Osteogenic Sarcoma: A 21st Century Review

Osasan, Stephen; Zhang, Mingyong; Shen, Fan; Paul, Paulose J; Persad, Sujata; Sergi, Consolato

doi:10.21873/anticanres.10982

Cited by 46 publications

(37 citation statements)

References 59 publications

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“…IGFBP proteins have known growth-inhibitory effects and inhibit proliferation by blocking insulin growth factors IGF1 and 2 to activate their receptor and stimulate proliferation 24 . The fourth member of the IGFBP gene family, IGFBP4, was previously shown to be silenced by DNA hypermethylation and associated with clonogenicity in GCTB 18 .…”

Section: Resultsmentioning

confidence: 99%

The histone variant H3.3 G34W substitution in giant cell tumor of the bone link chromatin and RNA processing

Lim

Park

Baude

et al. 2017

Sci Rep

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While transcription as regulated by histones and their post-translational modifications has been well described, the function of histone variants in this process remains poorly characterized. Potentially important insight into this process pertain to the frequently occurring mutations of H3.3, leading to G34 substitutions in childhood glioblastoma and giant cell tumor of the bone (GCTB). In this study, we have established primary cell lines from GCTB patients and used them to uncover the influence of H3.3 G34W substitutions on cellular growth behavior, gene expression, and chromatin compaction. Primary cell lines with H3.3 G34W showed increased colony formation, infiltration and proliferation, known hallmarks of tumor development. Isogenic cell lines with H3.3 G34W recapitulated the increased proliferation observed in primary cells. Transcriptomic analysis of primary cells and tumor biopsies revealed slightly more downregulated gene expression, perhaps by increased chromatin compaction. We identified components related to splicing, most prominently hnRNPs, by immunoprecipitation and mass spectrometry that specifically interact with H3.3 G34W in the isogenic cell lines. RNA-sequencing analysis and hybridization-based validations further enforced splicing aberrations. Our data uncover a role for H3.3 in RNA processing and chromatin modulation that is blocked by the G34W substitution, potentially driving the tumorigenic process in GCTB.

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Section: Resultsmentioning

confidence: 99%

The histone variant H3.3 G34W substitution in giant cell tumor of the bone link chromatin and RNA processing

Lim

Park

Baude

et al. 2017

Sci Rep

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“…2 Today, 5-y overall survival rates for patients with localized disease are up to 70-75%, but this drops to 20-30% for those with metastatic disease. 3 Whole genome sequencing of high-grade OS has confirmed that these cancers demonstrate significant chromosomal instability with high levels of somatic structural variations and copy number alterations. 4,5 In addition, cancers with higher mutational loads and tumor-specific neoantigens have been associated with a higher level of immune infiltration.…”

Section: Introductionmentioning

confidence: 99%

CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for the therapeutic stratification of osteosarcoma patients: An immunohistochemical analysis of the biopsies fromthe French OS2006 phase 3 trial

et al. 2017

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The French phase 3 trial (OS 2006) testing zoledronic acid, an osteoclast inhibitor, with chemotherapy and surgery did not improve the outcome of patients with osteosarcoma (OS). To understand this unexpected result, the presence of infiltrating immune cells was investigated in 124 pre-therapeutic biopsies of patients enrolled in the trial. The percentage of CD68/CD163 tumor-infiltrating macrophages (TAMs), CD8 lymphocytes, osteoclasts, and the PD1/PDL-1 checkpoint were assessed by immunohistochemistry. M1/M2 macrophage polarization was characterized by pSTAT1/CMAF staining. The expression of these biomarkers was correlated with clinical outcome. No statistical correlations were found with response to chemotherapy. High CD163 levels (>50% of cells per core; 43.8% of patients) were associated with CMAF nuclear expression and significantly correlated with better overall survival ( = 0.0025) and longer metastasis progression-free survival (MPFS, = 0.0315) independently of metastatic status ( = 0.002). Only a trend was observed for patients with high CD68-positive cells ( = 0.0582). CD8 staining was positive in >50% of cases with a median staining of 1%. Lower CD8 levels were associated with metastatic disease at diagnosis and the presence of CD8-positive cells significantly correlated with improved overall survival in zoledronate-treated patients ( = 0.0415). PD1/PDL-1 staining was negative in >80% of cases and was not correlated with outcome. Finally, CD163-positive TAMs and CD8 positive cells are crucial prognostic biomarkers in OS, whereas PD1/PDL-1 checkpoint plays a minor role. For the first time, we described a correlation between CD8 positive cells and survival in zoledronate-treated patients. The immunohistochemical analysis of the microenvironment in biopsies may represent a novel tool for therapeutic stratification.

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“…At present, radical surgery is still the first choice of treatment for osteosarcoma, and is accompanied by adjuvant chemotherapy at high doses (8)(9)(10). With the promotion of radical surgery and high-dose chemotherapy, the 5-year survival rate of patients with osteosarcoma has increased to approximately 70% (11).…”

Section: Introductionmentioning

confidence: 99%

miR-27a-3p promotes the malignant phenotypes of osteosarcoma by targeting ten-eleven translocation 1

Liu

et al. 2018

Int J Oncol

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Osteosarcoma has become one of the most common primary malignant tumors affecting children and adolescents. Although increasing evidence has indicated that microRNAs (miRNAs or miRs) play important roles in the development of osteosarcoma, the expression of miR‑27a‑3p and its effects on osteosarcoma are not yet fully understood. In the present study, our data demonstrated that the expression of miR‑27a‑3p in osteosarcoma cell lines was significantly higher than that in the normal human osteoblastic cell line, hFOB 1.19 cell (P<0.01). In order to explore the role of miR‑27a‑3p in the development and progression of osteosarcoma, the expression of miR‑27a‑3p was inhibited by transfection of the MG-63 cells with miR‑27a‑3p inhibitor. The results revealed that the cell proliferative ability significantly decreased (P<0.01), the number of apoptotic cells significantly increased (P<0.01) and the number of cells passing through the Transwell membrane was significantly reduced in the group transfected with the miR‑27a‑3p inhibitor (P<0.01). At the same time, the expression of E-cadherin and α-catenin was significantly upregulated (P<0.01), while the expression of vimentin was significantly downregulated in the group transfected with the miR‑27a‑3p inhibitor (P<0.01). Our results also revealed that the mRNA expression of ten-eleven translocation 1 (TET1) in the osteosarcoma cells was significantly downregulated compared with that in the hFOB 1.19 cells (P<0.01). Luciferase reporter system analysis indicated that miR‑27a‑3p recognized the TET1 3'-UTR. The protein expression of TET1 significantly increased in the group transfected with the miR‑27a‑3p inhibitor. The results from CCK-8 assay, flow cytometric assay and Transwell invasion analysis revealed that TET1 knockdown inhibited the biological effects induced by the downregulation of miR‑27a‑3p. Taken together, the findings of this study indicate that miR‑27a‑3p is upregulated, while TET1 is downregulated in human osteosarcoma cells. miR‑27a‑3p inhibition suppresses the proliferation and invasion of osteosarcoma cells, and promotes cell apoptosis via the negative regulation of TET1. miR‑27a‑3p/TET1 may thus be a potential target for the treatment of osteosarcoma.

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Osteogenic Sarcoma: A 21st Century Review

Cited by 46 publications

References 59 publications

The histone variant H3.3 G34W substitution in giant cell tumor of the bone link chromatin and RNA processing

The histone variant H3.3 G34W substitution in giant cell tumor of the bone link chromatin and RNA processing

CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for the therapeutic stratification of osteosarcoma patients: An immunohistochemical analysis of the biopsies fromthe French OS2006 phase 3 trial

miR-27a-3p promotes the malignant phenotypes of osteosarcoma by targeting ten-eleven translocation 1

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