Current treatment and novel insights regarding ROS1-targeted therapy in malignant tumors.

BACKGROUND: The proto-oncogene ROS1 encodes an intrinsic type I membrane protein of the tyrosine kinase/insulin receptor family. ROS1 facilitates the progression of various malignancies via self-mutations or rearrangements. Studies on ROS1-directed tyrosine kinase inhibitors have been conducted, and some have been approved by the FDA for clinical use. However, the adverse effects and mechanisms of resistance associated with ROS1 inhibitors remain unknown. In addition, next-generation ROS1 inhibitors, which have the advantage of treating central nervous system metastases and alleviating endogenous drug resistance, are still in the clinical trial stage. METHOD: In this study, we searched relevant articles reporting the mechanism and clinical application of ROS1 in recent years; systematically reviewed the biological mechanisms, diagnostic methods, and research progress on ROS1 inhibitors; and provided perspectives for the future of ROS1-targeted therapy. RESULTS: ROS1 is most expressed in malignant tumours. Only a few ROS1 kinase inhibitors are currently approved for use in NSCLC, the efficacy of other TKIs for NSCLC and other malignancies has not been ascertained. There is no effective standard treatment for adverse events or resistance to ROS1-targeted therapy. Next-generation TKIs appear capable of overcoming resistance and delaying central nervous system metastasis, but with a greater incidence of adverse effects. CONCLUSIONS: Further research on next-generation TKIs regarding the localization of ROS1 and its fusion partners, binding sites for targeted drugs, and coadministration with other drugs is required. The correlation between TKIs and chemotherapy or immunotherapy in clinical practice requires further study.

ARHGAP44-mediated regulation of the p53/C-myc/Cyclin D1 pathway in modulating the malignant biological behavior of osteosarcoma cells.

OBJECTIVE: Osteosarcoma is a rare primary malignant tumor of the bone characterized by poor survival rates, owing to its unclear pathogenesis. Rho GTPase-activating protein 44 (ARHGAP44), which belongs to the Rho GTPase-activating protein family, has promising applications in the targeted therapy of tumors. Therefore, this study aimed to investigate the biological function of ARHGAP44 in osteosarcoma and its possible application as a therapeutic target. METHODS: The expression level of ARHGAP44 in osteosarcoma and its relationship with tumor prognosis were detected using Gene Expression Omnibus database analysis and immunohistochemical staining of clinical specimens. The cell model of ARHGAP44 knockdown was constructed, and the effects of this gene on the malignant biological behavior of osteosarcoma cells were investigated using CCK-8, clone formation, transwell invasion, wound healing, and flow cytometry assays. Western blotting was performed to detect the expression of ARHGAP44, p53, C-myc, and Cyclin D1 in osteosarcoma. RESULTS: Biogenic analysis showed that ARHGAP44 was highly expressed in osteosarcoma. This result was associated with poor tumor prognosis and negatively correlated with the expression of the tumor suppressor gene p53. Immunohistochemistry and western blotting revealed significantly upregulated expression of ARHGAP44 in osteosarcoma tissues. Additionally, Kaplan-Meier analysis of clinical specimens suggested that ARHGAP44 was negatively correlated with tumor prognosis. CCK-8, clone formation, transwell invasion, wound healing, and flow cytometry assays showed that downregulation of ARHGAP44 expression significantly reduced the malignant biological behavior of osteosarcoma cells. Furthermore, western blotting showed that the expression level of p53 in osteosarcoma cells was significantly increased after the downregulation of ARHGAP44 expression, whereas the expression of C-myc and Cyclin D1 was significantly decreased compared with that in the control group. CONCLUSION: ARHGAP44 was highly expressed in osteosarcoma and was negatively correlated with its prognosis. The downregulation of ARHGAP44 expression reduced the malignant biological behavior of osteosarcoma cells. These findings suggest that the downregulation of ARHGAP44 expression inhibits the malignant progression of osteosarcoma by regulating the p53/C-myc/Cyclin D1 pathway, demonstrating the potential of ARHGAP44 as a therapeutic target for osteosarcoma.

[Retracted] Ursolic acid suppresses the biological function of osteosarcoma cells.

[This retracts the article DOI: 10.3892/ol.2019.10561.].

Primary sternal tumour resection and reconstruction with LARS mesh-bone cement sandwich by 3D-printing: Case reports.

Background: There are many reconstruction methods after sternal tumor resection, but the method that LARS mesh combines with bone-cement has not been reported. Case report: A 54-year-old female patient and a 55-year-old male patient admitted to our department all presented with sternum masses, but neither presented with respiratory disorders. In women with limited manubrium sternum lesions, we resected the manubrium sternum completely. In men with sternal lesions, we removed part of the sternum and part of the sternocostal joint. The patients recovered well after surgery, and there were no respiratory complications and no tumor recurrence during the 1-year follow-up respectively. Conclusion: We report two cases of sternal defect repair using LARS mesh combined with bone cement. This method is safe and stable, and can achieve satisfactory results.

A semiautomatic segmentation method framework for pelvic bone tumors based on CT-MR multimodal images.

The pelvic structure is complex and the tumor is poorly defined from the surrounding tissues. Finding the exact tumor resection margin based on the surgeon's clinical experience alone is a time-consuming and difficult task, which is a major factor leading to surgical failure. An accurate method for segmenting pelvic bone tumors is needed. In this paper, a semiautomatic segmentation method for pelvic bone tumors based on CT-MR multimodal images is presented. The method combines multiple medical prior knowledge and image segmentation algorithms. Finally, the segmentation results are visualized in three dimensions. We tested the proposed method on a collection of 10 cases (97 tumor MR images in total). The segmentation results were compared with the manual annotation of the physicians. On average, our method has an accuracy of 0.9358, a recall of 0.9278, an IOU value of 0.8697, a Dice value of 0.9280, and an AUC value of 0.9632. The average error of the 3D model was within the allowable range of the surgery. The proposed algorithm can accurately segment bone tumors in pelvic MR images regardless of tumor location, size, and other factors. It provides the possibility to assist pelvic bone tumor preservation surgery.

PROTACs: Novel tools for improving immunotherapy in cancer.

Posttranslational modifications (PTMs), such as phosphorylation, methylation, ubiquitination, and acetylation, are important in governing protein expression levels. Proteolysis targeting chimeras (PROTACs) are novel structures designed to target a protein of interest (POI) for ubiquitination and degradation, leading to the selective reduction in the expression levels of the POI. PROTACs have exhibited great promise due to their ability to target undruggable proteins, including several transcription factors. Recently, PROTACs have been characterized to improve anticancer immunotherapy via the regulation of specific proteins. In this review, we describe how the PROTACs target several molecules, including HDAC6, IDO1, EGFR, FoxM1, PD-L1, SHP2, HPK1, BCL-xL, BET proteins, NAMPT, and COX-1/2, to regulate immunotherapy in human cancers. PROTACs may provide potential treatment benefits by enhancing immunotherapy in cancer patients.

The E3 ubiquitin ligases regulate PD-1/PD-L1 protein levels in tumor microenvironment to improve immunotherapy.

The tumor microenvironment (TME) is the tumor surrounding environment, which is critical for tumor development and progression. TME is also involved in clinical intervention and treatment outcomes. Modulation of TME is useful for improving therapy strategies. PD-L1 protein on tumor cells interacts with PD-1 protein on T cells, contributing to T cell dysfunction and exhaustion, blockage of the immune response. Evidence has demonstrated that the expression of PD-1/PD-L1 is associated with clinical response to anti-PD-1/PD-L1 therapy in cancer patients. It is important to discuss the regulatory machinery how PD-1/PD-L1 protein is finely regulated in tumor cells. In recent years, studies have demonstrated that PD-1/PD-L1 expression was governed by various E3 ubiquitin ligases in TME, contributing to resistance of anti-PD-1/PD-L1 therapy in human cancers. In this review, we will discuss the role and molecular mechanisms of E3 ligases-mediated regulation of PD-1 and PD-L1 in TME. Moreover, we will describe how E3 ligases-involved PD-1/PD-L1 regulation alters anti-PD-1/PD-L1 efficacy. Altogether, targeting E3 ubiquitin ligases to control the PD-1/PD-L1 protein levels could be a potential strategy to potentiate immunotherapeutic effects in cancer patients.

Targeted therapy for osteosarcoma: a review.

BACKGROUND: Osteosarcoma is a common primary malignant tumour of the bone that usually occurs in children and adolescents. It is characterised by difficult treatment, recurrence and metastasis, and poor prognosis. Currently, the treatment of osteosarcoma is mainly based on surgery and auxiliary chemotherapy. However, for recurrent and some primary osteosarcoma cases, owing to the rapid progression of disease and chemotherapy resistance, the effects of chemotherapy are poor. With the rapid development of tumour-targeted therapy, molecular-targeted therapy for osteosarcoma has shown promise. PURPOSE: In this paper, we review the molecular mechanisms, related targets, and clinical applications of targeted osteosarcoma therapy. In doing this, we provide a summary of recent literature on the characteristics of targeted osteosarcoma therapy, the advantages of its clinical application, and development of targeted therapy in future. We aim to provide new insights into the treatment of osteosarcoma. CONCLUSION: Targeted therapy shows potential in the treatment of osteosarcoma and may offer an important means of precise and personalised treatment in the future, but drug resistance and adverse effects may limit its application.

Current status and future challenges of CAR-T cell therapy for osteosarcoma.

Osteosarcoma, the most common bone malignancy in children and adolescents, poses considerable challenges in terms of prognosis, especially for patients with metastatic or recurrent disease. While surgical intervention and adjuvant chemotherapy have improved survival rates, limitations such as impractical tumor removal or chemotherapy resistance hinder the treatment outcomes. Chimeric antigen receptor (CAR)-T cell therapy, an innovative immunotherapy approach that involves targeting tumor antigens and releasing immune factors, has shown significant advancements in the treatment of hematological malignancies. However, its application in solid tumors, including osteosarcoma, is constrained by factors such as low antigen specificity, limited persistence, and the complex tumor microenvironment. Research on osteosarcoma is ongoing, and some targets have shown promising results in pre-clinical studies. This review summarizes the current status of research on CAR-T cell therapy for osteosarcoma by compiling recent literature. It also proposes future research directions to enhance the treatment of osteosarcoma.

Case report: Resection of a massive primary sacrococcygeal mature teratoma in an adult using 3-dimensional reconstruction and mixed reality technology.

Introduction: Teratomas are rare neoplasms that arise from pluripotent germ cells. Sacrococcygeal teratomas are often diagnosed in infants but are rare in adults; a mature teratoma can contain hair, teeth, bony tissue, and other mature tissue types. Herein, we report for the first time a patient with a teratoma containing intact bones that formed a pseudoarthrosis. Case report: A 49-year-old woman was admitted to hospital after a massive life-long sciatic tumor had begun to grow larger over the past year. A 16 cm × 25 cm solid mass with a clear boundary was palpable in the sacrococcygeal region. Radiography, computed tomography, and magnetic resonance imaging indicated a sacrococcygeal teratoma, although blood alpha-fetoprotein levels were normal. The teratoma was completely excised using 3-dimensional reconstruction mixed reality (MR) technology with no notable complications. Postoperative pathological examination of the excised lesion confirmed a mature teratoma. Interestingly, two intact irregular bones that formed a pseudoarthrosis were isolated; one was 11 cm and the other 6 cm. The patient is currently healthy and has experienced no recurrences. Conclusion: Sacrococcygeal teratomas are rare, especially in adults, and often comprised lots of components, such as fat, bony tissue. However, it's first reported that formation of pseudoarthrosis in this case so far. It is difficult for surgeons to achieve complete excision without complications owing to the complex anatomic structure of the sacrum. The 3-dimensional reconstruction and mixed reality (MR) technology based on computed tomography can provide spatial visualization, which allows surgeons to examine the teratoma at different angles preoperatively. Combining 3-dimensional reconstruction and mixed reality (MR) technology in this case facilitated complete resection and prevented recurrence.

Long Intergenic Noncoding RNA00265 Enhances Cell Viability and Metastasis via Targeting miR-485-5p/USP22 Axis in Osteosarcoma.

Osteosarcoma is one of the bone malignancies in children and adolescents. Long noncoding RNAs (lncRNAs) have been demonstrated to participate in osteosarcoma development and progression. Linc00265 has been shown to involve in osteosarcoma oncogenesis; however, the underlying mechanism is largely unclear. In this study, we investigated the function of linc00265 in osteosarcoma cells, including cell viability, migration and invasion. Moreover, we elucidated mechanistically the involvement of linc00265 in osteosarcoma. We found that linc00265 overexpression promoted viability, migration and invasion of osteosarcoma cells. Notably, linc00265 sponged miR-485-5p and increased the expression of USP22, one target of miR-485-5p, in osteosarcoma cells. Strikingly, linc00265 exerted its oncogenic function via regulating miR-485-5p and USP22 in osteosarcoma. Taken together, targeting linc00265 is a promising approach for treating osteosarcoma patients.

Targeting matrix metalloproteinases by E3 ubiquitin ligases as a way to regulate the tumor microenvironment for cancer therapy.

The tumor microenvironment (TME) plays an important role in neoplastic development. Matrix metalloproteinases (MMPs) are critically involved in tumorigenesis by modulation of the TME and degradation of the extracellular matrix (ECM) in a large variety of malignancies. Evidence has revealed that dysregulated MMPs can lead to ECM damage, the promotion of cell migration and tumor metastasis. The expression and activities of MMPs can be tightly regulated by TIMPs, multiple signaling pathways and noncoding RNAs. MMPs are also finely controlled by E3 ubiquitin ligases. The current review focuses on the molecular mechanism by which MMPs are governed by E3 ubiquitin ligases in carcinogenesis. Due to the essential role of MMPs in oncogenesis, they have been considered the attractive targets for antitumor treatment. Several strategies that target MMPs have been discovered, including the use of small-molecule inhibitors, peptides, inhibitory antibodies, natural compounds with anti-MMP activity, and RNAi therapeutics. However, these molecules have multiple disadvantages, such as poor solubility, severe side-effects and low oral bioavailability. Therefore, it is necessary to discover the novel inhibitors that suppress MMPs for cancer therapy. Here, we discuss the therapeutic potential of targeting E3 ubiquitin ligases to inhibit MMPs. We hope this review will stimulate the discovery of novel therapeutics for the MMP-targeted treatment of a variety of human cancers.

The Roles of Noncoding RNAs in the Development of Osteosarcoma Stem Cells and Potential Therapeutic Targets.

Osteosarcoma (OS) is the common bone tumor in children and adolescents. Because of chemotherapy resistance, the OS patients have a poor prognosis. The one reason of chemotherapeutic resistance is the development of cancer stem cells (CSCs). CSCs represent a small portion of tumor cells with the capacity of self-renewal and multipotency, which are associated with tumor initiation, metastasis, recurrence and drug resistance. Recently, noncoding RNAs (ncRNAs) have been reported to critically regulate CSCs. Therefore, in this review article, we described the role of ncRNAs, especially miRNAs, lncRNAs and circRNAs, in regulating CSCs development and potential mechanisms. Specifically, we discussed the role of multiple miRNAs in targeting CSCs, including miR-26a, miR-29b, miR-34a, miR-133a, miR-143, miR-335, miR-382, miR-499a, miR-1247, and let-7days. Moreover, we highlighted the functions of lncRNAs in regulating CSCs in OS, such as B4GALT1-AS1, DANCR, DLX6-AS1, FER1L4, HIF2PUT, LINK-A, MALAT1, SOX2-OT, and THOR. Due to the critical roles of ncRNAs in regulation of OS CSCs, targeting ncRNAs might be a novel strategy for eliminating CSCs for OS therapy.

Direct 3D model extraction method for color volume images.

BACKGROUND: There is a great demand for the extraction of organ models from three-dimensional (3D) medical images in clinical medicine diagnosis and treatment. OBJECTIVE: We aimed to aid doctors in seeing the real shape of human organs more clearly and vividly. METHODS: The method uses the minimum eigenvectors of Laplacian matrix to automatically calculate a group of basic matting components that can properly define the volume image. These matting components can then be used to build foreground images with the help of a few user marks. RESULTS: We propose a direct 3D model segmentation method for volume images. This is a process of extracting foreground objects from volume images and estimating the opacity of the voxels covered by the objects. CONCLUSIONS: The results of segmentation experiments on different parts of human body prove the applicability of this method.

Magnoflorine inhibits the malignant phenotypes and increases cisplatin sensitivity of osteosarcoma cells via regulating miR-410-3p/HMGB1/NF-κB pathway.

AIMS: Magnoflorine is an essential type of alkaloid and possesses anti-tumor activity in multiple cancers. Recent studies have demonstrated that magnoflorine plays tumor-suppressive roles in gastric and breast cancers. However, its role in osteosarcoma (OS) tumorigenesis is enigmatic. This study aimed to investigate the role and mechanism of magnoflorine in OS. MATERIALS AND METHODS: Two human OS cells (MG-63 and U-2 OS) were treated with different concentrations of magnoflorine. Cell viability and invasion were then detected by Cell Counting Kit-8 and Transwell assay, respectively. And the effects of magnoflorine on the epithelial-mesenchymal transition (EMT) and cisplatin sensitivity were also measured. To explore the potential mechanism, we assayed the influence of magnoflorine on the miR-410-3p/HMGB1/NF-κB signaling pathway. Additionally, rescue experiments were performed to further confirm the regulation mechanism of magnoflorine. KEY FINDINGS: Magnoflorine inhibited the viability, invasion, and EMT of OS cells in a dose-dependent manner. And it increased the sensitivity of OS cells to cisplatin. Magnoflorine significantly suppressed HMGB1 expression and NF-κB activation, but upregulated miR-410-3p level. Overexpression of HMGB1 promoted NF-κB activation and reversed the effects of magnoflorine on the viability, invasion, EMT and cisplatin sensitivity of OS cells. miR-410-3p mimic inhibited the EMT of OS cells, which was restored by HMGB1 upregulation. And miR-410-3p inhibitor abrogated the influence of magnoflorine on HMGB1 expression in OS cells. SIGNIFICANCE: Magnoflorine inhibited the malignant phenotypes and increased cisplatin sensitivity of OS cells via modulating miR-410-3p/HMGB1/NF-κB pathway. These results indicated that magnoflorine might be a novel drug for the treatment of OS.

Upregulation of cell division cycle 20 in cisplatin resistance-induced epithelial-mesenchymal transition in osteosarcoma cells.

Cell division cycle 20 homologue (Cdc20) is characterized as an oncoprotein that is involved in carcinogenesis. Accumulated evidence reveals that Cdc20 plays an oncogenic role by governing cell growth, apoptosis, motility, and metastasis. The role of Cdc20 in drug resistance is elusive. In the present study, we exploited whether Cdc20 is involved in the cisplatin (DDP) resistance-induced epithelial-mesenchymal transition (EMT) of osteosarcoma cells. We found that DDP resistant U2OS and MG63 cells underwent EMT. Moreover, DDP-resistant cells exhibit the mesenchymal features such as enhanced attachment and detachment and increased invasion activity and migration. Mechanistically, Cdc20 was highly expressed in DDP-resistant osteosarcoma cells compared to parental cells. Consistently, downregulation of CdcC20 in DDP-resistant cells reversed the EMT phenotypes and changed the expression of EMT biomarkers. Our studies provide evidence for targeting Cdc20 as a promising approach to enhancing drug sensitivity for the treatment of osteosarcoma.

Long non-coding RNA AFAP1-AS1 accelerates the progression of melanoma by targeting miR-653-5p/RAI14 axis.

BACKGROUND: Melanoma is the most aggressive skin cancer that derived from pigment cells, accounting for the majority of the skin-cancer-related deaths. Despite great development and evolution have been made in surgery, radiotherapy and adjuvant chemotherapy, the prognosis of melanoma patients exhibited no significant improvement. Long noncoding RNAs (lncRNAs) are frequently dysregulated and involved in the development of cancers. LncRNA AFAP1-AS1 has been explored in various cancers, whereas its role and regulatory mechanism in melanoma are not well understood. METHODS: The expression of AFAP1-AS1 was detected by qRT-PCR. CCK-8, colony formation, transwell and western blot assays were performed to investigate the biological role of AFAP1-AS1 in melanoma. Male BALB/c nude mice were applied for in vivo experiments. The interaction among AFAP1-AS1, miR-653-5p and RAI14 was investigated by RNA pull down, RIP and luciferase reporter assays. RESULTS: AFAP1-AS1 was highly expressed in melanoma cell lines. Suppression of AFAP1-AS1 impaired cell proliferation, migration, invasion and EMT in melanoma. Moreover, AFAP1-AS1 was a ceRNA of RAI14 by competitively binding with miR-653-5p. Besides, miR-653-5p overexpression or RAI14 inhibition could repress tumor growth. Eventually, rescue assays indicated that the function of AFAP1-AS1 in the cellular process of melanoma was dependent on miR-653-5p and RAI14. CONCLUSIONS: AFAP1-AS1 exerts its oncogenic function in melanoma by targeting miR-653-5p/RAI14 axis.

Notch-1 promotes the malignant progression of osteosarcoma through the activation of cell division cycle 20.

The molecular mechanism of osteosarcoma (OS) pathogenesis is poorly understood. The Notch signaling pathway has been shown to be critically involved in tumorigenesis, including OS. Therefore, we explored the molecular mechanism by which the Notch-1 signaling pathway is involved in OS progression. Several approaches were carried out to determine the biological function of Notch-1 in OS cells. The MTT results revealed that Notch-1 overexpression increased the viability of OS cells, whereas Notch-1 downregulation reduced cell viability. Consistently, modulation of Notch-1 regulated apoptosis and the migratory and invasive abilities of OS cells. Mechanistic studies showed that Notch-1 overexpression augmented cell division cycle 20 (Cdc20) expression in OS cells. Moreover, overexpression of Cdc20 alleviated the inhibitory effects of Notch-1 downregulation on the viability, migration and invasion of OS cells. Our study offers a promising OS treatment strategy by inhibiting Notch-1.

Ursolic acid suppresses the biological function of osteosarcoma cells.

Osteosarcoma is a highly malignant tumour that occurs in adolescents. Upregulation or the constitutive activation of epidermal growth factor receptor (EGFR) is a hallmark of osteosarcoma. To investigate the effect of ursolic acid on the biological function of osteosarcoma, MTT assay was used to detect the effect of ursolic acid on the proliferation of HOS and MG63 cells, while flow cytometry was used to analyse the effect on the cell cycle and apoptosis. Transwell and Matrigel assays were used to detect the effect of ursolic acid on cell migration and invasion, respectively. Western blot analysis and reverse transcription-quantitative polymerase chain reaction were used to detect the effects of different concentrations of ursolic acid on EGFR signaling pathway-related proteins, cell cycle, apoptosis and cell migration-related proteins. After overexpression or silencing of EGFR, the effects of ursolic acid on EGFR pathway and cell biological function were subsequently detected, using the same methods. The present study identified that ursolic acid had inhibitory effects on the growth and metastatic ability of osteosarcoma cells by suppressing EGFR.