Chondrosarcoma Resistance to Radiation Therapy: Origins and Potential Therapeutic Solutions

Abstract

Chondrosarcoma is a malignant cartilaginous tumor that is particularly chemoresistant and radioresistant to X-rays. The first line of treatment is surgery, though this is almost impossible in some specific locations. Such resistances can be explained by the particular composition of the tumor, which develops within a dense cartilaginous matrix, producing a resistant area where the oxygen tension is very low. This microenvironment forces the cells to adapt and dedifferentiate into cancer stem cells, which are described to be more resistant to conventional treatments. One of the main avenues considered to treat this type of tumor is hadrontherapy, in particular for its ballistic properties but also its greater biological effectiveness against tumor cells. In this review, we describe the different forms of chondrosarcoma resistance and how hadrontherapy, combined with other treatments involving targeted inhibitors, could help to better treat high-grade chondrosarcoma.

Hypoxic Conditions Modulate Chondrogenesis through the Circadian Clock: The Role of Hypoxia-Inducible Factor-1α

“…Oxygen levels in tumor niches determine disease progression as cellular responses to hypoxia mainly promote neoplastic evolution [ 116 ]. In all skeletal tumors, the common cellular mechanisms affected by HIF-1α are cell proliferation, tissue vascularization and metastasis formation [ 117 , 118 , 119 ]. Although cartilage-related malignancies are referenced in a rich literature regarding hypoxia, the role of HIF-1α is also implicated in enchondromas [ 100 ].…”

Dedifferentiated Chondrosarcoma from Molecular Pathology to Current Treatment and Clinical Trials

“…Other essential markers in DDCS are B-cell lymphoma 2 (Bcl-2), mouse double minute 2 homologue (MDM2), and PD-L1 [84][85][86][87]. DDCS also stains positive for Ki-67, cyclin D1, desmin, collagen type 1 (Col I) and p16 [7,[86][87][88][89][90]. Furthermore, inactivation of polycomb repressive complex 2 (PRC2) results in trimethylation of histone 3 in lysine 27 (H3K27me3) deficiency, which is detected as a complete loss of H3K27me3 staining [91].…”

Mesenchymal Chondrosarcoma from Diagnosis to Clinical Trials

“…Because of that, in areas that are difficult to target with a sufficiently high dose of RT due to limitations related to organs at risk, treatment with particles such as protons or heavy ion therapy can be considered. As delivering a dose higher than 70 Gy is mandatory to obtain local control of ChSa, modern techniques such as intensive modulated radiotherapy (IMRT), stereotactic radiosurgery, or finally hadron therapy should be considered [ 87 , 88 ]. The cyberknife system with hypofractionated doses was described in single reports an effective treatment in these tumors, alongside Gamma knife radiosurgery which has also been reported as a useful djuvant strategy after surgery with local control up to 80% after 5 years [ 89 , 90 ].…”