Chondrosarcoma (ChS), a malignant cartilage-producing tumor, is the second most frequently diagnosed osseous sarcoma after osteosarcoma. It represents a very heterogeneous group of malignant chemo- and radiation-resistant neoplasms, accounting for approximately 20% of all bone sarcomas. The majority of ChS patients have a good prognosis after a complete surgical resection, as these tumors grow slowly and rarely metastasize. Conversely, patients with inoperable disease, due to the tumor location, size, or metastases, represent a great clinical challenge. Despite several genetic and epigenetic alterations that have been described in distinct ChS subtypes, very few therapeutic options are currently available for ChS patients. Therefore, new prognostic factors for tumor progression as well as new treatment options have to be explored, especially for patients with unresectable or metastatic disease. Recent studies have shown that a correlation between immune infiltrate composition, tumor aggressiveness, and survival does exist in ChS patients. In addition, the intra-tumor microvessel density has been proven to be associated with aggressive clinical behavior and a high metastatic potential in ChS. This review will provide an insight into the ChS microenvironment, since immunotherapy and antiangiogenic agents are emerging as interesting therapeutic options for ChS patients.

Chondrosarcomas (ChSs) are mesenchymal chemo- and radiation-resistant tumors, representing the second most frequently diagnosed bone sarcoma after osteosarcoma and 20% of all bone sarcomas. Most of ChS patients have a good prognosis after complete surgical resection. Conversely, patients with inoperable disease, due to the tumor location or metastatic dissemination, represent a great clinical challenge due to the lack of effective therapeutic options. In this study, to the best of our knowledge, we document, for the first time in human ChS tissues, the existence of CD-31- and Podoplanin-negative vascular-like channels containing red blood cells, allowing us to hypothesize the occurrence of vasculogenic mimicry (VM) in ChSs. By using patient-derived ChS cells and a stabilized ChS cell line, we demonstrate that ChS cells are able to form in vitro tubules apparently similar to those formed by endothelial cells. Further characterization of these vessels revealed the pivotal role of the Urokinase Plasminogen Activator Receptor (uPAR) in mediating the capability of ChS cells to form VM. Finally, we provide evidence that, unlike bevacizumab, which did not exert any effect, the uPAR-derived antiangiogenic peptide RI-3 behaves as a potent inhibitor of VM.