Critical signaling pathways in bone sarcoma: Candidates for therapeutic interventions

Abstract

Bone sarcomas cause disproportionate morbidity and mortality and desperately need new therapies as there has been little improvement in outcomes in 20 years. Identification of critical signaling pathways, including type 1 insulin-like growth factor receptor (IGF-1R) for Ewing sarcoma and possibly osteosarcoma, and the ERBB and the Wnt signaling pathways for osteosarcoma, have emerged as receptors mediating vital signals for bone sarcoma. Akt, mammalian target of rapamycin (mTOR), phosphoinositide 3-kinases, mitogen-activated protein kinase kinase, extracellular signal-regulated kinases, and Ras pathway play key roles in at least some tumors, and inhibition of mTOR in particular will likely lead to improved survival, although clinical trials are still underway. The Notch pathway and ezrin are essential for osteosarcoma metastasis, and Fas downregulation is necessary for survival of metastases in lungs. As little is known about chondrosarcoma signaling, more preclinical work is needed. By defining vital signaling pathways in bone sarcomas, small molecule inhibitors can be applied rationally, leading to longer survival and reducing morbidity and late effects from intensive chemotherapy.

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

“…K-Ras mutation also drives sarcoma initiation 28 where ZEB1 is induced and Pten is likewise downregulated, as opposed to mutated [28][29][30][31][32] . In addition, as noted above, a ZEB1 high/PTEN low pattern also marks fibroblasts in the stroma of K-Ras mutant tumours, and such loss of Pten in the tumour stroma has been shown to be important for tumour progression 33 .…”

“…Indeed, it has been demonstrated recently that Pten can be secreted and taken up by adjacent cells 43 , raising the possibility that elimination of Pten in fibroblasts is necessary to remove a secondary source of secreted Pten that would otherwise be taken up by adjacent tumour cells. K-Ras mutation also drives sarcoma initiation 28 where ZEB1 is induced and Pten is likewise downregulated as opposed to mutated [28][29][30][31][32] . Thus, the ZEB1, PTEN pathway can be induced by K-Ras in mesenchymal cells in the absence of adjacent carcinoma cells.…”

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

“…Candidate genes are frequently altered in human osteosarcoma and are enriched in cancer-associated signaling pathways, including PI3K-AKT-mTOR, ErbB, MAPK and axon guidance signaling. These pathways have previously been implicated in osteosarcoma, but the genes identified in these pathways are likely driving these pathways in human osteosarcoma and represent potential therapeutic targets 62–64 .…”

Sequential Inductions of the ZEB1 Transcription Factor Caused by Mutation of Rb and Then Ras Proteins Are Required for Tumor Initiation and Progression

“…Ras also drives sarcoma formation, and ZEB1 expression is linked to invasion and metastasis in these tumors, where epithelial-to-mesenchymal transition would not appear to be a factor. Taken together, these findings raise the possibility that ZEB1 may have roles in tumor progression extending beyond the ZEB1/miR-200 loop thought to facilitate invasion and metastasis (21)(22)(23)(24)(25).…”