Abstract
Unlike other malignant bone tumors including osteosarcomas and Ewing sarcomas with a peak incidence in adolescents and young adults, conventional and dedifferentiated chondrosarcomas mainly affect people in the 4th to 7th decade of life. To date, the cell type of chondrosarcoma origin is not clearly defined. However, it seems that mesenchymal stem and progenitor cells (MSPC) in the bone marrow facing a pro-proliferative as well as predominantly chondrogenic differentiation milieu, as is implicated in early stage osteoarthritis (OA) at that age, are the source of chondrosarcoma genesis. But how can MSPC become malignant? Indeed, only one person in 1,000,000 will develop a chondrosarcoma, whereas the incidence of OA is a thousandfold higher. This means a rare coincidence of factors allowing escape from senescence and apoptosis together with induction of angiogenesis and migration is needed to generate a chondrosarcoma. At early stages, chondrosarcomas are still assumed to be an intermediate type of tumor which rarely metastasizes. Unfortunately, advanced stages show a pronounced resistance both against chemo- and radiation-therapy and frequently metastasize. In this review, we elucidate signaling pathways involved in the genesis and therapeutic resistance of chondrosarcomas with a focus on MSPC compared to signaling in articular cartilage (AC).
Highlights
Chondrosarcomas are rare mesenchymal tumors with a cartilage-like appearance
phosphatidylinositol 3-kinase (PI3K)-Akt murine thymoma viral oncogene homolog (AKT) signaling is activated by many growth factors including fibroblast growth factor 2 (FGF2) and IGF1 as well as inflammatory cytokines like CCL5 (Figure 2), which have been implicated in chondrosarcoma genesis and progression [185]
Increased notch homolog 1 (NOTCH1), hairy and enhancer of split 1 (HES1), hairy/enhancer-of-split related with YRPW motif (HEY) 1 and HEY2 protein expression indicating active NOTCH signaling has been detected in human chondrosarcoma tissues [206]
Summary
Chondrosarcomas are rare mesenchymal tumors with a cartilage-like appearance. They account for 10–20% of all malignant bone tumors [1]. Peripheral chondrosarcomas may arise from the cartilaginous cap of osteochondromas, which are benign bone tumors of childhood and adolescence [13,14]. There are very rare low-grade entities like clear cell chondrosarcomas, which often involve the epiphysis of the proximal femur and humerus and extend to the articular cartilage (AC) of the acetabulofemoral joint and glenohumeral joint [15,16]. Conventional and dedifferentiated chondrosarcomas have their peak incidence at the ages of 40–70 years [8,17]. About 20% of low grade tumors locally recur [6]
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