Risk-Based Therapy for Localized Osteosarcoma

Venkatramani, Rajkumar; Murray, Jeffrey C.; Helman, Lee J.; Meyer, William H.; Hicks, M. John; Krance, Robert; Lau, Ching C.; Jo, Eunji; Chintagumpala, Murali

doi:10.1002/pbc.25808

Cited by 12 publications

(15 citation statements)

References 27 publications

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“…Surgery remains the primary treatment option for patients with osteosarcoma; however, the incidence of relapse for these patients is high (1). For patients with advanced stage osteosarcoma who have missed the opportunity for surgical therapy, comprehensive treatments, including radiotherapy, chemotherapy and biological agents, have become the main option for therapy (2,3). Therefore, it is important to improve understating of the mechanisms underlying the occurrence, progression, invasion and metastasis of osteosarcoma to provide better treatments for this disease.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of miRNA‑21 attenuates the proliferation and metastasis of human osteosarcoma by upregulating PTEN

Miu

et al. 2017

Exp Ther Med

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Abstract. The present study aimed to investigate the expression of micro (mi)RNA-21 in osteosarcoma cells, and its role in inhibiting the invasion and metastasis of osteosarcoma. Human osteosarcoma MG-63 cells and osteoblast hFOB1.19 cells were used to compare the expression of miRNA-21 using reverse transcription-quantitative polymerase chain reaction analysis. A miRNA-21 mimic or inhibitor were transfected into the MG-63 cells to upregulate and downregulate the expression of miRNA-21, respectively. The present study investigated the proliferation and invasion of transfected MG-63 cells using MTT and Transwell assays. Western blot analyses were used to investigate the regulation of important proteins in the phosphatase and tensin homolog/phosphoinositide 3-kinase/RAC-α serine/threonine-protein kinase (PTEN/PI3K/AKT) signaling pathway. Compared with hFOB1.19 cells, miRNA-21 expression was significantly upregulated in the MG-63 cells (P<0.01), which lead to increased proliferation. Downregulating miRNA-21 expression reduced the proliferation of MG-63 cells compared with hFOB1.19 cells. Invasion assays and western blot analyses revealed that the overexpression of miRNA-21 significantly enhanced the invasion ability of MG-63 cells and the expression of phosphorylated (p-)AKT, while downregulation of miRNA-21 expression reduced the protein level of AKT and p-AKT. In the MG-63 cells, miRNA-21 upregulation significantly inhibited the protein level of PTEN, resulting in significantly increased AKT and PI3K protein levels (P<0.01). In conclusion, the results of the present study indicate that the expression of miRNA-21, PI3K and AKT is increased in the osteosarcoma cell line MG-63, which results in reduced expression of PTEN and increased expression of proteins in the PI3K/AKT signaling pathway, and thus increases the aggressiveness of osteosarcoma cells.

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Section: Introductionmentioning

confidence: 99%

Inhibition of miRNA‑21 attenuates the proliferation and metastasis of human osteosarcoma by upregulating PTEN

Miu

et al. 2017

Exp Ther Med

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“…Anyone arguing that the alkylator doses used in EURAMOS-1 were not sufficient and that high-dose chemotherapy (HDCT) with autologous blood stem cell transplant (ASCT) was a better idea should be duly cautioned by results from recent uncontrolled prospective trials: in an American study, 18 patients with newly diagnosed localized high-grade osteosarcoma and poor histologic response received HDCT/ASCT with melphalan and cyclophosphamide; 5-year EFS and overall survival were 28% and 48%, respectively 57 . A Scandinavian–Italian study investigating postoperative high-dose carboplatin/etoposide with ASCT involved 71 patients with primary metastatic or axial osteosarcoma, of whom 29 received two and 10 one course of HDCT; 5-year EFS and overall survival were 27% and 31%, respectively.…”

Section: Advances In Systemic Treatmentmentioning

confidence: 99%

Advances in the management of osteosarcoma

et al. 2016

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Osteosarcoma, a bone cancer most commonly seen in adolescents and young adults, is usually a high-grade malignancy characterized by a very high risk for the development of pulmonary metastases. High-grade osteosarcomas are usually treated by preoperative and postoperative chemotherapy and surgery, with a very limited number of active agents available. Rarer lower-grade variants such as parosteal and periosteal osteosarcoma or low-grade central osteosarcoma are treated by surgery only. Imaging to search for possible metastases focuses on the lung. Computed tomography is the most sensitive method but cannot reliably distinguish small metastases from benign lesions. Advances of local imaging and surgical reconstruction now allow the use of limb-salvage in an ever-increasing proportion of patients. While still troubled by complications, non-invasive endoprosthesis-lengthening mechanisms have led to an increased uptake of limb-salvage, even for young, skeletally immature patients. Radiotherapy is employed when osteosarcomas cannot be removed with clear margins, but very high doses are required, and both proton and carbon-ion radiotherapy are under investigation. Unfortunately, the past 30 years have witnessed few, if any, survival improvements. Novel agents have not led to universally accepted changes of treatment standards. In patients with operable high-grade osteosarcomas, the extent of histological response to preoperative chemotherapy is a significant predictive factor for both local and systemic control. Attempts to improve prognosis by adapting postoperative treatment to response, recently tested in a randomized, prospective setting by the European and American Osteosarcoma Study Group, have not been proven to be beneficial. Many agree that only increased knowledge about osteosarcoma biology will lead to novel, effective treatment approaches and will be able to move the field forward.

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“…YUH-FENG TSAI 1,2 , CHING-WEN HUANG 1 , JO-HUA CHIANG 3 , FUU-JEN TSAI 4,5 , YUAN-MAN HSU 6 , CHI-CHENG LU 7 , CHEN-YU HSIAO 1 and JAI-SING YANG 8 proteins elicits ER-specific pathway aggregating in ER by excessive protein traffic (12). The hallmarks of ER stress are known to stimulate the protein level of growth arrest-and DNA damage-inducible gene 153 (GADD153), glucose-regulated protein 78 (GRP78), GRP94 and activating transcription factor 4 (ATF-4), which can induce intracellular Ca 2+ level to activate calpain and caspase-12 and/or caspase-4 molecules (13,14).…”

Section: Gadolinium Chloride Elicits Apoptosis In Human Osteosarcoma mentioning

confidence: 99%

“…Currently, there is still a limited role in radiotherapy which should be reserved for inoperable situations. Doxorubicin, cisplatin, ifosfamide and high-dose methotrexate with leucovorin rescue are recognized as the most effective agents against osteosarcoma, but the ideal combination remains to be defined and needs to further well investigated (5). Targeting apoptosis (programmed cell death type I) is a promising approach in the fight against osteosarcoma (6).…”

Section: Introductionmentioning

confidence: 99%

Gadolinium chloride elicits apoptosis in human osteosarcoma U-2 OS cells through extrinsic signaling, intrinsic pathway and endoplasmic reticulum stress

Tsai¹,

Huang²,

Chiang³

et al. 2016

Oncology Reports

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Gadolinium (Gd) compounds are important as magnetic resonance imaging (MRI) contrast agents, and are potential anticancer agents. However, no report has shown the effect of gadolinium chloride (GdCl3) on osteosarcoma in vitro. The present study investigated the apoptotic mechanism of GdCl3 on human osteosarcoma U-2 OS cells. Our results indicated that GdCl3 significantly reduced cell viability of U-2 OS cells in a concentration-dependent manner. GdCl3 led to apoptotic cell shrinkage and DNA fragmentation in U-2 OS cells as revealed by morphologic changes and TUNEL staining. Colorimetric assay analyses also showed that activities of caspase-3, caspase-8, caspase-9 and caspase-4 occurred in GdCl3-treated U-2 OS cells. Pretreatment of cells with pan-caspase inhibitor (Z-VAD-FMK) and specific inhibitors of caspase-3/-8/-9 significantly reduced cell death caused by GdCl3. The increase of cytoplasmic Ca2+ level, ROS production and the decrease of mitochondria membrane potential (ΔΨm) were observed by flow cytometric analysis in U-2 OS cells after GdCl3 exposure. Western blot analyses demonstrated that the levels of Fas, FasL, cytochrome c, Apaf-1, GADD153 and GRP78 were upregulated in GdCl3-treated U-2 OS cells. In conclusion, death receptor, mitochondria-dependent and endoplasmic reticulum (ER) stress pathways contribute to GdCl3-induced apoptosis in U-2 OS cells. GdCl3 might have potential to be used in treatment of osteosarcoma patients.

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Risk-Based Therapy for Localized Osteosarcoma

Abstract: Postoperative alkylator intensification with high-dose cyclophosphamide and melphalan in patients with localized osteosarcoma with poor histological response failed to improve survival.

Cited by 12 publications

References 27 publications

Inhibition of miRNA‑21 attenuates the proliferation and metastasis of human osteosarcoma by upregulating PTEN

Inhibition of miRNA‑21 attenuates the proliferation and metastasis of human osteosarcoma by upregulating PTEN

Advances in the management of osteosarcoma

Gadolinium chloride elicits apoptosis in human osteosarcoma U-2 OS cells through extrinsic signaling, intrinsic pathway and endoplasmic reticulum stress

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