IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor. However, the therapeutic results of the advanced cases at the first visit were still extremely poor. Therefore, more effective therapeutic options based on molecular profiling of OS are needed. In this study, we investigated the functions of endoplasmic reticulum (ER) stress activities in OS and elucidated whether ER stress inhibitors could exert antitumor effects. The expression of 84 key genes associated with unfolded protein response (UPR) was assessed in four OS cells (143B, MG63, U2OS and KHOS) by RT2 Profiler PCR Arrays. Based on results, we performed both siRNA and inhibitor assays focusing on IRE1α-XBP1 and PERK pathways. All OS cell lines showed resistance to PERK inhibitors. Furthermore, ATF4 and EIF2A inhibition by siRNA did not affect the survival of OS cell lines. On the other hand, IRE1α-XBP1 inhibition by toyocamycin suppressed OS cell growth (IC50: < 0.075 μM) and cell viability was suppressed in all OS cell lines by silencing XBP1 expression. The expression of XBP1s and XBP1u in OS cell lines and OS surgical samples were confirmed using qPCR. In MG63 and U2OS, toyocamycin decreased the expression level of XBP1s induced by tunicamycin. On the other hand, in 143B and KHOS, stimulation by toyocamycin did not clearly change the expression level of XBP1s induced by tunicamycin. However, morphological apoptotic changes and caspase activation were observed in these two cell lines. Inhibition of the IRE1α-XBP1s pathway is expected to be a promising new target for OS.

Chondrosarcoma of the Nasal Septum—A Rare Subsite: Case Report with Review of Literature

Chondrosarcomas are the second most common primary malignant bone tumors. Head and neck chondrosarcomas constitute less than 10% of these tumors, rarely arising from the nasal septum. These are locally aggressive malignant tumors arising from the cartilaginous framework of the nasal septum. Rarity of the tumor coupled with nonspecific symptoms makes it a diagnostic dilemma. Diagnosis requires endoscopy, radiology, and final histopathology for confirmation. Treatment is mainly surgical, requiring complete surgical excision with clear margins. Radiation has a role in unresectable tumors or for tumors with positive margins after surgery. Survival depends on the grade of tumor that predicts the metastatic potential of the tumor. We present a rare case of chondrosarcoma arising from the nasal septum in a 29-year-old young female presenting with complaints of nasal obstruction. Computed tomography was suggestive of a calcified cartilaginous tumor arising from the nasal septum. Endoscopic excision was done and postoperative histopathology showed grade II chondrosarcoma with clear margins. No adjuvant treatment was given to our patient and 2 years post-excision patient is disease free.To conclude, chondrosarcoma of the nasal septum is a rare tumor, with nonspecific symptoms. Surgery with clear margins remains the treatment of choice. Prognosis depends on the extent of tumor at presentation, resection margins, and grade of tumor.

Metacarpal chondrosarcoma, from negligence to rareness : a case report and review of the literature

Chondrosarcoma is rarely found in the extremities but it remains the most common primary malignant bone tumor of the hand. We report an unusual case of a 46-year-old man with a huge chondrosarcoma on his left hand that has been evolving for more than 30 years. The mass has always been painless, the symptoms were only the deformation and a slight loss of motion. We did a subtotal resection since the patient refused the amputation. The investigation, which in- cluded thoracoabdominal tomography, scintigraphy and blood analysis, turned out to be negative. In the literature, CS are usually associated with a locally destructive growth but metastasis hasn’t been often described. CS seems to be an aggressive tumor locally but, unlike in other sites, it seems to rarely metastasize when in the hands.

Current Therapeutic Approaches for osteosarcoma

Osteosarcoma is classically defined as a high-grade spindle-shaped neoplasm with malignant cells that produce osteoid. It is the most common primary malignant bone tumor in children and young adults. It is <1% of all cancers diagnosed, approximately 3.4% of all childhood cancers. The age-adjusted incidence of osteosarcoma is bimodal, with an initial peak in adolescence and then a second peak in patients over 60 years of age. Osteosarcoma is divided into two main groups. In most of the osteosarcomas, the etiological agent cannot be determined and it is called primary osteosarcoma. Osteosarcoma, which develops due to etiologies such as Paget’s disease, radiotherapy or osteonecrosis, is called seconder osteosarcoma. Osteosarcomas are most commonly located in the appendicular skeleton. The most common settlement here is the knee circumference. The distal femur and proximal tibia are the most common locations in the knee. A multidisciplinary approach is indicated in the management of osteosarcoma. The treatment is multimodal, including systemic chemotherapy and local therapy. In this section, we will outline the current standard of care for the systemic and surgical approach to osteosarcoma treatment, as well as an overview of current studies.

Chondrosarcoma-From Molecular Pathology to Novel Therapies

Chondrosarcoma (CHS) is the second most common primary malignant bone sarcoma. Overall survival and prognosis of this tumor are various and often extreme, depending on histological grade and tumor subtype. CHS treatment is difficult, and surgery remains still the gold standard due to the resistance of this tumor to other therapeutic options. Considering the role of differentiation of CHS subtypes and the need to develop new treatment strategies, in this review, we introduced a multidisciplinary characterization of CHS from its pathology to therapies. We described the morphology of each subtype with the role of immunohistochemical markers in diagnostics of CHS. We also summarized the most frequently mutated genes and genome regions with altered pathways involved in the pathology of this tumor. Subsequently, we discussed imaging methods and the role of currently used therapies, including surgery and the limitations of chemo and radiotherapy. Finally, in this review, we presented novel targeted therapies, including those at ongoing clinical trials, which can be a potential future target in designing new therapeutics for patients with CHS.

Pathogenesis and Current Treatment of Osteosarcoma: Perspectives for Future Therapies

Osteosarcoma is the most common primary malignant bone tumor in children and young adults. The standard-of-care curative treatment for osteosarcoma utilizes doxorubicin, cisplatin, and high-dose methotrexate, a standard that has not changed in more than 40 years. The development of patient-specific therapies requires an in-depth understanding of the unique genetics and biology of the tumor. Here, we discuss the role of normal bone biology in osteosarcomagenesis, highlighting the factors that drive normal osteoblast production, as well as abnormal osteosarcoma development. We then describe the pathology and current standard of care of osteosarcoma. Given the complex heterogeneity of osteosarcoma tumors, we explore the development of novel therapeutics for osteosarcoma that encompass a series of molecular targets. This analysis of pathogenic mechanisms will shed light on promising avenues for future therapeutic research in osteosarcoma.

AHA1 upregulates IDH1 and metabolic activity to promote growth and metastasis and predicts prognosis in osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Although activator of HSP90 ATPase activity 1 (AHA1) is reported to be a potential oncogene, its role in osteosarcoma progression remains largely unclear. Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis, the relationship between AHA1 and cancer metabolism is unknown. In this study, we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients. AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo. Mechanistically, AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma. Notably, we identified that isocitrate dehydrogenase 1 (IDH1) is a novel client protein of Hsp90-AHA1. Furthermore, the IDH1 protein level was positively correlated with AHA1 in osteosarcoma. And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma. Moreover, high IDH1 level was also associated with poor prognosis of osteosarcoma patients. This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis, which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.

Bio-analytical identification of key genes that could contribute to the progression and metastasis of osteosarcoma

Background: Osteosarcoma (OS) is one of the most common primary malignant bone tumors in children and adolescents. OS metastasis has been a challenge for the treatment of OS The present study screened progression related genes in OS by analyzing a public dataset GSE42352, and identified 691 up-regulated and 945 down-regulated genes in advanced stage OS compared to early stage OS samples. Methods: Protein-protein interaction (PPI) networks were further conducted to reveal the interaction among these genes. Bioinformatics analysis showed that progression related differently expressed genes (DEGs) were significantly associated with the regulation of cell proliferation and metabolisms. Results: This study revealed progression related DEGs were dysregulated in metastatic OS compared to non-metastatic OS samples. Further analysis showed CSF1R, CASP1, CD163, AP1B1, LAPTM5, PEX19, SLA, STAB1, YWHAH, PLCB2, and GPR84 were associated with the metastasis free survival time in patient with OS. Conclusions: These findings provided novel information for us to understand the mechanisms underlying the progression and metastasis of OS.

LncRNA SNHG15 regulates osteosarcoma progression in vitro and in vivo via sponging miR-346 and regulating TRAF4 expression

Osteosarcoma (OS) is a common primary malignant bone tumor around the world. It has been reported that long noncoding RNAs (lncRNAs) take part in diverse pathological processes of OS; however, the mechanism remains unknown. This study aimed to uncover the profile of lncRNA small nucleolar RNA host gene 15 (SNHG15), its biological function, and its potential involvement in the mechanism of OS progression in vitro and in vivo. The expression of SNHG15 and TRAF4 was promoted in OS tissues opposite for that of miR-346. The silencing of SNHG15 limited the proliferation, invasion, and enhanced apoptosis of SaoS2 and HOS cells. Moreover, the putative binding sites between miR-346 and SNHG15 or TRAF4 were predicted by starBase and Targetscan software online, individually. Also, miR-346 deletion reversed the positive effects of SNHG15 elimination on proliferation, apoptosis, and invasion in cells. In addition, the upregulation of TRAF4 disrupted the biofunctional results from miR-346 promotion subsequently. Finally, SNHG15 knockdown repressed OS tumor growth in a xenograft tumor model. SNHG15 enhanced the progression of OS by regulating the miR-346/TRAF4 axis in vitro and in vivo.

Cytokeratin-Positive Osteosarcoma Simulating Sarcomatoid Metastatic Carcinoma

Osteosarcoma, the most common primary malignant bone tumor, rarely stains positive for epithelial markers such as cytokeratin on immunohistochemical analysis. We describe a 52-year-old man with a destructive distal femoral metaphyseal lesion who was initially treated for metastatic sarcomatoid carcinoma based on extensive radiographic and histopathologic evaluation. Ultimately, wide resection of the distal femur was performed, revealing high-grade conventional osteosarcoma with intense and diffuse cytokeratin positivity. Such immunohistochemical staining in osteosarcoma is rare, making it difficult to distinguish cytokeratin-positive osteosarcoma from metastatic carcinoma. The presence of a cytokeratin-positive bone neoplasm with malignant osteoid formation on histological studies as well as integration with clinical and radiologic data can help confirm osteosarcoma as the ultimate diagnosis.