Bone Cancers
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Primary bone tumours are tumours that start in the bone. In contrast, secondary bone cancer is where the cancer started in another part of the body but has then spread to the bones. The most common types of primary bone tumour are osteosarcoma and Ewing's sarcoma, both of which are most frequently diagnosed in children and young adults. Other less common types of bone cancer include: Chondrosarcoma (a cancer arising in cartilage cells, usually found in adults between ages 50-75, though the less common mesenchymal-chondrosarcoma is more frequent in younger patients), Malignant Fibrous Histiocytoma of bone (MFH), Chondoma (a rare low grade malignancy occuring mostly between ages 30 -70), and other rare tumours.

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Information for Patients and the Public
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Ewing's Sarcoma
Primary Lymphoma of Bone
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Information Patients and the Public (9 links)

Information for Health Professionals / Researchers (11 links)

Latest Research Publications

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

Tang YJ, Wang JL, Nong LG, et al.
Associations of IL-27 polymorphisms and serum IL-27p28 levels with osteosarcoma risk.
Medicine (Baltimore). 2014; 93(10):e56 [PubMed] Related Publications
Interleukin (IL)-27 is a novel cytokine secreted by stimulation of antigen-presenting cells. No previous studies currently reported the role of IL-27 in the carcinogenesis of osteosarcoma. We aimed to investigate the association of IL-27 polymorphisms and serum IL-27p28 with osteosarcoma risk in a Chinese population.One hundred and sixty osteosarcoma patients and 250 health controls were selected. IL-27 gene -964 A/G, 2905 T/G, and 4730 T/C polymorphisms were determined by using polymerase chain reaction-restriction fragment length polymorphism. Enzyme-linked immunosorbent assay were used to detect serum IL-27p28 levels.The serum IL-27p28 levels were significantly lower in osteosarcoma patients compared with those in controls (P < 0.01). Serum IL-27p28 levels in stages III-IV were lower than those in stages I-II of osteosarcoma (P < 0.05); similar results were also found in patients with metastasis, that is, patients with metastasis have higher IL-27p28 levels than those without metastasis (P < 0.05). There were no associations between genotype and allele frequencies of IL-27 -964 A/G, 2905 T/G, 4730 T/C, and the risk of osteosarcoma (P > 0.05). Stratification analysis also failed to show the associations between -964 A/G, 2905 T/G, and 4730 T/C polymorphisms and the clinical stage and metastasis of osteosarcoma (P > 0.05). Three possible haplotypes (ATT, GTT, and GGC) were identified, but no associations were found between them and the osteosarcoma risk (P > 0.05).This study indicates that the lower serum IL-27p28 levels may be associated with development and progression of osteosarcoma, but IL-27 gene -964 A/G, 2905 T/G, and 4730 T/C polymorphisms and their haplotypes are not associated with osteosarcoma risk.

Related: Osteosarcoma

Brown MT, Gikas PD, Bhamra JS, et al.
How safe is curettage of low-grade cartilaginous neoplasms diagnosed by imaging with or without pre-operative needle biopsy?
Bone Joint J. 2014; 96-B(8):1098-105 [PubMed] Related Publications
The pre-operative differentiation between enchondroma, low-grade chondrosarcoma and high-grade chondrosarcoma remains a diagnostic challenge. We reviewed the accuracy and safety of the radiological grading of cartilaginous tumours through the assessment of, first, pre-operative radiological and post-operative histological agreement, and second the rate of recurrence in lesions confirmed as high-grade on histology. We performed a retrospective review of major long bone cartilaginous tumours managed by curettage as low grade between 2001 and 2012. A total of 53 patients with a mean age of 47.6 years (8 to 71) were included. There were 23 men and 30 women. The tumours involved the femur (n = 20), humerus (n = 18), tibia (n = 9), fibula (n = 3), radius (n = 2) and ulna (n = 1). Pre-operative diagnoses resulted from multidisciplinary consensus following radiological review alone for 35 tumours, or with the addition of pre-operative image guided needle biopsy for 18. The histologically confirmed diagnosis was enchondroma for two (3.7%), low-grade chondrosarcoma for 49 (92.6%) and high-grade chondrosarcoma for two (3.7%). Three patients with a low-grade tumour developed a local recurrence at a mean of 15 months (12 to 17) post-operatively. A single high-grade recurrence (grade II) was treated with tibial diaphyseal replacement. The overall recurrence rate was 7.5% at a mean follow-up of 4.7 years (1.2 to 12.3). Cartilaginous tumours identified as low-grade on pre-operative imaging with or without additional image-guided needle biopsy can safely be managed as low-grade without pre-operative histological diagnosis. A few tumours may demonstrate high-grade features histologically, but the rates of recurrence are not affected.

Related: Chondrosarcoma

Leddy LR, Holmes RE
Chondrosarcoma of bone.
Cancer Treat Res. 2014; 162:117-30 [PubMed] Related Publications
Chondrosarcoma is a cartilage forming neoplasm, which is the second most common primary malignancy of bone. Clinicians who treat chondrosarcoma patients must determine the grade of the tumor, and must ascertain the likelihood of metastasis. Acral lesions are unlikely to metastasize, regardless of grade, whereas axial, or more proximal lesions are much more likely to metastasize than tumors found in the distal extremities with equivalent histology. Chondrosarcoma is resistant to both chemotherapy and radiation, making wide local excision the only treatment. Local recurrence is frequently seen after intralesional excision, thus wide local excision is sometimes employed despite significant morbidity, even in low-grade lesions. Chondrosarcoma is difficult to treat. The surgeon must balance the risk of significant morbidity with the ability to minimize the chance of local recurrence and maximize the likelihood of long-term survival.

Related: Chondrosarcoma

Moore DD, Haydon RC
Ewing's sarcoma of bone.
Cancer Treat Res. 2014; 162:93-115 [PubMed] Related Publications
Ewing's sarcoma of bone is a primary bone sarcoma found predominantly in patients during their second decade of life. It is a high-grade aggressive small round blue cell tumor that is part of the Ewing's family of tumors. Its exact eitiology is unknown but it commonly demonstrates reproducible staining of CD99 and translocations of the EWS gene. Historically, this diagnosis was associated with near certain metastasis and subsequent mortality. However, current management consists of extensive chemotherapy in addition to local control with surgical resection and/or radiation. As a result, survival has improved to the 55-75% range in those patients who present without known metastases. Current research aims to continue this improvement by looking further into the associated gene abnormalities and possibly targeted therapies.

Related: Ewing's Sarcoma

Moore DD, Luu HH
Cancer Treat Res. 2014; 162:65-92 [PubMed] Related Publications
Osteosarcoma is a malignant tumor that primarily affects the long bones but can also involve other bones in the body.  It has a bimodal distribution with peaks in the second decade of life and late adulthood.  This chapter will highlight the clinical presentation, diagnosis, and treatment of osteosarcoma.

Related: Osteosarcoma

Xia T, Guan Y, Chen Y, Li J
Askin tumor: CT and FDG-PET/CT imaging findings and follow-up.
Medicine (Baltimore). 2014; 93(6):e42 [PubMed] Related Publications
The aim of the study was to describe the imaging findings of Askin tumors on computed tomography (CT) and fluorine 18 fluorodeoxyglucose-positron emission tomography (FDG-PET/CT).Seventeen cases of Askin tumors confirmed by histopathology were retrospectively analyzed in terms of CT (17 cases) and FDG-PET/CT data (6 cases).Fifteen of the tumors were located in the chest wall and the other 2 were in the anterior middle mediastinum. Of the 15 chest wall cases, 13 demonstrated irregular, heterogeneous soft tissue masses with cystic degeneration and necrosis, and 2 demonstrated homogeneous soft tissue masses on unenhanced CT scans. Two mediastinal tumors demonstrated the irregular, heterogeneous soft tissue masses. Calcifications were found in 2 tumors. The tumors demonstrated heterogeneously enhancement in 16 cases and homogeneous enhancement in 1 case on contrast-enhanced scans. FDG-PET/CT images revealed increased metabolic activity in all 6 cases undergone FDG-PET/CT scan, and the lesion SUVmax ranged from 4.0 to 18.6. At initial diagnosis, CT and FDG-PET/CT scans revealed rib destruction in 9 cases, pleural effusion in 9 cases, and lung metastasis in 1 case. At follow-up, 12 cases showed recurrence and/or metastases, 4 cases showed improvement or remained stable, and 1 was lost to follow-up.In summary, CT and FDG-PET/CT images of Askin tumors showed heterogeneous soft tissue masses in the chest wall and the mediastinum, accompanied by rib destruction, pleural effusion, and increased FDG uptake. CT and FDG-PET/CT imaging play important roles in the diagnosis and follow-up of patients with Askin tumors.

Related: Ewing's Sarcoma

Iwata S, Nakamura T, Gaston CL, et al.
Diaphyseal osteosarcomas have distinct clinical features from metaphyseal osteosarcomas.
Eur J Surg Oncol. 2014; 40(9):1095-100 [PubMed] Related Publications
AIMS: The aim of this study was to clarify the clinical features and outcomes of diaphyseal osteosarcoma.
METHODS: Patients with newly-diagnosed high-grade osteosarcoma occurring in the long bone were eligible for this retrospective study. Clinicopathological information was collected from our database and compared with 36 diaphyseal, 405 proximal and 519 distal metaphyseal, and 14 whole bone osteosarcoma patients. Additionally, case-control study matching by age, gender, site, and metastatic status at diagnosis with 1:3 ratio of 36 diaphyseal to 108 metaphyseal osteosarcomas patients was also conducted.
RESULTS: Five-year overall survival and metastasis-free survival of the three groups including diaphyseal, metaphyseal, and whole bone osteosarcoma patients showed significant difference (P = .029 and P = .013, respectively), although there is no difference for the survivals between proximal and distal metaphyseal osteosarcoma patients. Case-control study showed that patients with diaphyseal osteosarcomas had a significantly larger tumour (mean 13.5 cm vs 10 cm, P = .026), and demonstrated higher pathologic fracture rate (28% vs 12%, P = .033), superior 5-year metastasis-free survival (74% vs 40%, P = .0068), and slightly better 5-year overall survival (68% vs 46%, P = .074). Prognostic factor analysis showed that a pathologic fracture significantly decreased the survival of the patients with diaphyseal osteosarcoma.
CONCLUSIONS: The current study showed that diaphyseal osteosarcoma has distinct clinical features from metaphyseal osteosarcoma having an increased risk of pathologic fractures but with favorable survival outcome.

Related: Osteosarcoma

Casey DL, Alektiar KM, Gerber NK, Wolden SL
Whole lung irradiation for adults with pulmonary metastases from Ewing sarcoma.
Int J Radiat Oncol Biol Phys. 2014; 89(5):1069-75 [PubMed] Related Publications
PURPOSE: To evaluate feasibility and patterns of failure in adult patients with Ewing sarcoma (ES) treated with whole lung irradiation (WLI) for pulmonary metastases.
METHODS AND MATERIALS: Retrospective review of all ES patients treated at age 18 or older with 12-15 Gy WLI for pulmonary metastases at a single institution between 1990 and 2014. Twenty-six patients met the study criteria.
RESULTS: The median age at WLI was 23 years (range, 18-40). The median follow-up time of the surviving patients was 3.8 years (range, 1.0-9.6). The 3-year cumulative incidence of pulmonary relapse (PR) was 55%, with a 3-year cumulative incidence of PR as the site of first relapse of 42%. The 3-year event-free survival (EFS) and overall survival (OS) were 38 and 45%, respectively. Patients with exclusively pulmonary metastases had better outcomes than did those with extrapulmonary metastases: the 3-year PR was 45% in those with exclusively lung metastases versus 76% in those with extrapulmonary metastases (P=.01); the 3-year EFS was 49% versus 14% (P=.003); and the 3-year OS was 61% versus 13% (P=.009). Smoking status was a significant prognostic factor for EFS: the 3-year EFS was 61% in nonsmokers versus 11% in smokers (P=.04). Two patients experienced herpes zoster in the radiation field 6 and 12 weeks after radiation. No patients experienced pneumonitis or cardiac toxicity, and no significant acute or late sequelae were observed among the survivors.
CONCLUSION: WLI in adult patients with ES and lung metastases is well tolerated and is associated with freedom from PR of 45% at 3 years. Given its acceptable toxicity and potential therapeutic effect, WLI for pulmonary metastases in ES should be considered for adults, as it is in pediatric patients. All patients should be advised to quit smoking before receiving WLI.

Zhang Z, Zheng Y, Zhu R, et al.
The ERK/eIF4F/Bcl-XL pathway mediates SGP-2 induced osteosarcoma cells apoptosis in vitro and in vivo.
Cancer Lett. 2014; 352(2):203-13 [PubMed] Related Publications
The aim of this study is to assess the molecular foundation of anti-tumor activity of SGP-2 in osteosarcoma cells. SGP-2 significantly blocks cell proliferation in human osteosarcoma U2OS cell model and inhibits tumor growth without causing apparent toxicity effect in mouse sarcoma S-180 cell-derived tumor model. Moreover, SGP-2 induces intrinsic apoptosis including the activation of caspase-3/7/9, the loss of mitochondrial transmembrane potential (ΔΨm), and the release of cytochrome c from mitochondrion, controlled by the down-regulation of B-cell lymphoma-extra large (Bcl-XL). Further research reveals that SGP-2 inhibits the assembly of eukaryotic initiation factor 4F (eIF4F) complex which is responsible for the decline of Bcl-XL. Finally, extracellular-signal-regulated kinase (ERK) controls SGP-2 induced intrinsic apoptosis. Taken together, SGP-2 exerts anti-tumor effect through intrinsic apoptotic pathway controlled by ERK/eIF4F/Bcl-XL pathway.

Related: Apoptosis Osteosarcoma Signal Transduction

Xiong S, Tu H, Kollareddy M, et al.
Pla2g16 phospholipase mediates gain-of-function activities of mutant p53.
Proc Natl Acad Sci U S A. 2014; 111(30):11145-50 [PubMed] Article available free on PMC after 29/01/2015 Related Publications
p53(R172H/+) mice inherit a p53 mutation found in Li-Fraumeni syndrome and develop metastatic tumors at much higher frequency than p53(+/-) mice. To explore the mutant p53 metastatic phenotype, we used expression arrays to compare primary osteosarcomas from p53(R172H/+) mice with metastasis to osteosarcomas from p53(+/-) mice lacking metastasis. For this study, 213 genes were differentially expressed with a P value <0.05. Of particular interest, Pla2g16, which encodes a phospholipase that catalyzes phosphatidic acid into lysophosphatidic acid and free fatty acid (both implicated in metastasis), was increased in p53(R172H/+) osteosarcomas. Functional analyses showed that Pla2g16 knockdown decreased migration and invasion in mutant p53-expressing cells, and vice versa: overexpression of Pla2g16 increased the invasion of p53-null cells. Furthermore, Pla2g16 levels were increased upon expression of mutant p53 in both mouse and human osteosarcoma cell lines, indicating that Pla2g16 is a downstream target of the mutant p53 protein. ChIP analysis revealed that several mutant p53 proteins bind the Pla2g16 promoter at E26 transformation-specific (ETS) binding motifs and knockdown of ETS2 suppressed mutant p53 induction of Pla2g16. Thus, our study identifies a phospholipase as a transcriptional target of mutant p53 that is required for metastasis.

Related: Li-Fraumeni Syndrome Osteosarcoma

Sadri N, Barroeta J, Pack SD, et al.
Malignant round cell tumor of bone with EWSR1-NFATC2 gene fusion.
Virchows Arch. 2014; 465(2):233-9 [PubMed] Related Publications
Gene rearrangements involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene are seen in a broad range of sarcomas and some nonmesenchymal neoplasms. Ewing sarcoma is molecularly defined by a fusion of the EWSR1 gene (or rarely the related FUS gene) to a member of the E26 transformation-specific (ETS) family of transcription factors, frequently the EWSR1-FLI1 fusion. More recently, EWSR1 gene fusion to non-ETS family members, including the nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 2 (NFATC2) gene, has been reported in a histological variant of Ewing sarcoma. Here, we report a malignant round cell tumor of bone with an EWSR1-NFATC2 fusion gene. This report builds upon the unusual morphological and clinical presentation of bone neoplasms containing an EWSR1-NFATC2 fusion gene.

Related: Ewing's Sarcoma EWSR1 gene

van der Ent W, Jochemsen AG, Teunisse AF, et al.
Ewing sarcoma inhibition by disruption of EWSR1-FLI1 transcriptional activity and reactivation of p53.
J Pathol. 2014; 233(4):415-24 [PubMed] Related Publications
Translocations involving ETS-transcription factors, most commonly leading to the EWSR1-FLI1 fusion protein, are the hallmark of Ewing sarcoma. Despite knowledge of this driving molecular event, an effective therapeutic strategy is lacking. To test potential treatment regimes, we established a novel Ewing sarcoma zebrafish engraftment model allowing time-effective, dynamic quantification of Ewing sarcoma progression and tumour burden in vivo, applicable for screening of single and combined compounds. In Ewing sarcoma the tumour-suppressor gene TP53 is commonly found to be wild-type, thus providing an attractive target for treatment. Here, we study TP53 wild-type (EW7, CADO-ES1 and TC32) and TP53-deleted (SK-N-MC) Ewing sarcoma cell lines to investigate the potentiating effect of p53 reactivation by Nutlin-3 on treatment with YK-4-279 to block transcriptional activity of EWSR1-FLI1 protein. Blocking EWSR1-FLI1 transcriptional activity reduced Ewing sarcoma tumour cell burden irrespective of TP53 status. We show that simultaneous YK-4-279 treatment with Nutlin-3 to stabilize p53 resulted in an additive inhibition of TP53 wild-type Ewing sarcoma cell burden, whilst not affecting TP53-deleted Ewing sarcoma cells. Improved inhibition of proliferation and migration by combinatorial treatment was confirmed in vivo by zebrafish engraftments. Mechanistically, both compounds together additively induced apoptosis of tumour cells in vivo by engaging distinct pathways. We propose reactivation of the p53 pathway in combination with complementary targeted therapy by EWSR1-FLI1 transcriptional activity disruption as a valuable strategy against p53 wild-type Ewing sarcoma.

Related: Ewing's Sarcoma Signal Transduction TP53

Takagi S, Takemoto A, Takami M, et al.
Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis.
Cancer Sci. 2014; 105(8):983-8 [PubMed] Related Publications
The interactions of tumor cells with platelets contribute to the progression of tumor malignancy, and the expression levels of platelet aggregation-inducing factors positively correlate with the metastatic potential of osteosarcoma cells. However, it is unclear how tumor-platelet interaction contributes to the proliferation of osteosarcomas. We report here that osteosarcoma-platelet interactions induce the release of platelet-derived growth factor (PDGF) from platelets, which promotes the proliferation of osteosarcomas. Co-culture of platelets with MG63 or HOS osteosarcoma cells, which could induce platelet aggregation, enhanced the proliferation of each cell line in vitro. Analysis of phospho-antibody arrays revealed that co-culture of MG63 cells with platelets induced the phosphorylation of platelet derived growth factor receptor (PDGFR) and Akt. The addition of supernatants of osteosarcoma-platelet reactants also increased the growth of MG63 and HOS cells as well as the level of phosphorylated-PDGFR and -Akt. Sunitinib or LY294002, but not erlotinib, significantly inhibited the platelet-induced proliferation of osteosarcoma cells, indicating that PDGF released from platelets plays an important role in the proliferation of osteosarcomas by activating the PDGFR and then Akt. Our results suggest that inhibitors that specifically target osteosarcoma-platelet interactions may eradicate osteosarcomas.

Related: Osteosarcoma AKT1 Signal Transduction

Xing D, Qasem SA, Owusu K, et al.
Changing prognostic factors in osteosarcoma: analysis of 381 cases from two institutions.
Hum Pathol. 2014; 45(8):1688-96 [PubMed] Related Publications
Osteosarcoma occurs most commonly in children and young adults, with a historic second incidence peak in the elderly. Most studies have focused on those occurring in adolescence. Detailed information on descriptive features and prognostic factors in patients of different age groups is lacking. We analyzed 381 osteosarcomas diagnosed between 1973 and 2012 to identify factors significantly associated with survival in various age groups. The peak incidence was seen in patients age <25, followed by a steady incidence rate thereafter until the sixth decade, when it started to decline. In the early onset diseases, significant factors for recurrence-free survival (RFS) were tumor site and size; whereas those for overall survival (OS) were gender, tumor site, type, grade and size. In patients age 25 to 54, tumor type and grade were significant for RFS, and the pathologic type was significant for OS. In those age ≥55, race and tumor size were significant for RFS; tumor site and size were significant for OS. In multivariate analysis, tumor size remained significant for RFS; gender, tumor site and size maintained their significance for OS in patients age <25. While no independent factor was identified in patients age 25 to 54, tumor size remained significant for RFS in those age ≥55. Chemotherapy-induced tumor necrosis was a prognosticator for RFS in patients age 25 to 54 by univariate analysis, but not as an independent factor in any stratified age group. Our data indicate that the distinctive prognostic factors differed significantly among different age groups, thus providing a rationale for age-based management strategies.

Related: Osteosarcoma

Clarke MJ, Zadnik PL, Groves ML, et al.
En bloc hemisacrectomy and internal hemipelvectomy via the posterior approach.
J Neurosurg Spine. 2014; 21(3):458-67 [PubMed] Related Publications
OBJECT: Traditionally, hemisacrectomy and internal hemipelvectomy procedures have required both an anterior and a posterior approach. A posterior-only approach has the potential to complete an en bloc tumor resection and spinopelvic reconstruction while reducing surgical morbidity.
METHODS: The authors describe 3 cases in which en bloc resection of the hemisacrum and ilium and subsequent lumbopelvic and pelvic ring reconstruction were performed from a posterior-only approach. Two more traditional anterior and posterior staged procedures are also included for comparison.
RESULTS: In all 3 cases, an oncologically appropriate surgery and spinopelvic reconstruction were performed through a posterior-only approach.
CONCLUSIONS: The advantage of a midline posterior approach is the ability to perform a lumbosacral reconstruction, necessary in cases in which the S-1 body is iatrogenically disrupted during tumor resection.

Related: Chondrosarcoma Soft Tissue Sarcomas

Tarek N, Lee DA
Natural killer cells for osteosarcoma.
Adv Exp Med Biol. 2014; 804:341-53 [PubMed] Related Publications
Natural killer (NK) cells are lymphocytes of the innate immune system that have the ability to recognize malignant cells through detection of a variety of cell-surface indicators of stress and danger. Once activated through such recognition, NK cells release cytokines and induce target cell lysis through a variety of mechanisms. NK cells are increasingly recognized as important mediators of other immunotherapeutic modalities, including cytokines, antibodies, immunomodulators, and stem cell transplantation. Adoptive immunotherapies with NK cells are being tested in early-stage clinical trials, and recent advances in manipulating their number and function have caused a renewed emphasis on this cancer-fighting cell. In this chapter we address the evidence for NK cell recognition of osteosarcoma in vitro and in vivo, discuss new therapies that are directly or indirectly dependent on NK cell function, and describe potential approaches for manipulating NK cell number and function to enhance therapy against osteosarcoma.

Related: Monoclonal Antibodies Cytokines Lung Cancer Osteosarcoma

DeRenzo C, Gottschalk S
Genetically modified T-cell therapy for osteosarcoma.
Adv Exp Med Biol. 2014; 804:323-40 [PubMed] Related Publications
T-cell immunotherapy may offer an approach to improve outcomes for patients with osteosarcoma, who fail current therapies. In addition, it has the potential to reduce treatment-related complications for all patients. Generating tumor-specific T cells with conventional antigen presenting cells ex vivo is time consuming and often results in T-cell products with a low frequency of tumor-specific T cells. In addition, the generated T cells remain sensitive to the immunosuppressive tumor microenvironment. Genetic modification of T cells is one strategy to overcome these limitations. For example, T cells can be genetically modified to render them antigen specific, resistant to inhibitory factors, or increase their ability to home to tumor sites. Most genetic modification strategies have only been evaluated in preclinical models, however early phase clinical trials are in progress. In this chapter we review the current status of gene-modified T-cell therapy with special focus on osteosarcoma, highlighting potential antigenic targets, preclinical and clinical studies, and strategies to improve current T-cell therapy approaches.

Related: Lung Cancer Osteosarcoma

Meyers PA, Chou AJ
Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) in the treatment of osteosarcoma.
Adv Exp Med Biol. 2014; 804:307-21 [PubMed] Related Publications
Bacille Calmette-Guerin (BCG) has been used for decades as an immune stimulant to treat cancer. Early work by Fidler and Kleinerman identified muramyl dipeptide (MDP) as a critical component of the BCG cell wall which retained most of the immunostimulatory properties of the native BCG. Addition of a peptide to MDP resulted in muramyl tripeptide (MTP) which allowed incorporation into liposomal membranes. The resulting pharmaceutical, liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE or mifamurtide) showed activity in preclinical models of human cancers. Phase I studies documented the safety of the compound for human administration. These trials did not reach a maximally tolerated dose (MTD), and the dose chosen for phase II trials was a biologically optimized dose, not an MTD. Phase II studies showed decreased risk of further recurrence in patients who received mifamurtide after surgical ablation of metastatic osteosarcoma. A phase III prospective randomized trial demonstrated a statistically significant reduction in the risk of death from osteosarcoma when MTP was added to systemic chemotherapy for the treatment of localized osteosarcoma. The same trial allowed treatment of patients who presented with initially metastatic disease. While the overall and event-free survival was improved in patients with metastatic osteosarcoma who received L-MTP-PE, the sample size was small and the improvement did not achieve conventional statistical significance. From 2008 to 2012, patients with metastatic and recurrent osteosarcoma were given L-MTP-PE in an expanded access trial, and the results suggest a decreased risk of subsequent recurrence and death with the inclusion of L-MTP-PE in the treatment strategy for these high-risk patients.

Anderson PM, Subbiah V, Rohren E
Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: samarium-153-EDTMP and radium-223.
Adv Exp Med Biol. 2014; 804:291-304 [PubMed] Related Publications
Osteosarcoma is a cancer characterized by formation of bone by malignant cells. Routine bone scan imaging with Tc-99m-MDP is done at diagnosis to evaluate primary tumor uptake and check for bone metastases. At time of relapse the Tc-99m-MDP bone scan also provides a specific means to assess formation of bone by malignant osteosarcoma cells and the potential for bone-seeking radiopharmaceuticals to deliver radioactivity directly into osteoblastic osteosarcoma lesions. This chapter will review and compare a bone-seeking radiopharmaceutical that emits beta-particles, samarium-153-EDTMP, with an alpha-particle emitter, radium-223. The charged alpha particles from radium-223 have far more mass and energy than beta particles (electrons) from Sm-153-EDTMP. Because radium-223 has less marrow toxicity and more radiobiological effectiveness, especially if inside the bone forming cancer cell than samarium-153-EDTMP, radium-223 may have greater potential to become widely used against osteosarcoma as a targeted therapy. Radium-223 also has more potential to be used with chemotherapy against osteosarcoma and bone metastases. Because osteosarcoma makes bone and radium-223 acts like calcium, this radiopharmaceutical could possibly become a new targeted means to achieve safe and effective reduction of tumor burden as well as facilitate better surgery and/or radiotherapy for difficult to resect large, or metastatic tumors.

Related: Lung Cancer Osteosarcoma

Lewis VO
IL-11Rα: a novel target for the treatment of osteosarcoma.
Adv Exp Med Biol. 2014; 804:285-9 [PubMed] Related Publications
Recent advances have shown that cell surface receptors are expressed differentially in normal and pathological conditions. Novel organ specific and disease specific proteins expressed on tumor vasculature have been identified by in vivo phage display technology and the diversity of the tumor-associated vasculature has provided the basis for the development of targeted therapeutics. Investigators recently screened a phage display library in a human cancer patient. An IL-11 mimic phage displaying the cyclic peptide CGRRAGGSC (single letter amino acid code) specifically bound to immobilized IL-11Rα. It has been demonstrated that the expression of the IL-11Rα is increased in several other types of tumors including osteosarcoma. The ability to selectively target the IL-11Rα may provide an alternative treatment of for a disease where new treatment options are truly needed.

Related: Lung Cancer Angiogenesis and Cancer Osteosarcoma Signal Transduction

Hingorani P, Sampson V, Lettieri C, Kolb EA
Oncolytic viruses for potential osteosarcoma therapy.
Adv Exp Med Biol. 2014; 804:259-83 [PubMed] Related Publications
Since the first anecdotal reports of dramatic tumor responses following a viral infection in early 1900s, the field of oncolytic virotherapy has evolved at a rapid pace finally making its way into clinical trials. A large number of both wild-type and genetically altered viruses with a preferential replication-competency for tumor cells have been studied in tissue cultures, animal models and in humans, with an ever increasing repertoire of new viruses being added to this pool. Although oncolytic viruses have caused dramatic antitumor responses in cell cultures and mouse models, their clinical effects in humans have been modest. Therefore, the current research is focused on understanding the mechanisms by which viruses kill tumor cells, the barriers to successful viral delivery and penetration into tumor cells, the role of the immune system in viral oncolysis and generating stronger target specific and replication competent viruses. Osteosarcoma is a challenging malignancy to identify novel targets for therapy due to its complex genetic make-up. Oncolytic virotherapy may be a promising approach as a novel therapeutic, not dependent on consistent expression of a single target. In this review we summarize the supportive evidence and rationale for use of viral oncolysis in osteosarcoma along with the specific challenges it may face.

Related: Lung Cancer Osteosarcoma

Rodriguez CO
Using canine osteosarcoma as a model to assess efficacy of novel therapies: can old dogs teach us new tricks?
Adv Exp Med Biol. 2014; 804:237-56 [PubMed] Related Publications
Since its domestication more than 10,000 years ago, the dog has been the animal that most intimately shares our work and homelife. Interestingly, the dog also shares many of our diseases including cancer such as osteosarcoma. Like the human, osteosarcoma is the most common bone malignancy of the dog and death from pulmonary metastasis is the most common outcome. The incidence of this spontaneous bone neoplasm occurs ten times more frequently that it does so in children with about 8,000-10,000 cases estimated to occur in dogs in the USA. Because there is no "standard of care" in veterinary medicine, the dog can also serve us by being a model for this disease in children. Although the most common therapy for the dog with osteosarcoma is amputation followed by chemotherapy, not all owners choose this route. Consequently, novel therapeutic interventions can be attempted in the dog with or without chemotherapy that could not be done in humans with osteosarcoma due to ethical concerns. This chapter will focus on the novel therapies in the dog that have been reported or are in veterinary clinical trials at the author's institution. It is hoped that collaboration between veterinary oncologists and pediatric oncologists will lead to the development of novel therapies for (micro- or macro-) metastatic osteosarcoma that improve survival and might ultimately lead to a cure in both species.

Related: Interleukin 2 (Aldesleukin) Signal Transduction Gemcitabine

Mohseny AB, Hogendoorn PC
Zebrafish as a model for human osteosarcoma.
Adv Exp Med Biol. 2014; 804:221-36 [PubMed] Related Publications
For various reasons involving biological comparativeness, expansive technological possibilities, accelerated experimental speed, and competitive costs, zebrafish has become a comprehensive model for cancer research. Hence, zebrafish embryos and full-grown fish have been instrumental for studies of leukemia, melanoma, pancreatic cancer, bone tumors, and other malignancies. Although because of its similarities to human osteogenesis zebrafish appears to be an appealing model to investigate osteosarcoma, only a few osteosarcoma specific studies have been accomplished yet. Here, we review interesting related and unrelated reports of which the findings might be extrapolated to osteosarcoma. More importantly, rational but yet unexplored applications of zebrafish are debated to expand the window of opportunities for future establishment of osteosarcoma models. Accordingly technological advances of zebrafish based cancer research, such as robotic high-throughput multicolor injection systems and advanced imaging methods are discussed. Furthermore, various use of zebrafish embryos for screening drug regimens by combinations of chemotherapy, novel drug deliverers, and immune system modulators are suggested. Concerning the etiology, the high degree of genetic similarity between zebrafish and human cancers indicates that affected regions are evolutionarily conserved. Therefore, zebrafish as a swift model system that allows for the investigation of multiple candidate gene-defects is presented.

Related: Osteosarcoma Signal Transduction

Huang G, Nishimoto K, Yang Y, Kleinerman ES
Participation of the Fas/FasL signaling pathway and the lung microenvironment in the development of osteosarcoma lung metastases.
Adv Exp Med Biol. 2014; 804:203-17 [PubMed] Related Publications
The lungs are the most common site for the metastatic spread of osteosarcoma. Success in using chemotherapy to improve overall survival has reached a plateau. Understanding the biologic properties that permit osteosarcoma cells to grow in the lungs may allow the identification of novel therapeutic approaches-the goal being to alter the tumor cells' expression of cell surface proteins so that there is no longer compatibility with the metastatic niche. We have demonstrated that the Fas Ligand positive (FasL(+)) lung microenvironment eliminates Fas(+) osteosarcoma cells that metastasize to the lungs. Indeed, osteosarcoma lung metastases from patients are Fas(-), similar to what we found in several different mouse models. The Fas(+) cells are cleared from the lungs through apoptosis induced by the Fas signaling pathway following interaction of Fas on the tumor cell surface with the lung FasL. Blocking the Fas signaling pathway interferes with this process, allowing the Fas(+) cells to grow in the lungs. Our investigations show that Fas expression in osteosarcoma cells is regulated epigenetically by the micro-RNA miR-20a, encoded by the miR-17-92 cluster. Our studies support the feasibility of finding agents that can re-induce Fas expression as a novel therapeutic approach to treat osteosarcoma patients with lung metastases. We have identified two such agents, the histone deacetylase inhibitor entinostat and the chemotherapeutic agent gemcitabine (GCB). Aerosol GCB and oral entinostat induce the upregulation of Fas and the regression of established osteosarcoma lung metastases. Aerosol GCB was not effective in the FasL-deficient gld mouse confirming that the lung microenvironment was central to the success of this therapy. Our studies establish the critical role of the lung microenvironment in the metastatic process of osteosarcoma to the lungs and suggest an alternative focus for therapy, that is, incorporating the lung microenvironment as part of the treatment strategy against established osteosarcoma disease in the lungs.

Related: Signal Transduction Gemcitabine

Ren L, Khanna C
Role of ezrin in osteosarcoma metastasis.
Adv Exp Med Biol. 2014; 804:181-201 [PubMed] Related Publications
The cause of death for the vast majority of cancer patients is the development of metastases at sites distant from that of the primary tumor. For most pediatric sarcoma patients such as those with osteosarcoma (OS), despite successful management of the primary tumor through multimodality approaches, the development of metastases, commonly to the lungs, is the cause of death. Significant improvements in long-term outcome for these patients have not been seen in more than 30 years. Furthermore, the long-term outcome for patients who present with metastatic disease is grave [1-5]. New treatment options are needed.Opportunities to improve outcomes for patients who present with metastases and those at-risk for progression and metastasis require an improved understanding of cancer progression and metastasis. With this goal in mind we and others have identified ezrin as a metastasis-associated protein that associated with OS and other cancers. Ezrin is the prototypical ERM (Ezrin/Radixin/Moesin) protein family member. ERMs function as linker proteins connecting the actin cytoskeleton and the plasma membrane. Since our initial identification of ezrin in pediatric sarcoma, an increasing understanding the role of ezrin in metastasis has emerged. Briefly, ezrin appears to allow metastatic cells to overcome a number of stresses experienced during the metastatic cascade, most notably the stress experienced as cells interact with the microenvironment of the secondary site. Cells must rapidly adapt to this environment in order to survive. Evidence now suggests a connection between ezrin expression and a variety of mechanisms linked to this important cellular adaptation including the ability of metastatic cells to initiate the translation of new proteins and to allow the efficient generation of ATP through a variety of sources. This understanding of the role of ezrin in the biology of metastasis is now sufficient to consider ezrin as an important therapeutic target in osteosarcoma patients. This chapter reviews our understanding of ezrin and the related ERM proteins in normal tissues and physiology, summarizes the expression of ezrin in human cancers and associations with clinical parameters of disease progression, reviews reports that detail a biological understanding of ezrin's role in metastatic progression, and concludes with a rationale that may be considered to target ezrin and ezrin biology in osteosarcoma.

Related: Signal Transduction

Gill J, Geller D, Gorlick R
HER-2 involvement in osteosarcoma.
Adv Exp Med Biol. 2014; 804:161-77 [PubMed] Related Publications
The major goals of translational research in osteosarcoma entail the identification of prognostic factors and therapeutic targets. Given the relevance of epidermal growth factor receptor pathway to breast cancer and the finding that HER-2 was expressed in a proportion of osteosarcoma, it was reasonable to investigate this pathway further. Investigations of HER-2 in osteosarcoma have led to the publication of numerous conflicting reports with regard to the level and prognostic value of HER-2 expression, which are reviewed and discussed. Numerous lessons provided by this research experience are described. This pathway has also been explored as a therapeutic target with at least one study of trastuzumab for the treatment of osteosarcoma completed. Other studies utilizing alternative approaches to target the HER-2 receptor for the treatment of osteosarcoma have been considered.

Related: Signal Transduction Trastuzumab (Herceptin)

O'Farrill JS, Gordon N
Autophagy in osteosarcoma.
Adv Exp Med Biol. 2014; 804:147-60 [PubMed] Related Publications
Osteosarcoma (OS) metastatic disease is resistant to conventional chemotherapy. Tumor resistance to chemotherapy has been one of the major areas of concern to clinicians and the topic of many laboratory investigators. Evaluation of mechanisms implicated in OS lung metastasis resistance to chemotherapy has been the focus of some of our most recent work. We have previously demonstrated the therapeutic efficacy of aerosol gemcitabine (GCB) in OS lung metastases. However, a subset of cells fails to respond to GCB treatment and persists as isolated lung metastases in vivo. Autophagy, a physiological mechanism that supports nutritional deprivation under stressful conditions, has been implicated in tumor resistance to chemotherapy. We demonstrated the induction of autophagy by GCB in LM7 metastatic human OS cells and K7M3 metastatic murine OS cells. Inhibition of autophagy resulted in increased sensitivity to GCB in LM7 cells. By contrast, inhibiting autophagy in K7M3 cells decreased GCB sensitivity. Defining the role autophagy plays in chemotherapy response in different tumor types has become of greater importance in order to identify the best suitable therapeutic approach. In this chapter, we summarize some of the most recent work related to autophagy in OS, identify some of the known mechanisms, and address the different roles autophagy plays in chemotherapy response.

Related: Gemcitabine

Lu L, Jin W, Liu H, Wang LL
RECQ DNA helicases and osteosarcoma.
Adv Exp Med Biol. 2014; 804:129-45 [PubMed] Related Publications
The RECQ family of DNA helicases is a conserved group of enzymes that are important for maintaining genomic integrity. In humans, there are five RECQ helicase genes, and mutations in three of them-BLM, WRN, and RECQL4-are associated with the genetic disorders Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome (RTS), respectively. Importantly all three diseases are cancer predisposition syndromes. Patients with RTS are highly and uniquely susceptible to developing osteosarcoma; thus, RTS provides a good model to study the pathogenesis of osteosarcoma. The "tumor suppressor" role of RECQL4 and the other RECQ helicases is an area of active investigation. This chapter reviews what is currently known about the cellular functions of RECQL4 and how these may relate to tumorigenesis, as well as ongoing efforts to understand RECQL4's functions in vivo using animal models. Understanding the RECQ pathways may provide insight into avenues for novel cancer therapies in the future.

Related: Osteosarcoma Rothmund-Thomson Syndrome Signal Transduction RECQL4

Kafchinski LA, Jones KB
MicroRNAs in osteosarcomagenesis.
Adv Exp Med Biol. 2014; 804:119-27 [PubMed] Related Publications
The etiology of osteosarcoma (OS) remains enigmatic. Particular clinical and molecular patterns, observed with high frequency in OS, suggest that it results from some yet-to-be-discovered central driver. How else can biology generate such an aggressive, metastatic, genetically and chromosomally unstable malignancy with virtually no apparent precursor neoplasms that are partway along a disease path toward OS? With this conundrum as a backdrop, the discovery of every new native molecule with power to impact a cell's biology is usually quickly followed by a search to see if this type of molecule contains the key to unlock OS biology.

Related: Apoptosis Signal Transduction

Mortus JR, Zhang Y, Hughes DP
Developmental pathways hijacked by osteosarcoma.
Adv Exp Med Biol. 2014; 804:93-118 [PubMed] Related Publications
Cancer of any type often can be described by an arrest, alteration or disruption in the normal development of a tissue or organ, and understanding of the normal counterpart's development can aid in understanding the malignant state. This is certainly true for osteosarcoma and the normal developmental pathways that guide osteoblast development that are changed in the genesis of osteogenic sarcoma. A carefully regulated crescendo-decrescendo expression of RUNX2 accompanies the transition from mesenchymal stem cell to immature osteoblast to mature osteoblast. This pivotal role is controlled by several pathways, including bone morphogenic protein (BMP), Wnt/β-catenin, fibroblast growth factor (FGF), and protein kinase C (PKC). The HIPPO pathway and its downstream target YAP help to regulate proliferation of immature osteoblasts and their maturation into non-proliferating mature osteoblasts. This pathway also helps regulate expression of the mature osteoblast protein osteocalcin. YAP also regulates expression of MT1-MMP, a membrane-bound matrix metalloprotease responsible for remodeling the extracellular matrix surrounding the osteoblasts. YAP, in turn, can be regulated by the ERBB family protein Her-4. Osteosarcoma may be thought of as a cell held at the immature osteoblast stage, retaining some of the characteristics of that developmental stage. Disruptions of several of these pathways have been described in osteosarcoma, including BMP, Wnt/b-catenin, RUNX2, HIPPO/YAP, and Her-4. Further, PKC can be activated by several receptor tyrosine kinases implicated in osteosarcoma, including the ERBB family (EGFR, Her-2 and Her-4 in osteosarcoma), IGF1R, FGF, and others. Understanding these functions may aid in the understanding the mechanisms underpinning clinical observations in osteosarcoma, including both the lytic and blastic phenotypes of tumors, the invasiveness of the disease, and the tendency for treated tumors to ossify rather than shrink. Through a better understanding of the relationship between normal osteoblast development and osteosarcoma, we may gain insights into novel therapeutic avenues and improved outcomes.

Related: Osteosarcoma Signal Transduction

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