Metastasis In Osteosarcoma Patients Research Articles

Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells.

Programmed cell death ligand 1 (PD-L1) is a transmembrane protein that is expressed on tumor cells that suppresses the T cell-mediated immune response. Therapies targeting the PD-L1 pathway promote anti-tumor immunity and have shown promising results in some types of cancers. However, the functional and therapeutic roles of PD-L1 in osteosarcoma remain largely unknown. In this study, we found that PD-L1 protein was expressed in osteosarcoma cell lines and tissue microarray of patient tumors. Tissue microarray immunohistochemistry analysis showed that the overall and five-year survival rates of patients with high levels of PD-L1 expression were significantly shorter than patients with low levels. High levels of PD-L1 expression were also associated with metastasis in osteosarcoma patients. Furthermore, we applied the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system to target PD-L1 gene at the DNA level in osteosarcoma cell lines. We found that the expression of PD-L1 could be efficiently disrupted by CRISPR/Cas9 system and PD-L1 knockdown increased drug sensitivities for doxorubicin and paclitaxel. These results suggest that PD-L1 is an independent prognostic factor in osteosarcoma and that PD-L1 knockout by CRISPR/Cas9 may be a therapeutic approach for the treatment of osteosarcoma.

PAI‐1, a target gene of miR‐143, regulates invasion and metastasis by upregulating MMP‐13 expression of human osteosarcoma

Despite recent improvements in the therapy for osteosarcoma, 30–40% of osteosarcoma patients die of this disease, mainly due to its lung metastasis. We have previously reported that intravenous injection of miR‐143 significantly suppresses lung metastasis of human osteosarcoma cells (143B) in a mouse model. In this study, we examined the biological role and mechanism of miR‐143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor‐1 (PAI‐1) as a direct target gene of miR‐143. To determine the role of PAI‐1 in human osteosarcoma cells, siRNA was transfected into 143B cells for knockdown of PAI‐1 expression. An in vitro study showed that downregulation of PAI‐1 suppressed cell invasion activity, but not proliferation. Moreover, injection of PAI‐1 siRNA into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control siRNA‐injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of PAI‐1 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase‐13 (MMP‐13), which is also a target gene of miR‐143 and a proteolytic enzyme that regulates tumor‐induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR‐143 expressing cases showed poor expression of PAI‐1 in the primary tumor cells. All such cases belonged to the lung metastasis‐negative group. Moreover, the frequency of lung metastasis‐positive cases was significantly higher in PAI‐1 and MMP‐13 double‐positive cases than in PAI‐1 or MMP‐13 single‐positive or double‐negative cases (P < 0.05). These results indicated that PAI‐1, a target gene of miR‐143, regulates invasion and lung metastasis via enhancement of MMP‐13 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients.

Interleukin 10 gene -1082A/G polymorphism is associated with osteosarcoma risk and poor outcomes in the Chinese population.

Interleukin-10 (IL-10) is a multifunctional cytokine that participates in the development and progression of various malignant tumors. However, data regarding the role of IL-10 polymorphisms in osteosarcoma development are not available. A case-control study was conducted in 260 patients with osteosarcoma and 260 healthy controls to investigate the possible association between IL-10 polymorphisms and the risk of osteosarcoma. Our results indicate the IL-10 -1082A/G (rs1800896) polymorphism is significantly associated with an increased risk of osteosarcoma in all genetic models (AG vs. AA, odds ratio (OR) = 1.56; 95% confidence interval (CI) = 1.28-2.32, P = 0.017; GG vs. AA, OR = 1.62, 95% CI 1.24-2.61, P = 0.013; AG + GG vs. CC, OR = 1.76, 95% CI = 1.31-3.01, P = 0.019). However, the genotype and allele frequencies of IL-10 -819C/T (rs1800871) and -592A/C (rs1800872) polymorphisms in osteosarcoma patients did not significantly differ from controls. Further analyses revealed that the IL-10 -1082A/G (rs1800896) genotypes were associated with advanced tumor stages and metastasis in osteosarcoma patients. Additionally, a statistically significant association between the IL-10 -1082A/G (rs1800896) genotype and poor survival in osteosarcoma patients was observed. Our results demonstrate that the IL-10 -1082A/G (rs1800896) genotype is associated with an increased susceptibility and worse outcome for osteosarcoma patients in the Chinese Han population.

The evolution of the role of surgery in the management of breast cancer lung metastasis.

Breast cancer is the second leading cause of cancer death among women in the United States. Patients with metastatic disease have a median survival of 12 to 24 months and most present with disseminated disease; however, some present with isolated pulmonary metastases which may benefit from surgical resection. Although the initial experience with resection of pulmonary metastases in the late 19th and early 20th centuries produced some encouraging results, patient selection criteria for resection were strict until the mid-1960's when a significant improvement in survival resulted from aggressive management of pulmonary metastasis in osteosarcoma patients. The application of this approach to breast cancer patients similarly produced encouraging results, with five year survival rates in select patients ranging from 36-54%, but this was not without controversy. In this review, we discuss the evaluation of the breast cancer patient with a pulmonary nodule, the historical evolution of the role of surgery in the management of pulmonary metastasis, as well as the latest evidence to guide patient selection and management.

Expression of Integrin α4 in Osteosarcoma and Significance

Objective: To investigate the expression of integrin α4 in osteosarcoma and significance. Methods: Forty-six patients with osteosarcoma (Enneking I-III) were analyzed for the expression of α4 integrin subunit using immunohistochemical method. Results: Twenty-nine (63.04%) of 46 samples demonstrated positive (+-++) integrin α4 expression. Loss expression of integrin α4 was observed in the patients with advanced Enneking stage (P=0.0040) and with metastatic disease at presentation (P=0.0158). Integrin α4 expression correlated with cell differentiation, the level of malignancy and the invasive behavior of osteosarcoma. Conclusion: The loss expression of integrin α4 subunit might be a predictor indicating the invasive potential of osteosarcoma and play a role in metastasis of osteosarcoma patients.