Notch and Hedgehog pathway
Notch proteins are transmembrane receptors activated by ligands on adjacent cells. Following activation, the Notch intracellular domain (NICD) is released and enters the nucleus where it regulates expressions of Hey and Hes family proteins. These are involved in the maintenance of stem cells [65]. Dysregulation of Notch signaling was shown to result in osteosarcoma, demonstrating the significance of Notch signaling in the initiation and progression of osteosarcoma [41] and [42]. Furthermore, cell lines derived from Notch-induced osteosarcoma formed aggressive high-grade-type tumors in nude mice; and Notch-activated mutation acted as a second hit in a p53-loss-driven osteosarcoma model, significantly shortening tumor latency and aggressiveness [43]. Meanwhile, both the aggressive metastatic phenotype and ALDH activity were reduced in a murine osteosarcoma cell model following inhibition of Notch signaling. This finding suggests that Notch signaling may influence OSCs via suppression of ALDH [44]. Hedgehog pathways have been shown to participate in the regulation of CSCs in a variety of tumors, including glioblastoma [66] and [67] and melanoma [68]; furthermore, they have been implicated in the initiation and regulation of OSCs [45]. Hedgehog signaling regulates the expressions of downstream genes by activating GLi through membrane receptors, such as PTCH and Smoothened [69]. Recent reports have shown that Hedgehog is overexpressed in osteosarcoma cell lines; however, cell growth could be suppressed through inhibition of Smoothened [46]. Confirmation of the role of Hedgehog signaling in osteosarcoma development was demonstrated in a mouse model: aberrant Hedgehog signaling in mature osteoblasts via Yes-associated protein 1 (Yap1) and H19 led to the development of osteoblastic osteosarcoma [47].
Notch and Hedgehog pathwayNotch proteins are transmembrane receptors activated by ligands on adjacent cells. Following activation, the Notch intracellular domain (NICD) is released and enters the nucleus where it regulates expressions of Hey and Hes family proteins. These are involved in the maintenance of stem cells [65]. Dysregulation of Notch signaling was shown to result in osteosarcoma, demonstrating the significance of Notch signaling in the initiation and progression of osteosarcoma [41] and [42]. Furthermore, cell lines derived from Notch-induced osteosarcoma formed aggressive high-grade-type tumors in nude mice; and Notch-activated mutation acted as a second hit in a p53-loss-driven osteosarcoma model, significantly shortening tumor latency and aggressiveness [43]. Meanwhile, both the aggressive metastatic phenotype and ALDH activity were reduced in a murine osteosarcoma cell model following inhibition of Notch signaling. This finding suggests that Notch signaling may influence OSCs via suppression of ALDH [44]. Hedgehog pathways have been shown to participate in the regulation of CSCs in a variety of tumors, including glioblastoma [66] and [67] and melanoma [68]; furthermore, they have been implicated in the initiation and regulation of OSCs [45]. Hedgehog signaling regulates the expressions of downstream genes by activating GLi through membrane receptors, such as PTCH and Smoothened [69]. Recent reports have shown that Hedgehog is overexpressed in osteosarcoma cell lines; however, cell growth could be suppressed through inhibition of Smoothened [46]. Confirmation of the role of Hedgehog signaling in osteosarcoma development was demonstrated in a mouse model: aberrant Hedgehog signaling in mature osteoblasts via Yes-associated protein 1 (Yap1) and H19 led to the development of osteoblastic osteosarcoma [47].
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