Osteosarcoma Pathogenesis Leads the Way to New Target Treatments

Osteosarcoma (OS) is a rare condition with very poor prognosis in a metastatic setting. Basic research has enabled a better understanding of OS pathogenesis and the discovery of new potential therapeutic targets. Phase I and II clinical trials are already ongoing, with some promising results for these patients. This article reviews OS pathogenesis and new potential therapeutic targets.     

A Novel Drug Delivery System for Osteosarcoma Chemotherapy

1Introduction Osteosarcoma,35%ofhumanprimarybonecan cers,ishighlymalignantandtendstotransferandgrow permeantly.Chemotherapyisaneffectiveandbasicthera pyforosteosarcoma,buttheside effectofantineoplasticdrugslimitstheconcentrationofthemwhichinfluences thecu…     

The Bulk Osteosarcoma and Osteosarcoma Stem Cell Activity of a Necroptosis-Inducing Nickel(II)–Phenanthroline Complex

We report the anti-osteosarcoma and anti-osteosarcoma stem cell (OSC) properties of a nickel(II) complex, 1 . Complex 1 displays similar potency towards bulk osteosarcoma cells and OSCs, in the micromolar range. Notably, 1 displays similar or better OSC potency than the clinically approved platinum(II) anticancer drugs cisplatin and carboplatin in two- and three-dimensional osteosarcoma cell cultures. Mechanistic studies revealed that 1 induces osteosarcoma cell death by necroptosis, an ordered form of necrosis. The nickel(II) complex, 1 triggers necrosome-dependent mitrochondrial membrane depolarisation and propidium iodide uptake. Interestingly, 1 does not evoke necroptosis by elevating intracellular reactive oxygen species (ROS) or hyperactivation of poly ADP ribose polymerase (PARP-1). ROS elevation and PARP-1 activity are traits that have been observed for established necroptosis inducers such as shikonin, TRAIL and glutamate. Thus the necroptosis pathway evoked by 1 is distinct. To the best of our knowledge, this is the first report into the anti-osteosarcoma and anti-OSC properties of a nickel complex.     

生物可降解镁植入物——骨肿瘤患者的潜在支架

骨癌患者切除术后可能发生复发和转移.传统的金属支架可以对骨缺损部位提供力学支撑,但无法有效清除复发的肿瘤细胞.本文中,我们介绍了一种可以抑制骨肉瘤生长的生物可降解镁丝植入物.简而言之,镁丝释放镁离子激活锌指蛋白Snail1从胞浆到细胞核的转运,通过下游的miRNA-181d-5p/TIMP3和miRNA-181c-5p...     

Hyperthermia Induces Apoptosis through Endoplasmic Reticulum and Reactive Oxygen Species in Human Osteosarcoma Cells

Osteosarcoma (OS) is a relatively rare form of cancer, but OS is the most commonly diagnosed bone cancer in children and adolescents. Chemotherapy has side effects and induces drug resistance in OS. Since an effective adjuvant therapy was insufficient for treating OS, researching novel and adequate remedies is critical. Hyperthermia can induce cell death in various cancer cells, and thus, in this study, we investigated the anticancer method of hyperthermia in human OS (U-2 OS) cells. Treatment at 43 °C for 60 min induced apoptosis in human OS cell lines, but not in primary bone cells. Furthermore, hyperthermia was associated with increases of intracellular reactive oxygen species (ROS) and caspase-3 activation in U-2 OS cells. Mitochondrial dysfunction was followed by the release of cytochrome c from the mitochondria, and was accompanied by decreased anti-apoptotic Bcl-2 and Bcl-xL, and increased pro-apoptotic proteins Bak and Bax. Hyperthermia triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels, as well as increased calpain expression and activity. In addition, cells treated with calcium chelator (BAPTA-AM) blocked hyperthermia-induced cell apoptosis in U-2 OS cells. In conclusion, hyperthermia induced cell apoptosis substantially via the ROS, ER stress, mitochondria, and caspase pathways. Thus, hyperthermia may be a novel anticancer method for treating OS.     

Engineering 2D Mesoporous Silica@MXene‐Integrated 3D‐Printing Scaffolds for Combinatory Osteosarcoma Therapy and NO‐Augmented Bone Regeneration

The rising concerns of the recurrence and bone deficiency in surgical treatment of malignant bone tumors have raised an urgent need of the advance of multifunctional therapeutic platforms for efficient tumor therapy and bone regeneration. Herein, the construction of a multifunctional biomaterial system is reported by the integration of 2D Nb₂C MXene wrapped with S‐nitrosothiol (R? SNO)‐grafted mesoporous silica with 3D‐printing bioactive glass (BG) scaffolds (MBS). The near infrared (NIR)‐triggered photonic hyperthermia of MXene in the NIR‐II biowindow and precisely controlled nitric oxide (NO) release are coordinated for multitarget ablation of bone tumors to enhance localized osteosarcoma treatment. The in situ formed phosphorus and calcium components degraded from BG scaffold promote bone‐regeneration bioactivity, augmented by sufficient blood supply triggered by on‐demand NO release. The tunable NO generation plays a crucial role in sequential adjuvant tumor ablation, combinatory promotion of coupled vascularization, and bone regeneration. This study demonstrates a combinatory osteosarcoma ablation and a full osseous regeneration as enabled by the implantation of MBS. The design of multifunctional scaffolds with the specific features of controllable NO release, highly efficient photothermal conversion, and stimulatory bone regeneration provides an intriguing biomaterial platform for the diversified treatment of bone tumors.     

Convolutional Neural Network for Histopathological Osteosarcoma Image Classification

Osteosarcoma is one of the most widespread causes of bone cancer globally and has a high mortality rate. Early diagnosis may increase the chances of treatment and survival however the process is time-consuming (reliability and complexity involved to extract the hand-crafted features) and largely depends on pathologists’ experience. Convolutional Neural Network (CNN—an end-to-end model) is known to be an alternative to overcome the aforesaid problems. Therefore, this work proposes a compact CNN architecture that has been rigorously explored on a Small Osteosarcoma histology Image Dataaseet (a high-class imbalanced dataset). Though, during training, class-imbalanced data can negatively affect the performance of CNN. Therefore, an oversampling technique has been proposed to overcome the aforesaid issue and improve generalization performance. In this process, a hierarchical CNN model is designed, in which the former model is non-regularized (due to dense architecture) and the later one is regularized, specifically designed for small histopathology images. Moreover, the regularized model is integrated with CNN’s basic architecture to reduce overfitting. Experimental results demonstrate that oversampling might be an effective way to address the imbalanced class problem during training. The training and testing accuracies of the non-regularized CNN model are 98% & 78% with an imbalanced dataset and 96% & 81% with a balanced dataset, respectively. The regularized CNN model training and testing accuracies are 84% & 75% for an imbalanced dataset and 87% & 86% for a balanced dataset.     

15d-PGJ2 Promotes ROS-Dependent Activation of MAPK-Induced Early Apoptosis in Osteosarcoma Cell In Vitro and in an Ex Ovo CAM Assay

Osteosarcoma (OS) is the most common type of bone tumor, and has limited therapy options. 15-Deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) has striking anti-tumor effects in various tumors. Here, we investigated molecular mechanisms that mediate anti-tumor effects of 15d-PGJ₂ in different OS cell lines. Human U2-OS and Saos-2 cells were treated with 15d-PGJ₂ and cell survival was measured by MTT assay. Cell proliferation and motility were investigated by scratch assay, the tumorigenic capacity by colony forming assay. Intracellular ROS was estimated by H₂DCFDA. Activation of MAPKs and cytoprotective proteins was detected by immunoblotting. Apoptosis was detected by immunoblotting and Annexin V/PI staining. The ex ovo CAM model was used to study growth capability of grafted 15d-PGJ₂-treated OS cells, followed by immunohistochemistry with hematoxylin/eosin and Ki-67. 15d-PGJ₂ substantially decreased cell viability, colony formation and wound closure capability of OS cells. Non-malignant human osteoblast was less affected by 15d-PGJ₂. 15d-PGJ₂ induced rapid intracellular ROS production and time-dependent activation of MAPKs (pERK1/2, pJNK and pp38). Tempol efficiently inhibited 15d-PGJ₂-induced ERK1/2 activation, while N-acetylcystein and pyrrolidine dithiocarbamate were less effective. Early but weak activation of cytoprotective proteins was overrun by induction of apoptosis. A structural analogue, 9,10-dihydro-15d-PGJ₂, did not show toxic effects in OS cells. In the CAM model, we grafted OS tumors with U2-OS, Saos-2 and MG-63 cells. 15d-PGJ₂ treatment resulted in significant growth inhibition, diminished tumor tissue density, and reduced tumor cell proliferation for all cell lines. Our in vitro and CAM data suggest 15d-PGJ₂ as a promising natural compound to interfere with OS tumor growth.