Osteosarcoma
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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.

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See also: Genetic features of Osteosarcoma

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Shirazian S, Agha-Hosseini F
Oral osteosarcoma: a case report and analysis of previously reported cases.
N Y State Dent J. 2014; 80(2):50-4 [PubMed] Related Publications
Osteosarcoma is the most common malignancy of mesenchymal cells after hematopoietic neoplasms. Most originate within bones, but the occurrence of this malignancy in the jaw bones is rare. There is controversy about the characteristics of this tumor in the literature. The aim of this paper was to collect the previous reported data and provide a statistical analysis of them. Additionally, we have reported a case of mandibular osteosarcoma.


Aoki M, Nishio J, Iwasaki H, et al.
Osteosarcoma of the patella mimicking giant cell tumor: imaging features with histopathological correlation.
Anticancer Res. 2014; 34(5):2541-5 [PubMed] Related Publications
Patellar tumors represent an uncommon etiology of anterior knee pain and their diagnosis is often delayed. We present an unusual case of conventional osteosarcoma arising in the patella of a 47-year-old man. The patient presented with a 1-year history of increasing anterior knee pain and swelling. Plain radiographs revealed a multi-locular lytic lesion in the inferolateral side of the patella. Computed tomography scans demonstrated an intraosseous lytic lesion with cortical thinning/breakthrough anteriorly. On magnetic resonance imaging, the lesion exhibited low signal intensity on T1-weighted images and heterogeneous high signal intensity on T2-weighted images. Fluid-fluid levels were also observed on T2-weighted images. Contrast-enhanced fat-suppressed T1-weighted images demonstrated strong enhancement of the lesion. These imaging features were suggestive of a benign condition; however, the diagnosis of osteosarcoma was confirmed by histopathology. After neoadjuvant chemotherapy, a wide resection with a free anterolateral thigh flap was performed. The patient subsequently underwent adjuvant chemotherapy and had no evidence of local recurrence or distant metastasis six months after surgery. Our case highlights the difficulty in the diagnosis of patellar osteosarcoma and the importance of performing a biopsy before definitive treatment.

Related: Bone Cancers


Kwon HY, Kim KS, An HK, et al.
Triptolide induces apoptosis through extrinsic and intrinsic pathways in human osteosarcoma U2OS cells.
Indian J Biochem Biophys. 2013; 50(6):485-91 [PubMed] Related Publications
Triptolide, a diterpene derived from Tripterygium wilfordii Hook f., a Chinese medicinal herb, has been reported to inhibit cell proliferation and induce apoptosis in various human cancer cells, but its anticancer effects on human osteosarcoma cells have not yet been elucidated. In this study, we investigated whether triptolide induces apoptosis in human osteosarcoma cells and the underlying molecular mechanisms. We firstly demonstrated that triptolide inhibited cell growth and induced apoptosis in U2OS cells. Western blot analysis showed that the levels of procaspase-8, -9, Bcl-2, Bid and mitochondrial cytochrome c were downregulated in triptolide-treated U2OS cells, whereas the levels of Fas, FasL, Bax, cytosolic cytochrome c, cleaved caspase-3 and cleaved PARP were upregulated. These results suggest that triptolide induces apoptosis in U2OS cells by activating both death receptor and mitochondrial apoptotic pathways.

Related: Apoptosis Mitochondrial Mutations in Cancer


Chung SW, Han I, Oh JH, et al.
Prognostic effect of erroneous surgical procedures in patients with osteosarcoma: evaluation using propensity score matching.
J Bone Joint Surg Am. 2014; 96(8):e60 [PubMed] Related Publications
BACKGROUND: Little is known concerning erroneous surgical procedures of malignant bone tumors, and the prognostic effect of erroneous surgical procedures in osteosarcoma has not been determined.
METHODS: We retrospectively reviewed 240 patients with initially non-metastatic high-grade osteosarcoma of the pelvis and extremities and, of these, identified twenty-six who had undergone previous less appropriate surgical procedures due to misdiagnosis followed by adequate treatment at our institution. We evaluated the clinicopathologic characteristics of these twenty-six patients compared with the remaining 214 patients treated with regular protocol. Subsequently, thirty-eight patients (nineteen in the matched case group and nineteen in the matched control group) were matched for multiple different variables using propensity score matching, and the oncologic results in terms of event-free survival and overall survival were analyzed.
RESULTS: The patients undergoing erroneous surgical procedures were typically older, with small, non-osteoblastic-type tumors that were in an unusual location, showed an osteolytic pattern on radiographs, had a tendency toward marginal or intralesional excision with positive histologic margin, and had not been treated with neoadjuvant chemotherapy (all p < 0.05). After adjustment of confounding variables by propensity score matching, there was no significant difference between matched groups with regard to event-free survival (p = 0.46) and overall survival (p = 0.99).
CONCLUSIONS: Distinct differences existed in the clinicopathologic characteristics of the patients who underwent erroneous surgical procedures due to misdiagnosis. We failed to detect a prognostic relevance of the presence of previous erroneous procedures followed by adequate treatment.

Related: Bone Cancers


Lopez-Beltran A, Montironi R, Carazo JL, et al.
Primary renal osteosarcoma.
Am J Clin Pathol. 2014; 141(5):747-52 [PubMed] Related Publications
OBJECTIVES: To investigate primary osteosarcoma (osteogenic sarcoma) of the kidney, a rare and aggressive neoplasm.
METHODS: We present clinical and pathologic features of three female patients, aged 50, 66, and 78 years, affected by primary osteosarcoma of the kidney. The diagnosis was made by H&E-stained samples from totally (cases 1 and 2) or partially (case 3) embedded tumors.
RESULTS: Reported cases showed histologic features of low-grade (n = 1), chondroblastic (n = 1), and osteoblastic (n = 1) osteosarcoma. Tumor size ranged from 3 to 7 cm, and pT category was pT1a (n = 1), pT1b (n = 1), and pT3a (n = 1). Immunohistochemistry gave focal positive results with PAX2 and CD10 in case 1 and S100 in case 2. On follow-up, two patients were disease free at 25 and 68 months and one died of metastases.
CONCLUSIONS: Surgically treated primary renal osteosarcoma might not be as aggressive as previously thought if diagnosed early with low pT status.

Related: Kidney Cancer


Valenti MT, Zanatta M, Donatelli L, et al.
Ascorbic acid induces either differentiation or apoptosis in MG-63 osteosarcoma lineage.
Anticancer Res. 2014; 34(4):1617-27 [PubMed] Related Publications
BACKGROUND/AIM: Osteosarcoma originates from mesenchymal stem cells with impaired bone differentiation. In the present study we investigated the effect of ascorbic acid (AsA) on osteogenic differentiation and apoptosis of the MG-63 osteosarcoma cell line.
MATERIALS AND METHODS: We evaluated the expression of runt-related transcription factor-2 (RUNX2) and secreted phosphoprotein 1 (SPP1) genes by real-time Polymerase Chain Reaction (PCR) and of endogenous bone morphogenetic protein-2 (BMP2) and osteocalcin proteins by immunohistochemistry. We analyzed osteoblast maturation by phosphatase alkaline synthesis and calcium deposition, and apoptosis by (TUNEL) test and Annexin staining.
RESULTS: Our results showed that RUNX2 and SPP1 gene expression was increased in cells treated with low concentrations of AsA with respect to untreated cells. At higher concentrations, AsA induced apoptosis of osteosarcoma cells, possibly with the involvement of p21.
CONCLUSION: Our findings support the ability of AsA to induce both differentiation, by affecting the target involved in early and late phases of osteogenic maturation, and apoptosis in poorly-differentiated osteosarcoma cells.

Related: Apoptosis Bone Cancers SPP1


Lin P, Mobasher ME, Alawi F
Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis.
Biochem Biophys Res Commun. 2014; 446(4):1268-75 [PubMed] Related Publications
Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita (DC). Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening.

Related: Apoptosis Bone Cancers


Kenney LB, Duffey-Lind E, Ebb D, et al.
Impaired testicular function after an ifosfamide-containing regimen for pediatric osteosarcoma: a case series and review of the literature.
J Pediatr Hematol Oncol. 2014; 36(3):237-40 [PubMed] Related Publications
To assess testicular function after standard dose ifosfamide, we evaluated 6 young adult osteosarcoma survivors (median age at diagnosis, 16.5 y; median follow-up, 4 y) treated with ifosfamide (median dose, 45.5 g/m) as part of a chemotherapy regimen (adriamycin/cisplatin/methotrexate/ifosfamide/± muramyl-tripeptide-phosphatidyl-ethanolamine). Four of 6 survivors (67%) had abnormal semen analysis (2 oligospermic, 2 azoospermic). Of those, 1/4 had reduced testicular volume, and 2/3 elevated FSH levels. All reported adequate sexual function, 6/6 had normal testosterone levels, but 4/6 had elevated LH levels. Ifosfamide exposure in the context of this regimen was associated with a high likelihood of impaired spermatogenesis and Leydig cell insufficiency.

Related: Bone Cancers Cisplatin Doxorubicin Ifosfamide Methotrexate


Yu D, Fu S, Cao Z, et al.
Unraveling the novel anti-osteosarcoma function of coptisine and its mechanisms.
Toxicol Lett. 2014; 226(3):328-36 [PubMed] Related Publications
Uncontrolled cell proliferation and robust angiogenesis play critical roles in osteosarcoma growth and metastasis. In this study we explored novel agents derived from traditional Chinese medicinal herbs that potently inhibit osteosarcoma growth and metastasis. Coptisine, an active component of the herb Coptidis rhizoma, markedly inhibited aggressive osteosarcoma cell proliferation. Coptisine induced cell cycle arrest at the G0/G1 phase through downregulation of CDK4 and cyclin D1 expression and effectively suppressed tumor growth in a xenografted mouse model. Coptisine significantly impeded osteosarcoma cell migration, invasion, and capillary-like network formation by decreasing the expression of VE-cadherin and integrin ß3, and diminishing STAT3 phosphorylation. Coptisine significantly elevated blood erythrocyte and hemoglobin levels while still remaining within the normal range. It also moderately increased white blood cell and platelet counts. These data suggest that coptisine exerts a strong anti-osteosarcoma effect with very low toxicity and is a potential anti-osteosarcoma drug candidate.

Related: Bone Cancers Angiogenesis and Cancer


Fleuren ED, Versleijen-Jonkers YM, Boerman OC, van der Graaf WT
Targeting receptor tyrosine kinases in osteosarcoma and Ewing sarcoma: current hurdles and future perspectives.
Biochim Biophys Acta. 2014; 1845(2):266-76 [PubMed] Related Publications
Osteosarcoma (OS) and Ewing sarcoma (ES) are the two most common types of primary bone cancer, which mainly affect children and young adults. Despite intensive multi-modal treatment, the survival of both OS and ES has not improved much during the last decades and new therapeutic options are awaited. One promising approach is the specific targeting of transmembrane receptor tyrosine kinases (RTKs) implicated in these types of bone cancer. However, despite encouraging in vitro and in vivo results, apart from intriguing results of Insulin-like Growth Factor-1 Receptor (IGF-1R) antibodies in ES, clinical studies are limited or disappointing. Primary resistance to RTK inhibitors is frequently observed in OS and ES patients, and even patients that initially respond well eventually develop acquired resistance. There are, however, a few remarks to make concerning the current set-up of clinical trials and about strategies to improve RTK-based treatments in OS and ES. This review provides an overview concerning current RTK-mediated therapies in OS and ES and discusses the problems observed in the clinic. More importantly, we describe several strategies to overcome resistance to RTK inhibitors which may significantly improve outcome of OS and ES patients.

Related: IGF1R Ewing's Sarcoma


Khoury JF, Ben-Arush MW, Weintraub M, et al.
Alkaline phosphatase level change in patients with osteosarcoma: its role as a predictive factor of tumor necrosis and clinical outcome.
Isr Med Assoc J. 2014; 16(1):26-32 [PubMed] Related Publications
BACKGROUND: In osteosarcoma the histological response, measured by the percentage of tumor necrosis, constitutes one of the most significant predictive factors, with better survival in patients whose tumor necrosis is > or = 90%.
OBJECTIVES: To determine if the decrease rate of serum alkaline phosphatase (SAP) levels during the first month of neoadjuvant chemotherapy could serve as a predictive indicator of tumor necrosis and clinical outcome.
METHODS: We analyzed the medical files of 53 osteosarcoma patients (19 females, 34 males) (median age 16 years, range 8-24); the disease was metastatic in 12 and localized in the other 41.
RESULTS: The histological responses were good in 38 patients (71.7%) and poor in 15 (28.3%). At a median follow-up of 50 months, 34 patients (64.2%) had no evidence of disease and 19 (35.8%) had died from the disease. High levels of SAP at diagnosis correlated with worse survival (P = 0.002). There was no difference in overall survival between patients whose SAP decrease rate was > 25% and those with a rate < 25% (P = 0.14). Among female patients, "rapid" SAP responders had better survival than "slow" responders (P= 0.026). In patients with metastases the SAP decrease rate was positively correlated with survival (P = 0.042).
CONCLUSIONS: There was no evidence that "rapid" SAP responders had a higher percentage of tumor necrosis than "slow" responders, although female "rapid" SAP responders had a better prognosis than "slow" responders. Patients with metastases at presentation and "rapid" SAP response had better prognoses.


Wang D, Bi Z
Bufalin inhibited the growth of human osteosarcoma MG-63 cells via down-regulation of Bcl-2/Bax and triggering of the mitochondrial pathway.
Tumour Biol. 2014; 35(5):4885-90 [PubMed] Related Publications
Cinobufacini (Huachansu), a Chinese medicine prepared from the skin of Bufo bufo gargarizans Cantor (Bufonidae), has potent anti-tumor activity in vitro and in vivo. However, the molecular mechanism of cell apoptosis induced by Bufalin remains elusive. Here, we investigated the apoptosis in Bufalin-treated human osteosarcoma MG-63 cells. The results showed that Bufalin could inhibit cell proliferation and induce apoptosis in a dose- and time-dependent manner. Further investigation revealed that a disruption of mitochondrial transmembrane potential (MMP) and an up-regulation of reactive oxygen species (ROS) in Bufalin-treated cells. By western blot analysis, we found that the up-regulation of Apaf-1, cleaved PARP, cleaved caspase-3, cleaved caspase-9, and Bax/Bcl-2, varies with different concentration of Bufalin. These protein interactions may play a pivotal role in the regulation of apoptosis. Taken together, these results overall indicate that Bufalin could be used as an effective anti-tumor agent in therapy of osteosarcoma targets the mitochondrial-dependent signaling pathway.

Related: Apoptosis Bone Cancers Mitochondrial Mutations in Cancer


Yu W, Zhang Z, Min D, et al.
Mediator of RNA polymerase II transcription subunit 19 promotes osteosarcoma growth and metastasis and associates with prognosis.
Eur J Cancer. 2014; 50(6):1125-36 [PubMed] Related Publications
Osteosarcoma (OS) is the most common primary malignant tumour of bone. Nearly 30-40% of OS patients have a poor prognosis despite multimodal treatments. Because the carcinogenesis of OS remains unclear, the identification of new oncogenes that control the tumourigenesis and progression of OS is crucial for developing new therapies. Here, we found that the expression of Mediator of RNA polymerase II transcription subunit 19 (Med19) was increased in OS samples from patients compared to normal bone tissues. Cyclin D1 and cyclin B1 are upregulated in Med19 positive OS tissues. Importantly, among 97 OS patients of Enneking stage IIB or IIIB, Med19 expression was correlated with metastasis (P<0.05) and poor prognosis (P<0.01). Med19 knockdown significantly induced growth inhibition, reduced colony-forming ability and suppressed migration in the OS cell lines Saos-2 and U2OS, along with the downregulated expression of cyclin D1 and cyclin B1. Med19 knockdown also induced apoptosis in Saos-2 cells via induction of caspase-3 and poly ADP-ribose polymerase (PARP). In addition, Med19 knockdown significantly suppressed tumour growth in an OS xenograft nude mouse model via suppression of cyclin D1 and cyclin B1. Simultaneously, Med19 downregulation decreased the expression of Ki67 and proliferating cell nuclear antigen (PCNA) in tumour samples from OS xenograft nude mice. Med19 depletion remarkably reduced tumour metastasis in a model of OS metastatic spreading. Taken together, our data suggest that Med19 acts as an oncogene in OS via a possible cyclin D1/cyclin B1 modulation pathway.

Related: Apoptosis Bone Cancers


Kim KO, Hsu AC, Lee HG, et al.
Proteomic identification of 14-3-3ϵ as a linker protein between pERK1/2 inhibition and BIM upregulation in human osteosarcoma cells.
J Orthop Res. 2014; 32(6):848-54 [PubMed] Related Publications
Despite advancements in multimodality chemotherapy, conventional cytotoxic treatments still remain ineffective for a subset of patients with aggressive metastatic or multifocal osteosarcoma. It has been shown that pERK1/2 inhibition enhances chemosensitivity to doxorubicin and promotes osteosarcoma cell death in vivo and in vitro. One of the pro-apoptotic mechanisms is upregulation of Bim by pERK1/2 inhibitors. To this end, we examined proteomic changes of 143B human osteosarcoma cells with and without treatment of PD98059, pERK1/2 inhibitor. Specifically, we identified 14-3-3ϵ protein as a potential mediator of Bim expression in response to inhibition of pERK1/2. We hypothesized that 14-3-3ϵ mediates upregulation of Bim expression after pERK1/2 inhibition. We examined the expression of Bim after silencing 14-3-3ϵ using siRNA. The 14-3-3ϵ gene silencing resulted in downregulation of Bim expression after PD98059 treatment. These data indicate that 14-3-3ϵ is required for Bim expression and that it has an anti-cancer effect under pERK1/2 inhibition in 143B cells. By playing an essential role upstream of Bim, 14-3-3ϵ may potentially be a coadjuvant factor synergizing the effect of pERK1/2 inhibitors in addition to conventional cytotoxic agents for more effective osteosarcoma treatments.

Related: Apoptosis


Carter JM, Inwards CY, Jin L, et al.
Activating GNAS mutations in parosteal osteosarcoma.
Am J Surg Pathol. 2014; 38(3):402-9 [PubMed] Related Publications
Parosteal osteosarcoma is a surface-based osteosarcoma that often exhibits deceptively bland cytologic features, hindering diagnosis in small biopsies or when correlative radiologic imaging is not readily available. A number of benign and malignant fibro-osseous lesions, including fibrous dysplasia (FD) and low-grade central osteosarcoma, fall within the morphologic differential diagnosis of parosteal osteosarcoma. Somatic mutations in GNAS, encoding the α-subunit of the heterotrimeric G protein complex (Gsα), occur in FD and McCune-Albright syndrome but have not been reported in parosteal osteosarcoma. We evaluated GNAS mutational status in parosteal osteosarcoma and several of its histologic mimics to determine its utility in differentiating these entities. Eleven of 14 (79%) FD cases had GNAS mutations within codon 201 (5 R201C and 6 R201H mutations). GNAS mutations were not detected in any cases of adamantinoma or osteofibrous dysplasia. Direct sequencing of 9 parosteal osteosarcomas, including 3 of low grade and 6 with dedifferentiation, revealed activating GNAS mutations in 5 cases (55%), distributed as 4 R201C-mutated tumors and 1 tumor with an R201H mutation. GNAS codon 227 mutations were not detected in any of the cases. There was no association between GNAS mutational status and patient demographics, histologic dedifferentiation, or clinical outcome. To our knowledge, we report the first series of parosteal osteosarcomas harboring activating GNAS mutations. Our data suggest that GNAS mutational status may have limited utility as an ancillary technique in differentiating benign and malignant fibro-osseous lesions of the bone.

Related: Bone Cancers


Shimbo K, Miyaki S, Ishitobi H, et al.
Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration.
Biochem Biophys Res Commun. 2014; 445(2):381-7 [PubMed] Related Publications
MicroRNAs (miRNAs) have emerged as potential anticancer agents, but their clinical application is limited by the lack of an effective delivery system to tumors. Exosomes are small vesicles that play important roles in intercellular communication. Here, we show that synthetic miR-143 introduced into cells is released enveloped in exosomes and that the secreted exosome-formed miR-143 is transferred to osteosarcoma cells. The delivery of exosome-formed miR-143 significantly reduced the migration of osteosarcoma cells. The delivery efficiency of exosome-formed miR-143 was less than that achieved with lipofection, but the migratory potential of osteosarcoma cells was similarly inhibited after both strategies. Our results suggest that exosomes can deliver synthetic miR-143 and are a potentially efficient and functional delivery system.


Zhuang Y, Wei M
Impact of vascular endothelial growth factor expression on overall survival in patients with osteosarcoma: a meta-analysis.
Tumour Biol. 2014; 35(3):1745-9 [PubMed] Related Publications
Osteosarcoma is the most common primary malignant bone tumor of childhood. Vascular endothelial growth factor (VEGF) expression has been implicated in tumor development and progression of osteosarcoma, but previous studies investigating the impact of VEGF expression on overall survival in patients with osteosarcoma report conflicting findings. A meta-analysis of published studies was performed. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) was used to assess the impact of VEGF expression on overall survival in patients with osteosarcoma. Nine studies with a total of 432 osteosarcoma patients were included into this meta-analysis. There was no between-study heterogeneity among those nine studies (I (2) = 0.0%). Overall, high VEGF expression was obviously associated with poorer overall survival (HR = 1.68, 95% CI 1.33-2.12, P < 0.001). Sensitivity analysis performed by excluding single study in turns showed the pooled estimate was stable. Egger's test also did not suggest evidence for publication bias (P = 0.216). Therefore, this meta-analysis suggests that VEGF expression has an important impact on overall survival in patients with osteosarcoma and high VEGF expression is associated with poorer overall survival.

Related: Bone Cancers VEGFA


Qiang W, Wu Q, Zhou F, et al.
Suppression of telomere-binding protein TPP1 resulted in telomere dysfunction and enhanced radiation sensitivity in telomerase-negative osteosarcoma cell line.
Biochem Biophys Res Commun. 2014; 445(2):363-8 [PubMed] Related Publications
Mammalian telomeres are protected by the shelterin complex that contains the six core proteins POT1, TPP1, TIN2, TRF1, TRF2 and RAP1. TPP1, formerly known as TINT1, PTOP, and PIP1, is a key factor that regulates telomerase recruitment and activity. In addition to this, TPP1 is required to mediate the shelterin assembly and stabilize telomere. Previous work has found that TPP1 expression was elevated in radioresistant cells and that overexpression of TPP1 led to radioresistance and telomere lengthening in telomerase-positive cells. However, the exact effects and mechanism of TPP1 on radiosensitivity are yet to be precisely defined in the ALT cells. Here we report on the phenotypes of the conditional deletion of TPP1 from the human osteosarcoma U2OS cells using ALT pathway to extend the telomeres.TPP1 deletion resulted in telomere shortening, increased apoptosis and radiation sensitivity enhancement. Together, our findings show that TPP1 plays a vital role in telomere maintenance and protection and establish an intimate relationship between TPP1, telomere and cellular response to ionizing radiation, but likely has the specific mechanism yet to be defined.

Related: Apoptosis


Jia M, Hu J, Li W, et al.
Trps1 is associated with the multidrug resistance of osteosarcoma by regulating MDR1 gene expression.
FEBS Lett. 2014; 588(5):801-10 [PubMed] Related Publications
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.

Related: Bone Cancers Doxorubicin


Hadley C, Gressot LV, Patel AJ, et al.
Osteosarcoma of the cranial vault and skull base in pediatric patients.
J Neurosurg Pediatr. 2014; 13(4):380-7 [PubMed] Related Publications
Cranial osteosarcoma is very rare in children, rendering the development of optimal treatment algorithms challenging. The authors present 3 cases of pediatric cranial osteosarcoma: a primary calvarial tumor, a cranial metastasis, and a primary osteosarcoma of the cranial base. A review of the literature demonstrates significant variation in the management of cranial osteosarcomas and the outcome for patients with these tumors. This series and literature review is presented to improve the understanding of pediatric cranial osteosarcoma and to reinforce the importance of maximal resection in optimizing outcome.


Jakovljevic SD, Spasic MB, Milosavljevic MZ, et al.
Pure primary osteosarcoma of the breast: a case report.
Eur J Gynaecol Oncol. 2013; 34(5):476-9 [PubMed] Related Publications
INTRODUCTION: Mammary sarcomas are relatively uncommon and they represent less than one percent of all primary breast malignancies. Osteosarcoma of the breast, unassociated with other tumors, is distinctly rare, with published references generally limited to case reports and occasional cases in several series encompassing a heterogeneous group of mammary sarcomas and extraosseous osteosarcomas at various sites. The authors present a patient with pure osteosarcoma of the breast, osteoblastic type, with biologically aggressive pattern.
CASE REPORT: A 79-year-old lady became aware of a rapidly enlarging lump in the lateral part of the right breast. Clinical examination revealed a firm to hard, mobile, irregular, and painful breast lump measuring about six by four cm. On examination there was no axillary or supraclavicular lymphadenopathy. After initial diagnosis, excisional biopsy without dissection of the axillary lymph nodes was performed. Therefore, the histological and immunohistochemical findings established the diagnosis of pure primary osteosarcoma of the breast.
CONCLUSION: Pure osteosarcoma of the breast is extremely rare and needs to be distinguished from a variety of benign and malignant breast lesions producing metaplastic bone. Less than a hundred cases of pure osteosarcoma of the breast were reported, but diagnostic confirmation with immunohistochemistry has been performed in relatively few of these cases.

Related: Breast Cancer


Li Y, Geng P, Jiang W, et al.
Enhancement of radiosensitivity by 5-Aza-CdR through activation of G2/M checkpoint response and apoptosis in osteosarcoma cells.
Tumour Biol. 2014; 35(5):4831-9 [PubMed] Related Publications
Radiation resistance is a major problem preventing successful treatment. Therefore, identifying sensitizers is vitally important for radiotherapy success. Epigenetic events such as DNA methylation have been proposed to mediate the sensitivity of tumor therapy. In this study, we investigated the influence of demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-CdR) on the radiosensitivity of human osteosarcoma cell lines. 5-Aza-CdR was capable of sensitizing three osteosarcoma cells to irradiation in a time-dependent manner, with the maximum effect attained by 48 h. Pretreatment with 5-Aza-CdR synchronized cells in G2/M phase of the cell cycle and enhanced irradiation-induced apoptosis compared with irradiation alone in SaOS2, HOS, and U2OS cells. Moreover, 5-Aza-CdR restored mRNA expressions of 14-3-3σ, CHK2, and DAPK-1 in the three cells, accompanied with demethylation of their promoters. These findings demonstrate that demethylation with 5-Aza-CdR increases radiosensitivity in some osteosarcoma cells through arresting cells at G2/M phase and increasing apoptosis, which is partly mediated by upregulation of 14-3-3σ, CHK2, and DAPK-1 genes, suggesting that 5-Aza-CdR may be a potential radiosensitizer to improve the therapy effect in osteosarcoma.

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Gao Y, Luo LH, Li S, Yang C
miR-17 inhibitor suppressed osteosarcoma tumor growth and metastasis via increasing PTEN expression.
Biochem Biophys Res Commun. 2014; 444(2):230-4 [PubMed] Related Publications
MicroRNAs (miRNAs) play essential roles in cancer development and progression. Here, we investigated the role of miR-17 in the progression and metastasis of osteosarcoma (OS). miR-17 was frequently increased in OS tissues and cell lines. Inhibition of miR-17 in OS cell lines substantially suppressed cell proliferation, migration, and invasion. Phosphatase and tensin homolog (PTEN) was identified as a target of miR-17, and ectopic expression of miR-17 inhibited PTEN by direct binding to its 3'-untranslated region (3'-UTR). Expression of miR-17 was negatively correlated with PTEN in OS tissues. Together, these findings indicate that miR-17 acts as an oncogenic miRNA and may contribute to the progression and metastasis of OS, suggesting miR-17 as a potential novel diagnostic and therapeutic target of OS.

Related: PTEN


Tsai HC, Huang CY, Su HL, Tang CH
CTGF increases drug resistance to paclitaxel by upregulating survivin expression in human osteosarcoma cells.
Biochim Biophys Acta. 2014; 1843(5):846-54 [PubMed] Related Publications
Osteosarcoma is the most common primary malignant tumor, and its treatments require more effective therapeutic approaches. Paclitaxel has a broad range of antitumor activities, including apoptosis-inducing effects. However, the majority of tumors in patients with advanced cancer eventually develop chemoresistance. Connective tissue growth factor (CTGF) is a secreted protein that modulates the invasiveness of certain human cancer cells by binding to integrins. However, the effect of CTGF in paclitaxel-mediated chemotherapy is unknown. Here, we report that the expression of CTGF in osteosarcoma patients was significantly higher than that of the CTGF expression in normal bone tissues. Overexpression of CTGF increased the resistance to paclitaxel-mediated cell apoptosis. In contrast, knockdown of CTGF expression by CTGF shRNA increased the chemotherapeutic effect of paclitaxel. In addition, CTGF increased resistance to paclitaxel-induced apoptosis through upregulation of survivin expression. Moreover, the AMP-activated protein kinase (AMPK)-dependent nuclear factor kappa B (NF-κB) pathway mediated paclitaxel-increased chemoresistance and survivin expression. In a mouse xenograft model, overexpression of CTGF promoted resistance to paclitaxel. In contrast, knockdown of CTGF expression increased the therapeutic effect of paclitaxel in this model. In conclusion, our data indicate that CTGF might be a critical oncogene of human osteosarcoma involved in resistance to paclitaxel treatment.

Related: Paclitaxel BIRC5


Kobayashi E, Satow R, Ono M, et al.
MicroRNA expression and functional profiles of osteosarcoma.
Oncology. 2014; 86(2):94-103 [PubMed] Related Publications
OBJECTIVE: Osteosarcoma (OS) is the most frequent primary malignant bone tumor in children and young adults. Although the introduction of combined neoadjuvant chemotherapy has significantly prolonged survival, the outcome for OS patients showing a poor response to chemotherapy is still unfavorable. In order to develop new therapeutic approaches, elucidation of the entire molecular pathway regulating OS cell proliferation would be desirable.
METHODS: MicroRNA (miRNA) are highly conserved noncoding RNA that play important roles in the development and progression of various other cancers. Using miRNA microarrays capable of detecting a known number of 933 miRNA, 108 miRNA were found to be commonly expressed in 24 samples of OS tissue and subjected to a cell proliferation assay.
RESULTS: We found that inhibition of 5 let-7 family miRNA (hsa-let-7a, b, f, g and i) significantly suppressed the proliferation of OS cells. Using a quantitative shotgun proteomics approach, we also found that the let-7 family miRNA regulated the expression of vimentin and serpin H1 proteins.
CONCLUSIONS: Our present results indicate the involvement of let-7 family miRNA in regulation of the cell proliferation as well as epithelial-mesenchymal transition of OS. Thus, let-7 family miRNA may potentially provide novel targets for the development of therapeutic strategies against OS.

Related: Bone Cancers


Wang J, Xu G, Shen F, Kang Y
miR-132 targeting cyclin E1 suppresses cell proliferation in osteosarcoma cells.
Tumour Biol. 2014; 35(5):4859-65 [PubMed] Related Publications
In this study, we investigated the roles of miR-132 in tumor growth of osteosarcoma. We found that overexpression of miR-132 significantly suppressed in vitro cell proliferation and in vivo tumor growth. In addition, miR-132 overexpression induced G1/S cell cycle arrest of osteosarcoma cells. Further study showed that miR-132 could interact with the 3'-untranslated region of cyclin E1 (CCNE1) gene and repress its expression. Re-expression of CCNE1 (without the 3'UTR) could partially abrogate the miR-132-induced cell proliferation inhibition. Of significance, contrary to CCNE1, expression level of miR-132 was significantly lower in osteosarcoma tissues than in the adjacent normal tissues. Taken together, these results indicate that miR-132 functions as a tumor suppressor in osteosarcoma and that its suppressive effects are mediated chiefly by repressing CCNE1 expression.

Related: Bone Cancers


Yang W, Maolin H, Jinmin Z, Zhe W
High expression of metabotropic glutamate receptor 4: correlation with clinicopathologic characteristics and prognosis of osteosarcoma.
J Cancer Res Clin Oncol. 2014; 140(3):419-26 [PubMed] Related Publications
PURPOSE: Analyze protein and gene expression of mGluRs (mGluR1, mGluR5, mGluR4) in osteosarcoma tissues and discuss the relation between expression level and clinical characteristics of osteosarcoma, and study the clinical significance.
METHODS: Detect protein and mRNA expression level of mGluRs (mGluR1, mGluR5, mGluR4) in 40 osteosarcoma tissues and the corresponding adjacent normal tissues by Western blot and RT-PCR accordingly. Immunohistochemistry was adopted to detect the expression of mGluRs (mGluR1, mGluR5, mGluR4) in 118 paraffin embedded osteosarcoma tissues and eight normal bone tissues. Then, the correlation between the expression and clinical characteristics of patients was analyzed. Furthermore, survival analysis of osteosarcoma was performed to study the relation between expression level of mGluRs and patient prognosis.
RESULTS: No correlation of mGluR1 and mGluR5 with clinicopathologic characteristics of osteosarcoma was found. Statistical analysis demonstrated that the expression level of mGluR4 shared no significant correlation with gender, age, histologic type and tumor location of patient, but was related to Enneking stage and tumor metastasis (P < 0.05). High mGluR4 expression is more frequently noted in the osteosarcoma tissues with higher Enneking stage and metastasis. The results of Western blot and RT-PCR indicated a significantly increased expression level of mGluR4 gene and protein in osteosarcoma tissues compared with normal tissues. Though higher gene and protein expression of mGluR5 and mGluR1 were also indicated in osteosarcoma tissues compared with normal tissues, no statistical significance was noted for the difference (P > 0.05). According to the survival analysis of 118 osteosarcoma patients, cases in the mGluR4 high-expression group showed inferior disease-free survival rate and poorer overall survival rate.
CONCLUSION: High expression of mGluR4 in osteosarcoma tissues is related to poor prognosis, thus holding certain reference value for estimating prognosis of osteosarcoma patients.

Related: Bone Cancers


Cheng C, Chen ZQ, Shi XT
MicroRNA-320 inhibits osteosarcoma cells proliferation by directly targeting fatty acid synthase.
Tumour Biol. 2014; 35(5):4177-83 [PubMed] Related Publications
Increasing evidence has demonstrated that small noncoding microRNAs (miRNAs) could contribute to cancer development and progression. Besides, they are differentially expressed in human tumor tissues. In the current study, we found that miR-320 was significantly downregulated in human osteosarcoma tissues, compared with adjacent normal tissues. Introduction of miR-320 mimics into U2OS and MG63 cells inhibited cell proliferation, while cell apoptosis rate remained unaltered. Additionally, miR-320 overexpression could also suppress tumor growth in the nude mice. At the molecular level, our results further revealed that the expression of fatty acid synthase (FASN), a key enzyme for de novo biosynthesis of fatty acids, was negatively regulated by miR-320. Therefore, our results suggest that miR-320 may act as a tumor suppressor for osteosarcoma.

Related: Bone Cancers


Choi LE, Healey JH, Kuk D, Brennan MF
Analysis of outcomes in extraskeletal osteosarcoma: a review of fifty-three cases.
J Bone Joint Surg Am. 2014; 96(1):e2 [PubMed] Related Publications
BACKGROUND: Extraskeletal osteosarcoma is a rare soft-tissue sarcoma about which little is known. The objectives of this study were to describe the clinical features and natural history of extraskeletal osteosarcoma and to investigate factors affecting outcomes.
METHODS: A retrospective review of a prospectively maintained database of patients diagnosed with soft-tissue sarcoma was conducted. Patients with pathologically confirmed extraskeletal osteosarcoma from 1982 to 2012 were identified and were included in the analysis. Medical records were reviewed for clinical features, treatment, and outcomes.
RESULTS: Fifty-three patients were identified from the database: forty-two presented with localized disease, two presented with metastatic disease, and nine presented with recurrent (local and/or distant) disease. The median patient age at diagnosis was sixty-four years, with a median follow-up time of thirty-four months (range, one to 290 months) for survivors. Of the fifty-three patients who were identified, forty-one had lesions in the extremities, fifty-one had high-grade lesions, forty had lesions >5 cm, and forty-two had deep lesions. For patients presenting with localized disease, the median survival was 45.8 months with a three-year cumulative incidence of death due to disease of 39%. All patients with localized disease were managed with surgical resection of the primary tumor: nineteen with surgery only, ten with adjuvant radiation, five with adjuvant chemotherapy, and eight with both radiation and chemotherapy. Eighteen patients relapsed: two patients had local recurrences, ten patients had distant metastases, and six patients had local recurrences and distant metastases. In log-rank analysis, patients with superficial tumors and negative margins at resection had a higher three-year event-free survival. No significant association of disease-specific or event-free survival was found with the addition of radiation, chemotherapy, or both to surgery.
CONCLUSIONS: For patients presenting with localized extraskeletal osteosarcoma, three-year event-free survival was higher for patients with superficial tumors and negative margins at resection. Radiation and chemotherapeutic treatment were not associated with a lower incidence of death due to disease or a longer event-free survival.


Zhang Y, Ma Q, Liu T, et al.
Tumor self-seeding by circulating tumor cells in nude mouse models of human osteosarcoma and a preliminary study of its mechanisms.
J Cancer Res Clin Oncol. 2014; 140(2):329-40 [PubMed] Related Publications
PURPOSE: The purpose of this study is to determine whether and how tumor self-seeding by circulating tumor cells (CTCs) plays a role in the initiation and progression of osteosarcoma.
METHODS: Two different nude mouse models of human osteosarcoma were established for detecting tumor self-seeding by fluorescently labeled CTCs. Various tumor growth indicators were quantitated for seeded and unseeded groups. Growth mechanisms were characterized using cell proliferation assays and immunohistochemical staining. Conditioned media of primary osteosarcoma cells was characterized in a Transwell migration assay and enzyme-linked immunosorbent assay. The effect of cytokines secreted by primary tumor cells was verified by small interfering RNA and recombinant human cytokine experiments.
RESULTS: Red fluorescent protein-labeled CTCs seeded primary tumors in both models. Seeded primary tumors groups grew faster than control groups (P < 0.05), which was partially attributed to the CTCs having a higher proliferation rate and higher vascular endothelial growth factor expression after self-seeding. Conditioned media of primary osteosarcoma cells attracted CTCs, through an IL-6-dependent mechanism.
CONCLUSIONS: CTC tumor self-seeding occurs in osteosarcoma and promotes the growth of primary osteosarcoma. CTCs appear to be recruited by cytokines secreted by primary osteosarcoma cells, particularly IL-6.

Related: Bone Cancers VEGFA


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