Signaling pathways in cranial chondrosarcoma: potential molecular targets for directed chemotherapy

Cranial chondrosarcoma is an indolent tumor of the skull base, which is difficult to treat due to its inaccessible location. The current mainstay of treatment is surgical resection followed by adjuvant radiation therapy. To date, chemotherapy has been largely ineffective for chondrosarcoma due to a lack of targeted therapies. This review highlights numerous active signaling pathways that have been described in human chondrosarcoma. A limited number of functional experiments suggest that integrin activation at the cell surface results in upregulation of matrix metalloproteinases and extracellular matrix degradation, leading to increased tumor cell migration. This pathway appears to be dependent on phosphoinositide-3 kinase and MEK–extracellular signal-regulated kinase (ERK) signaling. Additionally, chondrosarcoma cell proliferation and degradation is dependent on peroxisome proliferator-activated receptor-gamma (PPAR-γ) activity, with a loss of PPAR-γ expression and associated apoptosis in high-grade tumors. The data suggest that targeting these pathways may improve control of cranial chondrosarcoma and decrease the need for hazardous recurrent operations.