Osteogenic Sarcoma (osteosarcoma) is a bone forming cancer. It is the most frequent type of bone tumour and is most common between the ages of 15 to 25. Over 90% of tumours are located in the metaphysis (the growing ends of the bone), the most common sites are the bones around the knee which account for 80% of cases. Osteosarcomas vary greatly in radiological and pathological features and therefore needs careful diagnosis to differentiate this from other bone tumours. Most are high grade intramedullary osteosarcomas, about 5% are low grade lesions, some are secondary osteosarcomas (for example those caused by radiation therapy).
Figure 1. Radiograph showing an osteolytic and osteoblastic intra-medullary tumor characteristic of osteosarcoma. From Layfield J et al. Clin Med Pathol. 2008; 1: 55-59. Available under a Creative Commons CC-BY-3.0 license.
NHS Choices NHS Choices information is quality assured by experts and content is reviewed at least every 2 years. Further info. Overview of promary bone cancers in general, though does include some specific information about Osteosarcoma, Ewing's Sarcoma, Chondrosarcoma and Spindle cell sarcoma.
Bone Cancer Research Trust Information is reviewed by a panel of scientific and clinical experts, patients, parents/ carers, Further info. BCRT became a registered the charity in 2006 and raises funds for research into primary bone cancer, and provides information and support for patients and their families. The Website includes information booklets, personal stories and a section for teenagers.
Bone Cancer Research Trust Information is reviewed by a panel of scientific and clinical experts, patients, parents/ carers, Further info. Overview of Osteosarcoma and the different types of the disease.
Mayo Clinic Dr. Carola Arndt discusses osteosarcoma which is one of the most common malignant tumors of bone in teenagers and young adults. She discusses diagnosis, evaluation, and treatment of osteosarcoma. Also mentions the Children's Oncology group and EURAMOS study. Mentions the multi-disciplinary approach at Mayo Clinic.
Liddy Shriver Sarcoma Initiative Founded in 2003 the initiative aims improve the quality of life for people dealing with sarcomas around the world, raising awareness and research funds. It has an international panel of medical experts.
PubMed Central search for free-access publications about Osteosarcoma MeSH term: Osteosarcoma US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
Bonetumor.org A website by orthopedic surgeon Dr. Henry DeGroot, with contributions from numerous clinical colleagues. It includes numerous case studies, including radiology and pathology images, and information covering a comprehensive range of bone tumours.
This list of publications is regularly updated (Source: PubMed).
Bonda-Shkedi E, Arush MW, Kaplinsky C, et al. The Correlation Between Dose of Folinic Acid and Neurotoxicity in Children and Adolescents Treated for Osteosarcoma With High-dose Methotrexate (HDMTX): A Neuropsychological and Psychosocial Study. J Pediatr Hematol Oncol. 2013; 35(4):271-5 [PubMed]
BACKGROUND: : This study has been performed to examine the currently used doses of folinic acid (FA) and to determine the importance of the dose of FA in preventing subtle neurotoxicity. Thirty osteosarcoma patients were an appropriate population studied as they have no intrinsic neurological involvement. The neuropsychological and psychosocial status was tested in 2 groups of patients treated with similar protocols containing repeated doses of high-dose methotrexate, but different doses of FA. The patients received 300 to 600 mg/m or 120 to 250 mg/m FA in their protocols. METHODS: : Eighteen tests or subtests of neuropsychological assessment were tested. RESULTS: : Eleven of 18 tests were significant at the P=0.025 level favoring the group treated with high dose of FA. There were no clear results in the psychosocial measures with only a single measure of self-esteem (understanding) being significantly higher (P=0.024) in the group treated with high dose of FA, other measures had no statistical significance. CONCLUSIONS: : A correlation between a higher dose of FA after high-dose methotrexate and a better neuropsychological status was clearly shown. The doses of FA used in the low FA group, 120 to 250 mg/m, were similar to those used by several groups treating children with leukemia; some have used even lower doses and report gross neurotoxicity.
Uehara F, Tome Y, Yano S, et al. A color-coded imaging model of the interaction of αv integrin-GFP expressed in osteosarcoma cells and RFP expressing blood vessels in Gelfoam® vascularized in vivo. Anticancer Res. 2013; 33(4):1361-6 [PubMed]
The integrin family of proteins has been shown to be involved in the malignant behavior of cells. We report here development of a color-coded imaging model that can visualize the interaction between αv integrin linked to green fluorescent protein (GFP) in osteosarcoma cells and blood vessels in Gelfoam® vascularized after implantation in red fluorescent protein (RFP) transgenic nude mice. Human 143B osteosarcoma cells expressing αv integrin-GFP were generated by transfection with an αv integrin-GFP vector. Gelfoam® (5×5 mm) was transplanted subcutaneously in transgenic RFP nude mice. The implanted Gelfoam® became highly vascularized with RFP vessels within 14 days. Skin flaps were made at days 7, 14, 21, 28 after transplantation of Gelfoam® for observing vascularization of the Gelfoam® using fluorescence imaging. Gelfoam® is a useful tool to observe angiogenesis in vivo. 143B cells (5 × 10(5)) expressing αv integrin-GFP were injected into the Gelfoam® seven days after transplantation of Gelfoam®. Seven days after cancer-cell injection, cancer cells and blood vessels were observed in the Gelfoam® by color-coded confocal microscopy via the skin flap. The 143B cells expressing αv integrin-GFP proliferated into the Gelfoam®, which contained RFP-expressing blood vessels. Strong expression of αv integrin-GFP in 143B cells was observed near RFP vessels in the Gelfoam®. The observation of the behavior of αv integrin-GFP and blood vessels will allow further understanding of the role of αv integrin in cancer cells.
Berndt K, Campanile C, Muff R, et al. Evaluation of quercetin as a potential drug in osteosarcoma treatment. Anticancer Res. 2013; 33(4):1297-306 [PubMed]
BACKGROUND: Osteosarcoma is the most common malignant bone tumor in children and young adults. Since the introduction of chemotherapy, the 5-year survival rate of patients with non-metastatic osteosarcoma is ~70%. The main problems in osteosarcoma therapy are the occurrence of metastases, severe side-effects and chemoresistance. Antiproliferative and apoptotic effects of quercetin were shown in several types of cancers, including breast cancer and lung carcinoma. MATERIALS AND METHODS: The present study investigates the cytotoxic potential of quercetin, a dietary flavonoid, in a highly metastasizing human osteosarcoma cell line, 143B. RESULTS: We found that quercetin induces growth inhibition, G2/M phase arrest, and apoptosis in the 143B osteosarcoma cell line. We also observed impaired adhesion and migratory potential after the addition of quercetin. CONCLUSION: Since quercetin has already been shown to have low side effects in a clinical phase I trial in advanced cancer patients, this compound may have considerable potential for osteosarcoma treatment.
Chen L, Wang Q, Wang GD, et al. miR-16 inhibits cell proliferation by targeting IGF1R and the Raf1-MEK1/2-ERK1/2 pathway in osteosarcoma. FEBS Lett. 2013; 587(9):1366-72 [PubMed]
Several miRNAs have been implicated in the development and progression of osteosarcoma (OS). In this study, we found that miR-16 is downregulated in OS cell lines and tissues. Overexpression of miR-16 suppresses OS cell proliferation and tumor growth in nude mice. Furthermore, we confirmed that IGF1R is a direct target of miR-16. Mechanistic investigation revealed that miR-16 overexpression inhibits the Raf1-MEK1/2-ERK1/2 pathway. In clinical specimens, IGF1R levels inversely correlate with miR-16 expression. Our results provide significant clues regarding the role of miR-16 as a tumor suppressor by targeting IGF1R in OS.
Li JP, Liu LH, Li J, et al. Microarray expression profile of long noncoding RNAs in human osteosarcoma. Biochem Biophys Res Commun. 2013; 433(2):200-6 [PubMed]
Long noncoding RNAs (lncRNAs) are pervasively transcribed and have a critical role in genome regulation. Alterations in the expression of several lncRNAs have been observed in some types of cancers; however, the contributions of lncRNAs to osteosarcoma remain unknown. Here, we describe the expression profile of lncRNAs in osteosarcomas compared with paired adjacent noncancerous tissue using microarray analysis. In our study, 25,733 lncRNAs were expressed in osteosarcoma; 403 lncRNAs were consistently over-regulated and 798 lncRNAs were consistently under-regulated in all samples analyzed (⩾2.0-fold, p<0.05). Quantitative real-time polymerase chain reaction (PCR) was used to validate six over-regulated and four under-regulated lncRNAs. Bioinformatic analysis (gene ontology analysis, pathway analysis and network analysis) was used for further research. Pathway analysis indicated that 32 pathways corresponded to under-regulated transcripts and that 34 pathways corresponded to over-regulated transcripts (p-value cut-off is 0.05). Our results are the first to reveal differentially expressed lncRNAs in osteosarcoma and suggest that lncRNAs may be novel candidate biomarkers for the diagnosis of osteosarcoma and potential targets for therapy.
Fujiwara-Okada Y, Matsumoto Y, Fukushi J, et al. Y-box binding protein-1 regulates cell proliferation and is associated with clinical outcomes of osteosarcoma. Br J Cancer. 2013; 108(4):836-47 [PubMed] Article available free on PMC after 05/03/2014
BACKGROUND: Prognosis of osteosarcoma (OS) with distant metastasis and local recurrence is still poor. Y-box binding protein-1 (YB-1) is a multifunctional protein that can act as a regulator of transcription and translation and its high expression of YB-1 protein was observed in OS, however, the role of YB-1 in OS remains unclear. METHODS: Y-box binding protein-1 expression in OS cells was inhibited by specific small interfering RNAs to YB-1 (si-YB-1). The effects of si-YB-1 in cell proliferation and cell cycle transition in OS cells were analysed in vitro and in vivo. The association of nuclear expression of YB-1 and clinical prognosis was also investigated by immunohistochemistry. RESULTS: Proliferation of OS cell was suppressed by si-YB-1 in vivo and in vitro. The expression of cyclin D1 and cyclin A were also decreased by si-YB-1. In addition, si-YB-1 induced G1/S arrest with decreased cyclin D1 and cyclin A in OS cell lines. Direct binding of YB-1 in OS cell lines was also observed. Finally, the nuclear expression of YB-1 was significantly related to the poorer overall survival in OS patients. CONCLUSION: Y-box binding protein-1 would regulate cell cycle progression at G1/S and tumour growth in human OS cells in vitro and in vivo. Nuclear expression of YB-1 was closely associated with the prognosis of OS, thus, YB-1 simultaneously could be a potent molecular target and prognostic biomarker for OS.
Duo J, Ma Y, Wang G, et al. Metformin synergistically enhances antitumor activity of histone deacetylase inhibitor trichostatin a against osteosarcoma cell line. DNA Cell Biol. 2013; 32(4):156-64 [PubMed]
Oral hypoglycemic agent metformin is commonly used for treating type II diabetes; however, initial reports demonstrated that it could be used for suppressing tumor growth in vitro and in vivo. Moreover, novel potential anticancer drug histone deacetylase (HDAC) and inhibitor trichostatin A (TSA) have been extensively studied for inducing various malignancies growth inhibition, cell cycle arrest, and apoptosis. The object of the present study was to investigate the anti-proliferation and apoptosis induction effects of metformin and TSA in osteosarcoma cell line, and to explore the mechanism of metformin and TSA in combination to inhibit the proliferation of osteosarcoma cells. After treating with metformin and TSA, the viability of osteosarcoma cell lines (MG-63 and LM8) was analyzed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) at various concentrations, cell cycle analysis of MG-63 and LM8 cell was performed by flow cytometry. Real-time polymerase chain reaction and Western Blotting were performed to determine the expression of apoptosis-related genes and proteins such as Caspase-3, Bcl-2/Bax, Cyclin D1, and p21. Protein expression of the molecules involved in 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway after treatment with combination was determined by Western blotting. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish the murine model; tumor weight and tumor volume were monitored after drug administration separately or combined via the intraperitoneal (i.p.) route. MTT assays showed that the viability of osteosarcoma cell lines in the combination group (10 mM metformin, 0.3 μM TSA) decreased in a concentration- and time-dependent manner; moreover, the cell cycle of MG-63 and LM8 in the combination group could be arrested in G1/G2 phase higher number compared with drug use separately. Furthermore, a combination of these drugs does not act via the AMPK signaling pathway to induce MG-63 osteosarcoma cell line growth inhibition and apoptosis. As data have showed here, metformin cotreatment increased TSA antitumor effects and have a synergistic effect on osteosarcoma cell line proliferation and apoptosis.
Brusić SK, Pusić M, Cvjetković N, et al. Osteosarcoma of the mastoid process following radiation therapy of mucoepidermoid carcinoma of the parotid gland--a case report. Coll Antropol. 2012; 36 Suppl 2:223-5 [PubMed]
Radiation therapy is frequently used method in treatment of the head and neck malignancies. Osteosarcoma is a rare complication of radiation therapy and usually occurs after a long latent period. We report the case of 75-year-old female with osteosarcoma of the mastoid process. Twelve years before presentation she received radiation therapy after total parotidectomy and radical neck dissection in treatment of mucoepidermoid carcinoma of the parotid gland. Diagnostic procedures included contrast-enhanced CT and MRI of the head and neck and HRCT of the temporal bone. The final diagnosis of the low grade osteosarcoma was confirmed by biopsy. Diagnostic criteria were fulfilled and the lesion was classified as a radiation induced osteosarcoma.
Ferrari S, Palmerini E, Fabbri N, et al. Osteosarcoma of the pelvis: a monoinstitutional experience in patients younger than 41 years. Tumori. 2012; 98(6):702-8 [PubMed]
AIMS AND BACKGROUND: Information is scarce on systemic treatment of pelvic osteosarcoma because most chemotherapy protocols for osteosarcoma include patients with extremity tumors and aged up to 30-40 years. METHODS: Data on patients <41 years of age with high-grade pelvic osteosarcoma were prospectively collected. Patients received two chemotherapy protocols consisting of methotrexate, cisplatin, doxorubicin (MAP) and standard-dose or high-dose ifosfamide. RESULTS: Forty patients between 11 and 36 years were included. The most frequent histological subtype was osteoblastic followed by chondroblastic (37.5%). Complete surgical remission was achieved in 65% of patients. Eighteen patients had MAP/standard-dose ifosfamide, 22 MAP/high-dose ifosfamide. Primary chemotherapy was given to 25 patients and 6 (24%) of them had a good histological response. Median follow-up was 32 months (range, 4-134). Five-year overall survival was 27.5%: 33% in localized and 0 in metastatic patients ( P = 0.02); 45% in patients with complete surgical remission and 0 for patients without complete surgical remission (P = 0.001). Local recurrence rate was 46%. In patients with complete surgical remission, 5-year overall survival was 32% with MAP/standard-dose ifosfamide and 59% with MAP/high-dose ifosfamide regimen (P = 0.3). CONCLUSIONS: Local control is the major issue in the treatment of pelvic osteosarcoma. Poor pathological response and high incidence of chondroblastic variant indicate different characteristics between pelvic and extremity osteosarcoma. Chemotherapy with MAP and high-dose ifosfamide might be beneficial in patients with pelvic osteosarcoma and warrants further investigation.
Jianwei Z, Enzhong B, Fan L, et al. Effects of Kruppel-like factor 6 on osteosarcoma cell biological behavior. Tumour Biol. 2013; 34(2):1097-105 [PubMed]
Kruppel-like factor 6 (KLF6) is a tumor suppressor gene frequently downregulated in a number of human cancers, including osteosarcoma. However, the role of KLF6 in osteosarcoma remains unclear. This study was aimed at investigating the effects of KLF6 on osteosarcoma cell biological behavior. First, the expression of KLF6 in osteosarcoma cell lines (MG63, SaOS-2, U2OS, and HOS) and a human osteoblastic cell line (hFOB1.19) was detected by Western blotting. Results showed that KLF6 displayed a significant downregulation in osteosarcoma cell lines (MG63, SaOS-2, U2OS, and HOS) compared with human osteoblastic cell line (hFOB1.19). To investigate the role of KLF6 in osteosarcoma cell proliferation, apoptosis, and invasion, we generated human osteosarcoma MG63 cells in which KLF6 was either overexpressed or depleted. The MG63 cell viability, cycle, apoptosis, and invasive ability were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide staining, propidium iodide (PI) staining, Annexin-V-FITC/PI double staining, and Transwell invasion experiment, respectively. Results showed that the viability, proliferation, and invasive abilities were suppressed, and the apoptosis was enhanced in MG63 cells with overexpression of KLF6. The viability, proliferation, and invasive abilities were improved, and the apoptosis was inhibited in MG63 cells with knockdown of KLF6. At the same time, these molecules, including p21, bcl-2, and MMP-9, associated with the events about cell cycle, apoptosis, and invasion, were detected. Results showed that the expressions of bcl-2 and MMP-9 were downregulated, and the expressions of p21 were upregulated in the MG-63 cells with overexpression of KLF6. Taken together, our results suggested that KLF6 could inhibit proliferation and invasion, and facilitate apoptosis of osteosarcoma cells, which might be a potential target for the treatment of osteosarcoma.
Liu Y, Wang L, Wu Y, et al. Pterostilbene exerts antitumor activity against human osteosarcoma cells by inhibiting the JAK2/STAT3 signaling pathway. Toxicology. 2013; 304:120-31 [PubMed]
Osteosarcoma is a high-grade malignant bone tumor. Pterostilbene (PTE) is a natural, dimethylated analog of resveratrol with higher bioavailability. While PTE has been shown to have potent antitumor activity against various types of cancer, the molecular mechanisms underlying the effects of PTE remain largely unknown. The Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway plays a crucial role in tumorigenesis and immune development. In this study, we assessed the antitumor activity of PTE against human osteosarcoma cells and explored the role of JAK2/STAT3 and apoptosis-related signaling pathways on the activity of PTE. PTE treatment resulted in a dose- and time-dependent inhibition of osteosarcoma cell viability. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration and mitochondrial membrane potential (MMP) but also by increases in the apoptotic index, reactive oxygen species (ROS) and several biochemical parameters. Furthermore, PTE treatment directly inhibited the phosphorylation of JAK2 at Tyr 1007 and the downstream activation of STAT3. PTE also down-regulated the expression of STAT3 target genes, including the anti-apoptotic proteins Bcl-xL and Mcl-1, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, Bak, cytosolic Cytochrome c, and cleaved Caspase3) and cyclin-dependent kinase inhibitors such as p21 and p27. PTE, used in combination with a known JAK2/STAT3 inhibitor, AG490, further decreased the viability of osteosarcoma cells. Taken together, PTE is a potent inhibitor of osteosarcoma cell growth that targets the JAK2/STAT3 signaling pathway. These data suggest that inhibition of JAK2/STAT3 signaling is a novel mechanism of action for PTE during therapeutic intervention in osteosarcoma cancers.
Liang W, Gao B, Fu P, et al. The miRNAs in the pathgenesis of osteosarcoma. Front Biosci. 2013; 18:788-94 [PubMed]
Osteosarcoma is an aggressive sarcoma of the bone characterized by a high level of genetic instability and recurrent DNA deletions and amplifications. MicroRNAs (miRNAs) are non-coding small RNAs, usually 18-25 nucleotides in length, which repress translation and cleave mRNA by base-pairing to the 3 untranslated region of the target genes. miRNAs have demonstrated far-reaching effects on the cellular biology of development and cancer. Their role in osteosarcomagenesis remains largely unexplored. A number of reports have investigated the role of microRNAs in osteosarcoma. This review summeizes the recent research progress of miRNA in the osteosarcome.
Chou AJ, Gupta R, Bell MD, et al. Inhaled lipid cisplatin (ILC) in the treatment of patients with relapsed/progressive osteosarcoma metastatic to the lung. Pediatr Blood Cancer. 2013; 60(4):580-6 [PubMed]
BACKGROUND: Osteosarcoma treatment failure is most often from the inability to control metastatic disease in the lungs. Encapsulating cisplatin within lipid complexes and delivering the agent via inhalation targets lung metastases with minimal systemic exposure. An open-label, phase Ib/IIa study was performed to characterize the safety and efficacy of inhaled lipid cisplatin (ILC) in recurrent osteosarcoma patients who only had pulmonary metastases. PROCEDURE: ILC was administered via nebulizer every 2 weeks (=1 cycle). Response was evaluated radiographically every 2 cycles. Cisplatin levels were measured in patients. When possible, metastasectomy was undertaken in patients after 2 cycles. RESULTS: Nineteen patients were treated. No patients experienced hematologic toxicity, nephrotoxicity or ototoxicity. Nausea/vomiting (≥grade 3) was attributed to study drug in one patient. Respiratory symptoms were observed in 13/19 patients with only one patient experiencing a ≥grade 3 respiratory symptom (not related to study drug). Systemic cisplatin exposure was minimal. Eleven patients had bulky disease, and all progressed prior to cycle 7. Eight patients had all lesions ≤2 cm. One patient had a sustained partial response. An additional two patients had stable disease after 2 cycles, underwent metastasectomy, and remained free from pulmonary recurrence 1 year after initiation of therapy. CONCLUSIONS: ILC is well tolerated in heavily treated osteosarcoma patients and did not appear to have the typical toxicities associated with intravenous cisplatin. Three of eight patients with less bulky disease had sustained benefit. Further study of ILC is warranted.
Rao-Bindal K, Rao CK, Yu L, Kleinerman ES Expression of c-FLIP in pulmonary metastases in osteosarcoma patients and human xenografts. Pediatr Blood Cancer. 2013; 60(4):575-9 [PubMed]
OBJECTIVE(S): We have previously shown that Fas expression inversely correlates with the metastatic potential of osteosarcoma (OS) to the lung. FasL is constitutively expressed in the lung microenvironment and eliminates Fas(+) OS cells leaving Fas(-) cells to form metastases. Absence of FasL in the lung epithelium or blocking the Fas-signaling pathway interfered with this clearance mechanism allowing Fas(+) cells to remain and form lung metastases. We also demonstrated that while the majority of patient OS lung metastases were Fas(-), 10-20% of the lesions contained Fas(+) cells, suggesting that these cells were not sensitive to FasL-induced apoptosis. The expression of c-FLIP, an inhibitor of the Fas pathway, has been associated with tumor development, progression, and resistance to chemotherapy. We therefore evaluated the expression of c-FLIP in OS patient tumor specimens and human xenograft lung metastases. METHODS: OS patient tissues, which included both primary and metastatic lesions, were evaluated for the expression of c-FLIP. In addition, tumors from human OS xenografts were examined for c-FLIP expression. RESULTS: c-FLIP expression was significantly higher in the lung metastases than in the primary tumors. CONCLUSION(S): c-FLIP may play an important role in the metastatic potential of OS to the lung. Inhibition of c-FLIP may be a future therapeutic target.
Zoccali G, Cota C, Marolda G, et al. Chemotherapeutically induced cutaneous tuberculosis after BCG injection in a patient with pelvic osteosarcoma. Surg Infect (Larchmt). 2012; 13(6):406-8 [PubMed]
BACKGROUND: Tuberculosis (TB) is a serious infection afflicting a multitude of people worldwide. Recently, its prevalence has increased. The incidence of skin involvement generally is low. Bacillus Calmette-Guérin (BCG) is a live attenuated strain of Mycobacterium bovis that typically is administered as a vaccine to stimulate the immune system when treating some early neoplasms or to guard against tuberculosis. METHODS: Case report and literature review. CASE REPORT: The authors describe a young man with osteosarcoma of the left hemipelvis who received intradermal BCG injection for immune stimulation prior to surgery. In the course of neoadjuvant chemotherapy, he developed cutaneous tuberculosis. CONCLUSION: It is our opinion that BCG injection should be avoided in all patients requiring surgery, especially in oncologic patients, where the immunodeficiency brought on by chemotherapy predisposes to active opportunistic infection.
Ueki A, Shimizu T, Masuda K, et al. Up-regulation of Imp3 confers in vivo tumorigenicity on murine osteosarcoma cells. PLoS One. 2012; 7(11):e50621 [PubMed] Article available free on PMC after 05/03/2014
Osteosarcoma is a high-grade malignant bone tumor that manifests ingravescent clinical behavior. The intrinsic events that confer malignant properties on osteosarcoma cells have remained unclear, however. We previously established two lines of mouse osteosarcoma cells: AX cells, which are able to form tumors in syngeneic mice, and AXT cells, which were derived from such tumors and acquired an increased tumorigenic capacity during tumor development. We have now identified Igf2 mRNA-binding protein3 (Imp3) as a key molecule responsible for this increased tumorigenicity of AXT cells in vivo. Imp3 is consistently up-regulated in tumors formed by AX cells, and its expression in these cells was found to confer malignant properties such as anchorage-independent growth, loss of contact inhibition, and escape from anoikis in vitro. The expression level of Imp3 also appeared directly related to tumorigenic ability in vivo which is the critical determination for tumor-initiating cells. The effect of Imp3 on tumorigenicity of osteosarcoma cells did not appear to be mediated through Igf2-dependent mechanism. Our results implicate Imp3 as a key regulator of stem-like tumorigenic characteristics in osteosarcoma cells and as a potential therapeutic target for this malignancy.
Nishio J, Iwasaki H, Takagi S, et al. Low-grade central osteosarcoma of the metatarsal bone: a clinicopathological, immunohistochemical, cytogenetic and molecular cytogenetic analysis. Anticancer Res. 2012; 32(12):5429-35 [PubMed]
Low-grade central osteosarcoma (LGCOS) is a very rare low-grade malignant neoplasm that is often confused with a variety of benign fibro-osseous lesions. It rarely involves the small tubular bones of the feet. We present an unusual case of LGCOS arising in the third metatarsal bone of a 16-year-old boy. The radiographic appearance was suggestive of a benign lesion. An open biopsy was performed and the initial diagnosis was fibrous dysplasia. The patient underwent curettage of the lesion and packing of the bony defect with a synthetic bone substitute. Histologically, the curetted specimens consisted of spindle cells admixed with irregular bony trabeculae and osteoid. The spindle cells were fairly uniform with mild atypia, and cellularity varied from low to high. Immunohistochemistry showed that the tumor cells were focally-positive for cyclin-dependent kinase 4 and p53, but negative for murine double minute-2. The MIB-1 labeling index was 36.7% in the highest focus. Cytogenetic analysis exhibited the following clonal karyotypic abnormalities: 48,XY,del(6)(p11),add(8)(q24),add(12)(p11.2),+mar1,+mar-2. Spectral karyotyping demonstrated that marker chromosomes were composed mainly of chromosome 6. Metaphase-based comparative genomic hybridization analysis showed a high-level amplification of 6p12-p21 and gains of 8q21-q24, 10p15, 12q13-q15, and 16q23-q24. Based on these findings, the final diagnosis was revised to LGCOS and the patient was treated with an additional wide excision, followed by reconstruction with a free-vascularized osteocutaneous scapular flap. At 18 months of follow-up, the patient is well with no evidence of local recurrence or distant metastasis. Our case highlights the diagnostic difficulty of this tumor with limited tissue samples and the importance of immunohistochemical and molecular cytogenetic analyses in ambiguous cases.
Tzeng HE, Tsai CH, Chang ZL, et al. Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma. Biochem Pharmacol. 2013; 85(4):531-40 [PubMed]
Osteosarcoma is characterized by a high malignant and metastatic potential. Angiogenesis is essential for the caner metastasis. Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes of cancers. However, the relationship between IL-6 and vascular endothelial growth factor (VEGF) expression in human osteosarcoma is mostly unknown. Here we found that the IL-6 and VEGF expression was correlated with tumor stage and significantly higher than that in normal bone. Incubation of osteosarcoma cells with IL-6 increased VEGF mRNA and protein expression. Pretreatment of cells with IL-6R antibody reduced IL-6-mediated VEGF production. The apoptosis signal-regulating kinase 1 (ASK1)/p38/AP-1 pathway was activated after IL-6 treatment, and IL-6-induced VEGF expression was abolished by the specific inhibitor and siRNA of ASK1, p38, and AP-1 cascades. Importantly, knockdown IL-6 reduced VEGF expression and abolished osteosarcoma conditional medium-mediated angiogenesis. Taken together, these results indicate that IL-6 occurs through ASK1 and p38, which in turn activates AP-1, resulting in the activations of VEGF expression and contributing the angiogenesis of human osteosarcoma cells.
Tan ML, Friedhuber AM, Dass CR Co-nanoencapsulated doxorubicin and Dz13 control osteosarcoma progression in a murine model. J Pharm Pharmacol. 2013; 65(1):35-43 [PubMed]
OBJECTIVES: Chitosan is a green (natural, abundant, biodegradable, biocompatible) biopolymer that can be formulated to encapsulate a variety of therapeutic compounds. This study aimed to investigate chitosan nanoparticles (NPs) as a means of improving delivery of the clinically used anti-cancer agent doxorubicin (Dox) and the preclinical lead compound Dz13 oligonucleotide together. METHODS: A novel chitosan NP system encapsulating Dox and Dz13 was designed, biophysically characterised and tested in a clinically relevant model of the metastasising bone tumour, osteosarcoma (OS). KEY FINDINGS: By careful alteration of the concentration of the individual components, a final formulation of Dz13-Dox NPs (DDNPs) was achieved, with high (>91%) loading of both compounds, which consisted of individual 50-nm particles forming aggregates as large as 500 nm, with a large positive ζ-potential. The DDNPs could be stored at various temperatures for a week without loss in activity but were prone to degradation in serum. DDNPs successfully inhibited OS tumour growth more effectively than treatment with NPs of Dz13 and Dox-chitosan, as well as Dox administered intraperitoneally. Apart from inhibiting tumour growth, DDNPs protected the affected bone from substantial destruction by aggressive tumour growth and reduced the incidence of metastasis to the lungs without causing adverse effects in mice. CONCLUSION: This NP is a promising formulation that could be useful for clinical management of OS.
Anninga JK, Picci P, Fiocco M, et al. Osteosarcoma of the hands and feet: a distinct clinico-pathological subgroup. Virchows Arch. 2013; 462(1):109-20 [PubMed]
Osteosarcomas of hands or feet are rare, and seemingly these cases differ in presentation and behavior compared to those in usual locations. The clinico-pathological presentation of patients with osteosarcomas of the hand or foot was studied and compared with published cases. Forty osteosarcomas were identified among 4,221 cases, representing 0.95 % of all osteosarcomas. Thirty of these were well documented. Mean age at diagnosis was 43 years (hands) and 36 years (feet) and male-female ratio was 1.2:1 and 2.0:1, respectively. In the hand, 62 % of the osteosarcomas presented in the metacarpals and 23 % in the phalanges, and only two cases occurred in the carpal bones. Distribution in the foot was tarsal bones 56 %, metatarsal bones 33 %, and phalanges 11 %.Of the cases in the hand 54 % were of high grade and of those in the foot 71 %. Survival of osteosarcomas of the hand or foot was 81 %. Only patients with high-grade osteosarcoma died of the disease. Histological grade was the only significant variable related to survival. High-grade osteosarcoma of the hand or feet should be treated similar to those in conventional sites. Osteosarcomas of hands or feet are rare and in a relative high proportion are of low grade. Survival in high-grade cases is comparable to that in conventional sites.
Li G, Cai M, Fu D, et al. Heat shock protein 90B1 plays an oncogenic role and is a target of microRNA-223 in human osteosarcoma. Cell Physiol Biochem. 2012; 30(6):1481-90 [PubMed]
BACKGROUND/AIMS: Over the past decade, heat shock protein 90 (Hsp90) has emerged as a potential therapeutic target for cancer. However, the molecular mechanisms of down-regulation Hsp90 expression in osteosarcoma are incompletely understood. To develop potential therapy targeting Heat shock protein 90B1 (Hsp90B1), we studied the roles of miR- 223 in the proliferation and apoptosis of human osteosarcoma. METHODS: pcDNA3.1(+)- miR-223 plasmid vectors were constructed and transfected into MG63 cells. Co-transfection of miR-223 expression vector with pMIR-Hsp90B1 (The recombined vector of pMIR-GLOTM luciferase vector containing Hsp90B1-3'UTR) led to the reduced activity of luciferase in a dual-luciferase reporter gene assay, suggesting that Hsp90B1 is a target gene of miR-223. Expression of HSP90B1 was detected by RT-PCR and western blotting analysis. Cell proliferation was determined using the MTT assay. Cell-cycle distribution and apoptosis were examined by flow cytometry. PI3K, p-Akt, Akt, mTOR, Bcl-2 and Bid were also detected by western blotting analysis. After a mouse xenograft model of human MG63 tumors was constructed, tumor growth, microvessel density and proliferation in each group was determined. RESULTS: The pcDNA3.1(+)-miR-223 vector efficiently suppressed the expression of HSP90B1, while silencing miR-223 increased expression of Hsp90B1. Furthermore, overexpression of miR-223 results in significant inhibition of cell growth on culture plates. Moreover, cancer cells showed significant G0/G1 arrest and increased apoptosis due to gene silencing. Protein levels of PI3k, p-Akt, mTOR, and Bcl-2 were decreased, whereas Bid levels were increased. Microvessel density as assessed by CD34 levels and cell growth by PCNA levels decreased according to immunohistochemical analysis. CONCLUSION: Hsp90B1 is a direct target of miR-223 and miR- 223 may have a tumor suppressor function in osteosarcoma through the PI3K/Akt/mTOR pathway and could be used in anticancer therapies in osteosarcoma.
Carter CJ, Ward WG Osteosarcoma diagnostic delay associated with alendronate-induced pain relief. J Surg Orthop Adv. 2012; 21(3):165-9 [PubMed]
A 32-year-old man with a painful osteoblastic osteosarcoma of the right hip was initially diagnosed as having Paget's disease of bone. He was treated with alendronate for presumptive Paget's disease. The patient's bone pain was dramatically reduced by the administration of alendronate for 7 months. Following discontinuation of alendronate, his pain promptly recurred, culminating in a more thorough evaluation that led to the correct diagnosis. Despite chemotherapy, the patient succumbed to metastatic osteosarcoma. The main purpose of this publication is to report the potential for pain relief when an osteosarcoma is treated with bisphosphonate medication. Clinicians are advised not to consider an alendronate-associated pain reduction in an osteoblastic lesion as an indicator of an underlying benign process of bone. The evaluation of painful sclerotic bone lesions is briefly reviewed.
Yu M, Wan Y, Zou Q Reduced mitochondrial DNA copy number in Chinese patients with osteosarcoma. Transl Res. 2013; 161(3):165-71 [PubMed]
A plethora of somatic mutations and germline variations in mitochondrial DNA (mtDNA) have been increasingly reported in numerous cancer entities including osteosarcoma. However, it remains largely unclear whether mtDNA copy number changes occur during the multistep process of osteosarcoma carcinogenesis. For this purpose, we determined quantitative mtDNA levels in 31 primary osteosarcoma specimens and 5 normal bone tissue samples using a real-time polymerase chain reaction assay. Our data showed that the average mtDNA amount was significantly reduced in osteosarcoma tissues compared with normal bone controls. The copy number of mtDNA was statistically associated with tumor metastasis. There was an approximately 2-fold decrease of mtDNA quantity in tumors with metastasis than that in low-grade tumors without metastasis. Furthermore, change in mtDNA content was linked with somatic mutations in the D-loop regulatory region. Tumors carrying somatic D-loop mutations, at the polycytidine stretch between nucleotide positions 303 and 309 or close to the replication origin sites of the heavy strand, had significantly lowered mtDNA levels in comparison with those without mutations. Taken together, these results provide evidence for the first time that reduced mtDNA content may be critically implicated in the development and/or progression of osteosarcoma. Somatic D-loop mutation is likely one key factor among others leading to altered mtDNA amount in osteosarcoma.
Fayda M, Kebudi R, Dizdar Y, et al. Spontaneous pneumothorax in children with osteosarcoma: report of three cases and review of the literature. Acta Chir Belg. 2012 Sep-Oct; 112(5):378-81 [PubMed]
Spontaneous pneumothorax is a rare manifestation of primary lung cancer or metastasis. It is estimated that < 1% of all cases of spontaneous pneumothorax are tumor-associated and metastatic osteogenic or soft-tissue sarcomas are associated most commonly with pneumothorax especially in the setting of cytotoxic chemotherapy or radiotherapy. In this article, we report three pediatric cases with osteosarcoma that developed spontaneous pneumothorax during chemotherapy with a review of the literature. Two of them had lung metastasis at the time of the detection of pneumothorax and the remaining patient was found to have a bronchopleural fistula. SPx is an emergency situation and early diagnosis and management can improve prognosis and quality of life of the patient however the optimal management has yet to be determined.
Chen Z, Chen QX, Hou ZY, et al. Clinical predictive value of serum angiogenic factor in patients with osteosarcoma. Asian Pac J Cancer Prev. 2012; 13(9):4823-6 [PubMed]
OBJECTIVE: To explore serum angiogenic factor expression in patients with osteosarcoma and its relationship with metastasis. METHODS: Immunohistochemistry was used to test the expression of CD34 and FVIII-Rag in osteosarcoma tissues of 36 patients (osteosarcoma group) and microvessel density (MVD) was also recorded. In addition, ELISA was used to test the level of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-β1 (TGF-β1) and endostatin (ES) in the osteosarcoma group and in a control group. RESULTS: VEGF and ES level were significantly higher than in the control group before operation (P<0.01), VEGF, bFGF and TGF-β1 correlating with the ES level (P<.01). Serum VEGF and ES levels of osteosarcoma patients before surgery were closely related to relapse and metastasis; moreover, serum VEGF increased with MVD (P<0.01). Postoperative VEGF and ES levels were lower than the preoperation values (P<0.01); ES level in relapse group was significantly higher than that of the non-relapse group (P<0.01). CONCLUSION: Preoperative serum VEGF and postoperative ES levels have great predictive value with regard to relapse of osteosarcoma patients.
Kresse SH, Rydbeck H, Skårn M, et al. Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma. PLoS One. 2012; 7(11):e48262 [PubMed] Article available free on PMC after 05/03/2014
BACKGROUND: Osteosarcomas are the most common non-haematological primary malignant tumours of bone, and all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. PRINCIPAL FINDINGS: The cell lines showed complex patterns of DNA copy number changes, where genomic copy number gains were significantly associated with gene-rich regions and losses with gene-poor regions. By integrating the datasets, 350 genes were identified as having two types of aberrations (gain/over-expression, hypo-methylation/over-expression, loss/under-expression or hyper-methylation/under-expression) using a recurrence threshold of 6/19 (>30%) cell lines. The genes showed in general alterations in either DNA copy number or DNA methylation, both within individual samples and across the sample panel. These 350 genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. The aberrations of three selected genes, CXCL5, DLX5 and RUNX2, were validated in five cell lines and five tumour samples using PCR techniques. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2'-deoxycytidine treatment for four genes tested; AKAP12, CXCL5, EFEMP1 and IL11RA. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for detrimental genes. CONCLUSIONS: Integrative analysis of genome-wide genetic and epigenetic alterations identified dependencies and relationships between DNA copy number, DNA methylation and mRNA expression in osteosarcomas, contributing to better understanding of osteosarcoma biology.
Inoue T, Hagiyama M, Enoki E, et al. Cell adhesion molecule 1 is a new osteoblastic cell adhesion molecule and a diagnostic marker for osteosarcoma. Life Sci. 2013; 92(1):91-9 [PubMed]
AIMS: An immunohistochemical screen for mouse embryos showed that cell adhesion molecule 1 (CADM1), which is an immunoglobulin superfamily member, was expressed in developing bones. Here, we determined the cell types expressing CADM1 and examined its usefulness in the differential diagnosis of osteosarcoma. MAIN METHODS: Serial sections of murine developing mandibles were stained with anti-CADM1 antibody, by a coloring substrate reactive to alkaline phosphatase (ALP), a broad osteoblastic marker for preosteoblasts to osteoblasts, and by in situ hybridization for osteopontin (OPN), a marker for mature osteoblasts. CADM1 immunohistochemistry was also performed on human remodeling bones, osteosarcomas and other soft tissue tumors. KEY FINDINGS: CADM1 immunohistochemistry for the mandible revealed that morphologically identifiable osteoblasts expressed CADM1 on their plasma membranes, but neither osteocytes nor bone lining cells did. At the mandibular margin, not only OPN-positive cells but also OPN-negative, ALP-positive cells were CADM1-positive, whereas inside the mandible, OPN-positive cells were often CADM1-negative. Clear membranous staining was detected in the majority of osteosarcomas (46/57), whereas only 13% (6/46) of the other soft tissue tumors were CADM1-positive (P<0.001). SIGNIFICANCE: These results indicated that CADM1 was a novel osteoblastic adhesion molecule that is expressed transiently during osteoblastic maturation, and a useful diagnostic marker for osteosarcoma cells.
Rabah F, Al-Mashaikhi N, Beshlawi I, et al. Brain is not always the last fortress; osteosarcoma with large brain metastasis. J Pediatr Hematol Oncol. 2013; 35(2):e91-3 [PubMed]
Osteosarcomas are the most common malignant primary bone tumors in children and adolescents. Brain metastases of osteosarcoma are very rare and carry a dismal prognosis. We report a case of chondroblastic osteosarcoma of right humerus presented with right frontal lobe metastasis in a 10-year-old girl with small pulmonary lesions.
Angstadt AY, Thayanithy V, Subramanian S, et al. A genome-wide approach to comparative oncology: high-resolution oligonucleotide aCGH of canine and human osteosarcoma pinpoints shared microaberrations. Cancer Genet. 2012; 205(11):572-87 [PubMed]
Molecular cytogenetic evaluation of human osteosarcoma (OS) has revealed the characteristically high degree of genomic reorganization that is the hallmark of this cancer. The extent of genomic disorder in OS has hindered identification of the genomic aberrations driving disease progression. With pathophysiological similarities to its human counterpart, canine OS represents an ideal model for comparison of conserved regions of genomic instability that may be disease-associated rather than genomic passengers. This study used high-resolution oligonucleotide array comparative genomic hybridization and a variety of informatics tools to aid in the identification of disease-associated genome-wide DNA copy number aberrations in canine and human OS. Our findings support and build upon the high level of cytogenetic complexity, through the identification of shared regions of microaberration (<500 kb) and functional analysis of possible orthologous OS-associated genes to pinpoint the cellular processes most commonly affected by aberration in human and canine OS. Aberrant regions contained previously reported genes such as CDC5L, MYC, RUNX2, and CDKN2A/CDKN2B, while expanding the gene of interest list to include ADAM15, CTC1, MEN1, CDK7, and others. Such regions of instability may thus have functional significance in the etiology of OS, the most common primary bone tumor in both species.
Kupeli S, Varan A, Akyuz C, et al. Maxillofacial osteosarcoma successfully treated with surgery and adjuvant chemotherapy in a child. Bratisl Lek Listy. 2012; 113(11):661-3 [PubMed]
Maxillofacial osteosarcoma constitutes a minor percentage of all the head and neck tumors. We describe a 10 year-old girl presenting with swelling and pain in left maxillary region and diagnosed as low grade osteosarcoma. The patient was operated and given a chemotherapy protocol consisted of Cisplatin and Doxorubicin. After six courses of chemotherapy the patient was in complete remission and she is well with no evidence of disease for five years. Since high local recurrence rates have been reported in craniofacial osteoarcoma and we know the deleterious side effects of radiation therapy in children, we believe that best management strategy for osteosarcomas in maxillofacial region in children is radical surgical excision and postoperative chemotherapy (Fig. 3, Ref. 11).