Emerging signaling pathways for future therapies in osteosarcoma: Wnt, notch and hedgehog signaling

Introduction: The molecular alterations that induce sarcomagenesis are incompletely understood. This review will examine three important pathways in bone biology and their relation to the development of osteosarcoma: Wnt, Hedgehog and Notch signaling. We will briefly review basic signaling pathways, delineate what is known and yet unknown regarding their role in osteosarcoma formation and disease progression, and describe future treatment strategies. Results: Wnt, Hedgehog and Notch signaling have been examined as deregulated signaling pathways in osteosarcoma and potential molecular therapeutic targets. Canonical Wnt signaling activation has known roles in oncogenesis, and exogenous inhibition of Wnt signaling may have therapeutic benefit. For example, FHL2 (four and a half LIM domain 2) silencing reduces Wnt signaling and osteosarcoma tumorigenesis. Likewise, Wnt inhibition has been shown to sensitize osteosarcoma to chemotherapy, potentially via interaction with TWIST transcription factors. In the case of Hedgehog signaling, constitutive activation has been observed in various malignancies. Specific to osteosarcoma, Hedgehog receptors and downstream mediators show overexpression. In addition, inhibition of Smoothened (SMO) with pharmaceuticals and/or siRNA has led to diminished osteosarcoma cell proliferation in vitro and reduced osteosarcoma growth in vivo. Further studies have demonstrated the importance of GLI2 (glioma-associated oncogene homolog 2) Hedgehog signaling transduction for osteosarcoma growth. In the case of Notch signaling, aberrant upregulations of Notch signaling have been observed both in human osteosarcoma and TP53 mutant mice osteosarcoma. Inhibition of Notch via either liposome transfection or small molecule delivery has resulted in reduced osteosarcoma cell proliferation and in vivo osteosarcoma growth. Moreover, Notch signaling and target gene HES1 (hairy and enhancer of split-1) have been associated with osteosarcoma invasion and metastasis. Discussion: The role of Wnt, Hedgehog and Notch signaling in osteosarcoma is incompletely understood. All three pathways are fundamental in growth and patterning of the embryo, mesenchymal stem cell proliferation and differentiation, and skeletogenesis. The interest in manipulating these signaling pathways for chemotherapeutic purposes exceeds the scope of mesenchymal tumors, and includes epithelial and hematopoietic malignancies as well. Moreover, the interest in manipulating these signaling pathways, especially Wnt, is of tremendous interest to those researching osteoporosis. Potential cross over between fields may help in the rapid development of new, targeted therapies for osteosarcoma.