Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is surgery combined with chemotherapy, but the treatment outcomes are typically unsatisfactory. High rates of metastasis and post-treatment recurrence rates are major challenges in the treatment of OS. This underlines the need for studying the in-depth characterization of the pathogenetic mechanisms of OS and development of more effective therapeutic modalities. Previous studies have demonstrated the important role of the bone microenvironment and the regulation of signaling pathways in the occurrence and development of OS. In this review, we discussed the available evidence pertaining to the mechanisms of OS development and identified therapeutic targets for OS. We also summarized the available treatment modalities for OS and identified future priorities for therapeutics research.
Child ; Adolescent ; Humans ; Bone Neoplasms/drug therapy* ; Signal Transduction ; Bone and Bones/metabolism* ; Treatment Outcome ; Osteosarcoma/drug therapy* ; Tumor Microenvironment

Objective To explore the cell subsets and characteristics related to the prognosis of osteosarcoma by analyzing the cellular composition of tumor tissue samples from different osteosarcoma patients.Methods The single-cell sequencing data and bulk sequencing data of different osteosarcoma patients were downloaded.We extracted the information of cell samples for dimensionality reduction,annotation,and cell function analysis,so as to identify the cell subsets and clarify the cell characteristics related to the prognosis of osteosarcoma.The development trajectory of macrophages with prognostic significance was analyzed,and the prognostic model of osteosarcoma was established based on the differentially expressed genes of macrophage differentiation.Results The cellular composition presented heterogeneity in the patients with osteosarcoma.The infiltration of mononuclear phagocytes in osteosarcoma had prognostic significance(P=0.003).Four macrophage subsets were associated with prognosis,and their signature transcription factors included RUNX3(+),ETS1(+),HOXD11(+),ZNF281(+),and PRRX1(+).Prog_Macro2 and Prog_Macro4 were located at the end of the developmental trajectory,and the prognostic ability of macrophage subsets increased with the progression of osteosarcoma.The prognostic model established based on the differentially expressed genes involved in macrophage differentiation can distinguish the survival rate of osteosarcoma patients with different risks(P<0.001).Conclusion Macrophage subsets are closely related to the prognosis of osteosarcoma and can be used as the key target cells for the immunotherapy of osteosarcoma.
Humans ; Prognosis ; Osteosarcoma/genetics* ; Immunotherapy ; Macrophages ; Transcription Factors ; Bone Neoplasms/genetics* ; Homeodomain Proteins ; Repressor Proteins

OBJECTIVE: To investigate the long-term effectiveness of uncemented allograft-prosthesis composite (APC) for reconstruction of bone defects after proximal femur tumor resection. METHODS: Between June 2007 and March 2014, 21 patients who underwent uncemented APC reconstruction of proximal femur after tumor resection were retrospectively evaluated. There were 9 males and 12 females with an average age of 33.2 years (range, 19-54 years). There were 9 cases of giant cell tumor of bone, 5 cases of osteosarcoma, 4 cases of osteoblastic osteosarcoma, 2 cases of chondrosarcoma, and 1 case of undifferentiated pleomorphic sarcoma. Thirteen cases of benign bone tumors were all classified as stage 3 by Enneking staging; and 8 cases of malignant bone tumors were classified as grade ⅡB in 7 cases and grade ⅡA in 1 case according to the American Joint Committee on Cancer (AJCC) staging system. Among them, 7 patients underwent reoperation after recurrence, and the rest were primary operations; 8 patients presented with pathological fractures. The preoperative Harris hip score (HHS) and American Musculoskeletal Tumor Society (MSTS) score was 40 (30, 49) and 9.1±3.5, respectively. The length of osteotomy was 80-154 mm, with an average of 110 mm. At 1 year after operation and last follow-up, HHS and MSTS scores were utilized to evaluate the function of hip joint; the gluteus medius strength score was used to evaluation of the hip abduction function. Image examinations were taken at 1, 3, 6, 9, and 12 months after operation and every year thereafter to assess the union of allograft-host bone interfaces. Intra- and post-operative complications were also recorded. RESULTS: All patients were followed up 84-163 months (mean, 123.5 months). At 1 year after operation and last follow-up, the HHS and MSTS scores significantly improved when compared with the preoperative scores ( P<0.05). However, there was no significant difference in the HHS score, MSTS score, and gluteus medius strength score between the two time points after operation ( P>0.05). Image examination showed that all allograft-host bone interfaces achieved union after 5-10 months (mean, 7.6 months). At last follow-up, all patients had bone resorption, including 11 severe cases, 4 moderate cases, and 6 mild cases; the bone resorption sites included Gruen 1, 2, and 7 regions. Complications included 10 fractures and 1 prosthetic fracture. Local recurrence occurred in 3 patients and pulmonary metastasis in 3 patients. CONCLUSION Uncemented APC is a reliable method for the reconstruction of bone defects after proximal femur tumor resection. It has the good long-term effectiveness and possesses obvious advantages in the union at the bone-bone surface.
Adult ; Female ; Humans ; Male ; Allografts/pathology* ; Bone Neoplasms/surgery* ; Bone Resorption/pathology* ; Bone Transplantation/methods* ; Femur/surgery* ; Osteosarcoma/pathology* ; Prostheses and Implants ; Retrospective Studies ; Treatment Outcome ; Young Adult ; Middle Aged

OBJECTIVE: To explore the effect of miR-143 regulating matrix metalloproteinase(MMP)-13 expression on migration and invasion of osteosarcoma cells. METHODS: The mouse osteosarcoma cell line 143B cells were cultured in 96-well plates, and blank group, negative group, positive group, and intervention group were set up. Then, the blank group did no treatment 50 μg miR-143 mimic was added to positive group, negative group added equal mimic NC (control sequence of miR-143 mimic), the intervention group was added 50 μg miR-143 mimic and 10 μg MMP-13 protein, all groups continued to culture for 3 to 6 hours, and finally the serum was aspirated to treat for half an hour. The protein expressions of miR-143 and MMP-13 in each group were measured by fluorescence quantitative PCR experiment and Western blot experiment, respectively, and the invasion and migration abilities of cells were measured by Transwell and scratch experiments. RESULTS: The expression of MMP-13 protein in the positive group and the intervention group was significantly lower than that in the blank group, and the positive group was lower than the intervention group (P<0.05);The mean numbers of invasive cells in blank group, negative group, positive group and intervention group were (1 000.01±44.77), (959.25±46.32), (245.04±4.33), (634.06±33.78) cells/field, respectively;the scratch healing rate of the positive group and the intervention group was significantly lower than that of the blank group, and the positive group was lower than the intervention group (P<0.05). CONCLUSION MMP-13 is a target of miR-143, which can reduce the migration and invasion ability of osteosarcoma cells by inhibiting the expression of MMP-13.
Osteosarcoma/pathology* ; MicroRNAs/genetics* ; Matrix Metalloproteinase 13/genetics* ; Neoplasm Invasiveness ; Animals ; Mice ; Cell Line, Tumor ; Cell Movement

Objective: To investigate the distribution and characteristics of gene mutations in osteosarcoma, and to analyze the frequency and types of detectable mutations, and to identify potential targets for individualized treatment of osteosarcoma. Methods: The fresh tissue or paraffin-embedded tissue samples of 64 cases of osteosarcoma that were surgically resected or biopsied and then subject to next generation sequencing, were collected from Beijing Jishuitan Hospital, China from November 2018 to December 2021. The tumor DNA was extracted to detect the somatic and germline mutations using targeted sequencing technology. Results: Among the 64 patients, 41 were males and 23 were females. The patient age ranged from 6 to 65 years with a median age of 17 years, including 36 children (under 18 years old) and 28 adults. There were 52 cases of conventional osteosarcoma, 3 cases of telangiectatic osteosarcoma, 7 cases of secondary osteosarcoma, and 2 cases of parosteosarcoma. The detection rate of gene mutations was overall 84.4% (54/64). There were 324 variations in 180 mutated genes, including 125 genes with copy number variations, 109 single nucleotide variants, 83 insertions or deletions, and 7 gene fusions. The most common mutated genes were TP53, VEGFA, CCND3, ATRX, MYC, RB1, PTEN, GLI1, CDK4 and PTPRD. Among them, TP53 had the highest mutation rate (21/64, 32.8%), single nucleotide variant was the main mutation type (14/23, 60.9%), and 2 cases carried the TP53 germline mutation. VEGFA and CCND3 showed copy number amplification simultaneously in 7 cases. Conclusions: The high-frequency mutation of TP53 suggests that it plays an important role in the pathogenesis and development of osteosarcoma. VEGFA, CCND3 and ATRX are mutated genes in osteosarcoma and worthy of further studies. Combination of pathologic diagnosis and next generation sequencing with clinical practice can guide individualized treatment for patients with refractory, recurrent and metastatic osteosarcoma.
Adult ; Male ; Child ; Female ; Humans ; Adolescent ; Young Adult ; Middle Aged ; Aged ; DNA Copy Number Variations ; Osteosarcoma/pathology* ; Mutation ; DNA, Neoplasm ; High-Throughput Nucleotide Sequencing ; Bone Neoplasms/pathology* ; Nucleotides

Humans ; MicroRNAs/genetics* ; Cell Line, Tumor ; Osteosarcoma/pathology* ; Neoplasm Invasiveness ; Cell Proliferation ; Bone Neoplasms/pathology* ; Cell Movement ; Neoplasm Metastasis

OBJECTIVE: To investigate the inhibitory effect of miR-125b-5p on proliferation and migration of osteosarcoma and the role of RAB3D in mediating this effect. METHODS: The expression level of miR-125b-5p was detected by qRT-PCR in a normal bone cell line (hFOB1.19) and in two osteosarcoma OS cell lines (MG63 and HOS). A miR-125b-5p mimic or inhibitor was transfected in the osteosarcoma cell lines via liposome and the changes in cell proliferation and migration were detected with EDU and Transwell experiments. Bioinformatic analysis was conducted for predicting the target gene of miR-125b-5p, and the expression level of RAB3D in hFOB1.19, MG63, and HOS cells was detected by Western blotting. In the two osteosarcoma cell lines transfected with miR-125b-5p mimic or inhibitor, the expression levels of RAB3D mRNA and protein in osteosarcoma cells were examined with qRT-PCR and Western blotting. The effects of RAB3D overexpression, RAB3D knockdown, or overexpression of both miR-125b-5p and RAB3D on the proliferation and migration of cells were assessed using EDU and Transwell experiments. RESULTS: The two osteosarcoma cell lines had significantly lower expression levels of miR-125b-5p (P < 0.05). Bioinformatic analysis predicted that RAB3D was a possible target gene regulated by miR-125b-5p. In osteosarcoma cells, overexpression of miR-125b-5p significantly lowered the expression of RAB3D protein (P < 0.05); inhibiting miR-125b-5p expression significantly decreased RAB3D expression only at the protein level (P < 0.05) without obviously affecting its mRNA level. Modulation of miR-125b-5p and RAB3D levels produced opposite effects on proliferation and migration of osteosarcoma cells, and in cells with overexpression of both miR-125b-5p and RAB3D, the effect of RAB3D on cell proliferation and migration was blocked by miR-125b-5p overexpression (P < 0.05). CONCLUSION Overexpression of miR-125b-5p inhibits the proliferation and migration of osteosarcoma cells by regulating the expression of RAB3D at the post-transcriptional level.
Humans ; Bone Neoplasms/genetics* ; Cell Proliferation ; MicroRNAs/genetics* ; Osteosarcoma/genetics* ; rab3 GTP-Binding Proteins/genetics* ; RNA, Messenger

OBJECTIVE: To investigate the prognostic value and mechanism of long non-coding RNA DLEU1(LncRNA DLEU1) in osteosarcoma. METHODS: The tissue samples and clinical data of 86 patients with osteosarcoma treated by orthopaedic surgery in our hospital from January 2012 to December 2014 were retrospectively collected. The expression of LncRNA DLEU1 in pathological tissues was detected by qRT-PCR, then the patients were divided into high and low expression of LncRNA DLEU1 groups. Osteosarcoma cell line HOS was divided into two groups, down-regulated expression group (si-DLEU1 group) and negative control group (si-NC group). LncRNA DLEU1 siRNA and negative control sequence were transfected by Lipofectamine 3000. Chi-square test was used to analyze the relationship between the expression of LncRNA DLEU1 and the clinicopathological factors of osteosarcoma. Kaplan-Meier method was used to compare the difference of the overall survival rate of osteosarcoma patients between the high and low expression groups of LncRNA DLEU1. The risk factors affecting the overall survival rate of osteosarcoma were analyzed by single factor and multifactor analysis. The number of invasive cells in the two groups was determined and compared by Transwell assay. RESULTS: The expression of LncRNA DLEU1 in osteosarcoma tissue was higher than that in adjacent tissues (P<0.001). The expression of LncRNA DLEU1 in human osteosarcoma cell lines (MG-63, U-2 OS, and HOS) was significantly higher than that in human osteoblast line hFOB 1.19 (P<0.001). The expression of LncRNA DLEU1 was significantly correlated with Enneking stage (P<0.001), distant metastasis (P=0.016), and histological grade (P=0.028). The 1-year overall survival rate of the LncRNA DLEU1 high expression group was significantly higher than that of the low expression group (90.7% vs 60.5%, P<0.001). The 5-year overall survival rate of the LncRNA DLEU1 high expression group was significantly higher than that of the low expression group (32.6% vs 11.6%, P<0.001). Univariate analysis showed that Enneking stage (P<0.001), tumor size (P=0.043), distant metastasis (P<0.001), histological grade (P<0.001), and expression of LncRNA DLEU1 (P<0.001) were risk factors for overall survival of osteosarcoma patients. Multivariate analysis showed that high expression of LncRNA DLEU1 [HR=1.948, 95% CI(1.141, 3.641), P=0.012] and distant metastasis[HR=4.108, 95% CI(2.169, 7.780), P<0.001] were independent risk factors for overall survival of osteosarcoma patients. The number of invasive cells in si-DLEU1 group was significantly lesser than that in si-NC group(139±13 vs 357±31, P<0.001). CONCLUSION High expression of LncRNA DLEU1 is a molecular marker affecting the prognosis of osteosarcoma patients. Downregulation of LncRNA DLEU1 can inhibit the invasion of osteosarcoma cells.
Humans ; Prognosis ; RNA, Long Noncoding/metabolism* ; Retrospective Studies ; Cell Proliferation/genetics* ; Cell Line, Tumor ; Osteosarcoma/genetics* ; Bone Neoplasms/pathology*

Humans ; Solitary Fibrous Tumors/pathology* ; Osteosarcoma/pathology* ; Fibrosarcoma ; Bone Neoplasms/surgery*

Objective: To investigate the clinical, imaging, histological, and molecular features and the differential diagnosis of radiation-associated sarcomas of bone and soft tissue. Methods: Forty-six cases of radiation-associated sarcomas of the bone and soft tissue in Beijing Jishuitan Hospital from January 2010 to January 2022 were retrospectively analyzed; and the imaging, histological features and immunophenotype were examined. Results: There were 33 females and 13 males, aged from 18 to 74 years, with a mean of 52 years. The most common site of radiation-associated sarcomas were the limbs and spine (15 cases), followed by the chest (9 cases). The primary diseases included epithelial tumors (15 breast cancer, 6 cervical cancer, and 5 bowel cancer), hematolymphoid tumors, bone and soft tissue tumors and infectious lesions. The latent period of radiation-associated sarcomas ranged from 2-22 years, with an average of 11.6 years. Histopathologically, the morphology was divergent from the primary tumor. The most common malignant tumor type was undifferentiated sarcoma (22 cases), followed by osteosarcoma (16 cases). The immunophenotype of radiation-related sarcoma was almost the same as the corresponding soft tissue sarcoma. Conclusions: Radiation-induced sarcoma has a wide range of primary tumor types and its imaging, morphology and immunohistochemical features are similar to those of the primary sarcoma of bone and soft tissue. Clinical correlation is often recommended for the differential diagnosis.
Male ; Female ; Humans ; Retrospective Studies ; Sarcoma/pathology* ; Osteosarcoma/diagnostic imaging* ; Soft Tissue Neoplasms/pathology* ; Bone Neoplasms/pathology*