Development of a Model System to Evaluate Local Recurrence in Osteosarcoma and Assessment of the Effects of Bone Morphogenetic Protein-2

Geller, David S.; Singh, Michael Y.; Zhang, Wendong; Gill, Jonathan; Roth, Michael; Kim, Mimi Y.; Xie, Xianhong; Singh, Christopher K.; Dorfman, Howard D.; Villanueva-Siles, Esperanza; Park, Amy; Piperdi, Sajida; Görlick, Richard

doi:10.1158/1078-0432.ccr-14-0986

Cited by 16 publications

(11 citation statements)

References 32 publications

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“…The exogenous application of BMP-2 to the surgical site following tumor excision does not increase the risk of local recurrence. 39 Furthermore, a recent study by Gill et al using xenografted OSA indicated that the addition of BMP-2 did not increase the risk of lung metastasis. 40 However, the major limitation of all the above studies was that the observations were mainly based on the subcutaneous model system.…”

Section: Introductionmentioning

confidence: 97%

BMP-2 inhibits lung metastasis of osteosarcoma: an early investigation using an orthotopic model

Xiong¹,

Wang²,

Wang³

et al. 2018

OTT

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BackgroundBone morphogenetic proteins (BMPs), members of the TGF-β superfamily, are known to regulate cell proliferation, differentiation, apoptosis, chemotaxis, and angiogenesis. BMPs also participate in the development of most tissues and organs in vertebrates. Recombinant human (rh) BMPs, such as rhBMP-2, rhBMP-4, and rhBMP-7, have been recently approved to augment spinal fusion and recalcitrant long-bone non-unions because of their equivalent or superior efficacy to autogenous bone graft in enhancing bony fusion. Nonetheless, the use of BMPs is contraindicated in surgery for bone tumors because of concerns that this anabolic growth factor may cause tumor proliferation. However, we have repeatedly reported that BMP-2 is effective in inducing osteogenic differentiation of a subpopulation of osteosarcoma (OSA) cells that acquire stem cell attributes and are capable of reconstituting tumor masses, which in turn suppress the malignancy of the bone tumor.Methods3×105/20 µL human OSA 143B cells were inoculated into 5–6 weeks old BABL/c nude mice to establish orthotopic OSA. X-ray device was used to monitor the developed tumors in animals. Necropsy was performed and the pathology of lung metastasis were tested by Haemotoxylin and Eosin. Moreover, bone formation induced by rhBMP-2 was investigated through micro-computed tomography. In addition, immunohistochemistry staining was used to evaluate the tumorigenicity and growth of OSA cells after rhBMP-2 treatment.ResultsIn the present study, we established an orthotopic model of OSA by inoculating 143B cells into BABL/c mice, which resulted in a tumor occurrence rate of 100%. Following the treatment with rhBMP-2, lung metastasis, which contributes to poor prognosis, was significantly restricted, indicating an additional aspect of rhBMP-2 to suppress expansion of OSA. Concurrently, our micro-computed tomography and radiographic analyses showed that rhBMP-2 reduced the invasion of tumor cells into adjacent bone tissue, which in turn helped to preserve the integrity of the affected bone tissue. Finally, the growth of Ki-67-positive cells and those cells that express high levels of aldehyde dehydrogenase (ALDHbr) was found to be inhibited in the developed tumors.ConclusionOn the basis of these results, we conclude that rhBMP-2 can impede the malignancy of OSA by reducing lung metastasis of the tumor. Induction of the tumor cells by rhBMP-2 also helps to preserve the impaired skeleton. These results imply that BMP-2 or BMP-2-mimetic drugs, if properly combined with traditional therapies, may provide a new therapeutic option for the treatment of OSA.

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Section: Introductionmentioning

confidence: 97%

BMP-2 inhibits lung metastasis of osteosarcoma: an early investigation using an orthotopic model

Xiong¹,

Wang²,

Wang³

et al. 2018

OTT

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“…The incidence of osteosarcoma in the world is approximately 3–4 per million new cases [3]. At present, the commonly used clinical treatment methods include systemic chemotherapy and local control surgery [4]. With the advancement of surgery and the introduction of neoadjuvant chemotherapy, great improvements have been made in the clinical response and long-range survival rate of osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

Differential expression and bioinformatics analysis of circRNA in osteosarcoma

Fowdur

Liu

et al. 2019

Bioscience Reports

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Aim: This research aims to investigate the expression profile of circRNA in osteosarcoma and to identify the underlying pathogenesis core genes of osteosarcoma. Methods: Illumina HiSeq was used to screen differentially expressed circRNAs between the tumour tissues and paracancerous tissues of three osteosarcoma patients. Bioinformatics analysis was used to analyse their potential functions. Five differentially expressed circRNAs were selected to detect the relative expression level in tumour and paracancerous tissues of ten osteosarcoma patients by real-time PCR. The databases such as DisGeNET and miRWalk were used to collect related genes or miRNAs. Results: A total of 259 differentially expressed circRNAs were evaluated in patients with osteosarcoma, of which 132 were up-regulated and 127 were down-regulated. Compared with that in paracancerous tissues, circ_32279 and circ_24831 were significantly down-regulated while circ_2137 and circ_20403 were significantly up-regulated in osteosarcoma tissues. The differential expression of circRNA is closely linked to biological processes and molecular functions. The difference in circRNA was mainly linked to the ‘phosphatidylinositol signalling system’ signal pathway and the ‘inositol phosphate metabolism’ signal pathway. Conclusion: The present study identified a profile of abnormal regulation of circRNA in osteosarcoma. Bioinformatics analysis indicates that the deregulated circRNAs may be related to the occurrence and development of osteosarcoma.

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“…On the other hand, Rici et al treated canine mesenchymal stem cells with BMP‐2 and then added them to cultures of canine osteosarcoma cells and their findings suggested that treatment of bone marrow cells with rhBMP‐2 may have therapeutic potential for osteosarcoma treatment . Furthermore, Park et al found that treatment with BMP‐2 combined with a MEK inhibitor inhibited the proliferation of MG‐63 osteosarcoma cells, and Geller et al reported that the application of BMP‐2 did not increase local recurrence of osteosarcoma in an orthotopic xenograft murine model …”

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confidence: 99%

Bone morphogenetic protein‐2 promotes osteosarcoma growth by promoting epithelial‐mesenchymal transition (EMT) through the Wnt/β‐catenin signaling pathway

Tian

Zhou

Chen

et al. 2019

Journal Orthopaedic Research

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The correlation between BMP-2 and osteosarcoma growth has gained increased interest in the recent years, however, there is still no consensus. In this study, we tested the effects of BMP-2 on osteosarcoma cells through both in vitro and in vivo experiments. The effect of BMP-2 on the proliferation, migration and invasion of osteosarcoma cells was tested in vitro. Subcutaneous and intratibial tumor models were used for the in vivo experiments in nude mice. The effects of BMP-2 on EMT of osteosarcoma cells and the Wnt/b-catenin signaling pathway were also tested using a variety of biochemical methods. In vitro tests did not show a significant effect of BMP-2 on tumor cell proliferation. However, BMP-2 increased the mobility of tumor cells and the invasion assay demonstrated that BMP-2 promoted invasion of osteosarcoma cells in vitro. In vivo animal study showed that BMP-2 dramatically enhanced tumor growth. We also found that BMP-2 induced EMT of osteosarcoma cells. The expression levels of Axin2 and Dkk-1 were both down regulated by BMP-2 treatment, while b-catenin, c-myc and Cyclin-D1 were all upregulated. The expression of Wnt3a and p-GSK-3b were also significantly upregulated indicating that the Wnt/b-catenin signaling pathway was activated during the EMT of osteosarcoma driven by BMP-2. From this study, we can conclude that BMP-2 significantly promotes growth of osteosarcoma cells (143B, MG63), and enhances mobility and invasiveness of tumor cells as demonstrated in vitro. The underlying mechanism might be that BMP-2 promotes EMT of osteosarcoma through the Wnt/b-catenin signaling pathway. ß

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Development of a Model System to Evaluate Local Recurrence in Osteosarcoma and Assessment of the Effects of Bone Morphogenetic Protein-2

Cited by 16 publications

References 32 publications

BMP-2 inhibits lung metastasis of osteosarcoma: an early investigation using an orthotopic model

BMP-2 inhibits lung metastasis of osteosarcoma: an early investigation using an orthotopic model

Differential expression and bioinformatics analysis of circRNA in osteosarcoma

Bone morphogenetic protein‐2 promotes osteosarcoma growth by promoting epithelial‐mesenchymal transition (EMT) through the Wnt/β‐catenin signaling pathway

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