was to perform a comprehensive literature review and analysis of reported cases dealing with R-OS in the pediatric population to identify the characteristics, prognostic factors, optimal treatment modalities, and overall survival of these patients. Methods and Materials: A MEDLINE/PubMed search of articles written in the English language dealing with OSs occurring after radiotherapy (RT) in the pediatric population yielded 30 studies from 1981 to 2004. Eligibility criteria included patients <21 years of age at the diagnosis of the primary cancer, cases satisfying the modified Cahan criteria, and information on treatment outcome. Factors analyzed included the type of primary cancer treated with RT, the radiation dose and beam energy, the latency period between RT and the development of R-OS, and the treatment, follow-up, and final outcome of R-OS. Results: The series included 109 patients with a median age at the diagnosis of primary cancer of 6 years (range, 0.08-21 years). The most common tumors treated with RT were Ewing's sarcoma (23.9%), rhabdomyosarcoma (17.4%), retinoblastoma (12.8%), Hodgkin's disease (9.2%), brain tumor (8.3%), and Wilms' tumor (6.4%). The median radiation dose was 47 Gy (range, 15-145 Gy). The median latency period from RT to the development of R-OS was 100 months (range, 36-636 months). The median follow-up after diagnosis of R-OS was 18 months (1-172 months). The 3- and 5-year cause-specific survival rate was 43.6% and 42.2%, respectively, and the 3- and 5-year overall survival rate was 41.7% and 40.2%, respectively. Variables, including age at RT, primary site, type of tumor treated with RT, total radiation dose, and latency period did not have a significant effect on survival. The 5-year cause-specific and overall survival rate for patients who received treatment for R-OS involving

  13. A systems biology approach reveals common metastatic pathways in osteosarcoma

    PubMed Central

    2012-01-01

    Background Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The survival rate of patients with metastatic disease remains very dismal. Nevertheless, metastasis is a complex process and a single-level analysis is not likely to identify its key biological determinants. In this study, we used a systems biology approach to identify common metastatic pathways that are jointly supported by both mRNA and protein expression data in two distinct human metastatic OS models. Results mRNA expression microarray and N-linked glycoproteomic analyses were performed on two commonly used isogenic pairs of human metastatic OS cell lines, namely HOS/143B and SaOS-2/LM7. Pathway analysis of the differentially regulated genes and glycoproteins separately revealed pathways associated to metastasis including cell cycle regulation, immune response, and epithelial-to-mesenchymal-transition. However, no common significant pathway was found at both genomic and proteomic levels between the two metastatic models, suggesting a very different biological nature of the cell lines. To address this issue, we used a topological significance analysis based on a “shortest-path” algorithm to identify topological nodes, which uncovered additional biological information with respect to the genomic and glycoproteomic profiles but remained hidden from the direct analyses. Pathway analysis of the significant topological nodes revealed a striking concordance between the models and identified significant common pathways, including “Cytoskeleton remodeling/TGF/WNT”, “Cytoskeleton remodeling/Cytoskeleton remodeling”, and “Cell adhesion/Chemokines and adhesion”. Of these, the “Cytoskeleton remodeling/TGF/WNT” was the top ranked common pathway from the topological analysis of the genomic and proteomic profiles in the two metastatic models. The up-regulation of proteins in the “Cytoskeleton remodeling/TGF/WNT” pathway in the SaOS-2/LM7 and HOS/143B models

  14. Fluoroquinolone-mediated inhibition of cell growth, S-G2/M cell cycle arrest, and apoptosis in canine osteosarcoma cell lines.

    PubMed

    Seo, Kyoung won; Holt, Roseline; Jung, Yong-Sam; Rodriguez, Carlos O; Chen, Xinbin; Rebhun, Robert B

    2012-01-01

    Despite significant advancements in osteosarcoma research, the overall survival of canine and human osteosarcoma patients has remained essentially static over the past 2 decades. Post-operative limb-spare infection has been associated with improved survival in both species, yet a mechanism for improved survival has not been clearly established. Given that the majority of canine osteosarcoma patients experiencing post-operative infections were treated with fluoroquinolone antibiotics, we hypothesized that fluoroquinolone antibiotics might directly inhibit the survival and proliferation of canine osteosarcoma cells. Ciprofloxacin or enrofloxacin were found to inhibit p21(WAF1) expression resulting in decreased proliferation and increased S-G(2)/M accumulation. Furthermore, fluoroquinolone exposure induced apoptosis of canine osteosarcoma cells as demonstrated by cleavage of caspase-3 and PARP, and activation of caspase-3/7. These results support further studies examining the potential impact of quinolones on survival and proliferation of osteosarcoma. PMID:22927942

  15. Fluoroquinolone-Mediated Inhibition of Cell Growth, S-G2/M Cell Cycle Arrest, and Apoptosis in Canine Osteosarcoma Cell Lines

    PubMed Central

    Seo, Kyoung won; Holt, Roseline; Jung, Yong-Sam; Rodriguez, Carlos O.; Chen, Xinbin; Rebhun, Robert B.

    2012-01-01

    Despite significant advancements in osteosarcoma research, the overall survival of canine and human osteosarcoma patients has remained essentially static over the past 2 decades. Post-operative limb-spare infection has been associated with improved survival in both species, yet a mechanism for improved survival has not been clearly established. Given that the majority of canine osteosarcoma patients experiencing post-operative infections were treated with fluoroquinolone antibiotics, we hypothesized that fluoroquinolone antibiotics might directly inhibit the survival and proliferation of canine osteosarcoma cells. Ciprofloxacin or enrofloxacin were found to inhibit p21WAF1 expression resulting in decreased proliferation and increased S-G2/M accumulation. Furthermore, fluoroquinolone exposure induced apoptosis of canine osteosarcoma cells as demonstrated by cleavage of caspase-3 and PARP, and activation of caspase-3/7. These results support further studies examining the potential impact of quinolones on survival and proliferation of osteosarcoma. PMID:22927942

  16. Lifetime effectiveness of mifamurtide addition to chemotherapy in nonmetastatic and metastatic osteosarcoma: a Markov process model analysis.

    PubMed

    Song, Hyun Jin; Lee, Jun Ah; Han, Euna; Lee, Eui-Kyung

    2015-09-01

    The mortality and progression rates in osteosarcoma differ depending on the presence of metastasis. A decision model would be useful for estimating long-term effectiveness of treatment with limited clinical trial data. The aim of this study was to explore the lifetime effectiveness of the addition of mifamurtide to chemotherapy for patients with metastatic and nonmetastatic osteosarcoma. The target population was osteosarcoma patients with or without metastasis. A Markov process model was used, whose time horizon was lifetime with a starting age of 13 years. There were five health states: disease-free (DF), recurrence, post-recurrence disease-free, post-recurrence disease-progression, and death. Transition probabilities of the starting state, DF, were calculated from the INT-0133 clinical trials for chemotherapy with and without mifamurtide. Quality-adjusted life-years (QALY) increased upon addition of mifamurtide to chemotherapy by 10.5 % (10.13 and 9.17 QALY with and without mifamurtide, respectively) and 45.2 % (7.23 and 4.98 QALY with and without mifamurtide, respectively) relative to the lifetime effectiveness of chemotherapy in nonmetastatic and metastatic osteosarcoma, respectively. Life-years gained (LYG) increased by 10.1 % (13.10 LYG with mifamurtide and 11.90 LYG without mifamurtide) in nonmetastatic patients and 42.2 % (9.43 LYG with mifamurtide and 6.63 LYG without mifamurtide) in metastatic osteosarcoma patients. The Markov model analysis showed that chemotherapy with mifamurtide improved the lifetime effectiveness compared to chemotherapy alone in both nonmetastatic and metastatic osteosarcoma. Relative effectiveness of the therapy was higher in metastatic than nonmetastatic osteosarcoma over lifetime. However, absolute lifetime effectiveness was higher in nonmetastatic than metastatic osteosarcoma. PMID:25835978

  17. Long noncoding RNA FGFR3-AS1 promotes osteosarcoma growth through regulating its natural antisense transcript FGFR3.

    PubMed

    Sun, Jiabing; Wang, Xuming; Fu, Chunjiang; Wang, Xiaoyu; Zou, Jilong; Hua, Hanbing; Bi, Zhenggang

    2016-05-01

    Long noncoding RNAs (lncRNAs), a new class of RNAs with no protein-coding potential, have been reported to have crucial roles in the regulation of a variety of tumors. However, the functions and molecular mechanisms of lncRNAs to osteosarcoma are still largely unknown. The purpose of this study is to examine the expression, functions and molecular mechanisms of a new lncRNA FGFR3 antisense transcript 1 (FGFR3-AS1) in osteosarcoma. The expression of FGFR3-AS1 was examined by real-time quantitative PCR. The regulation of FGFR3 by FGFR3-AS1 was examined by RNase protection assay, real-time quantitative PCR, western blotting, and luciferase reporter assay. The effects of FGFR3-AS1 on osteosarcoma cell proliferation and cell cycle were determined by Cell Counting Kit-8, Ethynyl deoxyuridine incorporation assay and flow cytometry. FGFR3-AS1 was upregulated in osteosarcoma. Increased FGFR3-AS1 expression correlates with large tumor size, advanced Enneking stage, metastasis and poor survival. Through antisense pairing with FGFR3 3'UTR, FGFR3-AS1 increases FGFR3 mRNA stability and upregulates FGFR3 expression. The expression of FGFR3-AS1 and FGFR3 is positively correlated in osteosarcoma tissues. Knockdown of FGFR3-AS1 inhibits the proliferation and cell cycle progression of osteosarcoma cells in vitro. Moreover, knockdown of FGFR3-AS1 inhibits xenograft tumor growth of osteosarcoma cells in vivo. These data demonstrate the mechanisms of how antisense noncoding RNA regulate the expression of sense genes, and show the pivotal functions of FGFR3-AS1 in osteosarcoma. PMID:27022737

  18. (99m)Tc-MDP- and (18F)-FDG-avid florid reactive periostitis ossificans mimicking recurrent osteosarcoma.

    PubMed

    Byun, Byung Hyun; Koh, Jae-Soo; Yoo, Ji Young; Lim, Sang Moo; Kong, Chang-Bae

    2013-06-01

    Florid reactive periostitis ossificans is a rare benign lesion usually affecting the tubular bones of the hands and feet, and its histological features may be confused with those of infection and osteosarcoma. We report a case with florid reactive periostitis ossificans of the femur showing increased tracer uptake on both Tc-MDP bone scan and F-FDG PET/CT mimicking a local recurrence in a 15-year-old patient with high-grade osteosarcoma. PMID:23603597

  19. miR-125b suppresses the proliferation and migration of osteosarcoma cells through down-regulation of STAT3

    SciTech Connect

    Liu, Li-hong; Li, Hui; Li, Jin-ping; Zhong, Hui; Zhang, Han-chon; Chen, Jia; Xiao, Tao

    2011-12-09

    Highlights: Black-Right-Pointing-Pointer miR-125b is frequently down-regulated in osteosarcoma samples and human osteosarcoma cell lines. Black-Right-Pointing-Pointer Ectopic restoration of miR-125b suppresses cell proliferation and migration in vitro. Black-Right-Pointing-Pointer STAT3 is the direct and functional downstream target of miR-125b. Black-Right-Pointing-Pointer STAT3 can bind to the promoter region of miR-125b and serves as a transactivator. -- Abstract: There is accumulating evidence that microRNAs are involved in multiple processes in development and tumor progression. Abnormally expressed miR-125b was found to play a fundamental role in several types of cancer; however, whether miR-125b participates in regulating the initiation and progress of osteosarcoma still remains unclear. Here we demonstrate that miR-125b is frequently down-regulated in osteosarcoma samples and human osteosarcoma cell lines. The ectopic restoration of miR-125b expression in human osteosarcoma cells suppresses proliferation and migration in vitro and inhibits tumor formation in vivo. We further identified signal transducer and activator of transcription 3 (STAT3) as the direct and functional downstream target of miR-125b. Interestingly, we discovered that the expression of miR-125b is regulated by STAT3 at the level of transcription. STAT3 binds to the promoter region of miR-125b in vitro and serves as a transactivator. Taken together, our findings point to an important role in the molecular etiology of osteosarcoma and suggest that miR-125b is a potential target in the treatment of osteosarcoma.

  20. Imatinib Mesylate Exerts Anti-Proliferative Effects on Osteosarcoma Cells and Inhibits the Tumour Growth in Immunocompetent Murine Models

    PubMed Central

    Ory, Benjamin; Charrier, Céline; Brion, Régis; Blanchard, Frederic; Redini, Françoise; Heymann, Dominique

    2014-01-01

    Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients

  1. Impaired cell cycle regulation of the osteoblast-related heterodimeric transcription factor Runx2-Cbfbeta in osteosarcoma cells.

    PubMed

    San Martin, Inga A; Varela, Nelson; Gaete, Marcia; Villegas, Karina; Osorio, Mariana; Tapia, Julio C; Antonelli, Marcelo; Mancilla, Edna E; Pereira, Barry P; Nathan, Saminathan S; Lian, Jane B; Stein, Janet L; Stein, Gary S; van Wijnen, Andre J; Galindo, Mario

    2009-12-01

    Bone formation and osteoblast differentiation require the functional expression of the Runx2/Cbfbeta heterodimeric transcription factor complex. Runx2 is also a suppressor of proliferation in osteoblasts by attenuating cell cycle progression in G(1). Runx2 levels are modulated during the cell cycle, which are maximal in G(1) and minimal beyond the G(1)/S phase transition (S, G(2), and M phases). It is not known whether Cbfbeta gene expression is cell cycle controlled in preosteoblasts nor how Runx2 or Cbfbeta are regulated during the cell cycle in bone cancer cells. We investigated Runx2 and Cbfbeta gene expression during cell cycle progression in MC3T3-E1 osteoblasts, as well as ROS17/2.8 and SaOS-2 osteosarcoma cells. Runx2 protein levels are reduced as expected in MC3T3-E1 cells arrested in late G(1) (by mimosine) or M phase (by nocodazole), but not in cell cycle arrested osteosarcoma cells. Cbfbeta protein levels are cell cycle independent in both osteoblasts and osteosarcoma cells. In synchronized MC3T3-E1 osteoblasts progressing from late G1 or mitosis, Runx2 levels but not Cbfbeta levels are cell cycle regulated. However, both factors are constitutively elevated throughout the cell cycle in osteosarcoma cells. Proteasome inhibition by MG132 stabilizes Runx2 protein levels in late G(1) and S in MC3T3-E1 cells, but not in ROS17/2.8 and SaOS-2 osteosarcoma cells. Thus, proteasomal degradation of Runx2 is deregulated in osteosarcoma cells. We propose that cell cycle control of Runx2 gene expression is impaired in osteosarcomas and that this deregulation may contribute to the pathogenesis of osteosarcoma. PMID:19739101

  2. CXCR4-targeted near-infrared imaging allows detection of orthotopic and metastatic human osteosarcoma in a mouse model.

    PubMed

    Guan, Guofeng; Lu, Yao; Zhu, Xiaodong; Liu, Lijuan; Chen, Jie; Ma, Qiong; Zhang, Yinglong; Wen, Yanhua; Yang, Lianjia; Liu, Tao; Wang, Wei; Ran, Henry; Qiu, Xiuchun; Ke, Shi; Zhou, Yong

    2015-01-01

    CXCR4 is expressed at primary and metastatic sites of osteosarcoma. We developed a novel CXCR4-targeted near-infrared (NIR) fluorescent imaging agent (referred to as CXCR4-IR-783). The binding to representative osteosarcoma cells (F5M2 and F4 for high- and low- CXCR4 expression) was examined. CXCR4-IR-783 fluorescence was also examined in a mouse xenograft model of human osteosarcoma using NIR fluorescence microscopy and a Kodak in-vivo multispectral system. Pulmonary metastases in mice bearing osteosarcoma xenografts were detected by micro CT, (18)F-PET scan and NIR imaging scan. Briefly, the binding of CXCR4-IR-783 was significantly higher in F5M2 than in F4 cells. Intense NIR fluorescence signals were detected in osteosarcoma xenografts, with signal/background ratio at 4.87 in mice bearing the F5M2 cell. At 4 weeks after F5M2 cell inoculation, metastatic lesions in the lungs were detectable using CXCR4-IR-783 and micro-CT scan, but not with (18)F-FDG PET scan. In conclusion, CXCR4-IR-783 is a promising tool for detection of high CXCR4-expressing osteosarcoma, and particularly for its metastatic lesions. PMID:26472699

  3. Antibacterial Activity of Elephant Garlic and Its Effect against U2OS Human Osteosarcoma Cells

    PubMed Central

    Huang, Zehao; Ren, Jianwu

    2013-01-01

    Objective(s): The present study was designed to investigate the antibacterial function and pharmacological effect of elephant garlic (Allium ampeloprasum var. ampeloprasum) on U2OS human osteosarcoma cells. Materials and Methods: Seven kinds of bacteria were reconstituted, inoculated and tested in this research to evaluate elephant garlic antibacterial activity. By the means of FACS analysis, cell proliferation assay, confocal laser scanning microscopy and Transwell migration assays, the effect of elephant garlic against U2OS human osteosarcoma cells was unveiled. Rerults: The antimicrobial activity of elephant garlic was stronger than ampicillin when used against Escherichia coli, Bacillus subtilis, Bacillus thuringiensis, Staphylococcus actinomycetes, and gray actinomycetes. Even at a very low concentration (12.5%), elephant garlic still had an antibacterial effect on common bacteria E. coli and S. aureus. The G0/G1 ratio of elephant garlic treated group cells increased while S phase decreased. Elephant garlic extract inhibited the growth of human osteosarcoma cells, U2OS, through preventing the transition from G1 phase to S phase. It reduced osteosarcoma cell, U2OS, invasion ability and significantly increased the proportion of apoptosis. It significantly affected the cytoskeleton generation. Conclusion: Elephant garlic exhibits antibacterial property and has an inhibitory effect on osteosarcoma cells (U2OS) proliferation and cell activity, suggesting the mechanism of its anticancer effects on U2OS human osteosarcoma cells. PMID:24379966

  4. CCL3 promotes angiogenesis by dysregulation of miR-374b/ VEGF-A axis in human osteosarcoma cells

    PubMed Central

    Chou, Pei-Yu; Wang, Shih-Wei; Chen, Hsien-Te; Lin, Yu-Min; Chiang, I-Ping; Chang, Tzu-Ming; Hsu, Shao-Keh; Chou, Ming-Chih; Tang, Chih-Hsin; Fong, Yi-Chin

    2016-01-01

    Osteosarcoma is the most frequent bone tumor, characterized by a high metastatic potential. However, the crosstalk between chemokine (C-C motif) ligand 3 (CCL3), which facilitates tumor progression and metastasis. Vascular endothelial growth factor-A (VEGF-A), an angiogenesis inducer and a highly specific mitogen for endothelial cells, has not been well explored in human osteosarcoma. Here we demonstrate the correlation of CCL3 and VEGF-A expressions, quantified by immunohistochemistry, with the tumor stage of human osteosarcoma tissues. Furthermore, CCL3 promotes VEGF-A expression in human osteosarcoma cells that subsequently induces human endothelial progenitor cell (EPC) migration and tube formation. Phosphorylation of JNK, ERK, and p38 was found after CCL3 stimulation. In addition, JNK, ERK, and p38 inhibitors also abolished CCL3-induced VEGF-A expression and angiogenesis. We noted that CCL3 reduces the expression of miR-374b and miR-374b mimic by reversing CCL3-promoted VEGF-A expression and angiogenesis in vitro and in vivo. This study shows that CCL3 promotes VEGF-A expression and angiogenesis in human osteosarcoma cells by down-regulating miR-374b expression via JNK, ERK, and p38 signaling pathways. Thus, CCL3 may be a new molecular therapeutic target in osteosarcoma angiogenesis and metastasis. PMID:26713602

  5. Human osteosarcoma CD49f−CD133+ cells: impaired in osteogenic fate while gain of tumorigenicity

    PubMed Central

    Ying, Meidan; Liu, Gang; Shimada, Hiroyuki; Ding, Wanjing; May, William A.; He, Qiaojun; Adams, Gregor B.; Wu, Lingtao

    2014-01-01

    The biological relationships among self-renewal, tumorigenicity, and lineage differentiation of human osteosarcoma-initiating cells (OSIC) remain elusive, making it difficult to identify and distinguish OSIC from osteosarcoma-forming cells (OSFC) for developing OSIC-targeted therapies. Using a new inverse lineage tracking strategy coupled with serial human-to-mouse xenotransplantation, we identified a subpopulation of osteosarcoma cells with OSIC-like properties and sought to distinguish them from their progeny, OSFC. We found that serial transplantation of cells from different osteosarcoma cell lines and primary osteosarcoma tissues progressively increased the CD49f+ subpopulation composing the bulk of the osteosarcoma mass. These CD49f+ cells displayed characteristics of OSFC: limited in vivo tumorigenicity, weak lineage differentiation, more differentiated osteogenic feature, and greater chemo-sensitivity. By contrast, their parental CD49f−CD133+ cells had an inhibited osteogenic fate, together with OSIC-like properties of self-renewal, strong tumorigenicity, and differentiation to CD49f+ progeny. Hence, the CD49f−CD133+ phenotype appears to identify OSIC-like cells that possess strong tumorigenicity correlated with an impaired osteogenic fate and the ability to initiate tumor growth through generation of CD49f+ progeny. These findings advance our understanding of OSIC-like properties and, for the first time, provide a much-needed distinction between OSIC and OSFC in this cancer. PMID:23045288

  6. Fibroblastic growth factor receptor 1 amplification in osteosarcoma is associated with poor response to neo-adjuvant chemotherapy.

    PubMed

    Fernanda Amary, M; Ye, Hongtao; Berisha, Fitim; Khatri, Bhavisha; Forbes, Georgina; Lehovsky, Katie; Frezza, Anna M; Behjati, Sam; Tarpey, Patrick; Pillay, Nischalan; Campbell, Peter J; Tirabosco, Roberto; Presneau, Nadège; Strauss, Sandra J; Flanagan, Adrienne M

    2014-08-01

    Osteosarcoma, the most common primary bone sarcoma, is a genetically complex disease with no widely accepted biomarker to allow stratification of patients for treatment. After a recent report of one osteosarcoma cell line and one tumor exhibiting fibroblastic growth factor receptor 1 (FGFR1) gene amplification, the aim of this work was to assess the frequency of FGFR1 amplification in a larger cohort of osteosarcoma and to determine if this biomarker could be used for stratification of patients for treatment. About 352 osteosarcoma samples from 288 patients were analyzed for FGFR1 amplification by interphase fluorescence in situ hybridization. FGFR1 amplification was detected in 18.5% of patients whose tumors revealed a poor response to chemotherapy, and no patients whose tumors responded well to therapy harbored this genetic alteration. FGFR1 amplification is present disproportionately in the rarer histological variants of osteosarcoma. This study provides a rationale for inclusion of patients with osteosarcoma in clinical trials using FGFR kinase inhibitors. PMID:24861215

  7. Apurinic/apyrimidinic endonuclease 1 regulates angiogenesis in a transforming growth factor β-dependent manner in human osteosarcoma

    PubMed Central

    Jiang, Xuan; Shan, Jinlu; Dai, Nan; Zhong, Zhaoyang; Qing, Yi; Yang, Yuxing; Zhang, Shiheng; Li, Chongyi; Sui, Jiangdong; Ren, Tao; Li, Mengxia; Wang, Dong

    2015-01-01

    Angiogenesis plays an important role in tumor growth and metastasis and has been reported to be inversely correlated with overall survival of osteosarcoma patients. It has been shown that apurinic/apyrimidinic endonuclease 1 (APE1), a dually functional protein possessing both base excision repair and redox activities, is involved in tumor angiogenesis, although these mechanisms are not fully understood. Our previous study showed that the expression of transforming growth factor β (TGFβ) was significantly reduced in APE1-deficient osteosarcoma cells. Transforming growth factor β promotes cancer metastasis through various mechanisms including immunosuppression, angiogenesis, and invasion. In the current study, we initially revealed that APE1, TGFβ, and microvessel density (MVD) have pairwise correlation in osteosarcoma tissue samples, whereas TGFβ, tumor size, and MVD were inversely related to the prognosis of the cohort. We found that knocking down APE1 in osteosarcoma cells resulted in TGFβ downregulation. In addition, APE1-siRNA led to suppression of angiogenesis in vitro based on HUVECs in Transwell and Matrigel tube formation assays. Reduced secretory protein level of TGFβ of culture medium also resulted in decreased phosphorylation of Smad3 of HUVECs. In a mouse xenograft model, siRNA-mediated silencing of APE1 downregulated TGFβ expression, tumor size, and MVD. Collectively, the current evidence indicates that APE1 regulates angiogenesis in osteosarcoma by controlling the TGFβ pathway, suggesting a novel target for anti-angiogenesis therapy in human osteosarcoma. PMID:26250694

  8. Osteosarcoma tissues and cell lines from patients with differing serum alkaline phosphatase concentrations display minimal differences in gene expression patterns.

    PubMed

    Rodrigues, L C de Sá; Holmes, K E; Thompson, V; Piskun, C M; Lana, S E; Newton, M A; Stein, T J

    2016-06-01

    Serum alkaline phosphatase (ALP) concentration is a prognostic factor for osteosarcoma in multiple studies, although its biological significance remains incompletely understood. To determine whether gene expression patterns differed in osteosarcoma from patients with differing serum ALP concentrations, microarray analysis was performed on 18 primary osteosarcoma samples and six osteosarcoma cell lines from dogs with normal and increased serum ALP concentration. No differences in gene expression patterns were noted between tumours or cell lines with differing serum ALP concentration using a gene-specific two-sample t-test. Using a more sensitive empirical Bayes procedure, defective in cullin neddylation 1 domain containing 1 (DCUN1D1) was increased in both the tissue and cell lines of the normal ALP group. Using quantitative PCR (qPCR), differences in DCUN1D1 expression between the two groups failed to reach significance. The homogeneity of gene expression patterns of osteosarcoma associated differing serum ALP concentrations are consistent with previous studies suggesting serum ALP concentration is not associated with intrinsic differences of osteosarcoma cells. PMID:25643733

  9. Sunitinib malate (SU-11248) reduces tumour burden and lung metastasis in an intratibial human xenograft osteosarcoma mouse model

    PubMed Central

    Kumar, Ram Mohan Ram; Arlt, Matthias JE; Kuzmanov, Aleksandar; Born, Walter; Fuchs, Bruno

    2015-01-01

    Osteosarcoma is a rare type of cancer that commonly occurs as a primary bone tumour in children and adolescents and is associated with a poor clinical outcome. Despite complex treatment protocols, including chemotherapy combined with surgical resection, the prognosis for patients with osteosarcoma and metastases remains poor and more effective therapies are required. In this study, we evaluated the therapeutic efficacy of sunitinib malate, a wide-spectrum tyrosine kinase inhibitor, in a preclinical mouse model of osteosarcoma. Sunitinib significantly inhibited proliferation, provoked apoptosis and induced G2/M cell cycle arrest in the human osteosarcoma cell lines SaOS-2 and 143B in vitro. Importantly, sunitinib treatment significantly reduced tumour burden, microvessel density and suppressed pulmonary metastasis in a 143B cell-derived intratibial osteosarcoma model in SCID mice. Sunitinib significantly decreased primary tumor tissue proliferation and reduced tumor vasculature. Our study indicates that sunitinib has potential for effective treatment of metastasizing osteosarcoma and provides the framework for future clinical trials with sunitinib alone or in combination with conventional and other novel therapeutics aiming at increased treatment efficacy and improved patient outcome. PMID:26328246

  10. Fibroblastic growth factor receptor 1 amplification in osteosarcoma is associated with poor response to neo-adjuvant chemotherapy

    PubMed Central

    Fernanda Amary, M; Ye, Hongtao; Berisha, Fitim; Khatri, Bhavisha; Forbes, Georgina; Lehovsky, Katie; Frezza, Anna M; Behjati, Sam; Tarpey, Patrick; Pillay, Nischalan; Campbell, Peter J; Tirabosco, Roberto; Presneau, Nadège; Strauss, Sandra J; Flanagan, Adrienne M

    2014-01-01

    Osteosarcoma, the most common primary bone sarcoma, is a genetically complex disease with no widely accepted biomarker to allow stratification of patients for treatment. After a recent report of one osteosarcoma cell line and one tumor exhibiting fibroblastic growth factor receptor 1 (FGFR1) gene amplification, the aim of this work was to assess the frequency of FGFR1 amplification in a larger cohort of osteosarcoma and to determine if this biomarker could be used for stratification of patients for treatment. About 352 osteosarcoma samples from 288 patients were analyzed for FGFR1 amplification by interphase fluorescence in situ hybridization. FGFR1 amplification was detected in 18.5% of patients whose tumors revealed a poor response to chemotherapy, and no patients whose tumors responded well to therapy harbored this genetic alteration. FGFR1 amplification is present disproportionately in the rarer histological variants of osteosarcoma. This study provides a rationale for inclusion of patients with osteosarcoma in clinical trials using FGFR kinase inhibitors. PMID:24861215

  11. miR-203 Acts as a Tumor Suppressor Gene in Osteosarcoma by Regulating RAB22A

    PubMed Central

    Yang, Dawei; Liu, Guangpeng; Wang, Kunzheng

    2015-01-01

    microRNAs (miRNAs), small noncoding RNAs of 19–25 nt, play an important roles in the pathological processes of tumorigenesis. The object of this study was to study the expression and function of miR-203 and to found its target gene in osteosarcoma. In our study, we found the expression level of miR-203 was significantly downregulated in osteosarcoma cell lines and tissues. In addition, overexpression of miR-203 inhibited the osteosarcoma cell proliferation and migration and inhibited Mesenchymal-to-Epithelial reversion Transition (MErT). Moreover, we identified RAB22A as a direct target of miR-203 and RAB22A overexpression blocks the roles of miR-203 in osteosarcoma cell. Furthermore, we demonstrated that RAB22A expression was upregulated in human osteosarcoma cell lines and tissues. Take together, our results demonstrated that miR-203 act as a tumor suppressor miRNA through regulating RAB22A expression and suggested its involvement in osteosarcoma progression and carcinogenesis. PMID:26382657

  12. CXCR4-targeted near-infrared imaging allows detection of orthotopic and metastatic human osteosarcoma in a mouse model

    PubMed Central

    Guan, Guofeng; Lu, Yao; Zhu, Xiaodong; Liu, Lijuan; Chen, Jie; Ma, Qiong; Zhang, Yinglong; Wen, Yanhua; Yang, Lianjia; Liu, Tao; Wang, Wei; Ran, Henry; Qiu, Xiuchun; Ke, Shi; Zhou, Yong

    2015-01-01

    CXCR4 is expressed at primary and metastatic sites of osteosarcoma. We developed a novel CXCR4-targeted near-infrared (NIR) fluorescent imaging agent (referred to as CXCR4-IR-783). The binding to representative osteosarcoma cells (F5M2 and F4 for high- and low- CXCR4 expression) was examined. CXCR4-IR-783 fluorescence was also examined in a mouse xenograft model of human osteosarcoma using NIR fluorescence microscopy and a Kodak in-vivo multispectral system. Pulmonary metastases in mice bearing osteosarcoma xenografts were detected by micro CT, 18F-PET scan and NIR imaging scan. Briefly, the binding of CXCR4-IR-783 was significantly higher in F5M2 than in F4 cells. Intense NIR fluorescence signals were detected in osteosarcoma xenografts, with signal/background ratio at 4.87 in mice bearing the F5M2 cell. At 4 weeks after F5M2 cell inoculation, metastatic lesions in the lungs were detectable using CXCR4-IR-783 and micro-CT scan, but not with 18F-FDG PET scan. In conclusion, CXCR4-IR-783 is a promising tool for detection of high CXCR4-expressing osteosarcoma, and particularly for its metastatic lesions. PMID:26472699

  13. Osteosarcoma tissues and cell lines from patients with differing serum alkaline phosphatase concentrations display minimal differences in gene expression patterns

    PubMed Central

    de Sá Rodrigues, L. C.; Holmes, K. E.; Thompson, V.; Piskun, C. M.; Lana, S. E.; Newton, M. A.; Stein, T. J.

    2016-01-01

    Serum alkaline phosphatase (ALP) concentration is a prognostic factor for osteosarcoma in multiple studies, although its biological significance remains incompletely understood. To determine whether gene expression patterns differed in osteosarcoma from patients with differing serum ALP concentrations, microarray analysis was performed on 18 primary osteosarcoma samples and six osteosarcoma cell lines from dogs with normal and increased serum ALP concentration. No differences in gene expression patterns were noted between tumours or cell lines with differing serum ALP concentration using a gene-specific two-sample t-test. Using a more sensitive empirical Bayes procedure, defective in cullin neddylation 1 domain containing 1 (DCUN1D1) was increased in both the tissue and cell lines of the normal ALP group. Using quantitative PCR (qPCR), differences in DCUN1D1 expression between the two groups failed to reach significance. The homogeneity of gene expression patterns of osteosarcoma associated differing serum ALP concentrations are consistent with previous studies suggesting serum ALP concentration is not associated with intrinsic differences of osteosarcoma cells. PMID:25643733

  14. MicroRNA-34a inhibits human osteosarcoma proliferation by downregulating ether à go-go 1 expression.

    PubMed

    Wu, Xinyu; Zhong, Daixing; Gao, Quan; Zhai, Wenliang; Ding, Zhenqi; Wu, Jin

    2013-01-01

    Aberrant expression of MicroRNAs (miRNAs) has been implicated in several types of cancer. As a direct target gene of p53, miR-34a has been suggested to mediate the tumor suppressor function of p53. Ether à go-go 1 (Eag1) channel is overexpressed in a variety of cancers and plays important roles in cancer progression. However, the link between miR-34a and Eag1 in cancer is unclear. In this study, we used human osteosarcoma as the model to demonstrate that miR-34a was significantly downregulated in osteosarcoma tissues and cell lines compared with normal brain tissues and osteoblastic cell line. Next we evaluated the role of miR-34a in the regulation of osteosarcoma cell proliferation by CCK-8 and colony formation assays. The results showed that overexpression of miR-34a inhibited the proliferation of MG-63 and Saos-2 cells. Furthermore, xenograft nude mice model showed that miR-34a inhibited osteosarcoma growth in vivo. Mechanistically, we found that overexpression of miR-34a led to decreased Eag1 expression in osteosarcoma cells while inhibition of miR-34a increased Eag1 expression. Taken together, our results suggest that miR-34a could inhibit osteosarcoma growth via the down regulation of Eag1 expression. PMID:23569431

  15. GLIPR1 inhibits the proliferation and induces the differentiation of cancer-initiating cells by regulating miR-16 in osteosarcoma.

    PubMed

    Dong, Jian; Bi, Binna; Zhang, Lianhai; Gao, Kaituo

    2016-09-01

    Osteosarcoma is a common, highly malignant and metastatic bone cancer. Elucidation of the molecular mechanisms of osteosarcoma may further help us to understand the pathogenesis of the disease, and offer novel targets for effective therapies. Human glioma pathogenesis-related protein 1 (GLIPR1) has been found to be downregulated in human cancers. However, its roles have not been reported in osteosarcoma. In the present study, we demonstrated that GLIPR1 protein was downregulated in osteosarcoma. Its overexpression inhibited the proliferation, migration and invasion and induced the differentiation of cancer-initiating cells (CICs) in osteosarcoma. Moreover, GLIPR1 overexpression upregulated miR-16 in osteosarcoma cells. The upregulation suppressed proliferation, migration and invasion as well as induced differentiation of CICs in osteosarcoma. Thus, we conclude that GLIPR1 inhibited the proliferation, migration and invasion and induced the differentiation of CICs by regulating miR-16 in osteosarcoma. The present study provides direct evidence that GLIPR1 is a bona fide tumor suppressor and identified GLIPR1 and miR-16 as key components for regulating the proliferation, migration, invasion and CICs in osteosarcoma. PMID:27460987

  16. MicroRNA-144 inhibits the proliferation, apoptosis, invasion, and migration of osteosarcoma cell line F5M2.

    PubMed

    Cui, Shao-Qian; Wang, Huan

    2015-09-01

    This study is aimed to investigate the role of microRNA-144 (miR-144) in osteosarcoma cell line F5M2 proliferation, apoptosis, invasion, and metastasis. Between 2007 and 2014, 66 cases of osteosarcoma samples in the corresponding adjacent normal tissue samples were selected from surgical resection or biopsy in the Department of Orthopedics, Shengjing Hospital, China Medical University. MiR-144 levels and Ezrin messenger RNA (mRNA) levels in osteosarcoma and the adjacent bone tissues were detected, and clinical and pathological features were analyzed. Exogenous miR-144 was transfected into human osteosarcoma cell lines at two different concentrations (low and high), and the expression levels of miR-144 and Ezrin protein between highly metastatic osteosarcoma cells and lowly metastatic osteosarcoma cells were compared. Real-time polymerase chain reaction (RT-PCR) and Western blot were used for detecting the expression levels of miR-144 or Ezrin protein, respectively. Cell proliferation was measured by methylthiazol tetrazolium (MTT) assay. Cell invasion and migration was evaluated by Transwell assays. Finally, flow cytometry was employed to determine the cell apoptosis. MiR-144 expression in osteosarcoma tissue was significantly lower than that in the surrounding normal bone tissue (P < 0.001), while Ezrin mRNA expression in osteosarcoma tissue was significantly higher than that in the surrounding normal bone tissue (P < 0.001); correlation analysis showed a significant negative correlation between miR-144 and Ezrin mRNA levels (r = 0.982, P < 0.001). MiR-144 and Ezrin mRNA expressions were significantly related with cell metastasis (P < 0.05) but were not related with other clinical factors such as gender, age, tumor location, tumor size, Enneking staging, and Dahlin's histological classification. The results of RT-PCR showed that the expression level of miR-144 in osteosarcoma cells increased after transfected with exogenous miR-144 mimics, and

  17. Osteosarcoma of the mandible--second cancer in a case of Hodgkin's lymphoma post-chemotherapy.

    PubMed

    De, Sumitava; Ghosh, Suparna; Mondal, Dodul; Sur, Prabir K

    2010-01-01

    Osteosarcoma as a second cancer occurring in an adolescent male previously treated with only chemotherapy for Hodgkin's lymphoma is rare. A 14 year old male presented with gradual swelling of right jaw and numbness of lip and chin for last three months. He was treated with only chemotherapy for Hodgkin's lymphoma four years back. Incisional biopsy was taken from mandibular swelling, histopathology suggesting osteosarcoma. Right hemimandibulectomy and reconstruction with metallic implant were done along with excision of right parotid lymph node. Chemotherapy was started with cisplatin and doxorubicin regimen. Absence of radiation as a risk factor and very young age of the patient presenting with a second cancer made this case a rarity and hence the case is being reported. PMID:21119269

  18. Aggressive aneurysmal bone cyst of the maxilla confused with telangiectatic osteosarcoma.

    PubMed

    Lee, Hyun-Min; Cho, Kyu-Sup; Choi, Kyung-Un; Roh, Hwan-Jung

    2012-06-01

    Aneurysmal bone cyst (ABC) is a benign, expansile lesion typically affecting the long bones and vertebrae of patients younger than 20 years. Approximately 2% of ABCs occur in the head and neck region, most commonly affecting the mandible. Although the most common co-existing lesion associated with ABCs is the giant cell tumor, ABCs can be radiologically confused with telangiectatic osteosarcoma in cases of aggressive behavior and rapid growth. Here, we report a case of an aggressive ABC of the maxilla confused with telangiectatic osteosarcoma in a patient who underwent several operations for an osteoblastoma that was diagnosed histopathologically. This case highlights the need for a differential diagnosis both radiologically and histopathologically, because ABCs can easily be interpreted as a giant cell tumor or an osteoblastoma, and, on occasion, can be mistaken for osteogenic malignancies. PMID:21862268

  19. Primary bone osteosarcoma in the pediatric age: state of the art.

    PubMed

    Longhi, Alessandra; Errani, Costantino; De Paolis, Massimiliano; Mercuri, Mario; Bacci, Gaetano

    2006-10-01

    The current combination treatment, chemotherapy and surgery, has significantly improved the cure rate and the survival rate of primary bone osteosarcoma. The 5-year survival rate has increased in the last 30 years from 10% to 70%. Even in patients with poor prognosis, such as those with metastases at diagnosis, the 5-year survival rate has reached 20-30% due to chemotherapy and the surgical removal of metastases and primary tumor. However, the most effective drugs are still the same as those employed over the last 20 years as front line neoadjuvant or adjuvant chemotherapy: Doxorubicin, Cisplatin, Methotrexate, Ifosfamide. No standard, second line therapy exists for those who relapse. At relapse, due to the lack of new non-cross-resistant drugs, surgery is still the main option when feasible. Other drugs have been employed in relapsed patients with poor results. This article reviews the state of the art of treatment for bone osteosarcoma in the pediatric age. PMID:16860938

  20. Response of osteosarcoma to preoperative intravenous high-dose methotrexate chemotherapy: CT evaluation

    SciTech Connect

    Mail, J.T.; Cohen, M.D.; Mirkin, L.D.; Provisor, A.J.

    1985-01-01

    The histologic response of an osteosarcoma to preamputation high-dose methotrexate therapy can be used to determine the optimum maintenance chemotherapy regimen to be administered after amputation. This study evaluates computed tomography (CT) as a method of assessing the response of the tumor to the methotrexate therapy. Nine patients with nonmetastatic osteosarcoma of an extremity had a CT scan of the tumor at initial presentation. This was compared with a second CT scan after four courses of high-dose intravenous methotrexate. Each set of scans was evaluated for changes in bony destruction, soft-tissue mass, pattern of calcification, and extent of tumor involvement of the marrow cavity. These findings were correlated with the histologic response of the tumor as measured by the degree of tumor necrosis. The changes seen on CT correlated well with the degree of the histologic response in seven of the nine patients.

  1. Estrogen binding, receptor mRNA, and biologic response in osteoblast-like osteosarcoma cells

    SciTech Connect

    Komm, B.S.; Terpening, C.M.; Benz, D.J.; Graeme, K.A.; Gallegos, A.; Korc, M.; Greene, G.L.; O'Malley, B.W.; Haussler, M.R.

    1988-07-01

    High specific activity estradiol labeled with iodine-125 was used to detect approximately 200 saturable, high-affinity (dissociation constant approximately equal to 1.0 nM) nuclear binding sites in rat (ROS 17/2.8) and human (HOS TE85) clonal osteoblast-like osteosarcoma cells. Of the steroids tested, only testosterone exhibited significant cross-reactivity with estrogen binding. RNA blot analysis with a complementary DNA probe to the human estrogen receptor revealed putative receptor transcripts of 6 to 6.2 kilobases in both rat and human osteosarcoma cells. Type I procollagen and transforming growth factor-beta messenger RNA levels were enhanced in cultured human osteoblast-like cells treated with 1 nM estradiol. Thus, estrogen can act directly on osteoblasts by a receptor-mediated mechanism and thereby modulate the extracellular matrix and other proteins involved in the maintenance of skeletal mineralization and remodeling.

  2. Analysis of serial radionuclide bone images in osteosarcoma and breast carcinoma

    SciTech Connect

    McNeil, B.J.; Hanley, J.

    1980-04-01

    The authors first describe and illustrate didactically the use of the Kaplan-Meier actuarial technique for serial diagnostic studies. They then present an analysis of previously published data on the results of serial radionuclide bone images in patients with osteosarcoma or breast carcinoma, using this technique. The data indicate that patients with osteosarcoma show an almost linear increase in the occurrence of bone metastates between 5 and 29 months after diagnosis; the rate is approximately 1% per month. Patients with breast cancer, on the other hand, show a biphasic rate of development, averaging only 0.5% per month during the first year after diagnosis but increasing rapidly to approximately 2% per month after 15 months.

  3. Absence of hypoxanthine:guanine phosphoribosyltransferase activity in murine Dunn osteosarcoma

    SciTech Connect

    Abelson, H.T.; Gorka, C.

    1983-09-01

    The transplantable murine Dunn osteosarcoma has no detectable hypoxanthine:guanine phosphoribosyltransferase (EC 2.4.2.8) activity. This was established from the tumors directly and from tissue culture cell lines derived from the tumor using a variety of assays: e.g., no (3H)hypoxanthine uptake into tumor or tissue culture cells, no conversion of (3H)hypoxanthine to (3H)IMP by cell extracts from tumors or tissue culture cells, no growth of tissue culture cells in hypoxanthine:aminopterin:thymidine medium, and normal growth of these cells in 10 microM 6-mercaptopurine. Ten human osteosarcomas have been assayed, and two have no apparent hypoxanthine:guanine phosphoribosyltransferase enzyme activity. After high-dose methotrexate treatment in vivo, murine tumors could be selectively killed and normal tissues could be spared by using a rescue regimen of hypoxanthine-thymidine-allopurinol.

  4. Imaging of bone tumors using a monoclonal antibody raised against human osteosarcoma

    SciTech Connect

    Armitage, N.C.; Perkins, A.C.; Pimm, M.V.; Wastie, M.; Hopkins, J.S.; Dowling, F.; Baldwin, R.W.; Hardcastle, J.D.

    1986-07-01

    The radiolabeled monoclonal antibody 791T/36 raised against a human osteosarcoma was injected into 20 patients with known or suspected bone tumors. Gamma camera images were acquired at 48 or 72 hours after injection, and assessed for antibody localization. Positive images were obtained in all five osteosarcomas and four other primary malignant sarcomas. Two of the four other primary bone tumors gave positive images. Three patients with trauma had negative images as did one patient with Paget's disease. Two patients with suppurative disease gave positive images. The antibody localized in the majority of malignant sarcomas tested. In one tumor where tissue was available, a tumor:non-tumor ratio of 2.8:1 was measured. Repeat imaging was performed in five patients. Immunoscintigraphy using the monoclonal antibody 791T/36 has shown tumor localization in patients with bone and soft tissue sarcomas.

  5. Cells of origin in osteosarcoma: mesenchymal stem cells or osteoblast committed cells?

    PubMed

    Mutsaers, Anthony J; Walkley, Carl R

    2014-05-01

    Osteosarcoma is a disease with many complex genetic abnormalities but few well defined genetic drivers of tumor initiation and evolution. The disease is diagnosed and defined through the observation of malignant osteoblastic cells that produce osteoid, however the exact cell of origin for this cancer remains to be definitively defined. Evidence exists to support a mesenchymal stem cell as well as committed osteoblast precursors as the cell of origin. Increasing numbers of experimental models have begun to shed light on to the likely cell population that gives rise to OS in vivo with the weight of evidence favoring an osteoblastic population as the cell of origin. As more information is gathered regarding osteosarcoma initiating cells and how they may relate to the cell of origin we will derive a better understanding of the development of this disease which may ultimately lead to clinical improvements through more personalized therapeutic approaches. PMID:24530473

  6. Trps1 is associated with the multidrug resistance of osteosarcoma by regulating MDR1 gene expression.

    PubMed

    Jia, Ming; Hu, Jing; Li, Weiwei; Su, Peng; Zhang, Hui; Zhang, Xiaofang; Zhou, Gengyin

    2014-03-01

    Multidrug resistance (MDR) is a significant clinical problem in the chemotherapy of osteosarcoma and has been linked to the cellular expression of several multidrug-efflux transporters such as MDR1/P-gp. Our inhibition of the transcription factor Trps1 led to repression of MDR1/P-gp while its overexpression resulted in upregulation of MDR1/P-gp. Flow cytometric analysis suggested Trps1 increased the release of several anti-cancer drugs, thus decreasing their accumulation. Immunohistochemical analysis of clinical samples indicated that the expression of Trps1 directly correlated with MDR1/P-gp. Trps1 inhibited TGFbeta-1 and directly bound to the MDR1 promoter. Our data demonstrate a role for Trps1 in the regulation of MDR1 expression in osteosarcoma. PMID:24491996

  7. Knockdown of Akt Sensitizes Osteosarcoma Cells to Apoptosis Induced by Cisplatin Treatment

    PubMed Central

    Zhang, Guoyou; Li, Ming; Zhu, Xiaodong; Bai, Yushu; Yang, Changwei

    2011-01-01

    Akt plays an important role in the inhibition of apoptosis induced by chemotherapy and other stimuli. We therefore investigated if knockdown of Akt2 promoted drug-induced apoptosis in cultured osteosarcoma cells in vitro. SAOS-2 cells were transfected with Akt2 siRNA. The sensitivity of the transformed cell line to the chemotherapeutic drug cisplatin was assessed. Reduced expression of Akt2 did not directly inhibit the growth rate of the transfected cells; however, it significantly increased their sensitivity to cisplatin. Knockdown of Akt2, together with cisplatin treatment, promoted the expression of p53 up-regulated modulator of apoptosis (PUMA). It is possible that the augmentation of cisplatin cytotoxicity may be mediated by PUMA activation. The results of this study suggest that knockdown of Akt2 expression may have therapeutic applications in enhancing the efficacy of chemotherapy in patients with osteosarcoma. PMID:21686164

  8. Extraosseous osteosarcoma arising in recurrent ossifying fibromyxoid tumor of soft tissue: a case report.

    PubMed

    Shelekhova, Ksenia V; Kazakov, Dmitriĭ V; Michal, Michal

    2013-01-01

    We present a case of an osteosarcoma arising in ossifying fibromyxoid tumor. The patient was a 50-year-old man when an initial tumor was identified. It was a soft tissue mass in the left popliteal area, measuring 14x9 cm. The tumor was surgically removed. Histologically, the primary tumor had the appearance of a conventional ossifying fibromyxoid tumor, although there were cellular areas with pleomorphism and high mitotic rate. The neoplasm recurred 4 times over the next 8 years, involving underlying tissues, including skeletal muscle and bone. The recurrent lesions features areas of osteoid, which increased with each recurrence and in the fourth recurrence the tumor had an appearance of extraskeletal osteosarcoma lacking the ossifying fibromyxoid tumor. The tumor generalized that killed the patient with widespread metastatic disease. PMID:23805469

  9. Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status

    PubMed Central

    Rosenblum, Jeremy M; Wijetunga, N Ari; Fazzari, Melissa J; Krailo, Mark; Barkauskas, Donald A; Gorlick, Richard; Greally, John M

    2015-01-01

    Osteosarcoma is the most common primary malignant bone tumor in children. Validated biological markers for disease prognosis available at diagnosis are lacking. No genome-wide DNA methylation studies linked to clinical outcomes have been reported in osteosarcoma to the best of our knowledge. To address this, we tested the methylome at over 1.1 million loci in 15 osteosarcoma biopsy samples obtained prior to the initiation of therapy and correlated these molecular data with disease outcomes. At more than 17% of the tested loci, samples obtained from patients who experienced disease relapse were more methylated than those from patients who did not have recurrence while patients who did not experience disease relapse had more DNA methylation at fewer than 1%. In samples from patients who went on to have recurrent disease, increased DNA methylation was found at gene bodies, intergenic regions and empirically-annotated candidate enhancers, whereas candidate gene promoters were unusual for a more balanced distribution of increased and decreased DNA methylation with 6.6% of gene promoter loci being more methylated and 2% of promoter loci being less methylated in patients with disease relapse. A locus at the TLR4 gene demonstrates one of strongest associations between DNA methylation and 5 y event-free survival (P-value = 1.7 × 10−6), with empirical annotation of this locus showing promoter characteristics. Our data indicate that DNA methylation information has the potential to be predictive of outcome in pediatric osteosarcoma, and that both promoters and non-promoter loci are potentially informative in DNA methylation studies. PMID:25531418

  10. Aerosol Gemcitabine: Preclinical Safety and In Vivo Antitumor Activity in Osteosarcoma-Bearing Dogs

    PubMed Central

    Crabbs, Torrie A.; Wilson, Dennis W.; Cannan, Virginia A.; Skorupski, Katherine A.; Gordon, Nancy; Koshkina, Nadya; Kleinerman, Eugenie; Anderson, Peter M.

    2010-01-01

    Abstract Background Osteosarcoma is the most common skeletal malignancy in the dog and in young humans. Although chemotherapy improves survival time, death continues to be attributed to metastases. Aerosol delivery can provide a strategy with which to improve the lung drug delivery while reducing systemic toxicity. The purpose of this study is to assess the safety of a regional aerosol approach to chemotherapy delivery in osteosarcoma-bearing dogs, and second, to evaluate the effect of gemcitabine on Fas expression in the pulmonary metastasis. Methods We examined the systemic and local effects of aerosol gemcitabine on lung and pulmonary metastasis in this relevant large-animal tumor model using serial laboratory and arterial blood gas analysis and histopathology and immunohistochemistry, respectively. Results and Conclusions Six hundred seventy-two 1-h doses of aerosol gemcitabine were delivered. The treatment was well tolerated by these subjects with osteosarcoma (n = 20). Aerosol-treated subjects had metastatic foci that demonstrated extensive, predominately central, intratumoral necrosis. Fas expression was decreased in pulmonary metastases compared to the primary tumor (p = 0.008). After aerosol gemcitabine Fas expression in the metastatic foci was increased compared to lung metastases before treatment (p = 0.0075), and even was higher than the primary tumor (p = 0.025). Increased apoptosis (TUNEL) staining was also detected in aerosol gemcitabine treated metastasis compared to untreated controls (p = 0.028). The results from this pivotal translational study support the concept that aerosol gemcitabine may be useful against pulmonary metastases of osteosarcoma. Additional studies that evaluate the aerosol route of administration of gemcitabine in humans should be safe and are warranted. PMID:19803732

  11. Characterization of mouse model-derived osteosarcoma (OS) cells in vitro and in vivo.

    PubMed

    Uluçkan, Özge; Bakiri, Latifa; Wagner, Erwin F

    2015-01-01

    Osteosarcoma (OS) is the most common primary tumor of bone with a high incidence in children. Treatment options for OS are limited, and once metastasized, the prognosis is very poor. Genetically engineered mouse models (GEMMs) are valuable tools to understand the mechanisms of tumorigenesis and to test possible therapies. In this chapter, we summarize the methods related to the isolation, characterization, and transplantation of OS cells obtained from GEMMs. PMID:25636475

  12. Sanguinarine induces apoptosis of human osteosarcoma cells through the extrinsic and intrinsic pathways

    SciTech Connect

    Park, Hyunjin; Bergeron, Eric; Senta, Helena; Guillemette, Kim; Beauvais, Sabrina; Blouin, Richard; Sirois, Joel; Faucheux, Nathalie

    2010-08-27

    Research highlights: {yields} We show for the first time the effect of sanguinarine (SA) on MG63 and SaOS-2 cells. {yields} SA altered osteosarcoma cell viability in a concentration and time dependent manner. {yields} SA induced osteosarcoma cell apoptosis and increased caspase-8 and -9 activities. {yields} SA decreased dose dependently the Bcl-2 protein level only in MG63 cells. {yields} SaOS-2 which are osteoblast-derived, seemed more resistant to SA than MG63. -- Abstract: The quaternary benzo[c]phenanthridine alkaloid sanguinarine inhibits the proliferation of cancerous cells from different origins, including lung, breast, pancreatic and colon, but nothing is known of its effects on osteosarcoma, a primary malignant bone tumour. We have found that sanguinarine alters the morphology and reduces the viability of MG-63 and SaOS-2 human osteosarcoma cell lines in concentration- and time-dependent manner. Incubation with 1 {mu}mol/L sanguinarine for 4 and 24 h killed more efficiently MG-63 cells than SaOS-2 cells, while incubation with 5 {mu}mol/L sanguinarine killed almost 100% of both cell populations within 24 h. This treatment also changed the mitochondrial membrane potential in both MG-63 and SaOS-2 cells within 1 h, caused chromatin condensation and the formation of apoptotic bodies. It activated multicaspases, and increased the activities of caspase-8 and caspase-9 in both MG-63 and SaOS-2 cells. These data highlight sanguinarine as a novel potential agent for bone cancer therapy.

  13. Identification of Novel Ezrin Inhibitors Targeting Metastatic Osteosarcoma by Screening Open Access Malaria Box.

    PubMed

    Çelik, Haydar; Hong, Sung-Hyeok; Colón-López, Daisy D; Han, Jenny; Kont, Yasemin Saygideger; Minas, Tsion Z; Swift, Matthew; Paige, Mikell; Glasgow, Eric; Toretsky, Jeffrey A; Bosch, Jürgen; Üren, Aykut

    2015-11-01

    Ezrin is a member of the ERM (ezrin, radixin, moesin) family of proteins and functions as a linker between the plasma membrane and the actin cytoskeleton. Ezrin is a key driver of tumor progression and metastatic spread of osteosarcoma. We discovered a quinoline-based small molecule, NSC305787, that directly binds to ezrin and inhibits its functions in promoting invasive phenotype. NSC305787 possesses a very close structural similarity to commonly used quinoline-containing antimalarial drugs. On the basis of this similarity and of recent findings that ezrin has a likely role in the pathogenesis of malaria infection, we screened antimalarial compounds in an attempt to identify novel ezrin inhibitors with better efficacy and drug properties. Screening of Medicines for Malaria Venture (MMV) Malaria Box compounds for their ability to bind to recombinant ezrin protein yielded 12 primary hits with high selective binding activity. The specificity of the hits on ezrin function was confirmed by inhibition of the ezrin-mediated cell motility of osteosarcoma cells. Compounds were further tested for phenocopying the morphologic defects associated with ezrin suppression in zebrafish embryos as well as for inhibiting the lung metastasis of high ezrin-expressing osteosarcoma cells. The compound MMV667492 exhibited potent anti-ezrin activity in all biologic assays and had better physicochemical properties for drug-likeness than NSC305787. The drug-like compounds MMV020549 and MMV666069 also showed promising activities in functional assays. Thus, our study suggests further evaluation of antimalarial compounds as a novel class of antimetastatic agents for the treatment of metastatic osteosarcoma. PMID:26358752

  14. Expression and immune recognition of SV40 Tag in transgenic mice that develop metastatic osteosarcomas.

    PubMed

    Marton, I; Johnson, S E; Damjanov, I; Currier, K S; Sundberg, J P; Knowles, B B

    2000-04-01

    Mature adult mice of the C57BL/6-TgN(Amy1TAg)501Knw transgenic mouse lineage, 501, containing a liver alpha-amylase promoted-SV40 Tag hybrid gene, routinely develop SV40 Tag-induced metastatic osteosarcomas. This form of alpha-amylase was known to be expressed in the liver, salivary glands, pancreas, and fat. Cells in the normal rib adjacent to the periosteum also express alpha-amylase suggesting that transgene expression is correctly targeted to generate osteosarcomas. 501 mice express SV40 Tag in the salivary glands but do not develop abnormalities in these organs by the time of their death from SV40-induced osteosarcomas. Mice of the C57BL/6 strain make a strong and effective anti-tumor immune response to SV40 Tag immunization. However, immunization of 501 mice with SV40 Tag early in life does not alter or prevent SV40 Tag-induced osteosarcomagenesis. 501 mice mount a significantly less effective cytotoxic T-lymphocyte response following SV40 Tag immunization while 501 osteosarcoma-derived cells are fully susceptible to SV40 Tag-specific T-cell lysis. This suggests that partial tolerance, not loss of antigen presentation by tumor cells, characterizes this mouse model of endogenous bone tumor development. To determine whether the immune recognition of endogenous SV40 Tag could influence tumorigenesis, the metastatic potential and time of death from tumor was investigated in CD4-null mutant 501 mice and beta-2 microglobulin-null mutant 501 mice. The size and number of metastases in these strains and longevity of these strains varied. We suggest that components of both the innate and adaptive immune response control tumor appearance and progression. PMID:10951695

  15. Proliferative activity (ki-67 expression) and outcome in high grade osteosarcoma: a study of 27 cases.

    PubMed

    Jong, R; Davis, A M; Mendes, M G; Wunder, J S; Bell, R S; Kandel, R

    2000-01-01

    Purpose. Although pre-operative chemotherapy has improved the prognosis for individuals with osteosarcoma, approximately 40% of patients will die of their disease.The aim of this study was to quantitate proliferative activity in high grade osteosarcomas and to determine whether proliferation is a prognostic factor.Patients. The study consisted of 27 patients with high grade non-metastatic osteosarcoma at various sites for whom pre-operative biopsies and resection specimens were available for review. All patients were treated similarly and had at least 24 months' follow-up from the date of diagnosis.Methods. Proliferative activity (Ki-67 expression) was examined in the diagnostic biopsies immunohistochemically using the MIB-1 antibody. Proliferation was quantitated in two ways; (1) the number of immunopositive cells was counted manually using an ocular grid; or (2) the percentage of immunopositive nuclear area was assessed using morphometric image analysis. Proliferative index was evaluated in relation to patient outcome.Results. Proliferative activity was seen in all biopsies.The median proliferative index as determined by counting cells was 24% (mean of 27%, range of 7-61%) and by image analysis was 2% (mean 3%, range 0.32-8.4).The correlation between MIB-1 proliferation indices determined either by image analysis methodology or manual cell counting was high (Spearman's rho=0.79). Proliferative index did not appear to predict either disease-free or overall survival.Discussion. Tumor proliferation does not appear to be prognostic for high grade osteosarcomas.Whether assessment of this feature in conjunction with other tumor characteristics might be prognostic requires further study. PMID:18521434

  16. Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

    PubMed Central

    NIU, FENG; ZHAO, SONG; XU, CHANG-YAN; SHA, HUI; BI, GUI-BIN; CHEN, LIN; YE, LONG; GONG, PING; NIE, TIAN-HONG

    2015-01-01

    Osteosarcoma is the most frequent primary malignant bone tumor that occurs in children and adolescents. The present study aimed to identify novel therapeutic strategies for osteosarcoma, by assessing the antitumor activity of the cannabinoid WIN-55,212-2 and its combined effect with adriamycin (ADM) against the MG-63 human osteosarcoma cell line. To evaluate the antiproliferative action of these molecules, a Cell Counting kit-8 (CCK-8) assay was used. The ability of cannabinoid to inhibit the migration, invasion and angiogenic activity of MG-63 cells were assessed by scratch, Transwell® chamber and angiogenesis assays, respectively, in vitro. To examine the alterations in expression of targeted genes, quantitative polymerase chain reaction and western blot analysis were used. The administration of cannabinoid combined with ADM was demonstrated to inhibit the growth of MG-63 cells, resulting in a cell viability of 32.12±3.13%, which was significantly lower (P<0.05) compared with the cell viability following treatment with cannabinoid (70.86±7.55%) and ADM (62.87±5.98%) alone. Greater antimetastasis and antiangiogenic activities were also observed following the coadministration of the two agents compared with individual treatments and controls. In addition, the expression levels of Notch-1, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in MG-63 cells were downregulated following the treatments with cannabinoid alone or in combination with ADM. In conclusion, the present findings demonstrated that cannabinoid WIN-55,212-2 may significantly potentiate the antiproliferative, antimetastasis and antiangiogenic effects of ADM against MG-63 cells via the downregulation of Notch-1, MMP-2 and VEGF. These findings may offer a novel strategy for the treatment of osteosarcoma. PMID:26622862

  17. Antitumor activity of neurokinin-1 receptor antagonists in MG-63 human osteosarcoma xenografts.

    PubMed

    Muñoz, Miguel; Berger, Michael; Rosso, Marisa; Gonzalez-Ortega, Ana; Carranza, Andrés; Coveñas, Rafael

    2014-01-01

    Osteosarcoma is a highly malignant bone tumor in children and adolescents. Aprepitant is a selective high‑affinity antagonist of the human neurokinin‑1 (NK‑1) receptor (NK1R) with robust antitumor activity. No data exist on the presence of NK1R in osteosarcoma and whether this tumor responds to NK1R antagonists. Here, we analyzed the expression of NK1R in the human osteosarcoma cell line MG-63 with western blot analysis and PCR and found significant expression both at the protein and mRNA levels. We further studied the growth inhibitory capacity of aprepitant and other NK1R antagonists on MG-63 in vitro using an MTS cytotoxicity assay and DAPI staining. All antagonists induced tumor growth inhibition and apoptosis. Synergism was observed for the combination of L-733,060 with common cytostatic drugs in MG-63, but not in non-malignant HEK293 cells. Pretreatment of HEK293 with L-733,060 prior to exposure to cytostatic drugs partially protected HEK293 cells from inhibition by these drugs. Furthermore, nanomolar concentrations of substance P (SP), the natural ligand of the NK1R, increased the growth rate of MG‑63 cells and micromolar concentrations of aprepitant inhibited SP-induced growth in a dose‑dependent manner. In vivo, a xenograft for MG-63 was created in nude mice and treated with peritumoral s.c. injections of fosaprepitant, which resulted in a significant reduction of tumor volume. Collectively, we demonstrated for the first time that the NK1R is expressed in human osteosarcoma cell line MG‑63 and that this receptor can be targeted with NK1R antagonists both in vitro as well as in vivo. PMID:24190675

  18. Molecular mechanisms of Polyphyllin I-induced apoptosis and reversal of the epithelial-mesenchymal transition in human osteosarcoma cells.

    PubMed

    Chang, Junli; Wang, Hongshen; Wang, Xianyang; Zhao, Yongjian; Zhao, Dongfeng; Wang, Chenglong; Li, Yimian; Yang, Zhilie; Lu, Sheng; Zeng, Qinghua; Zimmerman, Jacquelyn; Shi, Qi; Wang, Yongjun; Yang, Yanping

    2015-07-21

    Osteosarcoma is a most common highly malignant bone tumor in children and adolescents. Polyphyllin I (PPI) is an ethanol extraction from Paris polyphylla Smith var.yunnanensis (Franch.) Hand.-Mazz, which belongs to antipyretic-detoxicate family and has been used as a natural medicine in the treatment of infectious disease and cancer in China for centuries. The proteasome activity inhibitory and anti-osteosarcoma effects of PPI have not been known. Here we found PPI exhibited a selective inhibitory effect on proteasomal chymotrypsin (CT)-like activity, both in purified human proteasome and in cultured osteosarcoma cellular proteasome, and caused an accumulation of ubiquitinated proteins. PPI also inhibited viability, proliferation, migration, and invasion of MG-63, Saos-2, and U-2 OS osteosarcoma cells and resulted in S phase arrest and apoptosis. Furthermore, we explored the molecular targets involved. Exposure of osteosarcoma cells to PPI caused an inactivation of the intrinsic nuclear factor κB (NF-κB) and activation of unfolded protein response (UPR)/endoplasmic reticulum (ER) stress signaling cascade in osteosarcoma cells, followed by down-regulation of anti-apoptotic proteins, with up-regulation of pro-apoptotic proteins. We also demonstrated down-regulation of c-Myc, Cyclin B1, Cyclin D1, and CDK1, which are involved in the cell cycle and growth. Finally, we identified down-regulation of Vimentin, Snail, Slug, and up-regulation of E-cadherin, which are integral proteins involved in epithelial-mesenchymal transition (EMT). Taken together, our data provide insights into the mechanism underlying the anticancer activity of PPI in human osteosarcoma cells. PMID:25978954

  19. Identification of Dormancy-Associated MicroRNAs for the Design of Osteosarcoma-Targeted Dendritic Polyglycerol Nanopolyplexes.

    PubMed

    Tiram, Galia; Segal, Ehud; Krivitsky, Adva; Shreberk-Hassidim, Rony; Ferber, Shiran; Ofek, Paula; Udagawa, Taturo; Edry, Liat; Shomron, Noam; Roniger, Maayan; Kerem, Batsheva; Shaked, Yuval; Aviel-Ronen, Sarit; Barshack, Iris; Calderón, Marcelo; Haag, Rainer; Satchi-Fainaro, Ronit

    2016-02-23

    The presence of dormant, microscopic cancerous lesions poses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We established and comprehensively characterized pairs of dormant and fast-growing human osteosarcoma models. Using these pairs of mouse tumor models, we identified three novel regulators of osteosarcoma dormancy: miR-34a, miR-93, and miR-200c. This report shows that loss of these microRNAs occurs during the switch from dormant avascular into fast-growing angiogenic phenotype. We validated their downregulation in patients' tumor samples compared to normal bone, making them attractive candidates for osteosarcoma therapy. Successful delivery of miRNAs is a challenge; hence, we synthesized an aminated polyglycerol dendritic nanocarrier, dPG-NH2, and designed dPG-NH2-microRNA polyplexes to target cancer. Reconstitution of these microRNAs using dPG-NH2 polyplexes into Saos-2 and MG-63 cells, which generate fast-growing osteosarcomas, reduced the levels of their target genes, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, critical to cancer angiogenesis and cancer cells' migration. We further demonstrate that these microRNAs attenuate the angiogenic capabilities of fast-growing osteosarcomas in vitro and in vivo. Treatment with each of these microRNAs using dPG-NH2 significantly prolonged the dormancy period of fast-growing osteosarcomas in vivo. Taken together, these findings suggest that nanocarrier-mediated delivery of microRNAs involved in osteosarcoma tumor-host interactions can induce a dormant-like state. PMID:26815014

  20. L-MTP-PE and zoledronic acid combination in osteosarcoma: preclinical evidence of positive therapeutic combination for clinical transfer.

    PubMed

    Biteau, Kevin; Guiho, Romain; Chatelais, Mathias; Taurelle, Julien; Chesneau, Julie; Corradini, Nadège; Heymann, Dominique; Redini, Françoise

    2016-01-01

    Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for the treatment of osteosarcoma and Ewing sarcoma. The beneficial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential therapeutic benefit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma, as a prerequisite before translation to patients. The effects of ZA (100 μg/kg) and L-mifamurtide (1 mg/kg) were investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation, spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor site whatever the treatment. This study evidenced for the first time a significant inhibition of primary osteosarcoma progression when both drugs are combined. This result constitutes a first proof-of-principle for clinical application in osteosarcoma patients. PMID:27152244

  1. miR-200c and phospho-AKT as prognostic factors and mediators of osteosarcoma progression and lung metastasis.

    PubMed

    Berlanga, Pablo; Muñoz, Lisandra; Piqueras, Marta; Sirerol, J Antoni; Sánchez-Izquierdo, María Dolors; Hervás, David; Hernández, Miguel; Llavador, Margarita; Machado, Isidro; Llombart-Bosch, Antonio; Cañete, Adela; Castel, Victoria; Font de Mora, Jaime

    2016-08-01

    Lung metastasis is the major cause of death in osteosarcoma patients. However, molecular mechanisms underlying this metastasis remain poorly understood. To identify key molecules related with pulmonary metastasis of pediatric osteosarcomas, we analyzed high-throughput miRNA expression in a cohort of 11 primary tumors and 15 lung metastases. Results were further validated with an independent cohort of 10 primary tumors and 6 metastases. In parallel, we performed immunohistochemical analysis of activated signaling pathways in 36 primary osteosarcomas. Only phospho-AKT associated with lower overall survival in primary tumors, supporting its role in osteosarcoma progression. CTNNB1 expression also associated with lower overall survival but was not strong enough to be considered an independent variable. Interestingly, miR-200c was overexpressed in lung metastases, implicating an inhibitory feed-back loop to PI3K-AKT. Moreover, transfection of miR200c-mimic in U2-OS cells reduced phospho-AKT levels but increased cellular migration and proliferation. Notably, miR-200c expression strongly correlated with miR-141 and with the osteogenic inhibitor miR-375, all implicated in epithelial to mesenchymal transition. These findings contrast epithelial tumors where reduced miR-200c expression promotes metastasis. Indeed, we noted that osteosarcoma cells in the lung also expressed the epithelial marker CDH1, revealing a change in their mesenchymal phenotype. We propose that miR-200c upregulation occurs late in osteosarcoma progression to provide cells with an epithelial phenotype that facilitates their integration in the metastatic lung niche. Thus, our findings identify phospho-AKT in the primary tumor and miR-200c later during tumor progression as prognostic molecules and potential therapeutic targets to prevent progression and metastasis of pediatric osteosarcomas. PMID:27155790

  2. Long non-coding RNA tumor suppressor candidate 7 functions as a tumor suppressor and inhibits proliferation in osteosarcoma.

    PubMed

    Cong, Menglin; Li, Jianmin; Jing, Rui; Li, Zhenzhong

    2016-07-01

    Osteosarcoma is the most common malignant tumor of bone. Recent studies have proven long non-coding RNAs (lncRNAs) play important roles in the tumorigenesis and progression of cancer. However, few lncRNAs have been investigated in osteosarcoma. Here, we reported a novel lncRNA, tumor suppressor candidate 7 (TUSC7), was significantly downregulated in osteosarcoma tissues compared with paired non-tumor tissues and low expression of TUSC7 indicated poor survival (HR = 0.313, 95 % confidence interval (CI) 0.092-0.867) of osteosarcoma patients. Further analysis revealed that loss copy number of TUSC7 was correlated with low expression of TUSC7, and additionally, loss of TUSC7 copy number also indicated poor prognosis (HR = 3.994, 95 % CI 1.147-13.91) of osteosarcoma patients. Two osteosarcoma cell lines, HOS and MG63, were utilized to investigate biological function of TUSC7. Cell counting kit 8 (CCK-8) assay revealed that after silence of TUSC7, cell proliferation ability increased and the colony formation ability also increased. Further results showed that cell cycle was not affected by treatment of si-TUSC7, while the percentage of apoptotic cells decreased. Western blot showed that after silence of TUSC7, the proapoptotic Bcl2 expression was downregulated. Finally, we established xenograft tumor models in nude mice with MG63 cells. Compared with negative control group, silence of TUSC7 significantly promoted tumor growth in vivo. Thus, we demonstrated that TUSC7 could be a potential tumor suppressor in osteosarcoma. PMID:26781978

  3. Downregulation of RSK2 influences the biological activities of human osteosarcoma cells through inactivating AKT/mTOR signaling pathways.

    PubMed

    Qiu, Quanhe; Jiang, Jing; Lin, Liangbo; Cheng, Si; Xin, Daqi; Jiang, Wei; Shen, Jieliang; Hu, Zhenming

    2016-06-01

    RSK2 (90 kDa ribosomal S6 kinase) is a downstream effector of the Ras/ERK (extracellular signal-regulated kinase) signaling pathway that has major functions in cell biological activities, including regulating nuclear signaling, cell cycle progression, cell proliferation, cell growth, protein synthesis, cell migration and cell survival, and is expressed in most types of human malignant tumors, including lung cancer, prostate and breast tumors, skin cancer and osteosarcomas (OS). RSK2 was found to be essential for osteosarcoma formation. To investigate whether RSK2 is expressed at high levels in human osteosarcome tissues and whether its expression is correlated with the aggressive biological behavior of osteosarcoma cell line (OCLs), we assessed the association between RSK2 expression and OS cell progression, as well as the effects of RSK2 inhibition on the biological activities of osteosarcoma cells. We performed immunohistochemistry to analyze the expression of RSK2 in specimens from 30 humans with osteosarcoma, and 15 normal tissues. RSK2 gene expression levels in 30 specimens with osteosarcoma were significantly higher than those of normal tissues. We performed RNA interference on three OCLs to evaluate cell apoptosis, cell growth, cell proliferation, cell motility, chemosensitivity and oncogenicity. After transfection with RSK2 shRNA, increased cell apoptosis, cell growth inhibition, cell cycle progression, weaker cell proliferation, cell migration and weaker tumor formation were observed in all OCLs. These results suggested that RSK2 expression may mediate the biological activities of OS cells and RSK2 may be an effective therapeutic target for the treatment of osteosarcomas. The AKT/mTOR, MAPK/ERK/c-Fos and Bcl2/Bax pathways were analysed to clarify the mechanisms involved. PMID:27082640

  4. Impaired cell cycle regulation of osteoblast-related transcription factor Runx2/Cbfa1 in osteosarcoma cells

    PubMed Central

    San Martin, Inga; Varela, Nelson; Gaete, Marcia; Villegas, Karina; Osorio, Mariana; Tapia, Julio C.; Antonelli, Marcelo; Mancilla, Edna; Lian, Jane B.; Stein, Janet L.; Stein, Gary S; van Wijnen, Andre J.; Galindo, Mario

    2011-01-01

    In mammals, bone differentiation requires the functional expression of the Runx2/Cbfβ heterodimeric complex. Our previous results indicate that Runx2 is also a suppressor of pre-osteoblast proliferation by affecting cell cycle progression at G1. Runx2 levels are cell cycle regulated, oscillating from a maximum during early G1 to a minimum during late G1, S and mitosis phases in proliferating pre-osteoblasts Nevertheless, there is no information concerning Cbfβ gene expression during the cell cycle nor on Runx2 cell cycle expression in bone cancer cells. We analyzed Runx2 and Cbfβ gene expression during cell cycle progression in the pre-osteoblast MC3T3 and osteosarcoma ROS and SaOS cell lines. The expected reduction of Runx2 protein level was observed in MC3T3 cells arrested in late G1 or M phase using mimosine or nocodazole, respectively. However, this reduction was not observed in the cell cycle arrested osteosarcoma cells. Cbfβ protein levels were not regulated during the cell cycle in pre-osteoblasts and osteosarcoma cells. Using cells synchronized in late G1 and mitosis we found that Runx2 levels, but not Cbfβ levels, were cell cycle regulated in MC3T3 osteoblasts. Interestingly, both factors showed a constitutively elevated expression throughout the cell cycle in osteosarcoma cells. Proteasome inhibition by MG132 prevented cell cycle-dependent downregulation of Runx2 protein levels in osteoblasts, but not in osteosarcoma. We propose that Runx2 is involved in tumoral osteosarcoma progression. Altogether, deregulated Runx2 expression throughout the cell cycle seems to constitute a central mechanism in the pathogenesis of osteosarcoma. PMID:19739101

  5. Targeted apc;twist double-mutant mice: a new model of spontaneous osteosarcoma that mimics the human disease.

    PubMed

    Entz-Werlé, Natacha; Choquet, Philippe; Neuville, Agnès; Kuchler-Bopp, Sabine; Clauss, François; Danse, Jean-Marc; Simo-Noumbissie, Pauline; Guérin, Eric; Gaub, Marie-Pierre; Freund, Jean-Noel; Boehm, Nelly; Constantinesco, André; Lutz, Patrick; Guenot, Dominique; Perrin-Schmitt, Fabienne

    2010-01-01

    TWIST and adenomatosis polyposis coli (APC) are critical signaling factors in normal bone development. In previous studies examining a homogeneously treated cohort of pediatric osteosarcoma patients, we reported the frequent and concurrent loss of both TWIST and APC genes. On these bases, we created a related animal model to further explore the oncogenic cooperation between these two genes. We performed intercrosses between twist-null/+ and Apc1638N/+ mice and studied their progeny. The Apc1638N/+;twistnull/+ mice developed bone abnormalities observed by macroscopic skeletal analyses and in vivo imaging. Complementary histologic, cellular, and molecular analyses were used to characterize the identified bone tumors, including cell culture and immunofluorescence of bone differentiation markers. Spontaneous localized malignant bone tumors were frequently identified in Apc1638N/+;twist-null/+ mice by in vivo imaging evaluation and histologic analyses. These tumors possessed several features similar to those observed in human localized osteosarcomas. In particular, the murine tumors presented with fibroblastic, chondroblastic, and osteoblastic osteosarcoma histologies, as well as mixtures of these subtypes. In addition, cellular analyses and bone differentiation markers detected by immunofluorescence on tumor sections reproduced most murine and human osteosarcoma characteristics. For example, the early bone differentiation marker Runx2, interacting physically with hypophosphorylated pRb, was undetectable in these murine osteosarcomas, whereas phosphorylated retinoblastoma was abundant in the osteoblastic and chondroblastic tumor subtypes. These characteristics, similar to those observed in human osteosarcomas, indicated that our animal model may be a powerful tool to further understand the development of localized osteosarcoma. PMID:21151473

  6. Targeted Apc;Twist Double-Mutant Mice: A New Model of Spontaneous Osteosarcoma That Mimics the Human Disease123

    PubMed Central

    Entz-Werlé, Natacha; Choquet, Philippe; Neuville, Agnès; Kuchler-Bopp, Sabine; Clauss, François; Danse, Jean-Marc; Simo-Noumbissie, Pauline; Guérin, Eric; Gaub, Marie-Pierre; Freund, Jean-Noel; Boehm, Nelly; Constantinesco, André; Lutz, Patrick; Guenot, Dominique; Perrin-Schmitt, Fabienne

    2010-01-01

    TWIST and adenomatosis polyposis coli (APC) are critical signaling factors in normal bone development. In previous studies examining a homogeneously treated cohort of pediatric osteosarcoma patients, we reported the frequent and concurrent loss of both TWIST and APC genes. On these bases, we created a related animal model to further explore the oncogenic cooperation between these two genes. We performed intercrosses between twist-null/+ and Apc1638N/+ mice and studied their progeny. The Apc1638N/+;twistnull/+ mice developed bone abnormalities observed by macroscopic skeletal analyses and in vivo imaging. Complementary histologic, cellular, and molecular analyses were used to characterize the identified bone tumors, including cell culture and immunofluorescence of bone differentiation markers. Spontaneous localized malignant bone tumors were frequently identified in Apc1638N/+;twist-null/+ mice by in vivo imaging evaluation and histologic analyses. These tumors possessed several features similar to those observed in human localized osteosarcomas. In particular, the murine tumors presented with fibroblastic, chondroblastic, and osteoblastic osteosarcoma histologies, as well as mixtures of these subtypes. In addition, cellular analyses and bone differentiation markers detected by immunofluorescence on tumor sections reproduced most murine and human osteosarcoma characteristics. For example, the early bone differentiation marker Runx2, interacting physically with hypophosphorylated pRb, was undetectable in these murine osteosarcomas, whereas phosphorylated retinoblastoma was abundant in the osteoblastic and chondroblastic tumor subtypes. These characteristics, similar to those observed in human osteosarcomas, indicated that our animal model may be a powerful tool to further understand the development of localized osteosarcoma. PMID:21151473

  7. Genetic variability of genes involved in DNA repair influence treatment outcome in osteosarcoma.

    PubMed

    Wang, M J; Zhu, Y; Guo, X J; Tian, Z Z

    2015-01-01

    We conducted a perspective study to investigate the role of ERCC1 (rs11615), ERCC2 (rs13181 and rs1799793), ERCC4 (rs1800067), and ERCC5 (rs17655) in NER pathway in the prognosis of osteosarcoma patients. In total, 146 osteosarcoma patients were recruited between 2008 and 2013. ERCC1 rs11615, ERCC2 rs13181 and rs1799793, ERCC4 rs1800067, and ERCC5 rs17655 gene polymorphisms were assessed by polymerase chain reaction-restriction fragment length polymorphism assay. By multivariate Cox proportional hazards models, we found that carriers of ERCC1 rs11615 TT genotype showed significantly favorable survival compared to wide-type CC genotype, and the adjusted OR (95%CI) was 0.24 (0.08-0.96). Moreover, we found that subjects with ERCC2 rs1799793 AA genotype were associated with decreased hazards of death in multivariate analysis (HR = 0.22, 95%CI = 0.12-0.93). In conclusion, our results suggest that ERCC1 rs11615 and ERCC2 rs1799793 may be useful genetic prognostic markers for osteosarcoma in a Chinese population. PMID:26436406

  8. Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma.

    PubMed

    Mu, Xiaodong; Agarwal, Rashmi; March, Daniel; Rothenberg, Adam; Voigt, Clifford; Tebbets, Jessica; Huard, Johnny; Weiss, Kurt

    2016-01-01

    Skeletal muscle atrophy in cancer cachexia is mediated by the interaction between muscle stem cells and various tumor factors. Although Notch signaling has been known as a key regulator of both cancer development and muscle stem cell activity, the potential involvement of Notch signaling in cancer cachexia and concomitant muscle atrophy has yet to be elucidated. The murine K7M2 osteosarcoma cell line was used to generate an orthotopic model of sarcoma-associated cachexia, and the role of Notch signaling was evaluated. Skeletal muscle atrophy was observed in the sarcoma-bearing mice, and Notch signaling was highly active in both tumor tissues and the atrophic skeletal muscles. Systemic inhibition of Notch signaling reduced muscle atrophy. In vitro coculture of osteosarcoma cells with muscle-derived stem cells (MDSCs) isolated from normal mice resulted in decreased myogenic potential of MDSCs, while the application of Notch inhibitor was able to rescue this repressed myogenic potential. We further observed that Notch-activating factors reside in the exosomes of osteosarcoma cells, which activate Notch signaling in MDSCs and subsequently repress myogenesis. Our results revealed that signaling between tumor and muscle via the Notch pathway may play an important role in mediating the skeletal muscle atrophy seen in cancer cachexia. PMID:27378829

  9. Management of Pelvic Chondroblastic Osteosarcoma after Urgent Spinal Decompression - A Report of 2 Cases

    PubMed Central

    Scudday, Travis Spencer; Danisa, Olumide Ayodele; Zuckerman, Lee Michael

    2016-01-01

    Introduction: Pelvic sarcoma presenting with neurologic symptoms is rare. Workup of neurological deficits, whether elective or emergent should address the possibility of a space occupying lesion including pelvic sarcoma. Poor biopsy technique and incomplete workup of musculoskeletal tumors results in misdiagnosis or major errors in 18% of biopsies. The sequelae of a suboptimal biopsy include local recurrence, a more extensive resection, or extremity amputation. Pelvic chondroblastic osteosarcoma presenting with neurological deficits has not been previously reported. We report two cases of chondroblastic osteosarcoma that were treated with urgent decompression of the lumbar spine due to neurologic symptoms. Case presentations: Our two cases, a 25 year old Hispanic female and 22 year old Hispanic male, both presented with neurologic changes due to a space occupying tumor in the lumbar spine and pelvis. Both underwent spinal decompression following incomplete workup. A repeat biopsy was required in both cases due to a questionable initial diagnosis. Once the diagnosis was confirmed, they underwent definitive resection and treatment that was more morbid due to the primary decompressions. Conclusion: We stress the importance of proper biopsy techniques as well as the need to complete a full preoperative staging workup prior to any surgical procedures involving musculoskeletal tumors. We review the current literature on lumbar chondroblastic osteosarcomas and review the issues surrounding biopsy of musculoskeletal tumors. Our cases underline the need for complete workup and correct biopsy techniques to ensure patients have the best chance at tumor free survival with minimal morbidity. PMID:27299134

  10. 6-Gingerol inhibits osteosarcoma cell proliferation through apoptosis and AMPK activation.

    PubMed

    Fan, Jingzhang; Yang, Xin; Bi, Zhenggang

    2015-02-01

    6-Gingerol, a major component of ginger, is demonstrated to possess a variety of pharmacological activities. Despite demonstration of its anti-cancer activity, the exact mechanism underlying the effects of 6-gingerol against sarcoma remains sketchy. In the present study, we investigated the anti-cancer effects of 6-gingerol on osteosarcoma cells. MTT assay was performed to determine cell viability. Phosphorylation and protein levels were determined by immunoblotting. Cell cycle was determined using flow cytometry. Quantitative polymerase chain reaction was employed to determine the changes in the messenger RNA (mRNA) expression of genes. Treatment with 6-gingerol resulted in a significant decrease in the viability of osteosarcoma cells in a dose-dependent fashion. In parallel, the number of cells arrested at the sub-G1 cell cycle phase was significantly increased. The results showed that 6-gingerol induced activation of caspase cascades and regulated cellular levels of Bcl2 and Bax. Moreover, 6-gingerol activated AMP-activated protein kinase (AMPK) signaling associated with the apoptotic pathways. Our findings suggest that 6-gingerol suppresses the growth of osteosarcoma cells. The anti-cancer activity is attributed to the activation of apoptotic signaling and the inhibition of anti-apoptotic signaling incorporating with 6-gingerol-induced AMPK activation. The study identifies a new molecular mechanism by which AMPK is involved in anti-cancer effects of 6-gingerol. PMID:25330949

  11. Synthesis of polymeric phosphonates for selective delivery of radionuclides to osteosarcoma.

    PubMed

    Popwell, Sam J; Schulz, Michael D; Wagener, Kenneth B; Batich, Christopher D; Milner, Rowan J; Lagmay, Joanne; Bolch, Wesley E

    2014-09-01

    Discussed in detail is the synthesis and primary structure characterization of two polymers aimed at advancing the treatment of pediatric osteosarcoma. These polymers are designed to systemically deliver radiometals specifically to osteosarcomas using the passive targeting mechanism of enhanced permeability and retention (the EPR effect). The approach begins with the synthesis of a polymer capable of binding radiometals, for which prior data show improved site-specific targeting of solid tumors. Building on this success, a second polymer has been designed for improving the efficacy of currently available radionuclide therapies by incorporating the FDA-approved small-molecule ligand Quadramet directly onto the polymer structure. Time-activity curves of the phosphonate-functionalized polymers show rapid clearance from the central compartment and nontargeted organs, with up to 65% of injected activity being excreted within 3 hours. Both polymer ligands demonstrate good osteosarcoma targeting capability with little to no uptake in organs associated with the dose-limiting bone marrow. Additionally, biodistribution studies in nonosseous tumor models demonstrate the tumor targeting mechanism of the polymer ligands, which appears to be influenced by the high affinity of the phosphonate functionality for the positively charged hydroxyapatite mineral found in bone tumors. PMID:25111903

  12. Polyoxometalates as antitumor agents: Bioactivity of a new polyoxometalate with copper on a human osteosarcoma model.

    PubMed

    León, I E; Porro, V; Astrada, S; Egusquiza, M G; Cabello, C I; Bollati-Fogolin, M; Etcheverry, S B

    2014-10-01

    Polyoxometalates (POMs) are early transition metal oxygen anion clusters. They display interesting biological effects mainly related to their antiviral and antitumor properties. On the other hand, copper compounds also show different biological and pharmacological effects in cell culture and in animal models. We report herein for the first time, a detailed study of the mechanisms of action of a copper(II) compound of the group of HPOMs with the formula K7Na3[Cu4(H2O)2(PW9034)2]20H2O (PW9Cu), in a model of human osteosarcoma derived cell line, MG-63. The compound inhibited selectively the viability of the osteosarcoma cells in the range of 25-100μM (p<0.01). Besides, we have clearly shown a more deleterious action of PW9Cu on tumor osteoblasts than in normal cells. Cytotoxicity studies also showed deleterious effects for PW9Cu. The increment of reactive oxygen species (ROS) and the decrease of the GSH/GSSG ratio were involved in the antiproliferative effects of PW9Cu. Moreover, the compound caused cell cycle arrest in G2 phase, triggering apoptosis as determined by flow cytometry. As a whole, these results showed the main mechanisms of the deleterious effects of PW9Cu in the osteosarcoma cell line MG-63, demonstrating that this compound is a promissory agent for cancer treatments. PMID:25451568

  13. Secondary osteosarcoma developing 10 years after chemoradiotherapy for non-small-cell lung cancer.

    PubMed

    Yagishita, Shigehiro; Horinouchi, Hidehito; Yorozu, Takashi; Kitazono, Satoru; Mizugaki, Hidenori; Kanda, Shintaro; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru; Mori, Taisuke; Tsuta, Koji; Sumi, Minako; Tamura, Tomohide

    2014-02-01

    A 53-year-old female patient was admitted with pain and a progressively enlarging mass in the right upper chest. Chest computed tomography revealed a mass lesion in the region of the right upper ribs. Ten years prior to this admission, the patient had undergone right lobectomy for lung adenocarcinoma. One year after the surgery, follow-up computed tomography had revealed tumor recurrence in the mediastinal and supraclavicular lymph nodes, and the patient had been treated by chemoradiotherapy. Thereafter, regular follow-up had revealed no evidence of recurrence of the non-small-cell lung cancer. Histopathological findings revealed proliferation of spindle-shaped malignant tumor cells in a background of osteoid, consistent with the diagnosis of osteosarcoma. The location of the tumor was consistent with the radiation field. Based on the clinicopathological findings, the patient was diagnosed as having secondary osteosarcoma occurring as a result of the chemoradiotherapy administered previously for the recurrent non-small-cell lung cancer. Unfortunately, the patient died of rapid progression of the osteosarcoma within a week of admission to the hospital. The autopsy revealed contiguous invasion by the tumor of the heart, with massive thrombus formation. The peripheral pulmonary arteries were diffusely occluded by metastatic tumors. Our case serves to highlight the risk of development of secondary sarcoma as a life-threatening late complication after chemoradiotherapy for locally advanced non-small-cell lung cancer, even after complete cure of the primary tumor. PMID:24338556

  14. Chondroblastic osteosarcoma of the left zygomatic bone: Rare case report and review of the literature

    PubMed Central

    Khandekar, Shubhangi; Dive, Alka; Munde, Prashant; Fande, Prajakta Zade

    2014-01-01

    Chondroblastic osteosarcoma (COS), a subgroup of intramedullary osteosarcoma (OS), is the most common osteosarcoma that occurs in adolescents and early adulthood. The COS has similar clinical and radiological features to those of conventional OS. We present a case of 20-year-old male patient with the chief complaint of pain and swelling in the left zygomatic region. The computed tomography (CT) and three-dimensional (3D) CT face showed erosion, calcific foci, sunray type of spicules suggestive of OS. On fine-needle aspiration cytology (FNAC) examination, initial diagnosis was malignant chondroid lesion, with differential diagnosis of mesenchymal chrondrosarcoma, COS on incisional biopsy and finally COS on excisional biopsy. The patient underwent radical resection of left zygomatic arch, followed by chemotherapy. Although clinically unsuspected in this unusual site, histopathology along with immunohistochemistry (IHC) results confirmed the COS. Because zygomatic location of COS is very rare, this report aimed to discuss clinical, radiographic, histopathologic, IHC findings and diagnostic pitfalls of COS in light of the literature. PMID:25328313

  15. MicroRNA-26a inhibits osteosarcoma cell proliferation by targeting IGF-1

    PubMed Central

    Tan, Xinyu; Fan, Shicai; Wu, Wen; Zhang, Yin

    2015-01-01

    There are still controversies about the roles of microRNA-26a (miR-26a) in human malignancies, as it is a tumor suppressor in breast cancer, gastric cancer, and hepatocellular carcinoma, but is an oncogene in glioma and cholangiocarcinoma. Until now, the function of miR-26a in osteosarcoma remains largely elusive. Here, we found that miR-26a was downregualted in osteosarcoma tissues. Using in vitro and in vivo assays, we confirmed that miR-26a could inhibit the abilities of in vitro proliferation and suppress in vivo tumor growth in mouse model. Furthermore, we identified insulin-like growth factor 1 (IGF-1) as a novel and direct target of miR-26a and revealed that miR-26a exerted its tumor-suppressor function, at least in part, by inhibiting IGF-1 expression. These findings contribute to our understanding of the functions of miR-26a in osteosarcoma. PMID:27468358

  16. Antineoplastic effect of calycosin on osteosarcoma through inducing apoptosis showing in vitro and in vivo investigations.

    PubMed

    Qiu, Rubiao; Ma, Gang; Zheng, Chenguang; Qiu, Xiaoxia; Li, Xinning; Li, Xueyu; Mo, Jianlan; Li, Zhengzhao; Liu, Yun; Mo, Linjian; Bi, Guan; Ye, Yu

    2014-08-01

    Recently, increasing studies have documented that tumorigenesis closely relates to apoptotic processes. Thus, inducing apoptosis is an anti-cancer strategy against osteosarcoma. Here we investigated the anti-proliferative effect of calycosin on human osteosarcoma cell (143B) in vitro. The results showed that calycosin dose-dependently inhibited 143B cell proliferation as reflected in tetrazolium salt (MTT) assay (P<0.01). In addition, calycosin effectively down-regulated cellular mRNA expressions of IκBα, NF-κB p65 and cyclin D1 through RT-PCR assay (P<0.01). Next, calycosin-mediated inhibitory effect on 143B tumor-bearing nude mice and the underlying mechanism were evaluated and discussed. As a result, calycosin administration significantly blocked solid tumor growth in 143B-harbored nude mice (P<0.01). Furthermore, intracellular Bcl-2 protein expression was effectively reduced in 143B-harbored tumor tissue through western blotting analysis (P<0.01), while intratumoral Apaf-1 and cleaved Caspase-3 protein levels were up-regulated, respectively (P<0.01). Taken together, calycosin possesses the anti-osteosarcoma potential, in which the mechanism involved was associated with activation of apoptotic, thus inducing apoptosis. PMID:24797937

  17. Efficacy of pamidronate in pediatric osteosarcoma patients with low bone mineral density

    PubMed Central

    Lim, Se Won; Ahn, Ju Hyun; Choi, Aery; Cho, Wan Hyeong; Lee, Jun Ah; Kim, Dong Ho; Seo, Ju-Hee

    2016-01-01

    Purpose Most surviving pediatric osteosarcoma patients experience osteoporosis, bone pain, and pathologic fracture during and after therapy. The aim of this study was to evaluate the efficacy and side effects of pamidronate therapy in these patients. Methods Nine osteosarcoma patients (12.8±1.6 years of age; 5 boys and 4 girls) who had a history of nontraumatic fracture or severe pain after completing chemotherapy were included. Intravenous pamidronate (1.5 mg/kg) was given every 6 weeks for 4 to 6 cycles. Bone mineral density (BMD) of the lumbar spine was measured by dual-energy x-ray absorptiometry. Clinical outcomes including acute side effects were also evaluated. Results After pamidronate treatments, all patients experienced decreased pain. Seven of 9 patients could walk without a crutch. The BMD of lumbar spine was increased by 0.108±0.062 mg/cm2 after 8.4±1.0 months (n=8, P=0.017) and the mean z-score improved from –2.14±0.94 to –1.76±0.95 (P=0.161). Six patients (67%) had an acute-phase reaction, and 2 patients had symptomatic hypocalcemia. Conclusion Pamidronate appears to be safe and effective for the treatment of osteosarcoma in children with low BMD and bone pain. PMID:27104175

  18. Osteosarcomas among beagles exposed to /sup 239/Plutonium. Technical report No. 34

    SciTech Connect

    Whittemore, A S; McMillan, A

    1980-03-01

    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 to 1 ..mu..Ci/kg the osteosarcoma incidence rate h(t) at t days after injection can be fit by a quadratic function of the injected dose. The best fitting linear function was rejected by the data (p < 0.001). A different formula for h(t), derived from amultistage 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 agan 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.

  19. Misdiagnosis of osteosarcoma as cementoblastoma from an atypical mandibular swelling: A case report

    PubMed Central

    FANG, ZAO; JIN, SHUFANG; ZHANG, CHENPING; WANG, LIZHEN; HE, YUE

    2016-01-01

    Cementoblastoma is a form of benign odontogenic tumor, with the preferred treatment consisting of tooth extraction and follow-up examinations, while in certain cases, follow-up examinations without surgery are performed. Osteosarcoma of the jaw is a rare, malignant, mesenchymal tumor, associated with a high mortality rate and low incidence of metastasis. Cementoblastoma and osteosarcoma of the jaw are dissimilar in terms of their histological type and prognosis; however, there are a number of covert associations between them. The present study describes the case of a 20-year-old female with an unusual swelling in the left mandible that had been present for 2 years. The patient was initially clinically diagnosed with cementoblastoma; however, following pathological examination, a diagnosis of osteosarcoma was confirmed. A total mandibulectomy was performed on the left mandible, with a fibular osteomyocutaneous flap used for reconstruction. At the 6-month post-operative examination, the patient demonstrated normal occlusion and oral commissure, and no recurrence or metastasis was observed over 2 years of follow-up. PMID:27313689

  20. Anticancer Effects of Geopropolis Produced by Stingless Bees on Canine Osteosarcoma Cells In Vitro

    PubMed Central

    Cinegaglia, Naiara Costa; Bersano, Paulo Ricardo Oliveira; Araújo, Maria José Abigail Mendes; Búfalo, Michelle Cristiane; Sforcin, José Maurício

    2013-01-01

    Geopropolis is produced by indigenous stingless bees from the resinous material of plants, adding soil or clay. Its biological properties have not been investigated, such as propolis, and herein its cytotoxic action on canine osteosarcoma (OSA) cells was evaluated. OSA is a primary bone neoplasm diagnosed in dogs being an excellent model in vivo to study human OSA. spOS-2 primary cultures were isolated from the tumor of a dog with osteosarcoma and incubated with geopropolis, 70% ethanol (geopropolis solvent), and carboplatin after 6, 24, 48, and 72 hours. Cell viability was analyzed by the crystal violet method. Geopropolis was efficient against canine OSA cells in a dose- and time-dependent way, leading to a distinct morphology compared to control. Geopropolis cytotoxic action was exclusively due to its constituents since 70% ethanol (its solvent) had no effect on cell viability. Carboplatin had no effect on OSA cells. Geopropolis exerted a cytotoxic effect on canine osteosarcoma, and its introduction as a possible therapeutic agent in vivo could be investigated, providing a new contribution to OSA treatment. PMID:23690851

  1. Anticancer effects of geopropolis produced by stingless bees on canine osteosarcoma cells in vitro.

    PubMed

    Cinegaglia, Naiara Costa; Bersano, Paulo Ricardo Oliveira; Araújo, Maria José Abigail Mendes; Búfalo, Michelle Cristiane; Sforcin, José Maurício

    2013-01-01

    Geopropolis is produced by indigenous stingless bees from the resinous material of plants, adding soil or clay. Its biological properties have not been investigated, such as propolis, and herein its cytotoxic action on canine osteosarcoma (OSA) cells was evaluated. OSA is a primary bone neoplasm diagnosed in dogs being an excellent model in vivo to study human OSA. spOS-2 primary cultures were isolated from the tumor of a dog with osteosarcoma and incubated with geopropolis, 70% ethanol (geopropolis solvent), and carboplatin after 6, 24, 48, and 72 hours. Cell viability was analyzed by the crystal violet method. Geopropolis was efficient against canine OSA cells in a dose- and time-dependent way, leading to a distinct morphology compared to control. Geopropolis cytotoxic action was exclusively due to its constituents since 70% ethanol (its solvent) had no effect on cell viability. Carboplatin had no effect on OSA cells. Geopropolis exerted a cytotoxic effect on canine osteosarcoma, and its introduction as a possible therapeutic agent in vivo could be investigated, providing a new contribution to OSA treatment. PMID:23690851

  2. Hypoxia-induced autophagy as an additional mechanism in human osteosarcoma radioresistance.

    PubMed

    Feng, Helin; Wang, Jin; Chen, Wei; Shan, Baoen; Guo, Yin; Xu, Jianfa; Wang, Ling; Guo, Peng; Zhang, Yingze

    2016-06-01

    Osteosarcoma (OS) responds poorly to radiotherapy, but the mechanism is unclear. We found OS tumor tissues expressed high level of protein HIF-1α, a common biological marker indicative of hypoxia. It is known that hypoxic cells are generally radioresistant because of reduced production of irradiation-induced DNA-damaging reactive oxygen species (ROS) in the anaerobic condition. Here we report another mechanism how hypoxia induces radioresistance. In MG-63 human osteosarcoma cells, hypoxic pretreatment increased the cellular survival in irradiation. These hypoxia-exposed cells displayed compartmental recruitment of GFP-tagged LC3 and expression of protein LC3-II, and restored the radiosensitivity upon autophagy inhibition. The following immunohistochemistry of OS tumor tissue sections revealed upregulated LC3 expression in a correlation with HIF-1α protein level, implying the possibly causative link between hypoxia and autophagy. Further studies in MG-63 cells demonstrated hypoxic pretreatment reduced cellular and mitochondrial ROS production during irradiation, while inhibition of autophagy re-elicited them. Taken together, our study suggests hypoxia can confer cells resistance to irradiation through activated autophagy to accelerate the clearance of cellular ROS products. This might exist in human osteosarcoma as an additional mechanism for radioresistance. PMID:27335774

  3. Taurolidine: a novel anti-neoplastic agent induces apoptosis of osteosarcoma cell lines.

    PubMed

    Walters, Denise K; Muff, Roman; Langsam, Bettina; Gruber, Philipp; Born, Walter; Fuchs, Bruno

    2007-08-01

    Taurolidine, the active agent of Taurolin, is a broad spectrum anti-biotic that has been used for over 15 years for the treatment of severe surgical infections. Recently, taurolidine has been shown to possess anti-neoplastic properties in vitro and in vivo against a variety of cancers including ovarian, colon and prostate. In this study we assessed the cytotoxic activity of taurolidine against human osteosarcoma (OS) cell lines and normal human bone cells. Treatment with taurolidine inhibited the growth of all ten osteosarcoma cell lines tested and taurolidine was equally potent against cell lines with and without distinct genetic defects (i.e. p53, Rb). Moreover, taurolidine-induced growth inhibition was found to be associated with a dose dependent increase in the number of apoptotic cells and apoptosis was shown to be caspase-dependent. Taurolidine treatment was also found to inhibit adhesion of OS cell lines. Compared to OS cell lines, normal bone cells in primary culture were found to be less sensitive to the cytotoxic and anti-adhesive effects of taurolidine. These data indicate that taurolidine possesses potent anti-neoplastic activity against osteosarcoma cell lines and may have potential as a novel OS chemotherapeutic agent. PMID:17458504

  4. Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma

    PubMed Central

    Agarwal, Rashmi; March, Daniel; Voigt, Clifford

    2016-01-01

    Skeletal muscle atrophy in cancer cachexia is mediated by the interaction between muscle stem cells and various tumor factors. Although Notch signaling has been known as a key regulator of both cancer development and muscle stem cell activity, the potential involvement of Notch signaling in cancer cachexia and concomitant muscle atrophy has yet to be elucidated. The murine K7M2 osteosarcoma cell line was used to generate an orthotopic model of sarcoma-associated cachexia, and the role of Notch signaling was evaluated. Skeletal muscle atrophy was observed in the sarcoma-bearing mice, and Notch signaling was highly active in both tumor tissues and the atrophic skeletal muscles. Systemic inhibition of Notch signaling reduced muscle atrophy. In vitro coculture of osteosarcoma cells with muscle-derived stem cells (MDSCs) isolated from normal mice resulted in decreased myogenic potential of MDSCs, while the application of Notch inhibitor was able to rescue this repressed myogenic potential. We further observed that Notch-activating factors reside in the exosomes of osteosarcoma cells, which activate Notch signaling in MDSCs and subsequently repress myogenesis. Our results revealed that signaling between tumor and muscle via the Notch pathway may play an important role in mediating the skeletal muscle atrophy seen in cancer cachexia. PMID:27378829

  5. [Atipic osteosarcoma in the femoral shaft case report and review of the literature].

    PubMed

    Clara-Altamirano, M A; García-Ortega, D Y; Martínez-Tlahuel, J L; Martínez-Said, H; Caro-Sánchez, C H S; García-Ruíz, G C; Mejía-Salazar, C R; Cuellar-Hubbe, M

    2016-01-01

    Osteosarcoma is the most frequent primary malignant bone tumor. It is characterized by osteoid production by tumor cells. Its most frequent location is in the metaphyses of long bones, but a purely diaphyseal presentation is reported in 10% of cases. We report the case of a female 25 year-old patient whose symptoms of pain and swelling of the right mid thigh started four months before, without an apparent cause. Femur X-rays showed a tumor in the femoral shaft. The MRI showed extension to soft tissues with no compromise of the neurovascular bundle. The histopathologic report of the incisional biopsy was osteoblastic and chondroblastic osteosarcoma, classified as Enneking IIB, AJCC IIB. Treatment consisted of three cycles of neoadjuvant chemotherapy. Then intercalary femur resection plus reconstruction with centromedullary nailing and a diaphyseal spacer were performed. The histopathologic report was 95% necrosis (Huvos grade III). Three cycles of adjuvant chemotherapy were given and now, 18 months after completing the latter, the patient has no signs of local or distant tumor activity, and she can walk unassisted. Despite the fact that osteosarcoma does not occur usually in the mid shaft of long bones, we should always bear it in mind as part of the differential diagnosis for other conditions that occur more frequently in that region. Such location allows for a broad gamut of surgical approaches that spare the adjacent joints. PMID:27627776

  6. Ferulic acid inhibits proliferation and promotes apoptosis via blockage of PI3K/Akt pathway in osteosarcoma cell

    PubMed Central

    Wang, Ting; Gong, Xia; Jiang, Rong; Li, Hongzhong; Du, Weimin; Kuang, Ge

    2016-01-01

    Ferulic acid, a ubiquitous phenolic acid abundant in corn, wheat and flax, has potent anti-tumor effect in various cancer cell lines. However, the anti-tumor effect of ferulic acid on osteosarcoma remains unclear. Therefore, we conduct current study to examine the effect of ferulic acid on osteosarcoma cells and explore the underlying mechanisms. In present study, ferulic acid inhibited proliferation and induced apoptosis in both 143B and MG63 osteosarcoma cells dose-dependently, indicated by MTT assay and Annexin V-FITC apoptosis detection. Additionally, ferulic acid induced G0/G1 phase arrest and down-regulated the expression of cell cycle-related protein, CDK 2, CDK 4, CDK 6, confirmed by flow cytometry assay and western blotting. Moreover, ferulic acid upregulated Bax, downregulated Bcl-2, and subsequently enhanced caspase-3 activity. More importantly, ferulic acid dose-dependently inhibited PI3K/Akt activation. Using adenoviruses expressing active Akt, the anti-proliferation and pro-apoptosis of ferulic acid were reverted. Our results demonstrated that ferulic acid might inhibit proliferation and induce apoptosis via inhibiting PI3K/Akt pathway in osteosarcoma cells. Ferulic acid is a novel therapeutic agent for osteosarcoma. PMID:27158383

  7. MicroRNA profiling identifies MiR-195 suppresses osteosarcoma cell metastasis by targeting CCND1.

    PubMed

    Han, Kang; Chen, Xiang; Bian, Na; Ma, Baoan; Yang, Tongtao; Cai, Chengkui; Fan, QingYu; Zhou, Yong; Zhao, Ting Bao

    2015-04-20

    Metastasis is a leading cause of mortality for osteosarcoma patients. The molecular pathological mechanism remains to be elucidated. In the previously study, we established two osteosarcoma cell lines with different metastatic potentials. Differential expressed genes and proteins regarding metastatic ability have been identified. MicroRNAs are important regulators in tumorigenesis and tumor progression. In this study, microRNA microarray was used to assess the differential expressed miRNAs level between these two cell lines. One of the top ranked miRNAs-miR-195 was identified highly expressing in lowly metastatic cells. It was showed that over-expression of miR-195 substantially inhibits migration and invasion of osteosarcoma cells in vitro and pulmonary metastasis formation in vivo. Meanwhile, CCND1 was identified as the target gene of miR-195 and further studied. More importantly, using real-time PCR, we evaluated the expression of miR-195 and CCND1 in osteosarcoma samples from 107 frozen biopsy tissues and 99 formalin- or paraformalin-fixed, paraffin-embedded (FFPE) tissues. Results indicated lowly expressed miR-195 or highly CCND1 correlated with positive overall survival and their expression inversely related to each other. In summary, our study suggests miR-195 functions as a tumor metastasis suppressor gene by down-regulating CCND1 and can be used as a potential target in the treatment of osteosarcoma. PMID:25823925

  8. The oncolytic adenovirus Δ24-RGD in combination with cisplatin exerts a potent anti-osteosarcoma activity.

    PubMed

    Martinez-Velez, Naiara; Xipell, Enric; Jauregui, Patricia; Zalacain, Marta; Marrodan, Lucía; Zandueta, Carolina; Vera, Beatriz; Urquiza, Leire; Sierrasesúmaga, Luis; Julián, Mikel San; Toledo, Gemma; Fueyo, Juan; Gomez-Manzano, Candelaria; Torre, Wensceslao; Lecanda, Fernando; Patiño-García, Ana; Alonso, Marta M

    2014-10-01

    Osteosarcoma is the most common malignant bone tumor in children and adolescents. The presence of metastases and the lack of response to conventional treatment are the major adverse prognostic factors. Therefore, there is an urgent need for new treatment strategies that overcome both of these problems. Our purpose was to elucidate whether the use of the oncolytic adenovirus Δ24-RGD alone or in combination with standard chemotherapy would be effective, in vitro and in vivo, against osteosarcoma. Our results showed that Δ24-RGD exerted a potent antitumor effect against osteosarcoma cell lines that was increased by the addition of cisplatin. Δ24-RGD osteosarcoma treatment resulted in autophagy in vitro that was further enhanced when combined with cisplatin. Of importance, administration of Δ24-RGD and/or cisplatin, in novel orthotopic and two lung metastatic models in vivo resulted in a significant reduction of tumor burden meanwhile maintaining a safe toxicity profile. Together, our data underscore the potential of Δ24-RGD to become a realistic therapeutic option for primary and metastatic pediatric osteosarcoma. Moreover, this study warrants a future clinical trial to evaluate the safety and efficacy of Δ24-RGD for this devastating disease. PMID:24737304

  9. Texture feature extraction based on wavelet transform and gray-level co-occurrence matrices applied to osteosarcoma diagnosis.

    PubMed

    Hu, Shan; Xu, Chao; Guan, Weiqiao; Tang, Yong; Liu, Yana

    2014-01-01

    Osteosarcoma is the most common malignant bone tumor among children and adolescents. In this study, image texture analysis was made to extract texture features from bone CR images to evaluate the recognition rate of osteosarcoma. To obtain the optimal set of features, Sym4 and Db4 wavelet transforms and gray-level co-occurrence matrices were applied to the image, with statistical methods being used to maximize the feature selection. To evaluate the performance of these methods, a support vector machine algorithm was used. The experimental results demonstrated that the Sym4 wavelet had a higher classification accuracy (93.44%) than the Db4 wavelet with respect to osteosarcoma occurrence in the epiphysis, whereas the Db4 wavelet had a higher classification accuracy (96.25%) for osteosarcoma occurrence in the diaphysis. Results including accuracy, sensitivity, specificity and ROC curves obtained using the wavelets were all higher than those obtained using the features derived from the GLCM method. It is concluded that, a set of texture features can be extracted from the wavelets and used in computer-aided osteosarcoma diagnosis systems. In addition, this study also confirms that multi-resolution analysis is a useful tool for texture feature extraction during bone CR image processing. PMID:24211892

  10. The role of CTLA-4 and PD-1 in anti-tumor immune response and their potential efficacy against osteosarcoma.

    PubMed

    Wang, Sheng-Dong; Li, Heng-Yuan; Li, Bing-Hao; Xie, Tao; Zhu, Ting; Sun, Ling-Ling; Ren, Hai-Yong; Ye, Zhao-Ming

    2016-09-01

    Immunotherapy is proved to be a promising therapeutic strategy against human malignancies. Evasion of immune surveillance is considered to be a major factor of malignant progression. Inhibitory receptors, especially CTLA-4 and PD-1, are found to play critical roles in the mediation of anti-tumor immune efficacy. Thus, antibodies targeting these immune checkpoints have emerged as the attractive treatment approaches to those patients with cancer. Osteosarcoma is highly malignant and current treatment remains a challenge, especially for those patients with metastasis. Despite some achievements, the effect of immunotherapy against osteosarcoma is still unsatisfactory. The present review attempts to show the role and mechanism of CTLA-4 and PD-1 in immune response and summarize the recent findings related to the effect of inhibitory receptor antibodies on the immune response against tumors, especially osteosarcoma, and the correlation between PD-1 or/and CTLA-4 expression and outcome of osteosarcoma patients. We further discuss the utilization of the combination therapy against osteosarcoma. PMID:27258185

  11. VEGF Silencing Inhibits Human Osteosarcoma Angiogenesis and Promotes Cell Apoptosis via PI3K/AKT Signaling Pathway.

    PubMed

    Zhao, Jian; Zhang, Zi-Ru; Zhao, Na; Ma, Bao-An; Fan, Qing-Yu

    2015-11-01

    Vascular endothelial growth factor (VEGF) is one of the most effective angiogenic factors that promote generation of tumor vasculature. VEGF is usually up-regulated in multiple cancers including osteosarcoma and glioma. To further explore the potential molecular mechanism that inhibits tumor growth induced by interference of VEGF expression, we constructed a Lv-shVEGF vector and assessed the efficiency of VEGF silencing and its influence in U2OS cells. The data demonstrate that Lv-shVEGF has high inhibition efficiency on VEGF expression, which inhibits proliferation and promotes apoptosis of U2OS cells in vitro. Our results also indicate that inhibition of VEGF expression suppresses osteosarcoma tumor growth in vivo and reduces osteosarcoma angiogenesis. We also found that the activations of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) were considerably reduced after osteosarcoma cells were treated with Lv-shVEGF. Taken together, our data demonstrate that VEGF silencing suppresses cell proliferation, promotes cell apoptosis, and reduces osteosarcoma angiogenesis through inactivation of PI3K/AKT signaling pathway. PMID:27352347

  12. Ferulic acid inhibits proliferation and promotes apoptosis via blockage of PI3K/Akt pathway in osteosarcoma cell.

    PubMed

    Wang, Ting; Gong, Xia; Jiang, Rong; Li, Hongzhong; Du, Weimin; Kuang, Ge

    2016-01-01

    Ferulic acid, a ubiquitous phenolic acid abundant in corn, wheat and flax, has potent anti-tumor effect in various cancer cell lines. However, the anti-tumor effect of ferulic acid on osteosarcoma remains unclear. Therefore, we conduct current study to examine the effect of ferulic acid on osteosarcoma cells and explore the underlying mechanisms. In present study, ferulic acid inhibited proliferation and induced apoptosis in both 143B and MG63 osteosarcoma cells dose-dependently, indicated by MTT assay and Annexin V-FITC apoptosis detection. Additionally, ferulic acid induced G0/G1 phase arrest and down-regulated the expression of cell cycle-related protein, CDK 2, CDK 4, CDK 6, confirmed by flow cytometry assay and western blotting. Moreover, ferulic acid upregulated Bax, downregulated Bcl-2, and subsequently enhanced caspase-3 activity. More importantly, ferulic acid dose-dependently inhibited PI3K/Akt activation. Using adenoviruses expressing active Akt, the anti-proliferation and pro-apoptosis of ferulic acid were reverted. Our results demonstrated that ferulic acid might inhibit proliferation and induce apoptosis via inhibiting PI3K/Akt pathway in osteosarcoma cells. Ferulic acid is a novel therapeutic agent for osteosarcoma. PMID:27158383

  13. MicroRNA profiling identifies MiR-195 suppresses osteosarcoma cell metastasis by targeting CCND1

    PubMed Central

    Ma, Baoan; Yang, Tongtao; Cai, Chengkui; Fan, QingYu; Zhou, Yong; Zhao, TingBao

    2015-01-01

    Metastasis is a leading cause of mortality for osteosarcoma patients. The molecular pathological mechanism remains to be elucidated. In the previously study, we established two osteosarcoma cell lines with different metastatic potentials. Differential expressed genes and proteins regarding metastatic ability have been identified. MicroRNAs are important regulators in tumorigenesis and tumor progression. In this study, microRNA microarray was used to assess the differential expressed miRNAs level between these two cell lines. One of the top ranked miRNAs-miR-195 was identified highly expressing in lowly metastatic cells. It was showed that over-expression of miR-195 substantially inhibits migration and invasion of osteosarcoma cells in vitro and pulmonary metastasis formation in vivo. Meanwhile, CCND1 was identified as the target gene of miR-195 and further studied. More importantly, Using real-time PCR, we evaluated the expression of miR-195 and CCND1 in osteosarcoma samples from 107 frozen biopsy tissues and 99 formalin- or paraformalin-fixed, paraffin-embedded (FFPE) tissues. Results indicated lowly expressed miR-195 or highly CCND1 correlated with positive overall survival and their expression inverse relate to each other. In summary, our study suggests miR-195 function as a tumor metastasis suppressor gene by down-regulating CCND1 and can be used as a potential target in the treatment of osteosarcoma. PMID:25823925

  14. Silencing of Ether à go-go 1 by shRNA inhibits osteosarcoma growth and cell cycle progression.

    PubMed

    Wu, Jin; Zhong, Daixing; Fu, Xijin; Liu, Qingjun; Kang, Liangqi; Ding, Zhenqi

    2014-01-01

    Recently, a member of the voltage-dependent potassium channel (Kv) family, the Ether à go-go 1 (Eag1) channel was found to be necessary for cell proliferation, cycle progression and tumorigenesis. However, the therapeutic potential of the Eag1 channel in osteosarcoma remains elusive. In the present study, a recombinant adenovirus harboring shRNA against Eag1 was constructed to silence Eag1 expression in human osteosarcoma MG-63 cells. We observed that Eag1-shRNA inhibited the proliferation and colony formation of MG-63 cells due to the induction of G1 phase arrest. Moreover, in vivo experiments showed that Eag1-shRNA inhibited osteosarcoma growth in a xenograft nude mice model. In addition, selective inhibition of Eag1 significantly decreased the expression levels of cyclin D1 and E. Taken together, our data suggest that the Eag1 channel plays a crucial role in regulating the proliferation and cell cycle of osteosarcoma cells, and represents a new and effective therapeutic target for osteosarcoma. PMID:24694542

  15. Silencing of Ether à Go-Go 1 by shRNA Inhibits Osteosarcoma Growth and Cell Cycle Progression

    PubMed Central

    Wu, Jin; Zhong, Daixing; Fu, Xijin; Liu, Qingjun; Kang, Liangqi; Ding, Zhenqi

    2014-01-01

    Recently, a member of the voltage-dependent potassium channel (Kv) family, the Ether à go-go 1 (Eag1) channel was found to be necessary for cell proliferation, cycle progression and tumorigenesis. However, the therapeutic potential of the Eag1 channel in osteosarcoma remains elusive. In the present study, a recombinant adenovirus harboring shRNA against Eag1 was constructed to silence Eag1 expression in human osteosarcoma MG-63 cells. We observed that Eag1-shRNA inhibited the proliferation and colony formation of MG-63 cells due to the induction of G1 phase arrest. Moreover, in vivo experiments showed that Eag1-shRNA inhibited osteosarcoma growth in a xenograft nude mice model. In addition, selective inhibition of Eag1 significantly decreased the expression levels of cyclin D1 and E. Taken together, our data suggest that the Eag1 channel plays a crucial role in regulating the proliferation and cell cycle of osteosarcoma cells, and represents a new and effective therapeutic target for osteosarcoma. PMID:24694542

  16. Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice.

    PubMed

    Onimoe, Grace-Ifeyinwa; Liu, Aiguo; Lin, Li; Wei, Chang-Ching; Schwartz, Eric B; Bhasin, Deepak; Li, Chenglong; Fuchs, James R; Li, Pui-kai; Houghton, Peter; Termuhlen, Amanda; Gross, Thomas; Lin, Jiayuh

    2012-06-01

    Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma. PMID:21340507

  17. The utility of SATB2 immunohistochemical expression in distinguishing between osteosarcomas and their malignant bone tumor mimickers, such as Ewing sarcomas and chondrosarcomas.

    PubMed

    Machado, Isidro; Navarro, Samuel; Picci, Piero; Llombart-Bosch, Antonio

    2016-09-01

    SATB2 is commonly expressed in osteosarcomas. Although apparently being a valuable diagnostic marker for differentiating between small cell osteosarcoma (SCO) and other small round cell tumors of bone, for instance Ewing sarcoma family of tumors (ESFT), it has not been tested in a large series of ESFT and chondrosarcomas so far. We studied the immunohistochemical expression of SATB2 in 42 osteosarcomas, 31 chondrosarcomas, and 371 genetically confirmed ESFT. SATB2 positivity was detected in 90.4% of osteosarcomas, 87.5% of SCO, 91.3% of osteoblastic osteosarcomas, and in all chondroblastic and parosteal osteosarcomas. The osteoblastic and SCO subtypes expressed SATB2 more intensely than other histological types. SATB2 was expressed in 46.6% of chondrosarcomas, and in 1.3% of ESFT. Sensitivity and specificity of SATB2 immunoexpression were 90.4% and 95.3%, respectively. The positive and negative predictive values in osteosarcoma diagnosis were 66.6% and 98.9%, respectively. In chondrosarcoma, SATB2 immunoexpression was more frequent and intense in high-grade chondrosarcoma (Grade III) and uncommon in chondrosarcoma grade I. SATB2 positivity was detected in 55.6% of chondrosarcomas grade II. SATB2 apparently cannot distinguish between chondroblastic osteosarcoma and high-grade chondrosarcoma. Nevertheless, SATB2 is frequently expressed in osteogenic tumors, but is rarely positive in ESFT, and with the support of CD99 expression and specific molecular studies, it is very useful for distinguishing between these two lesions. Although SATB2 immunoexpression helps to distinguish osteosarcoma from their mimickers, the identification of malignant osteoid matrix formation and the integration of clinical and radiological data remain the corner stone of osteosarcoma diagnosis and as yet no antibody has equalled the diagnostic value of this important morphologic hallmark. PMID:27465835

  18. Carboplatin versus alternating carboplatin and doxorubicin for the adjuvant treatment of canine appendicular osteosarcoma: a randomized, phase III trial†

    PubMed Central

    Skorupski, K. A.; Uhl, J. M.; Szivek, A; Allstadt Frazier, S. D.; Rebhun, R. B.; Rodriguez, C. O.

    2016-01-01

    Despite numerous published studies describing adjuvant chemotherapy for canine appendicular osteosarcoma, there is no consensus as to the optimal chemotherapy protocol. The purpose of this study was to determine whether either of two protocols would be associated with longer disease-free interval (DFI) in dogs with appendicular osteosarcoma following amputation. Dogs with histologically confirmed appendicular osteosarcoma that were free of gross metastases and underwent amputation were eligible for enrollment. Dogs were randomized to receive either six doses of carboplatin or three doses each of carboplatin and doxorubicin on an alternating schedule. Fifty dogs were included. Dogs receiving carboplatin alone had a significantly longer DFI (425 versus 135 days) than dogs receiving alternating carboplatin and doxorubicin (P = 0.04). Toxicity was similar between groups. These results suggest that six doses of carboplatin may be associated superior DFI when compared to six total doses of carboplatin and doxorubicin. PMID:24118677

  19. Establishment and characterization of OS 99-1, a cell line derived from a highly aggressive primary human osteosarcoma.

    PubMed

    Gillette, Jennifer M; Gibbs, C Parker; Nielsen-Preiss, Sheila M

    2008-01-01

    Osteosarcoma is the most common form of primary bone cancer. In this study, we established a human osteosarcoma cell line (OS 99-1) from a highly aggressive primary tumor. G-banding karyotype analysis demonstrated a large number of clonal abnormalities, as well as extensive intercellular heterogeneity. Through the use of immunologic, molecular, and biochemical analyses, we characterized protein and gene expression profiles confirming the osteogenic nature of the cells. Further evaluation indicated that OS 99-1 cells maintain the capacity to differentiate in an in vitro mineralization assay as well as form tumors in the in vivo chicken embryo model. This cell line provides a useful tool to investigate the molecular mechanisms contributing to osteosarcoma and may have the potential to serve as a culture system for studies involving bone physiology. PMID:18247100

  20. A novel locus for canine osteosarcoma (OSA1) maps to CFA34, the canine orthologue of human 3q26.

    PubMed

    Phillips, Jeffrey C; Lembcke, Luis; Chamberlin, Tamara

    2010-10-01

    Spontaneous tumors in dogs share many of the same features of their human orthologues including clinical behavior, response to treatment, and molecular defects. It is therefore natural to consider the use of dogs and their spontaneous malignancies in the study of complex disease such as cancer. Scottish Deerhounds are a giant breed of dogs that exhibit a high incidence of bone cancer. Our previous work suggested that osteosarcoma within this breed could be explained by the presence of a major gene of dominant effect. Herein, we use a whole genome mapping approach to evaluate a four-generation pedigree of Scottish Deerhounds for linkage of their osteosarcoma phenotype. Using this approach we found evidence of linkage (Z(max)=5.766) between their phenotype and markers located on CFA34, in a region syntenic to human chromosome 3q26. The identification of this locus provides novel insight into the genetic basis of osteosarcoma in both canines and humans. PMID:20647041

  1. Specific Targeting of a Naturally Presented Osteosarcoma Antigen, Papillomavirus Binding Factor Peptide, Using an Artificial Monoclonal Antibody*

    PubMed Central

    Tsukahara, Tomohide; Emori, Makoto; Murata, Kenji; Hirano, Takahisa; Muroi, Norihiro; Kyono, Masanori; Toji, Shingo; Watanabe, Kazue; Torigoe, Toshihiko; Kochin, Vitaly; Asanuma, Hiroko; Matsumiya, Hiroshi; Yamashita, Keiji; Himi, Tetsuo; Ichimiya, Shingo; Wada, Takuro; Yamashita, Toshihiko; Hasegawa, Tadashi; Sato, Noriyuki

    2014-01-01

    Osteosarcoma is a rare but highly malignant tumor occurring most frequently in adolescents. The prognosis of non-responders to chemotherapy is still poor, and new treatment modalities are needed. To develop peptide-based immunotherapy, we previously identified autologous cytotoxic T lymphocyte-defined osteosarcoma antigen papillomavirus binding factor (PBF) in the context of HLA-B55 and the cytotoxic T lymphocyte epitope (PBF A2.2) presented by HLA-A2. PBF and HLA class I are expressed in ∼90 and 70% of various sarcomas, respectively. However, the expression status of peptide PBF A2.2 presented by HLA-A2 on osteosarcoma cells has remained unknown because it is difficult to generate a specific probe that reacts with the HLA·peptide complex. For detection and qualification of the HLA-A*02:01·PBF A2.2 peptide complex on osteosarcoma cells, we tried to isolate a single chain variable fragment (scFv) antibody directed to the HLA-*A0201·PBF A2.2 complex using a naïve scFv phage display library. As a result, scFv clone D12 with high affinity (KD = 1.53 × 10−9 m) was isolated. D12 could react with PBF A2.2 peptide-pulsed T2 cells and HLA-A2+PBF+ osteosarcoma cell lines and simultaneously demonstrated that the HLA·peptide complex was expressed on osteosarcoma cells. In conclusion, scFv clone D12 might be useful to select candidate patients for PBF A2.2 peptide-based immunotherapy and develop antibody-based immunotherapy. PMID:24962571

  2. Eradication of osteosarcoma by fluorescence-guided surgery with tumor labeling by a killer-reporter adenovirus.

    PubMed

    Yano, Shuya; Miwa, Shinji; Kishimoto, Hiroyuki; Urata, Yasuo; Tazawa, Hiroshi; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M

    2016-05-01

    In a previous study, we developed fluorescence-guided surgery (FGS) for osteosarcoma using an orthotopic model with 143B human osteosarcoma cells expressing red fluorescent protein (RFP) implanted into the intramedullary cavity of the tibia in nude mice. The FGS-treated mice had a significantly higher disease-free survival (DFS) rate than the bright-light surgery (BLS). However, although FGS significantly reduced the recurrence of the primary tumor, it did not reduce lung metastasis. In the present study, we utilized the OBP-401 telomerase-dependent killer-reporter adenovirus, carrying green fluorescent protein (GFP), to label human osteosarcoma in situ in orthotopic mouse models. OBP-401-illuminated human osteosarcoma cell lines, 143B and MNNG/HOS cells in vitro and in vivo. OBP-401 tumor illumination enabled effective FGS of the 143B-derived orthotopic mouse model of human osteosarcoma model as well as FGS eradication of residual cancer cells after BLS. OBP-401-assisted FGS significantly inhibited local recurrence and lung metastasis after surgery, thereby prolonging DFS and overall survival (OS), achieving a very important improvement of therapeutic outcomes over our previously reported FGS study. These therapeutic benefits of FGS were demonstrated using a clinically-viable methodology of direct labeling of human osteosarcoma in situ with the OBP-401 killer-reporter adenovirus in contrast with previous reports, which used genetically engineered labeled cells or antibody-based fluorescent labels for FGS. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:836-844, 2016. PMID:26479501

  3. Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations.

    PubMed

    Lorenz, Susanne; Barøy, Tale; Sun, Jinchang; Nome, Torfinn; Vodák, Daniel; Bryne, Jan-Christian; Håkelien, Anne-Mari; Fernandez-Cuesta, Lynnette; Möhlendick, Birte; Rieder, Harald; Szuhai, Karoly; Zaikova, Olga; Ahlquist, Terje C; Thomassen, Gard O S; Skotheim, Rolf I; Lothe, Ragnhild A; Tarpey, Patrick S; Campbell, Peter; Flanagan, Adrienne; Myklebost, Ola; Meza-Zepeda, Leonardo A

    2016-02-01

    In contrast to many other sarcoma subtypes, the chaotic karyotypes of osteosarcoma have precluded the identification of pathognomonic translocations. We here report hundreds of genomic rearrangements in osteosarcoma cell lines, showing clear characteristics of microhomology-mediated break-induced replication (MMBIR) and end-joining repair (MMEJ) mechanisms. However, at RNA level, the majority of the fused transcripts did not correspond to genomic rearrangements, suggesting the involvement of trans-splicing, which was further supported by typical trans-splicing characteristics. By combining genomic and transcriptomic analysis, certain recurrent rearrangements were identified and further validated in patient biopsies, including a PMP22-ELOVL5 gene fusion, genomic structural variations affecting RB1, MTAP/CDKN2A and MDM2, and, most frequently, rearrangements involving TP53. Most cell lines (7/11) and a large fraction of tumor samples (10/25) showed TP53 rearrangements, in addition to somatic point mutations (6 patient samples, 1 cell line) and MDM2 amplifications (2 patient samples, 2 cell lines). The resulting inactivation of p53 was demonstrated by a deficiency of the radiation-induced DNA damage response. Thus, TP53 rearrangements are the major mechanism of p53 inactivation in osteosarcoma. Together with active MMBIR and MMEJ, this inactivation probably contributes to the exceptional chromosomal instability in these tumors. Although rampant rearrangements appear to be a phenotype of osteosarcomas, we demonstrate that among the huge number of probable passenger rearrangements, specific recurrent, possibly oncogenic, events are present. For the first time the genomic chaos of osteosarcoma is characterized so thoroughly and delivered new insights in mechanisms involved in osteosarcoma development and may contribute to new diagnostic and therapeutic strategies. PMID:26672768

  4. Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations

    PubMed Central

    Lorenz, Susanne; Barøy, Tale; Sun, Jinchang; Nome, Torfinn; Vodák, Daniel; Bryne, Jan-Christian; Håkelien, Anne-Mari; Fernandez-Cuesta, Lynnette; Möhlendick, Birte; Rieder, Harald; Szuhai, Karoly; Zaikova, Olga; Ahlquist, Terje C.; Thomassen, Gard O. S.; Skotheim, Rolf I.; Lothe, Ragnhild A.; Tarpey, Patrick S.; Campbell, Peter; Flanagan, Adrienne

    2016-01-01

    In contrast to many other sarcoma subtypes, the chaotic karyotypes of osteosarcoma have precluded the identification of pathognomonic translocations. We here report hundreds of genomic rearrangements in osteosarcoma cell lines, showing clear characteristics of microhomology-mediated break-induced replication (MMBIR) and end-joining repair (MMEJ) mechanisms. However, at RNA level, the majority of the fused transcripts did not correspond to genomic rearrangements, suggesting the involvement of trans-splicing, which was further supported by typical trans-splicing characteristics. By combining genomic and transcriptomic analysis, certain recurrent rearrangements were identified and further validated in patient biopsies, including a PMP22-ELOVL5 gene fusion, genomic structural variations affecting RB1, MTAP/CDKN2A and MDM2, and, most frequently, rearrangements involving TP53. Most cell lines (7/11) and a large fraction of tumor samples (10/25) showed TP53 rearrangements, in addition to somatic point mutations (6 patient samples, 1 cell line) and MDM2 amplifications (2 patient samples, 2 cell lines). The resulting inactivation of p53 was demonstrated by a deficiency of the radiation-induced DNA damage response. Thus, TP53 rearrangements are the major mechanism of p53 inactivation in osteosarcoma. Together with active MMBIR and MMEJ, this inactivation probably contributes to the exceptional chromosomal instability in these tumors. Although rampant rearrangements appear to be a phenotype of osteosarcomas, we demonstrate that among the huge number of probable passenger rearrangements, specific recurrent, possibly oncogenic, events are present. For the first time the genomic chaos of osteosarcoma is characterized so thoroughly and delivered new insights in mechanisms involved in osteosarcoma development and may contribute to new diagnostic and therapeutic strategies. PMID:26672768

  5. Overexpression of miR-506 suppresses proliferation and promotes apoptosis of osteosarcoma cells by targeting astrocyte elevated gene-1

    PubMed Central

    Yao, Jie; Qin, Li; Miao, Sen; Wang, Xiangshan; Wu, Xuejian

    2016-01-01

    There is increasing evidence that microRNAs (miRs) are implicated in tumor development and progression; however, their specific roles in osteosarcoma are not well understood. The aim of the present study was to investigate the role of miR-506 in the pathogenesis of osteosarcoma. The expression levels of miR-506 and astrocyte elevated gene-1 (AEG-1) mRNA were detected using quantitative polymerase chain reaction, and the protein levels of AEG-1, β-catenin, c-myc and cyclin D1 were determined using western blot analysis. The effects of miR-506 and AEG-1 on cell viability, colony forming ability and apoptosis were assessed using MTT assay, colony formation assay, and flow cytometry, respectively. Lucifer reporter assays were used to demonstrate whether AEG-1 is a direct target of miR-506. The present study identified that miR-506 was downregulated in osteosarcoma tissues and cells. Overexpression of miR-506 suppressed the proliferation and induced apoptosis in osteosarcoma cells in vitro and inhibited tumor formation in vivo. Overexpression of miR-506 significantly inhibited the luciferase activity of AEG-1 with a wild-type 3′-untranslated region, providing clear evidence that AEG-1 was a direct and functional downstream target of miR-506. Similar to the overexpression of miR-506, downregulation of AEG-1 lead to an inhibitory effect on osteosarcoma in vitro. Furthermore, overexpression of miR-506 or downregulation of AEG-1 inhibited the Wnt/β-catenin signaling pathway, and inhibition of this pathway by β-catenin small interfering RNA or CGP049090, a small molecule inhibitor, suppressed cell proliferation and induced apoptosis in vitro. Overall, the present data indicated that miR-506 functions as a tumor suppressor by targeting AEG-1 in osteosarcoma via the regulation of the Wnt/β-catenin signaling pathway. PMID:27602115

  6. Reduced argininosuccinate synthetase is a predictive biomarker for the development of pulmonary metastasis in patients with osteosarcoma.

    PubMed

    Kobayashi, Eisuke; Masuda, Mari; Nakayama, Robert; Ichikawa, Hitoshi; Satow, Reiko; Shitashige, Miki; Honda, Kazufumi; Yamaguchi, Umio; Shoji, Ayako; Tochigi, Naobumi; Morioka, Hideo; Toyama, Yoshiaki; Hirohashi, Setsuo; Kawai, Akira; Yamada, Tesshi

    2010-03-01

    Pulmonary metastasis is the most significant prognostic determinant for osteosarcoma, but methods for its prediction and treatment have not been established. Using oligonucleotide microarrays, we compared the global gene expression of biopsy samples between seven osteosarcoma patients who developed pulmonary metastasis within 4 years after neoadjuvant chemotherapy and curative resection, and 12 patients who did not relapse. We identified argininosuccinate synthetase (ASS) as a gene differentially expressed with the highest statistical significance (Welch's t test, P = 2.2 x 10(-5)). Immunohistochemical analysis of an independent cohort of 62 osteosarcoma cases confirmed that reduced expression of ASS protein was significantly correlated with the development of pulmonary metastasis after surgery (log-rank test, P < 0.05). Cox regression analysis revealed that ASS was the sole significant predictive factor (P = 0.039; hazard ratio, 0.319; 95% confidence interval, 0.108-0.945). ASS is one of the enzymes required for the production of a nonessential amino acid, arginine. We showed that osteosarcoma cells lacking ASS expression were auxotrophic for arginine and underwent G(0)-G(1) arrest in arginine-free medium, suggesting that an arginine deprivation therapy could be effective in patients with osteosarcoma. Recently, phase I and II clinical trials in patients with melanoma and hepatocellular carcinoma have shown the safety and efficacy of plasma arginine depletion by stabilized arginine deiminase. Our data indicate that in patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention. PMID:20159990

  7. Fuse-binding protein 1 is a target of the EZH2 inhibitor GSK343, in osteosarcoma cells.

    PubMed

    Xiong, Xifeng; Zhang, Jinli; Liang, Weiguo; Cao, Wenjuan; Qin, Shengnan; Dai, Libing; Ye, Dongping; Liu, Zhihe

    2016-08-01

    Osteosarcoma is the primary cancer of leaf tissue and is regarded as a differentiation disease caused by genetic and epigenetic changes which interrupt the osteoblast differentiation from mesenchymal stem cells. Because of its high malignancy degree and rapid development, the morbidity and mortality are high. The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of polycomb repressive complex 2 (PRC2) and has been demonstrated to be involved in a variety of biological processes, such as cell proliferation and program cell death. EZH2 impairs gene expression by catalyzing the tri-methylation of histone H3 lysine 27 (H3K27me3) which controls gene transcription epigenetically. It is reported that EZH2 expression is higher in osteosarcoma than in osteoblastoma and the highest expression of EZH2 is found in osteosarcoma with metastasis. In the past few years, several potent inhibitors of EZH2 have been discovered, and GSK343 is one of them. In this study, we found that GSK343 inhibited osteosarcoma cell viability, restrained cell cycle transition and promoted programmed cell death. GSK343 not only inhibited the expression of EZH2 and its target, c-Myc and H3K27me3, but it also inhibited fuse binding protein 1 (FBP1) expression, another c-Myc regulator. Furthermore, we found that FBP1 physically interacts with EZH2. Based on these results, we believe that GSK343 is a potential molecule for osteosarcoma clinical treatment. Other than the inhibition on EZH2-c-Myc signal pathway, we postulate that the inhibition on FBP1-c-Myc signal pathway is another potential underlying mechanism with which GSK343 inhibits osteosarcoma cell viability. PMID:27278257

  8. Baicalein suppresses the viability of MG-63 osteosarcoma cells through inhibiting c-MYC expression via Wnt signaling pathway.

    PubMed

    He, Nengbin; Zhang, Zhichang

    2015-07-01

    The major reason responsible for the poor prognosis of osteosarcoma is the malignant proliferation of osteosarcoma cells. The activated Wnt/β-catenin signaling induces c-MYC gene transcription and results in osteocytes' carcinomatous change, which contributes to osteosarcoma development, so c-MYC gene is one of the therapeutic targets. The role of multiple botanical extracts in the expression of β-catenin's target gene c-MYC in osteosarcoma MG-63 cells was tested by cellomics high content screening. Baicalein was identified as the most effective one which can inhibit the proliferation and promote the apoptosis of MG-63 cells in a dose-dependent manner by cell counting kit-8 test and fluorescence-activated cell sorting, respectively. This process was associated with the decreased levels of β-catenin and its target gene c-MYC, identified by q-PCR and Western blotting, respectively. When MG-63 cells were treated with both baicalein and JNK inhibitor SP600125, the apoptosis and expression of c-MYC were not significantly decreased. After the construct pcDNA3.1-BANCR (BRAF-regulated lncRNA 1) was transfected into MG-63 cells, RT-PCR, Western blotting and CCK-8 assay showed that BANCR was positively correlated with baicalein. These results indicated that baicalein inhibited osteosarcoma cell proliferation and promoted apoptosis by targeting c-MYC gene through Wnt signaling, in which JNK and BANCR were also involved as well as β-catenin, suggesting a new potential mechanism for us to better understand the inhibiting effect of baicalein on osteosarcoma. PMID:25893737

  9. Upregulation of long non-coding RNA TUG1 correlates with poor prognosis and disease status in osteosarcoma.

    PubMed

    Ma, Bing; Li, Meng; Zhang, Lei; Huang, Ming; Lei, Jun-Bin; Fu, Gui-Hong; Liu, Chun-Xin; Lai, Qi-Wen; Chen, Qing-Quan; Wang, Yi-Lian

    2016-04-01

    The pathogenesis of osteosarcoma involves complex genetic and epigenetic factors. This study was to explore the impact and clinical relevance of long non-coding RNA (lncRNA), Taurine up-regulated gene 1 (TUG1) on patients with osteosarcoma. Seventy-six osteosarcoma tissues and matched adjacent normal tissues were included for analysis. The plasma samples were obtained from 29 patients with osteosarcoma at pre-operation and post-operation, 42 at newly diagnosed, 18 who experienced disease progression or relapse, 45 post-treatment, 36 patients with benign bone tumor, and 20 healthy donors. Quantitative real-time reverse transcript polymerase chain reactions were used to assess the correlation of the expression levels of TUG1 with clinical parameters of osteosarcoma patients. TUG1 was significantly overexpressed in the osteosarcoma tissues compared with matched adjacent normal tissues (P < 0.01) and was closely correlated with tumor size, post-operative chemotherapy, and Enneking surgical stage. Upregulation of TUG1 strongly correlated with poor prognosis and was an independent prognostic indicator for overall survival (HR = 2.78, 95% CI = 1.29-6.00, P = 0.009) and progression-free survival (HR = 1.81, 95% CI = 1.01-3.54, P = 0.037). Our constructed nomogram containing TUG1 had more predictive accuracy than that without TUG1 (c-index 0.807 versus 0.776, respectively). In addition, for plasma samples, TUG1 expression levels were obviously decreased in post-operative patients (mean ΔCT -4.98 ± 0.22) compared with pre-operation patients (mean ΔCT -6.09 ± 0.74), and the changes of TUG1 expression levels were significantly associated with disease status. Receiver operating characteristic (ROC) curve analysis demonstrated that TUG1 could distinguish patients with osteosarcoma from healthy individuals compared with alkaline phosphatase (ALP) (the area under curve 0.849 versus 0.544). TUG1 was overexpressed in patients with osteosarcoma

  10. An Evidence-Based Case Study of Unilateral Shin Splints: Do Red Flags Function in Paediatric Osteosarcoma?

    PubMed

    Rankin, Anne

    2015-01-01

    Physiotherapists use red flags to screen for serious pathology. Paediatric osteosarcoma is a rare disease, occurring predominantly in the area of the knee and shoulder, and it is not always included by physiotherapists on a differential diagnosis list. Traditional red flags do not always correspond to the initial signs and symptoms of osteosarcoma. Physiotherapists should routinely palpate along the length of the bone to detect a potential mass. The detection of a mass or symptoms that do not follow the expected course indicates the need for reassessment and possibly referral for further investigation. PMID:27504036

  11. Radiosensitizing effect of misonidazole in acute and fractionated irradiation of a human osteosarcoma xenograft. [/sup 60/Co

    SciTech Connect

    Rofstad, E.K.; Brustad, T.

    1980-09-01

    The radiosensitizing effect of misonidazole (Ro-07-0582) in acute and fractionated irradiation of a human osteosarcoma grown in the athymic mutant nude mouse was studied. Tumor regrowth delay was used as a measure of response. The enhancement ratio of misonidazole was found to be 1.45 for an actue dose of 12.50 Gy and 1.25 for four fractions of 3.75 Gy, delivered over four consecutive days. It is concluded that the present osteosarcoma xenograft reoxygenated inadequately during the three day period which elapsed from the first to the fourth fraction of 3.75 Gy.

  12. Serum levels of microRNA-133b and microRNA-206 expression predict prognosis in patients with osteosarcoma

    PubMed Central

    Zhang, Chun; Yao, Cong; Li, Haopeng; Wang, Guoyu; He, Xijing

    2014-01-01

    The aim of the present study was to investigate whether the aberrant expression of microRNA (miR)-133b and miR-206 can be used as potential prognostic markers of human osteosarcoma. Quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis was performed to detect the expression levels of miR-133b and miR-206 in 100 pairs of osteosarcoma tissues and matched noncancerous bone tissues, and serum samples from 100 patients with osteosarcoma as well as in serum samples from 100 healthy controls. As a result, expression levels of miR-133b and miR-206 were both significantly decreased in osteosarcoma tissues and patients’ sera (both P<0.001). Then, the downregulation of miR-133b and miR-206 both more frequently occurred in osteosarcoma patients with high tumor grade (both P=0.01), positive metastasis (both P<0.001) and recurrence (both P<0.001). Moreover, the patients with low miR-133b expression and low miR-206 expression both had shorter overall survival (OS, both P<0.001) and disease-free survival (DFS, both P<0.001) than those with high expressions. Of note, the OS and DFS of patients with combined low expression of miR-133b and miR-206 (miR-133b-low/miR-206-low) were the shortest (both P<0.001). Furthermore, low miR-133b expression, low miR-206 expression and conjoined expression of miR-133b/miR-206 were all independent prognostic factors for OS and DFS of osteosarcoma patients. Collectively, the aberrant expression of miR-133b and miR-206 may be implicated in tumorigenesis and tumor progression of osteosarcoma. More interestingly, detection of serum miR-133b and miR-206 expression could be further developed as novel, non-invasive and efficient markers for prognosis in patients with osteosarcomas. PMID:25120799

  13. The Expression of HSPD1, SCUBE3, CXCL14 and Its Relations with the Prognosis in Osteosarcoma.

    PubMed

    Liang, Wenqing; Yang, Chengwei; Peng, Jiahao; Qian, Yu; Wang, Zirui

    2015-12-01

    The aim of the study was to explore the expression of three genes, HSPD1, SCUBE3, and CXCL14, in osteosarcoma cells and tissue, as well as their association with the prognosis of patients with osteosarcoma. The expression of HSPD1, SCUBE3, and CXCL14 in osteosarcoma cells was detected by using Western blotting method. siRNA was used to knockdown the expression of the three genes. CCK8 cell proliferation assay was used to observe the effect of siRNA interference on U2OS cell proliferation. The expression of the three genes in osteosarcoma tissue was detected employing immunohistochemical method. Kaplan-Meier survival analysis was used to compare the relations between the expression of the three genes and prognosis. The Western blotting results showed that the expression of Hsp70, SCUBE3 protein, and CXCL14 chemotactic factor in osteosarcoma cells was significantly higher than that in normal osteocytes (p < 0.05). After the three genes were interfered by siRNA, the mRNA and protein expression levels of these genes in osteosarcoma cells were significantly decreased (p < 0.05). The growth rate of U2OS cell after the siRNA interference was significantly lower than that before interference and that in the control group transfected with negative control siRNA (p < 0.05). The result of immunohistochemistry demonstrated that the expression of Hsp70, SCUBE3 protein, and CXCL14 chemotactic factor in osteosarcoma tissues was significantly higher than that in adjacent muscle tissue (p < 0.05). Kaplan-Meier survival analysis indicated that the survival rate of the patients with high expression of those three kinds of genes was obviously lower than that of other patients (p < 0.05). There was no significant difference between the survival rates of patients with high or low expression of two genes (p > 0.05). The expression of HSPD1, SCUBE3, and CXCL14 was all high in osteosarcoma tissues and cells; moreover, the three kinds of genes had close correlations with the

  14. Primary mixed squamous carcinoma and osteosarcoma (carcinosarcomas) of the lung have a CGH mapping similar to primitive squamous carcinomas and osteosarcomas.

    PubMed

    Pardo, Javier; Aisa, Gregorio; de Alava, Enrique; Sola, Jesús J; Panizo, Angel; Rodríguez-Spiteri, Natalia; García, Juan L; Torre, Wenceslao

    2008-09-01

    Carcinosarcomas are malignant tumors with a mixture of carcinomatous and differentiated sarcomatous elements. We investigate the morphology, immunohistochemistry, and comparative genomic hybridization analysis of 3 mixed squamous carcinoma and osteosarcoma of the lung. All patients were male and their ages were 72, 43, and 58 years. The sizes of the neoplasms were 7, 5, and 5 cm in maximum diameter, respectively. Two patients died of the disease 9 and 14 months after surgery; and one is alive 6 months later. By light microscopy, all cases had both squamous and osteosarcomatous structures. Immunohistochemistry was positive for AE3AE1, p63, 34 E12, CAM 5.2 (2/3 cases), CK-7 (2/3 cases), epithelial membrane antigen, E-cadherin, p53, and carcinogenic embryonic antigen in carcinomatous areas, and for vimentin and CD-68 in sarcomatous component. Areas of transition positive for both cytokeratins and vimentin were seen in all cases. A total of 55 copy number changes were detected with a median of 18 abnormalities per case: 48 gains, 6 losses, and 1 high-level amplification. Chromosome alterations in osteosarcomatous areas were similar to those found in lung metastatic osteosarcoma, comparable to those found in carcinomatous areas and to lung squamous carcinomas. Coincidences between carcinomatous areas and osteosarcomatous zones were found as gains in chromosomes 1q, 3q, 5p, 8q, and 12p. These findings provide arguments that favor a common origin for both types of cells, supported by the mixture of cells, the existence of undifferentiated cells positive to both cytokeratin and vimentin markers, and the CGH overlaps of chromosomal gains between carcinomatous and sarcomatous areas. PMID:18382357

  15. Genetic polymorphisms in nucleotide excision repair pathway influences response to chemotherapy and overall survival in osteosarcoma

    PubMed Central

    Sun, Yongjian; Wu, Yi; Li, Weicheng; Kong, Zhen; Zou, Xiaoming

    2015-01-01

    We analyzed the role of genetic polymorphisms of six important NER pathway genes in response to chemotherapy and clinical outcome of osteosarcoma patients. A prospective study including 172 osteosarcoma patients was conducted between January 2009 and January 2011. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for ERCC1 rs11615 and rs2298881, ERCC2 rs13181 and rs1799793, ERCC4 rs1800067, ERCC5 rs1047768, XPA 1800975, and XPC rs2228000 and rs2228001 gene polymorphisms. By logistic regression analysis, TT genotype of ERCC1 rs11615 genetic polymorphism was significant correlated with poor response to chemotherapy when compared with wide-type genotype (OR=0.27, 95% CI=0.10-0.71). AC and CC genotype of ERCC1 rs2298881 were significantly associated with poor response to chemotherapy when compared with AA genotype (For AC genotype, OR=0.45, 95% CI=0.21-0.97; for CC genotype, OR=0.19, 95% CI=0.06-0.58). By Cox proportional hazards regression analysis, TT genotype of ERCC1 rs11615 and CC genotype of ERCC1 rs2298881 suffered a 3.16 and 3.57-fold increased hazards of death (For ERCC1 rs11615, HR=3.16, 95% CI=1.19-9.16; for ERCC1 rs2298881, HR=3.57, 95% CI=1.10-11.35). In conclusion, our findings suggest that ERCC1 rs11615 and ERCC1 rs2298881 genetic polymorphisms are significantly associated with poor response to chemotherapy and unfavourable survival of osteosarcoma. PMID:26339355

  16. Genetic polymorphisms in nucleotide excision repair pathway influences response to chemotherapy and overall survival in osteosarcoma.

    PubMed

    Sun, Yongjian; Wu, Yi; Li, Weicheng; Kong, Zhen; Zou, Xiaoming

    2015-01-01

    We analyzed the role of genetic polymorphisms of six important NER pathway genes in response to chemotherapy and clinical outcome of osteosarcoma patients. A prospective study including 172 osteosarcoma patients was conducted between January 2009 and January 2011. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for ERCC1 rs11615 and rs2298881, ERCC2 rs13181 and rs1799793, ERCC4 rs1800067, ERCC5 rs1047768, XPA 1800975, and XPC rs2228000 and rs2228001 gene polymorphisms. By logistic regression analysis, TT genotype of ERCC1 rs11615 genetic polymorphism was significant correlated with poor response to chemotherapy when compared with wide-type genotype (OR=0.27, 95% CI=0.10-0.71). AC and CC genotype of ERCC1 rs2298881 were significantly associated with poor response to chemotherapy when compared with AA genotype (For AC genotype, OR=0.45, 95% CI=0.21-0.97; for CC genotype, OR=0.19, 95% CI=0.06-0.58). By Cox proportional hazards regression analysis, TT genotype of ERCC1 rs11615 and CC genotype of ERCC1 rs2298881 suffered a 3.16 and 3.57-fold increased hazards of death (For ERCC1 rs11615, HR=3.16, 95% CI=1.19-9.16; for ERCC1 rs2298881, HR=3.57, 95% CI=1.10-11.35). In conclusion, our findings suggest that ERCC1 rs11615 and ERCC1 rs2298881 genetic polymorphisms are significantly associated with poor response to chemotherapy and unfavourable survival of osteosarcoma. PMID:26339355

  17. Clusterin inhibition using OGX-011 synergistically enhances zoledronic acid activity in osteosarcoma

    PubMed Central

    Lamoureux, Francois; Baud'huin, Marc; Ory, Benjamin; Guiho, Romain; Zoubeidi, Amina; Gleave, Martin; Heymann, Dominique; Rédini, Françoise

    2014-01-01

    Purpose Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. Among new therapeutic approaches, zoledronic acid (ZOL) represents a promising adjuvant molecule to chemotherapy to limit the osteolytic component of bone tumors. However, ZOL triggers the elevation of heat shock proteins (Hsp), including Hsp27 and clusterin (CLU), which could enhance tumor cell survival and treatment resistance. We hypothesized that targeting CLU using siRNA or the antisense drug, OGX-011, will suppress treatment-induced CLU induction and enhance ZOL-induced cell death in osteosarcoma (OS) cells. Methods The combined effects of OGX-011 and ZOL were investigated in vitro on cell growth, viability, apoptosis and cell cycle repartition of ZOL-sensitive or -resistant human OS cell lines (SaOS2, U2OS, MG63 and MNNG/HOS). Results In OS cell lines, ZOL increased levels of HSPs, especially CLU, in a dose- and time-dependent manner by mechanism including increased HSF1 transcription activity. The OS resistant cells to ZOL exhibited higher CLU expression level than the sensitive cells. Moreover, CLU overexpression protects OS sensitive cells to ZOL-induced cell death by modulating the MDR1 and farnesyl diphosphate synthase expression. OGX-011 suppressed treatment-induced increases in CLU and synergistically enhanced the activity of ZOL on cell growth and apoptosis. These biologic events were accompanied by decreased expression of HSPs, MDR1 and HSF1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 20mg/kg), potentiated the effect of ZOL (s.c; 50μg/kg), significantly inhibiting tumor growth by 50% and prolonging survival in MNNG/HOS xenograft model compared to ZOL alone. Conclusion These results indicate that ZOL-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of

  18. Aneurysmal bone cyst and telangiectatic osteosarcoma. A histopathological and morphometric study.

    PubMed

    Ruiter, D J; Cornelisse, C J; van Rijssel, T G; van der Velde, E A

    1977-04-29

    In a series of 105 cases of aneurysmal bone cyst, 18 showed an unusually high level of mitotic activity and/or increased nuclear pleomorphism which complicated the differential diagnosis with respect to telangiectatic osteosarcoma. An attempt was made to use semi-automatized morphometric and histophotometric techniques to establish objective morphological differences between these unusual cases of aneurysmal bone cyst and 16 cases of telangiectatic osteosarcoma. Three cases (two of aneurysmal bone cyst and one of telangiectatic osteosarcoma) proved unsuitable for analysis. In 24 of the remaining 31 cases (77%) a computerized discriminant analysis permitted correct discreimination with a high degree of certainty on the basis of quantitative nuclear characteristics determined in paraffin sections. In the other 7 cases the diagnosis was less certain (3), doubtful (2) or erroneous (2). The relevant nuclear characteristics were (in ascending sequence of discrimination): the largest nuclear surface area, the mitotic index, and the percentage of nuclear sections exceeding an arbitrarily chosen limit of 60 micron2. The criterion of nuclear size for discrimination between these benign and malignant lesions could be applied for two reasons: firstly, because a group of extremely large nuclei occur in malignant cases, and secondly, because the average nuclear size is larger in malignant than in benign lesions. The extremely large nuclei occur as only a small percentage of the total nuclear population. The other variables investigated, i.e., cellularity and nuclear contour ratio, did not contribute greatly to the differentiation. In 11 cases, the average nuclear Feulgen extinction was estimated as an additional variable. PMID:140511

  19. Butyl benzyl phthalate suppresses the ATP-induced cell proliferation in human osteosarcoma HOS cells

    SciTech Connect

    Liu, P.-S.; Chen, C.-Y.

    2010-05-01

    Butyl benzyl phthalate (BBP), an endocrine disruptor present in the environment, exerts its genomic effects via intracellular steroid receptors and elicits non-genomic effects by interfering with membrane ion-channel receptors. We previously found that BBP blocks the calcium signaling coupled with P2X receptors in PC12 cells (Liu and Chen, 2006). Osteoblast P2X receptors were recently reported to play a role in cell proliferation and bone remodeling. In this present study, the effects of BBP on ATP-induced responses were investigated in human osteosarcoma HOS cells. These receptors mRNA had been detected, named P2X4, P2X7, P2Y2, P2Y4, P2Y5, P2Y9, and P2Y11, in human osteosarcoma HOS cells by RT-PCR. The enhancement of cell proliferation and the decrease of cytoviability had both been shown to be coupled to stimulation via different concentrations of ATP. BBP suppressed the ATP-induced calcium influx (mainly coupled with P2X) and cell proliferation but not the ATP-induced intracellular calcium release (mainly coupled with P2Y) and cytotoxicity in human osteosarcoma HOS cells. Suramin, a common P2 receptor's antagonist, blocked the ATP-induced calcium signaling, cell proliferation, and cytotoxicity. We suggest that P2X is mainly responsible for cell proliferation, and P2Y might be partially responsible for the observed cytotoxicity. BBP suppressed the calcium signaling coupled with P2X, suppressing cell proliferation. Since the importance of P2X receptors during bone metastasis has recently become apparent, the possible toxic risk of environmental BBP during bone remodeling is a public problem of concern.

  20. Oncolytic Semliki forest virus vector as a novel candidate against unresectable osteosarcoma.

    PubMed

    Ketola, Anna; Hinkkanen, Ari; Yongabi, Felicitas; Furu, Petra; Määttä, Ann-Marie; Liimatainen, Timo; Pirinen, Risto; Björn, Marko; Hakkarainen, Tanja; Mäkinen, Kimmo; Wahlfors, Jarmo; Pellinen, Riikka

    2008-10-15

    Oncolytic viruses are a promising tool for treatment of cancer. We studied an oncolytic Semliki Forest virus (SFV) vector, VA7, carrying the enhanced green fluorescent protein gene (EGFP), as a novel virotherapy candidate against unresectable osteosarcoma. The efficiency and characteristics of the VA7-EGFP treatment were compared with a widely studied oncolytic adenovirus, Ad5Delta24, both in vitro and in vivo. VA7-EGFP resulted in more rapid oncolysis and was more efficient at low multiplicities of infection (MOI) when compared with Ad5Delta24 in vitro. Yet, in MG-63 cells, a subpopulation resistant to the VA7-EGFP vector emerged. In subcutaneous human osteosarcoma xenografts in nude mice treatment with either vector reduced tumor size, whereas tumors in control mice expanded quickly. The VA7-EGFP-treated tumors were either completely abolished or regressed to pinpoint size. The efficacy of VA7-EGFP vector was studied also in an orthotopic osteosarcoma nude mouse model characterized by highly aggressive tumor growth. Treatment with oncolytic SFV extended survival of the animals significantly (P < 0.01), yet none of the animals were finally cured. Sera from SFV-treated mice contained neutralizing antibodies, and as nude mice are not able to establish IgG response, the result points out the role of IgM class antibodies in clearance of virus from peripheral tumors. Furthermore, biodistribution analysis at the survival end point verified the presence of virus in some of the brain samples, which is in line with previous studies demonstrating that IgG is required for clearance of SFV from central nervous system. PMID:18922906

  1. On the measurement of human osteosarcoma cell elastic modulus using shear assay experiments.

    PubMed

    Cao, Yifang; Bly, Randy; Moore, Will; Gao, Zhan; Cuitino, Alberto M; Soboyejo, Wole

    2007-01-01

    This paper presents a method for determining the elastic modulus of human osteosarcoma (HOS) cells. The method involves a combination of shear assay experiments and finite element analysis. Following in-situ observations of cell deformation during shear assay experiments, a digital image correlation (DIC) technique was used to determine the local displacement and strain fields. Finite element analysis was then used to determine the Young's moduli of HOS cells. This involved a match of the maximum shear stresses estimated from the experimental shear assay measurements and those calculated from finite element simulations. PMID:17200819

  2. Primary osteosarcoma of bladder diverticulum mimicking intradiverticular calculus: a case report

    PubMed Central

    2011-01-01

    There is a well-documented relationship between urinary bladder diverticula and intradiverticular neoplasms. The great majorities of these tumors are urothelial carcinomas, but may also be of glandular or squamous type. Sarcomas occurring within bladder diverticula are exceptionally rare and highly malignant lesions, with only 20 well documented cases published in the literature to date (including carcinosarcomas). We report a case of osteosarcoma of the bladder diverticulum in a 68-year old man, which clinically mimicked intradiverticular calculus. To our knowledge, this is the second case described in the literature to date, and the first in English literature. PMID:21496355

  3. Extraosseous Osteosarcoma of the Liver Demonstrated on 18F-FDG PET/CT Imaging.

    PubMed

    Jiang, Lei; Luan, Lijuan; Yun, Hong; Hou, Yingyong; Shi, Hongcheng

    2016-08-01

    A 66-year-old woman presented with abdominal pain for 1 month. Ultrasonography displayed multiple hepatic masses that were thought as metastases. FDG PET/CT was performed to assess the nature of these masses and to search primary malignancy. The images showed elevated FDG activity in the partially calcified hypodense lesions in the liver without abnormality elsewhere. The lesions were subsequently confirmed as primary extraosseous osteosarcoma in the liver. The patient received liver transplantation. Six months later, her CA-125 was significantly increased. The follow-up PET/CT scan demonstrated the widespread metastases. PMID:27055145

  4. Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine

    PubMed Central

    Subbiah, Vivek; Wagner, Michael J.; McGuire, Mary F.; Sarwari, Nawid M.; Devarajan, Eswaran; Lewis, Valerae O.; Westin, Shanon; Kato, Shumei; Brown, Robert E.; Anderson, Pete

    2015-01-01

    Background Despite advances in molecular medicine over recent decades, there has been little advancement in the treatment of osteosarcoma. We performed comprehensive molecular profiling in two cases of metastatic and chemotherapy-refractory osteosarcoma to guide molecularly targeted therapy. Patients and Methods Hybridization capture of >300 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from tumor samples from two patients with recurrent, metastatic osteosarcoma. The DNA from each sample was sequenced to high, uniform coverage. Immunohistochemical probes and morphoproteomics analysis were performed, in addition to fluorescence in situ hybridization. All analyses were performed in CLIA-certified laboratories. Molecularly targeted therapy based on the resulting profiles was offered to the patients. Biomedical analytics were performed using QIAGEN's Ingenuity® Pathway Analysis. Results In Patient #1, comprehensive next-generation exome sequencing showed MET amplification, PIK3CA mutation, CCNE1 amplification, and PTPRD mutation. Immunohistochemistry-based morphoproteomic analysis revealed c-Met expression [(p)-c-Met (Tyr1234/1235)] and activation of mTOR/AKT pathway [IGF-1R (Tyr1165/1166), p-mTOR [Ser2448], p-Akt (Ser473)] and expression of SPARC and COX2. Targeted therapy was administered to match the P1K3CA, c-MET, and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib. In Patient #2, aberrations included NF2 loss in exons 2–16, PDGFRα amplification, and TP53 mutation. This patient was enrolled on a clinical trial combining targeted agents temsirolimus, sorafenib and bevacizumab, to match NF2, PDGFRα and TP53 aberrations. Both the patients did not benefit from matched therapy. Conclusions Relapsed osteosarcoma is characterized by complex signaling and drug resistance pathways. Comprehensive molecular profiling holds great promise for tailoring personalized

  5. Model for Osteosarcoma-9 as a potent factor in cell survival and resistance to apoptosis

    NASA Astrophysics Data System (ADS)

    Vourvouhaki, Ekaterini; Carvalho, Carla; Aguiar, Paulo

    2007-07-01

    In this paper we use a simple model to explore the function of the gene Osteosarcoma-9 (OS-9). We are particularly interested in understanding the role of this gene as a potent anti-apoptotic factor. The theoretical description is constrained by experimental data from induction of apoptosis in cells where OS-9 is overexpressed. The data available suggest that OS-9 promotes cell viability and confers resistance to apoptosis, potentially implicating OS-9 in the survival of cancer cells. Three different apoptosis-inducing mechanisms were tested and are modeled here. A more complex and realistic model is also discussed.

  6. Review of therapeutic strategies for osteosarcoma, chondrosarcoma, and Ewing’s sarcoma

    PubMed Central

    Dai, Xing; Ma, Wei; He, Xijing; Jha, Rajiv Kumar

    2011-01-01

    Summary The most prevalent forms of bone cancer are osteosarcoma, chondrosarcoma, and Ewing’s sarcoma. Although chemotherapy and radiotherapy have replaced traditional surgical treatments, survival rates have undergone only marginal improvements. Current knowledge of the molecular pathways involved in each type of cancer has led to better approaches in cancer treatment. A number of cell signaling molecules are involved in tumorigenesis, and specific targets have been identified based on these signal transducers. This review highlights some of the important cellular pathways and potential therapeutic targets, tumor site-specific irradiation techniques, and novel drug delivery systems used to administer these drugs. PMID:21804475

  7. Delivery of inhibitor of growth 4 (ING4) gene significantly inhibits proliferation and invasion and promotes apoptosis of human osteosarcoma cells

    PubMed Central

    Li, Mei; Zhu, Ye; Zhang, Hongbin; Li, Lihua; He, Peng; Xia, Hong; Zhang, Yu; Mao, Chuanbin

    2014-01-01

    Growing evidence has suggested that inhibitor of growth 4 (ING4), a novel member of ING family proteins, plays a critical role in the development and progression of different tumors via multiple pathways. However, the function of ING4 in human osteosarcoma remains unclear. To understand its potential roles and mechanisms in inhibiting osteosarcoma, we constructed an expression vector pEGFP-ING4 and transfected the human osteosarcoma cells using this vector. We then studied the effects of over-expressed ING4 in the transfected cells on the proliferation, apoptosis and invasion of the osteosarcoma cells. The up-regulation of ING4 in the osteosarcoma cells, arising from the stable pEGFP-ING4 gene transfection, was found to significantly inhibit the cell proliferation by the cell cycle alteration with S phase reduction and G0/G1 phase arrest, induce cell apoptosis via the activation of the mitochondria pathway, and suppress cell invasion through the down-regulation of the matrix metalloproteinase 2 (MMP-2) and MMP-9 expression. In addition, increased ING4 level evoked the blockade of NF-κB signaling pathway and down-regulation of its target proteins. Our work suggests that ING4 can suppress osteosarcoma progression through signaling pathways such as mitochondria pathway and NF-κB signaling pathway and ING4 gene therapy is a promising approach to treating osteosarcoma. PMID:25490312

  8. HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival.

    PubMed

    Koirala, Pratistha; Roth, Michael E; Gill, Jonathan; Chinai, Jordan M; Ewart, Michelle R; Piperdi, Sajida; Geller, David S; Hoang, Bang H; Fatakhova, Yekaterina V; Ghorpade, Maya; Zang, Xingxing; Gorlick, Richard

    2016-01-01

    Over the past four decades there have been minimal improvements in outcomes for patients with osteosarcoma. New targets and novel therapies are needed to improve outcomes for these patients. We sought to evaluate the prevalence and clinical significance of the newest immune checkpoint, HHLA2, in osteosarcoma. HHLA2 protein expression was evaluated in primary tumor specimens and metastatic disease using an osteosarcoma tumor microarray (TMA) (n = 62). The association of HHLA2 with the presence of tumor infiltrating lymphocytes (TILs) and five-year-event-free-survival were examined. HHLA2 was expressed in 68% of osteosarcoma tumors. HHLA2 was expressed in almost all metastatic disease specimens and was more prevalent than in primary specimens without known metastases (93% vs 53%, p = 0.02). TILs were present in 75% of all osteosarcoma specimens. Patients whose tumors were ≥25% or ≥50% HHLA2 positive had significantly worse five-year event-free-survival (33% vs 64%, p = 0.03 and 14% vs 59%, p = 0.02). Overall, we have shown that HHLA2 is expressed in the majority of osteosarcoma tumors and its expression is associated with metastatic disease and poorer survival. Along with previously reported findings that HHLA2 is a T cell co-inhibitor, these results suggest that HHLA2 may be a novel immunosuppressive mechanism within the osteosarcoma tumor microenvironment. PMID:27531281

  9. A Rare Cause of Bowel Obstruction: Peritoneal Metastases in Osteosarcoma at the Tibia in a Young Female Patient with Brain Metastasis. Case Report.

    PubMed

    Badiu, Dumitru Cristinel; Manea, Cristina Alexandra; Porojan, Vlad; Paraschiv, Marius; Mehedintu, Claudia; Coman, Ionut Simion; Grigorean, Valentin Titus

    2016-01-01

    Osteosarcomas are the most frequent primary malignant bone tumors in children and adolescents. Like brain metastases in osteosarcomas, the bowel metastases are very rare. We present the case of a 23-year-old female patient, diagnosed and operated in 2008 of osteosarcoma at the tibia, for which she had sessions of neoadjuvant and adjuvant chemotherapy, but presented lungs metastases for which she underwent surgery in 2014. Then, in March 2015, she was diagnosed with an intracranial expansive process, an osteosarcoma metastasis, for which a total ablation of the tumor was performed during the early postoperatory period, being transferred to the General Surgery Clinic for abdominal pain, abdominal distention, vomiting, and lack of intestinal transit regarding faeces and intestinal gas. Both clinically and imagistically, the diagnosis was of bowel obstruction. This was the reason for performing surgery, thus discovering a bowel obstruction secondary to a metastasis of the terminal ileum and liver metastases that were confirmed as osteosarcoma metastases from an anatomopathological and immunohistochemical point of view. The bowel metastases and the osteosarcoma brain metastases are very rare entities and, their association, most often with young patients, is exceptional. However, bowel metastases must be taken into account as a possible cause of bowel obstruction in patients with osteosarcoma. PMID:27452942

  10. The E3 ubiquitin protein ligase MDM2 dictates all-trans retinoic acid-induced osteoblastic differentiation of osteosarcoma cells by modulating the degradation of RARα.

    PubMed

    Ying, M; Zhang, L; Zhou, Q; Shao, X; Cao, J; Zhang, N; Li, W; Zhu, H; Yang, B; He, Q

    2016-08-18

    Retinoic acid receptor alpha (RARα) has a critical role in the differentiation process of osteosarcoma cells induced by all-trans retinoic acid (ATRA). However, degradation of RARα through ubiquitin proteasome pathway weakens the differentiation efficiency of osteosarcoma cells. In this study, we discover that murine double minute-2 (MDM2) acts as an E3 ubiquitin ligase to target RARα for degradation. We observe that MDM2 is required for RARα polyubiquitination and proteasomal degradation because downregulation of MDM2 by short hairpin RNA results in the accumulation of RARα, and MDM2 overexpression promotes the degradation of RARα. We also demonstrate that the N-terminal domain of MDM2 (amino acids 1-109) is the major RARα-binding site. Importantly, endogenous MDM2 levels are not only upregulated in human primary osteosarcoma blasts but are also inversely correlated with the level of osteopontin, which is a marker of bone differentiation. Moreover, MDM2 impairs the ATRA-induced osteoblastic differentiation of osteosarcoma cells, whereas an inhibitor of the MDM2 ubiquitin ligase synergizes with ATRA to enhance the differentiation of osteosarcoma cells and primary osteosarcoma blasts. Therefore, our study indicates that MDM2 serves as an E3 ubiquitin ligase to regulate the degradation of RARα and suggests that MDM2 is a novel therapeutic target for ATRA-based differentiation therapeutic approaches in osteosarcoma. PMID:26776160

  11. The downregulation of miR‑125a‑5p functions as a tumor suppressor by directly targeting MMP‑11 in osteosarcoma.

    PubMed

    Waresijiang, Niyazi; Sun, Jungang; Abuduaini, Rewuti; Jiang, Tayier; Zhou, Wenzheng; Yuan, Hong

    2016-06-01

    Osteosarcoma is one of the most common primary malignant bone cancers in juveniles and adults. Increasingly, reports indicate that microRNAs (miRNAs) may provide novel therapeutic targets for cancer treatment. The aim of the present study was to investigate the expression of miR‑125a‑5p and to identify its functional significance in osteosarcoma. This indicated that miR‑125a‑5p was downregulated in osteosarcoma tissue and cell lines using reverse transcription‑quantitative polymerase chain reaction. Following transfection with miR‑125a‑5p mimics or the negative control, cell migration, invasion and epithelial‑mesenchymal transition (EMT) assays were conducted in osteosarcoma cells. These results indicated that the overexpression of miR‑125a‑5p resulted in inhibited osteosarcoma cell migration, invasion and EMT in vitro. Furthermore, mechanistic studies showed that matrix metallopeptidase‑11 (MMP‑11), was a direct target of miR‑125a‑5p in osteosarcoma. Taken together, the data demonstrate that miR‑125a‑5p functions as a tumor suppressor gene and serves an important role in inhibiting osteosarcoma cell migration, invasion and EMT by targeting MMP‑11. PMID:27081863

  12. HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival

    PubMed Central

    Koirala, Pratistha; Roth, Michael E.; Gill, Jonathan; Chinai, Jordan M.; Ewart, Michelle R.; Piperdi, Sajida; Geller, David S.; Hoang, Bang H.; Fatakhova, Yekaterina V.; Ghorpade, Maya; Zang, Xingxing; Gorlick, Richard

    2016-01-01

    Over the past four decades there have been minimal improvements in outcomes for patients with osteosarcoma. New targets and novel therapies are needed to improve outcomes for these patients. We sought to evaluate the prevalence and clinical significance of the newest immune checkpoint, HHLA2, in osteosarcoma. HHLA2 protein expression was evaluated in primary tumor specimens and metastatic disease using an osteosarcoma tumor microarray (TMA) (n = 62). The association of HHLA2 with the presence of tumor infiltrating lymphocytes (TILs) and five-year-event-free-survival were examined. HHLA2 was expressed in 68% of osteosarcoma tumors. HHLA2 was expressed in almost all metastatic disease specimens and was more prevalent than in primary specimens without known metastases (93% vs 53%, p = 0.02). TILs were present in 75% of all osteosarcoma specimens. Patients whose tumors were ≥25% or ≥50% HHLA2 positive had significantly worse five-year event-free-survival (33% vs 64%, p = 0.03 and 14% vs 59%, p = 0.02). Overall, we have shown that HHLA2 is expressed in the majority of osteosarcoma tumors and its expression is associated with metastatic disease and poorer survival. Along with previously reported findings that HHLA2 is a T cell co-inhibitor, these results suggest that HHLA2 may be a novel immunosuppressive mechanism within the osteosarcoma tumor microenvironment. PMID:27531281

  13. MiR-34a and miR-203 Inhibit Survivin Expression to Control Cell Proliferation and Survival in Human Osteosarcoma Cells

    PubMed Central

    Chen, Xun; Chen, Xiao-Gang; Hu, Xiaojing; Song, Tao; Ou, Xuehai; Zhang, Caiguo; Zhang, Wentao; Zhang, Chun

    2016-01-01

    Elevated expression of survivin is observed in a number of cancer types, including human osteosarcoma. Few studies have demonstrated that survivin expression levels can be considered an independent predictor of survival for human osteosarcoma patients. However, the underlying molecular mechanisms of survivin in the process of human osteosarcoma carcinogenesis remain unclear. In the current study, we evaluated the biological effects of survivin knockdown on osteosarcoma cell proliferation, colony formation rate, and sensitivity to the chemotherapeutic agent cisplatin. We found that two different osteosarcoma cell lines, U2OS and Saos-2, have relatively higher expression levels of survivin, and specific knockdown of survivin resulted in a number of effects, such as inhibition of cell proliferation, decreased colony formation rate, cell cycle arrest at G2/M phase, induction of apoptosis, and increased sensitivity to cisplatin. In addition, we identified two microRNAs, miR-34a and miR-203, that are aberrantly expressed in human osteosarcoma cells and specifically target survivin by inhibiting its expression, therefore repressing osteosarcoma cell maintenance and proliferation. PMID:27326248

  14. Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients.

    PubMed

    Caronia, D; Patiño-García, A; Milne, R L; Zalacain-Díez, M; Pita, G; Alonso, M R; Moreno, L T; Sierrasesumaga-Ariznabarreta, L; Benítez, J; González-Neira, A

    2009-10-01

    Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio=4.9, 95% confidence interval=1.64-14.54, adjusted P-value=0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median=184 months, compared with 240 months for TT homozygotes; hazard ratio=5.76, 95% confidence interval=1.30-25.55; P-value=0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value= 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients. PMID:19434073

  15. A Randomized Study on Postrelapse Disease-Free Survival with Adjuvant Mistletoe versus Oral Etoposide in Osteosarcoma Patients.

    PubMed

    Longhi, Alessandra; Reif, Marcus; Mariani, Erminia; Ferrari, Stefano

    2014-01-01

    Background. Osteosarcoma is a highly malignant bone tumour. After the second relapse, the 12-month postrelapse disease-free survival (PRDFS) rate decreases below 20%. Oral Etoposide is often used in clinical practice after surgery as an "adjuvant" outside any protocol and with only limited evidence of improved survival. Viscum album fermentatum Pini (Viscum) is an extract of mistletoe plants grown on pine trees for subcutaneous (sc) injection with immunomodulatory activity. Methods. Encouraged by preliminary findings, we conducted a study where osteosarcoma patients free from disease after second metastatic relapse were randomly assigned to Viscum sc or Oral Etoposide. Our goal was to compare 12-month PRDFS rates with an equivalent historical control group. Results. Twenty patients have been enrolled, with a median age of 34 years (range 11-65) and a median follow-up time of 38.5 months (3-73). The median PRDSF is currently 4 months (1-47) in the Etoposide and 39 months (2-73) in the Viscum group. Patients getting Viscum reported a higher quality of life due to lower toxicity. Conclusion. Viscum shows promise as adjuvant treatment in prolonging PRDFS after second relapse in osteosarcoma patients. A larger study is required to conclusively determine efficacy and immunomodulatory mechanisms of Viscum therapy in osteosarcoma patients. PMID:24803944

  16. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma

    PubMed Central

    Perry, Jennifer A.; Kiezun, Adam; Tonzi, Peter; Van Allen, Eliezer M.; Carter, Scott L.; Baca, Sylvan C.; Cowley, Glenn S.; Bhatt, Ami S.; Rheinbay, Esther; Pedamallu, Chandra Sekhar; Helman, Elena; Taylor-Weiner, Amaro; McKenna, Aaron; DeLuca, David S.; Lawrence, Michael S.; Ambrogio, Lauren; Sougnez, Carrie; Sivachenko, Andrey; Walensky, Loren D.; Wagle, Nikhil; Mora, Jaume; de Torres, Carmen; Lavarino, Cinzia; Dos Santos Aguiar, Simone; Yunes, Jose Andres; Brandalise, Silvia Regina; Mercado-Celis, Gabriela Elisa; Melendez-Zajgla, Jorge; Cárdenas-Cardós, Rocío; Velasco-Hidalgo, Liliana; Roberts, Charles W. M.; Garraway, Levi A.; Rodriguez-Galindo, Carlos; Gabriel, Stacey B.; Lander, Eric S.; Golub, Todd R.; Orkin, Stuart H.; Getz, Gad; Janeway, Katherine A.

    2014-01-01

    Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo. PMID:25512523

  17. FBJ osteosarcoma virus in tissue culture. III. Isolation and characterization of non-virus-producing FBJ-transformed cells.

    PubMed Central

    Levy, J A; Kazan, P L; Reilly, C A; Finkel, M P

    1978-01-01

    Hamster and rat cell lines have been established that have been transformed by FBJ murine sarcoma virus (FBJ-MuSV) but that do not produce virus. The hamster cell line originated from an osteosarcoma that appeared in a hamster inoculated at birth with an extract of a CFNo1 mouse FBJ-osteosarcoma. The rat cell line was obtained by transferring the FBJ-MuSV genome to normal rat kidney cells in the absence of the FBJ type C virus (FBJ-MuLV), which, usually in high concentration, accompanies the FBJ-MuSV. Both transformed hamster and rat cell lines contain the FBJ-MuSV genome, which can be rescued by ecotropic and xenotropic murine type C viruses. This rescued genome produces characteristic FBJ-MuSV foci in tissue culture and, in appropriate animal hosts, induces osteosarcomas typical of those induced by FBJ-MuSV. FBJ-MuSV was isolated originally from a parosteal osteosarcoma that occurred naturally in a mouse. Since there was no previous history of passage of the agent through any other animal species, these non-virus-producing hamster and rat cells transformed by FBJ-MuSV should be very helpful in molecular studies examining the origin of spontaneous sarcoma genomes in mice. PMID:206718

  18. Polymeric nanoparticle-based delivery of microRNA-199a-3p inhibits proliferation and growth of osteosarcoma cells

    PubMed Central

    Zhang, Linlin; lyer, Arun K; Yang, Xiaoqian; Kobayashi, Eisuke; Guo, Yuqi; Mankin, Henry; Hornicek, Francis J; Amiji, Mansoor M; Duan, Zhenfeng

    2015-01-01

    Our prior screening of microRNAs (miRs) identified that miR-199a-3p expression is reduced in osteosarcoma cells, one of the most common types of bone tumor. miR-199a-3p exhibited functions of tumor cell growth inhibition, suggesting the potential application of miR-199a-3p as an anticancer agent. In the study reported here, we designed and developed a lipid-modified dextran-based polymeric nanoparticle platform for encapsulation of miRs, and determined the efficiency and efficacy of delivering miR-199a-3p into osteosarcoma cells. In addition, another potent miR, let-7a, which also displayed tumor suppressive ability, was selected as a candidate miR for evaluation. Fluorescence microscopy studies and real-time polymerase chain reaction results showed that dextran nanoparticles could deliver both miR-199a-3p and let-7a into osteosarcoma cell lines (KHOS and U-2OS) successfully. Western blotting analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that dextran nanoparticles loaded with miRs could efficiently downregulate the expression of target proteins and effectively inhibit the growth and proliferation of osteosarcoma cells. These results demonstrate that a lipid-modified dextran-based polymeric nanoparticle platform may be an effective nonviral carrier for potential miR-based anticancer therapeutics. PMID:25931818

  19. Osteosarcoma of the maxilla in Hong Kong Chinese postirradiation for nasopharyngeal carcinoma. A report of four cases

    SciTech Connect

    Dickens, P.; Wei, W.I.; Sham, J.S. )

    1990-11-01

    Postirradiation osteosarcoma of the maxilla was seen in four Hong Kong Chinese patients treated for nasopharyngeal carcinoma. These cases represent four of 42 (9%) cases of osteosarcoma at all sites in this institution during the period 1979 to 1989, when more than 1000 patients were treated with radiotherapy for nasopharyngeal carcinoma. The latent periods varied from 8 to 11 years from completion of radiotherapy treatment to development of osteosarcoma. The radiation dosage varied from 6000 to 6280 cGy in three of the patients. These cases fit the criteria for diagnosis of postirradiation sarcomas. Maxillary osteosarcomas after irradiation for nasopharyngeal carcinoma do not appear to have been described. The very high incidence of nasopharyngeal carcinoma (for which radiotherapy is the treatment of choice) in Hong Kong Chinese would make the occurrence of such tumors more likely in Hong Kong, although the small risk does not contraindicate the use of radiation in the treatment of nasopharyngeal carcinoma in view of its well-documented efficacy.

  20. Elevated ASCL2 expression is associated with metastasis of osteosarcoma and predicts poor prognosis of the patients.

    PubMed

    Liu, Ming-Han; Cui, You-Hong; Guo, Qiao-Nan; Zhou, Yue

    2016-01-01

    Achaetescute-like 2 (ASCL2), a basic helix-loop-helix (bHLH) transcription factor, plays an important role in the determination of neuronal precursors in the central and peripheral nervous system and involves in tumor progression. However, the role of ASCL2 expression in the osteosarcoma prognosis has not been elaborated. This study aimed to evaluate ASCL2 expression level in osteosarcoma and assess its prognostic value for patients. ASCL2 protein expression was detected by immunohistochemistry (IHC) in 73 cases of osteosarcoma. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate the prognostic significance of ASCL2. Immunohistochemistry analysis showed that the overall survival and metastasis-free survival of patients with positive ASCL2 expression were significantly shorter than patients with negative expression (both P<0.01). Multivariate Cox analysis identified ASCL2 expression as an independent prognostic factor to predict poor overall survival and metastasis-free survival (both P<0.01). Overexpression of ASCL2 expression greatly promoted cell proliferation and enhanced migration and invasion in vitro. This study indicates that increased expression of ASCL2 in primary osteosarcoma is a novel biomarker for predicting the development of metastases and poor outcomes of the patients. PMID:27429855

  1. A Randomized Study on Postrelapse Disease-Free Survival with Adjuvant Mistletoe versus Oral Etoposide in Osteosarcoma Patients

    PubMed Central

    Longhi, Alessandra; Reif, Marcus; Mariani, Erminia; Ferrari, Stefano

    2014-01-01

    Background. Osteosarcoma is a highly malignant bone tumour. After the second relapse, the 12-month postrelapse disease-free survival (PRDFS) rate decreases below 20%. Oral Etoposide is often used in clinical practice after surgery as an “adjuvant” outside any protocol and with only limited evidence of improved survival. Viscum album fermentatum Pini (Viscum) is an extract of mistletoe plants grown on pine trees for subcutaneous (sc) injection with immunomodulatory activity. Methods. Encouraged by preliminary findings, we conducted a study where osteosarcoma patients free from disease after second metastatic relapse were randomly assigned to Viscum sc or Oral Etoposide. Our goal was to compare 12-month PRDFS rates with an equivalent historical control group. Results. Twenty patients have been enrolled, with a median age of 34 years (range 11–65) and a median follow-up time of 38.5 months (3–73). The median PRDSF is currently 4 months (1–47) in the Etoposide and 39 months (2–73) in the Viscum group. Patients getting Viscum reported a higher quality of life due to lower toxicity. Conclusion. Viscum shows promise as adjuvant treatment in prolonging PRDFS after second relapse in osteosarcoma patients. A larger study is required to conclusively determine efficacy and immunomodulatory mechanisms of Viscum therapy in osteosarcoma patients. PMID:24803944

  2. Establishment of Four New Human Primary Cell Cultures from Chemo-Naïve Italian Osteosarcoma Patients.

    PubMed

    Laschi, Marcella; Bernardini, Giulia; Geminiani, Michela; Ghezzi, Lorenzo; Amato, Loredana; Braconi, Daniela; Millucci, Lia; Frediani, Bruno; Spreafico, Adriano; Franchi, Alessandro; Campanacci, Domenico; Capanna, Rodolfo; Santucci, Annalisa

    2015-11-01

    Osteosarcoma (OS) is a primary highly malignant tumor of bone, affecting predominately adolescents and young adults between 10 and 20 years of age. OS is characterized by an extremely aggressive clinical course, with a rapid development of metastasis to the lung and distant bones. PMID:25809010

  3. Wnt5a promotes migration of human osteosarcoma cells by triggering a phosphatidylinositol-3 kinase/Akt signals

    PubMed Central

    2014-01-01

    Wnt5a is classified as a non-transforming Wnt family member and plays complicated roles in oncogenesis and cancer metastasis. However, Wnt5a signaling in osteosarcoma progression remains poorly defined. In this study, we found that Wnt5a stimulated the migration of human osteosarcoma cells (MG-63), with the maximal effect at 100 ng/ml, via enhancing phosphorylation of phosphatidylinositol-3 kinase (PI3K)/Akt. PI3K and Akt showed visible signs of basal phosphorylation and elevated phosphorylation at 15 min after stimulation with Wnt5a. Pharmaceutical inhibition of PI3K with LY294002 significantly blocked the Wnt5a-induced activation of Akt (p-Ser473) and decreased Wnt5a-induced cell migration. Akt siRNA remarkably inhibited Wnt5a-induced cell migration. Additionally, Wnt5a does not alter the total expression and phosphorylation of β-catenin in MG-63 cells. Taken together, we demonstrated for the first time that Wnt5a promoted osteosarcoma cell migration via the PI3K/Akt signaling pathway. These findings could provide a rationale for designing new therapy targeting osteosarcoma metastasis. PMID:24524196

  4. Growth factors, their receptor expression and markers for proliferation of endothelial and neoplastic cells in human osteosarcoma.

    PubMed

    Bianchi, E; Artico, M; Di Cristofano, C; Leopizzi, M; Taurone, S; Pucci, M; Gobbi, P; Mignini, F; Petrozza, V; Pindinello, I; Conconi, M T; Della Rocca, C

    2013-01-01

    Osteosarcoma is the most common primary malignant tumour of the bone. Although new therapies continue to be reported, osteosarcoma-related morbidity and mortality remain high. Modern medicine has greatly increased knowledge of the physiopathology of this neoplasm. Novel targets for drug development may be identified through an understanding of the normal molecular processes that are deeply modified in pathological conditions. The aim of the present study is to investigate, by immunohistochemistry, the localisation of different growth factors and of the proliferative marker Ki-67 in order to determine whether these factors are involved in the transformation of osteogenic cells and in the development of human osteosarcoma. We observed a general positivity for NGF - TrKA - NT3 - TrKC - VEGF in the cytoplasm of neoplastic cells and a strong expression for NT4 in the nuclear compartment. TGF-beta was strongly expressed in the extracellular matrix and vascular endothelium. BDNF and TrKB showed a strong immunolabeling in the extracellular matrix. Ki-67/MIB-1 was moderately expressed in the nucleus of neoplastic cells. We believe that these growth factors may be considered potential therapeutic targets in the treatment of osteosarcoma, although proof of this hypothesis requires further investigation. PMID:24067459

  5. Changes in cell shape are correlated with metastatic potential in murine and human osteosarcomas

    PubMed Central

    Lyons, Samanthe M.; Alizadeh, Elaheh; Mannheimer, Joshua; Schuamberg, Katherine; Castle, Jordan; Schroder, Bryce; Turk, Philip; Thamm, Douglas; Prasad, Ashok

    2016-01-01

    ABSTRACT Metastatic cancer cells for many cancers are known to have altered cytoskeletal properties, in particular to be more deformable and contractile. Consequently, shape characteristics of more metastatic cancer cells may be expected to have diverged from those of their parental cells. To examine this hypothesis we study shape characteristics of paired osteosarcoma cell lines, each consisting of a less metastatic parental line and a more metastatic line, derived from the former by in vivo selection. Two-dimensional images of four pairs of lines were processed. Statistical analysis of morphometric characteristics shows that shape characteristics of the metastatic cell line are partly overlapping and partly diverged from the parental line. Significantly, the shape changes fall into two categories, with three paired cell lines displaying a more mesenchymal-like morphology, while the fourth displaying a change towards a more rounded morphology. A neural network algorithm could distinguish between samples of the less metastatic cells from the more metastatic cells with near perfect accuracy. Thus, subtle changes in shape carry information about the genetic changes that lead to invasiveness and metastasis of osteosarcoma cancer cells. PMID:26873952

  6. Bone-Targeted Acid-Sensitive Doxorubicin Conjugate Micelles as Potential Osteosarcoma Therapeutics

    PubMed Central

    2015-01-01

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic d-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data. PMID:25291150

  7. Nimbolide Induces ROS-Regulated Apoptosis and Inhibits Cell Migration in Osteosarcoma

    PubMed Central

    Liu, Ju-Fang; Hou, Chun-Han; Lin, Feng-Ling; Tsao, Ya-Ting; Hou, Sheng-Mou

    2015-01-01

    Osteosarcoma (OS) is a primary malignant tumor of bone and is most prevalent in children and adolescents. OS is frequently associated with pulmonary metastasis, which is the main cause of OS-related mortality. OS has a poor prognosis and is often unresponsive to conventional chemotherapy. In this study, we determined that Nimbolide, a novel anti-cancer therapy, acts by modulating multiple mechanisms in osteosarcoma cells. Nimbolide induces apoptosis by increasing endoplasmic reticulum (ER) stress, mitochondrial dysfunction, accumulation of reactive oxygen species (ROS), and finally, caspase activation. We also determined that Nimbolide inhibits cell migration, which is crucial for metastasis, by reducing the expression of integrin αvβ5. In addition, our results demonstrate that integrin αvβ5 expression is modulated by the PI3K/Akt and NF-κB signaling cascade. Nimbolide has potential as an anti-tumor drug given its multifunctional effects in OS. Collectively, these results help us to understand the mechanisms of action of Nimbolide and will aid in the development of effective therapies for OS. PMID:26426012

  8. Analysis of ERCC1 and ERCC2 gene variants in osteosarcoma, colorectal and breast cancer

    PubMed Central

    GÓMEZ-DÍAZ, BENJAMÍN; DE LA LUZ AYALA-MADRIGAL, MARÍA; GUTIÉRREZ-ANGULO, MELVA; VALLE-SOLIS, AURA ERAZO; LINARES-GONZÁLEZ, LUIS MIGUEL; GONZÁLEZ-GUZMÁN, ROBERTO; CRUZ-GUILLÉN, DAVID; CEDEÑO-GARCIDUEÑAS, ANA LILIA; CANTO, PATRICIA; LÓPEZ-HERNÁNDEZ, LUZ BERENICE

    2015-01-01

    The Asn118Asn (rs11615) variant in the ERCC1 gene, and the Lys751Gln (rs13181) and Asp312Asn (rs1799793) variants in the ERCC2 gene have been associated with the development of varied types of cancer. The aim of the present study was to test for any association between the ERCC1 and ERCC2 gene variants and three different types of cancer in Mexican-mestizo patients. Patients and their respective controls were formed into three groups: The osteosarcoma group, with 28 patients and 97 controls; the colorectal group, with 108 patients and 119 controls; and the breast cancer group, with 71 patients and 74 controls. Genotyping was performed using TaqMan probes and quantitative polymerase chain reaction. Allele and genotype frequencies were compared using a χ2 test. Only one SNP (rs1799793) was found to be associated with breast cancer. This is the first study analyzing the SNPs in ERCC1 and ERCC2 genes and the susceptibility to cancer in Mexican-mestizo patients with osteosarcoma, and colorectal and breast cancer. PMID:25789018

  9. Emodin mitigates the oxidative stress induced by cisplatin in osteosarcoma MG63 cells

    PubMed Central

    Yan, Li; Hu, Rui; Tu, Song; Cheng, Wen-Jun; Zheng, Qiong; Wang, Jun-Wen; Kan, Wu-Sheng; Ren, Yi-Jun

    2016-01-01

    Previously, the application of cisplatin in chemotherapy was limited due to the significant side effects on normal cell growth. In the present study, the concomitant application of emodin with cisplatin was demonstrated to ameliorate cisplatin-induced oxidative stress and markedly suppress tumor cell proliferation for the first time. Human osteosarcoma MG-63 cells were treated with cisplatin alone or in combination with emodin. The cell viability was determined by MTS assays and the augmentation of reactive oxygen species were determined by fluorogenic probes; in addition, a stable MG-63 subline bearing antioxidant response element (ARE)-driven luciferase expression was developed to monitor the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-ARE signaling pathway. The results indicated that cisplatin or emodin may inhibit MG-63 cell proliferation in a time- or dose-dependent manner, respectively. Concomitant treatment with cisplatin and emodin demonstrated synergic anti-tumor effects. Cisplatin augmented reactive oxygen species in the MG-63 cells, followed by the translocation of Nrf2 from the cytoplasm into the nucleus, which triggered ARE-driven luciferase expression. The addition of emodin diminished the previously described phenomenon, resulting in decreased ROS augmentation, translocation of Nrf2 and ARE-driven luciferase activity. In conclusion, emodin could ameliorate cisplatin-induced oxidative stress and protect the cells from oxidative stress-induced damage. The findings of the present study provide a novel strategy for the treatment of osteosarcoma using emodin and cisplatin. PMID:27602124

  10. Canine Osteosarcoma Treated by Post-Amputation Sequential Accelerated Doxorubicin and Carboplatin Chemotherapy: 38 Cases.

    PubMed

    Frimberger, Angela E; Chan, Catherine M; Moore, Antony S

    2016-01-01

    Canine appendicular osteosarcoma is an important clinical problem in veterinary medicine. Current standard therapy includes amputation followed by chemotherapy, which improves outcomes; however the percentage of long-term survival is still relatively low at 15-20%. Established prognostic factors include serum alkaline phosphatase level, histologic grade, and lymphocyte and monocyte counts. We used a protocol with shorter inter-treatment intervals than standard, but which we expected to still be well-tolerated, based on drugs known to be active agents, with the aim of improving outcomes by increasing dose intensity. Thirty-eight dogs with confirmed appendicular osteosarcoma and no pulmonary metastases that underwent amputation followed by this chemotherapy protocol were retrospectively evaluated. The median survival time was 317 days and 1- and 2-yr survival percentages were 43.2% and 13.9%, respectively. Toxicity was comparable to that seen with other standard dose protocols, with 5.2% of dogs hospitalized for complications that resolved with supportive care and no chemotherapy-related mortality. Serum alkaline phosphatase level (normal or high) (p = 0.004) and whether or not chemotherapy was completed (p = 0.001) were found to significantly impact survival time on multivariate analysis. Outcomes were similar to those reported with most other published chemotherapy protocols for dogs with this disease. PMID:27008320

  11. Changes in cell shape are correlated with metastatic potential in murine and human osteosarcomas.

    PubMed

    Lyons, Samanthe M; Alizadeh, Elaheh; Mannheimer, Joshua; Schuamberg, Katherine; Castle, Jordan; Schroder, Bryce; Turk, Philip; Thamm, Douglas; Prasad, Ashok

    2016-01-01

    Metastatic cancer cells for many cancers are known to have altered cytoskeletal properties, in particular to be more deformable and contractile. Consequently, shape characteristics of more metastatic cancer cells may be expected to have diverged from those of their parental cells. To examine this hypothesis we study shape characteristics of paired osteosarcoma cell lines, each consisting of a less metastatic parental line and a more metastatic line, derived from the former by in vivo selection. Two-dimensional images of four pairs of lines were processed. Statistical analysis of morphometric characteristics shows that shape characteristics of the metastatic cell line are partly overlapping and partly diverged from the parental line. Significantly, the shape changes fall into two categories, with three paired cell lines displaying a more mesenchymal-like morphology, while the fourth displaying a change towards a more rounded morphology. A neural network algorithm could distinguish between samples of the less metastatic cells from the more metastatic cells with near perfect accuracy. Thus, subtle changes in shape carry information about the genetic changes that lead to invasiveness and metastasis of osteosarcoma cancer cells. PMID:26873952

  12. Collagen Accumulation in Osteosarcoma Cells lacking GLT25D1 Collagen Galactosyltransferase.

    PubMed

    Baumann, Stephan; Hennet, Thierry

    2016-08-26

    Collagen is post-translationally modified by prolyl and lysyl hydroxylation and subsequently by glycosylation of hydroxylysine. Despite the widespread occurrence of the glycan structure Glc(α1-2)Gal linked to hydroxylysine in animals, the functional significance of collagen glycosylation remains elusive. To address the role of glycosylation in collagen expression, folding, and secretion, we used the CRISPR/Cas9 system to inactivate the collagen galactosyltransferase GLT25D1 and GLT25D2 genes in osteosarcoma cells. Loss of GLT25D1 led to increased expression and intracellular accumulation of collagen type I, whereas loss of GLT25D2 had no effect on collagen secretion. Inactivation of the GLT25D1 gene resulted in a compensatory induction of GLT25D2 expression. Loss of GLT25D1 decreased collagen glycosylation by up to 60% but did not alter collagen folding and thermal stability. Whereas cells harboring individually inactivated GLT25D1 and GLT25D2 genes could be recovered and maintained in culture, cell clones with simultaneously inactive GLT25D1 and GLT25D2 genes could be not grown and studied, suggesting that a complete loss of collagen glycosylation impairs osteosarcoma cell proliferation and viability. PMID:27402836

  13. Osteosarcoma development following single inhalation exposure to americium-241 in beagle dogs

    SciTech Connect

    Gillett, N.A.; Hahn, F.F.; Mewhinney, J.A.; Muggenberg, B.A.

    1985-10-01

    Young, mature Beagle dogs underwent single inhalation exposure to respirable aerosols of SU AmO2 to determine the radiation dose distribution to tissues. The dogs were serially sacrificed to assess the clearance of SU Am from the lung, the rate of translocation to internal organs, the pattern of retention in the organs, and the rates and modes of excretion. Americium dioxide was relatively soluble in the lung, leading to the translocation of significant quantities of SU Am to bone and liver, thus delivering radiation doses to these tissues nearly equal to that received by the lung. Osteoblastic osteosarcomas developed in four dogs surviving more than 1000 days after exposure. Histologically, all of the osteosarcomas were associated with areas of radiation osteodystrophy characterized by bone infarction, peritrabecular new bone formation, marrow fibrosis, and microresorptive cavities. The retention and translocation of inhaled SU Am in dogs is similar to that of man, indicating that 241Am inhaled by humans may potentially result in significant risk of bone tumor development.

  14. Matrix-Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis.

    PubMed

    Zandueta, Carolina; Ormazábal, Cristina; Perurena, Naiara; Martínez-Canarias, Susana; Zalacaín, Marta; Julián, Mikel San; Grigoriadis, Agamemnon E; Valencia, Karmele; Campos-Laborie, Francisco J; Rivas, Javier De Las; Vicent, Silvestre; Patiño-García, Ana; Lecanda, Fernando

    2016-08-01

    Osteosarcoma (OS) is the most prevalent osseous tumour in children and adolescents and, within this, lung metastases remain one of the factors associated with a dismal prognosis. At present, the genetic determinants driving pulmonary metastasis are poorly understood. We adopted a novel strategy using robust filtering analysis of transcriptomic profiling in tumour osteoblastic cell populations derived from human chemo-naive primary tumours displaying extreme phenotypes (indolent versus metastatic) to uncover predictors associated with metastasis and poor survival. We identified MGP, encoding matrix-Gla protein (MGP), a non-collagenous matrix protein previously associated with the inhibition of arterial calcification. Using different orthotopic models, we found that ectopic expression of Mgp in murine and human OS cells led to a marked increase in lung metastasis. This effect was independent of the carboxylation of glutamic acid residues required for its physiological role. Abrogation of Mgp prevented lung metastatic activity, an effect that was rescued by forced expression. Mgp levels dramatically altered endothelial adhesion, trans-endothelial migration in vitro and tumour cell extravasation ability in vivo. Furthermore, Mgp modulated metalloproteinase activities and TGFβ-induced Smad2/3 phosphorylation. In the clinical setting, OS patients who developed lung metastases had high serum levels of MGP at diagnosis. Thus, MGP represents a novel adverse prognostic factor and a potential therapeutic target in OS. Microarray datasets may be found at: http://bioinfow.dep.usal.es/osteosarcoma/ Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27172275

  15. Expression and function of microRNA-497 in human osteosarcoma.

    PubMed

    Liu, Qi; Wang, Huan; Singh, Ankit; Shou, Fenyong

    2016-07-01

    The expression and function of microRNA-497 (miR-497) has previously been reported in various types of human cancer; however, miR-497 has not previously been investigated in human osteosarcoma (OS). In the present study, the expression levels of miR‑497 were analyzed by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) in OS tissues and cell lines. In addition, post-transfection with miR‑497, RT‑qPCR, cell proliferation, migration and invasion assays, western blot analysis, and luciferase assays were performed in OS cell lines. The results of the present study demonstrated that miR‑497 was downregulated in OS tissues and cells compared with normal controls. Furthermore, upregulation of miR‑497 inhibited cell proliferation, migration and invasion in osteosarcoma cell lines compared with the negative control group. In addition, the present study demonstrated that miR‑497 may function by directly targeting insulin‑like growth factor 1 receptor in OS cells. These findings indicated that miR‑497 may be useful as a therapeutic target for the treatment of OS. PMID:27176490

  16. Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics.

    PubMed

    Low, Stewart A; Yang, Jiyuan; Kopeček, Jindřich

    2014-11-19

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic D-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data. PMID:25291150

  17. Allogeneic mRNA-based electrotransfection of autologous dendritic cells and specific antitumor effects against osteosarcoma in rats.

    PubMed

    Yu, Zhe; Qian, Jixian; Wu, Jiachang; Gao, Jie; Zhang, Minghua

    2012-12-01

    Vaccination with dendritic cells (DCs) transfected with tumor-derived mRNA antigen has emerged as a promising strategy for generating protective immunity in mammals. However, the integration of allogeneic osteosarcoma mRNA and autologous DCs has not been fully examined. This study was designed to investigate the antitumor effects of tumor vaccine produced by autologous DCs transfected of allogeneic osteosarcoma mRNA through electroporation in tumor-bearing rats model. In the present study, extraction of Wistar rat tumor mRNA was performed as a two-step procedure. First, total RNA was extracted by use of Trizol; then, mRNA purification was performed by use of polyT-coated magnetic beads. Then, we transfected the allogeneic-derived tumor mRNA to Sprague-Dawley (SD) rat bone marrow-derived DCs through electroporation. The tumor vaccine was applied to tumor-bearing rats model, and the specific antitumor effects of the tumor vaccine were observed. The immunization using autologous DCs electrotransfected with allogeneic osteosarcoma total RNA induced specific CTL responses, which were statistically significant (P < 0.05), and the cytotoxic activity was confirmed in cold target inhibition assays and using mAbs blocking MHC class I molecules. In in vivo experiments, 70 % of the rats immunized with allogeneic osteosarcoma RNA transfected to DCs were typically able to reject tumor challenge and remained tumor-free. Vaccinated survivors developed long immunological memory and were able to reject a subsequent rechallenge with the same tumor cells but not a syngeneic unrelated tumor line. In the present study, we demonstrated that allogeneic tumor mRNA isolated from rat osteosarcoma cell line could be applied to produce tumor vaccine inducing specific antitumor effects, especially in DC-based immunotherapy strategy. This study also provides the foundations for an effective and broadly applicable treatment to a wide range of cancer indications for which tumor-associated antigens

  18. The synergistic anticancer effect of cisplatin combined with Oldenlandia diffusa in osteosarcoma MG-63 cell line in vitro

    PubMed Central

    Pu, Feifei; Chen, Fengxia; Lin, Song; Chen, Songfeng; Zhang, Zhicai; Wang, Baichuan; Shao, Zengwu

    2016-01-01

    Background Oldenlandia diffusa (OD) is a well-known traditional Chinese medicine, which is used to prevent and treat many disorders, especially cancers. However, its role in osteosarcoma has not been well understood. Here, we used OD and cisplatin individually and combined in osteosarcoma MG-63 cell to explore whether OD could induce cellular apoptosis and suppress the ability of proliferation and invasion of osteosarcoma MG-63 cell. Methods The changes of cellular shape were analyzed by optical microscopy. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay was used to analyze cell survival rate in vitro. Flow cytometry was performed to detect cell cycle and cell death. Scratch migration assay was used to evaluate cell migration and invasion. Western blot was performed to determine the expression levels of pro-apoptotic and anti-apoptotic protein. Results In this study, we found that the survival rate reduced significantly in the combined group compared with the individual group and control group. The apoptosis-inducing effect of combined application was much more significant than that of individual application. The invasion ability of combined application was significantly lower than that of the individual application. In the combined group, there were high expression levels of pro-apoptotic protein and low expression of anti-apoptotic protein. Cell-cycle analysis showed a change in the cell-cycle distribution and arrested cells in G2-M phase. Conclusion In this study, we found that OD inhibited proliferation and induced apoptosis in the human osteosarcoma MG-63 cell line in a time-dependent and dose-dependent manner. In addition, OD displayed inhibitory activity on MG-63 cell proliferation and invasion and the study also showed that OD activity might be mediated by caspase activation. These data suggest that OD might represent a novel, efficient candidate agent for further experimentation in osteosarcoma treatment. PMID:26834484

  19. Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment.

    PubMed

    Ségaliny, Aude I; Mohamadi, Amel; Dizier, Blandine; Lokajczyk, Anna; Brion, Régis; Lanel, Rachel; Amiaud, Jérôme; Charrier, Céline; Boisson-Vidal, Catherine; Heymann, Dominique

    2015-07-01

    Interleukin-34 (IL-34) was recently characterized as the M-CSF "twin" cytokine, regulating the proliferation/differentiation/survival of myeloid cells. The implication of M-CSF in oncology was initially suspected by the reduced metastatic dissemination in knock-out mice, due to angiogenesis impairment. Based on this observation, our work studied the involvement of IL-34 in the pathogenesis of osteosarcoma. The in vivo effects of IL-34 were assessed on tissue vasculature and macrophage infiltration in a murine preclinical model based on a paratibial inoculation of human osteosarcoma cells overexpressing or not IL-34 or M-CSF. In vitro investigations using endothelial cell precursors and mature HUVEC cells were performed to analyse the involvement of IL-34 in angiogenesis and myeloid cell adhesion. The data revealed that IL-34 overexpression was associated with the progression of osteosarcoma (tumor growth, lung metastases) and an increase of neo-angiogenesis. In vitro analyses demonstrated that IL-34 stimulated endothelial cell proliferation and vascular cord formation. Pre-treatment of endothelial cells by chondroitinases/heparinases reduced the formation of vascular tubes and abolished the associated cell signalling. In addition, IL-34 increased the in vivo recruitment of M2 tumor-associated macrophages into the tumor tissue. IL-34 increased in vitro monocyte/CD34(+) cell adhesion to activated HUVEC monolayers under physiological shear stress conditions. This work also demonstrates that IL-34 is expressed by osteosarcoma cells, is regulated by TNF-α, IL-1β, and contributes to osteosarcoma growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages. By promoting new vessel formation and extravasation of immune cells, IL-34 may play a key role in tumor development and inflammatory diseases. PMID:25471534

  20. Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) in the treatment of osteosarcoma.

    PubMed

    Meyers, Paul A; Chou, Alexander J

    2014-01-01

    Bacille Calmette-Guerin (BCG) has been used for decades as an immune stimulant to treat cancer. Early work by Fidler and Kleinerman identified muramyl dipeptide (MDP) as a critical component of the BCG cell wall which retained most of the immunostimulatory properties of the native BCG. Addition of a peptide to MDP resulted in muramyl tripeptide (MTP) which allowed incorporation into liposomal membranes. The resulting pharmaceutical, liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE or mifamurtide) showed activity in preclinical models of human cancers. Phase I studies documented the safety of the compound for human administration. These trials did not reach a maximally tolerated dose (MTD), and the dose chosen for phase II trials was a biologically optimized dose, not an MTD. Phase II studies showed decreased risk of further recurrence in patients who received mifamurtide after surgical ablation of metastatic osteosarcoma. A phase III prospective randomized trial demonstrated a statistically significant reduction in the risk of death from osteosarcoma when MTP was added to systemic chemotherapy for the treatment of localized osteosarcoma. The same trial allowed treatment of patients who presented with initially metastatic disease. While the overall and event-free survival was improved in patients with metastatic osteosarcoma who received L-MTP-PE, the sample size was small and the improvement did not achieve conventional statistical significance. From 2008 to 2012, patients with metastatic and recurrent osteosarcoma were given L-MTP-PE in an expanded access trial, and the results suggest a decreased risk of subsequent recurrence and death with the inclusion of L-MTP-PE in the treatment strategy for these high-risk patients. PMID:24924182

  1. Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor

    PubMed Central

    2010-01-01

    Background Hypoxia regulates gene expression via the transcription factor HIF (Hypoxia-Inducible Factor). Little is known regarding HIF expression and function in primary bone sarcomas. We describe HIF expression and phenotypic effects of hypoxia, hypoglycaemia and HIF in Ewing's sarcoma and osteosarcoma. Methods HIF-1α and HIF-2α immunohistochemistry was performed on a Ewing's tumour tissue array. Ewing's sarcoma and osteosarcoma cell lines were assessed for HIF pathway induction by Western blot, luciferase assay and ELISA. Effects of hypoxia, hypoglycaemia and isoform-specific HIF siRNA were assessed on proliferation, apoptosis and migration. Results 17/56 Ewing's tumours were HIF-1α-positive, 15 HIF-2α-positive and 10 positive for HIF-1α and HIF-2α. Expression of HIF-1α and cleaved caspase 3 localised to necrotic areas. Hypoxia induced HIF-1α and HIF-2α in Ewing's and osteosarcoma cell lines while hypoglycaemia specifically induced HIF-2α in Ewing's. Downstream transcription was HIF-1α-dependent in Ewing's sarcoma, but regulated by both isoforms in osteosarcoma. In both cell types hypoglycaemia reduced cellular proliferation by ≥ 45%, hypoxia increased apoptosis and HIF siRNA modulated hypoxic proliferation and migration. Conclusions Co-localisation of HIF-1α and necrosis in Ewing's sarcoma suggests a role for hypoxia and/or hypoglycaemia in in vivo induction of HIF. In vitro data implicates hypoxia as the primary HIF stimulus in both Ewing's and osteosarcoma, driving effects on proliferation and apoptosis. These results provide a foundation from which to advance understanding of HIF function in the pathobiology of primary bone sarcomas. PMID:20637078

  2. Pirarubicin inhibits multidrug-resistant osteosarcoma cell proliferation through induction of G2/M phase cell cycle arrest

    PubMed Central

    Zheng, Shui-er; Xiong, Sang; Lin, Feng; Qiao, Guang-lei; Feng, Tao; Shen, Zan; Min, Da-liu; Zhang, Chun-ling; Yao, Yang

    2012-01-01

    Aim: Pirarubicin (THP) is recently found to be effective in treating patients with advanced, relapsed or recurrent high-grade osteosarcoma. In this study, the effects of THP on the multidrug-resistant (MDR) osteosarcoma cells were assessed, and the underlying mechanisms for the disruption of cell cycle kinetics by THP were explored. Methods: Human osteosarcoma cell line MG63 and human MDR osteosarcoma cell line MG63/DOX were tested. The cytotoxicity of drugs was examined using a cell proliferation assay with the Cell Counting Kit-8 (CCK-8). The distribution of cells across the cell cycle was determined with flow cytometry. The expression of cell cycle-regulated genes cyclin B1 and Cdc2 (CDK1), and the phosphorylated Cdc2 and Cdc25C was examined using Western blot analyses. Results: MG63/DOX cells were highly resistant to doxorubicin (ADM) and gemcitabine (GEM), but were sensitive or lowly resistant to THP, methotrexate (MTX) and cisplatin (DDP). Treatment of MG63/DOX cells with THP (200–1000 ng/mL) inhibited the cell proliferation in time- and concentration-dependent manners. THP (50–500 ng/mL) induced MG63/DOX cell cycle arrest at the G2/M phase in time- and concentration-dependent manners. Furthermore, the treatment of MG63/DOX cells with THP (200–1000 ng/mL) downregulated cyclin B1 expression, and decreased the phosphorylated Cdc2 at Thr161. Conversely, the treatment increased the phosphorylated Cdc2 at Thr14/Tyr15 and Cdc25C at Ser216, which led to a decrease in Cdc2-cyclin B1 activity. Conclusion: The cytotoxicity of THP to MG63/DOX cells may be in part due to its ability to arrest cell cycle progression at the G2/M phase, which supports the use of THP for managing patients with MDR osteosarcoma. PMID:22580740

  3. Polydatin promotes apoptosis through upregulation the ratio of Bax/Bcl-2 and inhibits proliferation by attenuating the β-catenin signaling in human osteosarcoma cells

    PubMed Central

    Xu, Ge; Kuang, Ge; Jiang, Wengao; Jiang, Rong; Jiang, Dianming

    2016-01-01

    Osteosarcoma is the most prevalent primary malignant bone tumor mainly endangering young adults. In this study, we explore whether polydatin (PD), a glycoside form of resveratrol, is effective for osteosarcoma. Our results showed that PD dose-dependently inhibited proliferation and promoted apoptosis in 143B and MG63 osteosarcoma cells, examined by MTT assay and Annexin V-FITC apoptosis detection. Further, we found PD increased expression of Bax and attenuated expression of Bcl-2, and consequently augmented caspase-3 activity. Moreover, PD also dose-dependently inhibited β-catenin signaling pathway as indicated by decreased β-catenin expression and activity, while overexpression of β-catenin by adenoviruses system could abrogate the anti-tumor effect of PD. Our finding indicated that PD could inhibit the proliferation by inhibiting the β-catenin signaling and induce apoptosis via upregulation the ratio of Bax/Bcl-2 in human osteosarcoma cells. PMID:27158379

  4. NVP-BEZ235, a dual PI3K/mTOR inhibitor, inhibits osteosarcoma cell proliferation and tumor development in vivo with an improved survival rate.

    PubMed

    Gobin, Bérengère; Battaglia, Séverine; Lanel, Rachel; Chesneau, Julie; Amiaud, Jérôme; Rédini, Françoise; Ory, Benjamin; Heymann, Dominique

    2014-03-28

    Despite recent improvements in chemotherapy and surgery, the problem of non-response osteosarcoma to chemotherapy remains, and is a parameter that is critical for prognosis. The present work investigated the therapeutic value of NVP-BEZ235, a dual class I PI3K/mTOR inhibitor. NVP-BEZ235 inhibited osteosarcoma cell proliferation by inducing G0/G1 cell cycle arrest with no caspase activation. In murine pre-clinical models, NVP-BEZ235 significantly slowed down tumor progression and ectopic tumor bone formation with decreased numbers of Ki67(+) cells and reduced tumor vasculature. Finally, NVP-BEZ235 considerably improved the survival rate of mice with osteosarcoma. Taken together, the results of the present work show that NVP-BEZ235 exhibits therapeutic interest in osteosarcoma and may be a promising adjuvant drug for bone sarcomas. PMID:24333720

  5. Osteosarcoma risk after simultaneous incorporation of the long-lived radionuclide sup 227 Ac and the short-lived radionuclide sup 227 Th

    SciTech Connect

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

    1990-01-01

    The effect of injection of 1.85 kBq/kg of the long-lived radionuclide {sup 227}Ac on the induction of osteosarcomas in female NMRI mice by different dose levels (18.5, 74, and 185 kBq/kg) of the short-lived radionuclide {sup 227}Th was investigated. The highest absolute osteosarcoma incidence was observed with the highest doses of {sup 227}Th. Addition of {sup 227}Ac resulted in an additional osteosarcoma incidence only at the lowest dose of {sup 227}Th and did not affect the osteosarcoma incidence resulting from higher doses of {sup 227}Th. The longest times to tumor appearance were observed with {sup 227}Ac alone. The latent period in two different age groups (4 weeks and 10-12 weeks) appeared to be similar following injection with combined doses of {sup 227}Th and {sup 227}Ac but different after injection of each radionuclide alone.

  6. Mesenchymal stem cells increase proliferation but do not change quiescent state of osteosarcoma cells: Potential implications according to the tumor resection status

    PubMed Central

    Avril, Pierre; Le Nail, Louis-Romée; Brennan, Meadhbh Á.; Rosset, Philippe; De Pinieux, Gonzague; Layrolle, Pierre; Heymann, Dominique; Perrot, Pierre; Trichet, Valérie

    2015-01-01

    Conventional therapy of primary bone tumors includes surgical excision with wide resection, which leads to physical and aesthetic defects. For reconstruction of bone and joints, allografts can be supplemented with mesenchymal stem cells (MSCs). Similarly, adipose tissue transfer (ATT) is supplemented with adipose-derived stem cells (ADSCs) to improve the efficient grafting in the correction of soft tissue defects. MSC-like cells may also be used in tumor-targeted cell therapy. However, MSC may have adverse effects on sarcoma development. In the present study, human ADSCs, MSCs and pre-osteoclasts were co-injected with human MNNG-HOS osteosarcoma cells in immunodeficient mice. ADSCs and MSCs, but not the osteoclast precursors, accelerated the local proliferation of MNNG-HOS osteosarcoma cells. However, the osteolysis and the metastasis process were not exacerbated by ADSCs, MSCs, or pre-osteoclasts. In vitro proliferation of MNNG-HOS and Saos-2 osteosarcoma cells was increased up to 2-fold in the presence of ADSC-conditioned medium. In contrast, ADSC-conditioned medium did not change the dormant, quiescent state of osteosarcoma cells cultured in oncospheres. Due to the enhancing effect of ADSCs/MSCs on in vivo/in vitro proliferation of osteosarcoma cells, MSCs may not be good candidates for osteosarcoma-targeted cell therapy. Although conditioned medium of ADSCs accelerated the cell cycle of proliferating osteosarcoma cells, it did not change the quiescent state of dormant osteosarcoma cells, indicating that ADSC-secreted factors may not be involved in the risk of local recurrence. PMID:26998421

  7. Disseminated metastatic disease of osteosarcoma of the femur in the abdomen: unusual metastatic pattern on Tc-99m MDP bone scan.

    PubMed

    Karacalioglu, Ozgur; Ilgan, Seyfettin; Kuzhan, Okan; Emer, Ozdes; Ozguven, Mehmet

    2006-07-01

    A 25-year-old patient with osteosarcoma of the right distal femur underwent a bone scintigraphy with Tc-99m methylene diphosphonate (MDP). Whole-body bone scan revealed extensive metastatic disease in the abdominal region. Abdominal computerized tomography confirmed the presence of ascites and calcified masses on the greater omentum and peritoneal surfaces. Here we describe a case of unusual metastatic pattern of an osteosarcoma showing extensive intraabdominal metastases without prominent lung involvement after intensive chemotherapy. PMID:16922473

  8. Pre-treatment serum lactate dehydrogenase and alkaline phosphatase as predictors of metastases in extremity osteosarcoma

    PubMed Central

    Marais, Leonard C.; Bertie, Julia; Rodseth, Reitze; Sartorius, Benn; Ferreira, Nando

    2015-01-01

    Background The prognosis of patients with metastatic osteosarcoma remains poor. However, the chance of survival can be improved by surgical resection of all metastases. In this study we investigate the value of serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in predicting the presence of metastatic disease at time of diagnosis. Methods Sixty-one patients with histologically confirmed conventional osteosarcoma of the extremity were included in the study. Only 19.7% of cases presented without evidence of systemic spread of the disease. Pre-treatment serum ALP and LDH were analysed in patients with and without skeletal or pulmonary metastases. Results Serum LDH and ALP levels were not significantly different in patients with or without pulmonary metastases (p=0.88 and p=0.47, respectively). The serum LDH and ALP levels did however differ significantly in patients with or without skeletal metastases (p<0.001 and p=0.02, respectively). The optimal breakpoint for serum LDH as a marker of skeletal metastases was 849 IU/L (AUC 0.839; Sensitivity=0.88; Specificity=0.73). LDH >454 IU/L equated to 100% sensitivity for detected bone metastases (positive diagnostic likelihood ratio (DLR)=1.32). With a cut-off of 76 IU/L a sensitivity of 100% was reached for serum ALP predicting the presence of skeletal metastases (positive DLR=1.1). In a multivariate analysis both LDH ≥850 IU/L (odds ratio [OR]=9; 95% confidence interval (CI) 1.8–44.3) and ALP ≥280 IU/L (OR=10.3; 95% CI 2.1–50.5) were predictive of skeletal metastases. LDH however lost its significance in a multivariate model which included pre-treatment tumour volume. Conclusion In cases of osteosarcoma with LDH >850 IU/L and/or ALP >280 IU/L it may be prudent to consider more sensitive staging investigations for detection of skeletal metastases. Further research is required to determine the value and the most sensitive cut-off points of serum ALP and LDH in the prediction of skeletal metastases. PMID

  9. A Rb1 promoter variant with reduced activity contributes to osteosarcoma susceptibility in irradiated mice

    PubMed Central

    2014-01-01

    Background Syndromic forms of osteosarcoma (OS) account for less than 10% of all recorded cases of this malignancy. An individual OS predisposition is also possible by the inheritance of low penetrance alleles of tumor susceptibility genes, usually without evidence of a syndromic condition. Genetic variants involved in such a non-syndromic form of tumor predisposition are difficult to identify, given the low incidence of osteosarcoma cases and the genetic heterogeneity of patients. We recently mapped a major OS susceptibility QTL to mouse chromosome 14 by comparing alpha-radiation induced osteosarcoma in mouse strains which differ in their tumor susceptibility. Methods Tumor-specific allelic losses in murine osteosacoma were mapped along chromosome 14 using microsatellite markers and SNP allelotyping. Candidate gene search in the mapped interval was refined using PosMed data mining and mRNA expression analysis in normal osteoblasts. A strain-specific promoter variant in Rb1 was tested for its influence on mRNA expression using reporter assay. Results A common Rb1 allele derived from the BALB/cHeNhg strain was identified as the major determinant of radiation-induced OS risk at this locus. Increased OS-risk is linked with a hexanucleotide deletion in the promoter region which is predicted to change WT1 and SP1 transcription factor-binding sites. Both in-vitro reporter and in-vivo expression assays confirmed an approx. 1.5 fold reduced gene expression by this promoter variant. Concordantly, the 50% reduction in Rb1 expression in mice bearing a conditional hemizygous Rb1 deletion causes a significant rise of OS incidence following alpha-irradiation. Conclusion This is the first experimental demonstration of a functional and genetic link between reduced Rb1 expression from a common promoter variant and increased tumor risk after radiation exposure. We propose that a reduced Rb1 expression by common variants in regulatory regions can modify the risk for a malignant

  10. The molecular landscape of extraskeletal osteosarcoma: A clinicopathological and molecular biomarker study

    PubMed Central

    Jour, George; Wang, Lu; Middha, Sumit; Zehir, Ahmet; Chen, Wen; Sadowska, Justyna; Healey, John; Agaram, Narasimhan P; Choi, Lisa; Nafa, Khedoudja

    2015-01-01

    Abstract Extraskeletal osteosarcoma (ESOSA) is a rare soft tissue neoplasm representing <5% of osteosarcomas and <1% of all soft‐tissue sarcomas. Herein, we investigate the clinicopathological and molecular features of ESOSA and explore potential parameters that may affect outcome. Thirty‐two cases were retrieved and histomorphology was reviewed. Clinical history and follow‐up were obtained through electronic record review. DNA from formalin‐fixed paraffin‐embedded (FFPE) tissue was extracted and processed from 27 cases. Genome‐wide DNA copy number (CN) alterations and allelic imbalances were analyzed by single nucleotide polymorphism array using Affymetrix OncoScan FFPE Assay. Massive high‐throughput deep parallel sequencing was performed using a customized panel targeting 410 cancer genes. Log rank, Fisher's exact test and Cox proportional hazards were used for statistical analysis. In this series of 32 patients (male n = 12, female n = 20), the average age was 66 years (19–93) and median follow up was 24 months (range 6–120 months). Frequent genomic alterations included CN losses in tumour suppressor genes including CDKN2A (70%), TP53 (56%) and RB1 (49%). Mutations affecting methylation/demethylation, chromatin remodeling and WNT/SHH pathways were identified in 40%, 27%, and 27%, respectively. PIK3CA and TERT promoter variant mutations were identified in 11% of the cases. Cases harbouring simultaneous TP53 and RB1 biallelic CN losses were associated with worse overall survival and local recurrence (p = 0.04, p = 0.02, respectively). CDKN2A losses and positive margins were also associated with worse overall survival (p = 0.002; p = 0.03, respectively). Our findings suggest that age above 60, positive margin status, simultaneous biallelic TP53 and RB1 losses and CDKN2A loss are associated with a worse outcome in ESOSA. Comparison between conventional paediatric osteosarcoma and ESOSA shows that, while both share genetic

  11. Differential regulation and expression of hyaluronan synthases in human articular chondrocytes, synovial cells and osteosarcoma cells.

    PubMed Central

    Recklies, A D; White, C; Melching, L; Roughley, P J

    2001-01-01

    Recently three isoforms of hyaluronan synthase (HAS), the enzyme responsible for hyaluronate/hyaluronan (HA) biosynthesis, have been cloned, allowing us to study their expression pattern. Our objective was to determine which of the HAS isoenzymes were expressed in human articular chondrocytes, synovial fibroblasts and osteosarcoma cells, whether their expression could be modulated by growth factors (insulin-like growth factor-1, basic fibroblast growth factor and transforming growth factor (TGF-beta1) and cytokines [interleukin 1beta1 (IL-1beta)], and whether changes in the rate of HA synthesis by the cells correlated with changes in mRNA levels for one or more of the HAS isoforms. All three HAS isoforms were found to be expressed in the cultured cells analysed in this study, although the relative proportions varied for each cell type. HAS2 mRNA was usually predominant in chondrocytes, whereas synovial cells contai