Current therapeutic protocols in OS and ES consist of
Current therapeutic protocols in OS and ES consist of neoadjuvant chemotherapy and local surgical resection, followed by adjuvant chemotherapy. These treatments lead to a 70% overall survival for localized disease but can decrease to 15% in case of metastasis. With CS being resistant to conventional chemotherapy and radiotherapy, the therapeutic surgical approach remains the only available treatment, with a 10-year survival between 30% and 80%, depending on the grade. Because the survival rates have not changed in the past 30 years, new therapeutic approaches are needed, and some studies described the potential of immunotherapy, including cytokine-based therapy, in combination with conventional treatment to eradicate primary bone tumors.
The IL-6 family of cytokines actually comprises nine members, such as leukemia inhibitory factor (LIF) and oncostatin M (OSM). All IL-6–type cytokines share the signal-transducing receptor subunit gp130 (or gp130 like), and receptor specificity is provided by additional receptor chains. IL-6 first binds to the IL-6 receptor subunit (IL-6R), which is either membrane associated or soluble, and then recruits gp130. OSM and LIF are functionally and structurally related, and both cytokines can bind to the type I receptor composed of gp130 and the LIF receptor (LIFR). OSM can also transduce a signal through the type II receptor, composed of gp130 and oncostatin M receptor (OSMR). Ligand-induced oligomerization of receptor subunits allows activation of Janus kinases and, subsequently, signal transducer and activator of transcription (mainly STAT3) and mitogen-activated protein kinase (mainly extracellular signal–regulated kinase 1/2).
OSM and LIF are Dihydroartemisinin receptor cytokines that play a crucial role in the systemic inflammatory response, hematopoiesis, and liver and neuronal regeneration; in addition, they activate endothelial cells., OSM is mainly produced by macrophages, neutrophils, and T lymphocytes, whereas LIF could also be produced by tumor cells., Interestingly, OSM was first identified by its capacity to inhibit melanoma cell growth , and this property was then enlarged to breast cancer, lung cancer, or hepatoma. LIF also inhibits proliferation of thyroid cancer and cervical carcinoma. Within primary bone tumors, OSM has anticancer effects on osteosarcoma through inhibition of proliferation, sensitization to p53-dependent apoptosis, and induction of differentiation into the osteoblastic pathway., , Recently, we also demonstrated that OSM inhibits proliferation of chondrosarcoma and . In contrast, OSM enhances proliferation of fibroblasts, myeloma, Kaposi\'s sarcoma, and cervical carcinoma., Primary melanoma cells are growth inhibited by OSM, but during the metastatic process, these cells become resistant or even growth stimulated and lose the OSM receptor. LIF also induces proliferation of embryonic stem cells and could participate in progression of breast cancer or melanoma.
The cytostatic effect of OSM or LIF occurs through STAT3 activation and induction of cell cycle inhibitors, such as p21 and/or p27,, or transcription factors linked to the differentiation process, such as C/EBPβ or δ. However, STAT3 has also been activated in numerous cancers, where it behaves as an oncogene. Through collaboration with other transcription factors, such as NF-κB or hypoxia-inducible factor-1, STAT3 regulates the expression of genes that mediate survival (SURVIVIN, BCLXL, and MCL1), proliferation (FOS, MYC, and cyclin D1), invasion (matrix metalloproteinase-2), and angiogenesis (vascular endothelial growth factor).
The Ewing\'s sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), represents a clinicopathological entity with a variable neural differentiation, usually appearing as a bone or soft tissue lesion in a child or young adult. The primary genetic event is chromosomal translocation resulting in fusion of the gene with a member of the ETS family of transcription factors. The most frequent translocation partner of is (90–95%), followed by (5–10%). These fusion products function as oncogenic aberrant transcription factors. Detection of these fusions is considered to be specific for ES/PNET, and has become a valuable tool for the differential diagnosis of primitive small round cell tumors.,