Osteosarcoma is a malignant osseous neoplasm. Osteosarcoma is a primary bone malignancy capable of producing osteoid tissue or immature bones. A subsequent malignant degeneration of the primary bone pathology occurs less frequently in adults. The over-expression of several proteins, including Heat shock proteins, Cofilin, Annexins, Insulin-like growth factor, transforming growth factor-β, Receptor tyrosine kinase, Ezrin, Runx2, SATB2, ATF4, Annexins, cofilin, EGFR, VEGF, retinoblastoma 1 (Rb1) and secreted protein, has been associated to the development and progression of osteosarcoma. These proteins are involved in cell adhesion, migration, invasion, and the control of cell cycle and apoptosis. In genomic studies, osteosarcoma has been associated with several genetic abnormalities, including chromosomal rearrangements, gene mutations, and gene amplifications. These differentially expressed proteins could be used as early identification biomarkers or treatment targets. Proteomics and genomics play significant parts in enhancing our molecular understanding of osteosarcoma, and their integration provides essential insights into this aggressive bone cancer. This review will discuss the tumour biology that has assisted in helping us better understand the causes of osteosarcoma and how they could potentially be used to find new treatment targets and enhance the survival rate for osteosarcoma patients.
Endothelin-1 (ET-1) is a neuroactive peptide produced by neurons, reactive astrocytes, and endothelial cells in the brain. Elevated levels of ET-1 have been detected in the post-mortem brains of individuals with Alzheimer's disease (AD). We have previously demonstrated that overexpression of astrocytic ET-1 exacerbates memory deficits in aged mice or in APPK670/M671 mutant mice. However, the effects of ET-1 on neuronal dysfunction remain elusive. ET-1 has been reported to mediate superoxide formation in the vascular system via NADPH oxidase (NOX) and to regulate the actin cytoskeleton of cancer cell lines via the cofilin pathway. Interestingly, oxidative stress and cofilin activation were both reported to mediate one of the AD histopathologies, cofilin rod formation in neurons. This raises the possibility that ET-1 mediates neurodegeneration via oxidative stress- or cofilin activation-driven cofilin rod formation. Here, we demonstrate that exposure to 100 nm ET-1 or to a selective ET type B receptor (ETB) agonist (IRL1620) induces cofilin rod formation in dendrites of primary hippocampal neurons, accompanied by a loss of distal dendrites and a reduction in dendritic length. The 100 nm IRL1620 exposure induced superoxide formation and cofilin activation, which were abolished by pretreatment with a NOX inhibitor (5 μm VAS2870). Moreover, IRL1620-induced cofilin rod formation was partially abolished by pretreatment with a calcineurin inhibitor (100 nm FK506), which suppressed cofilin activation. In conclusion, our findings suggest a role for ETB in neurodegeneration by promoting cofilin rod formation and dendritic loss via NOX-driven superoxide formation and cofilin activation.