周文灏　燕太强　郭卫　杨荣利　孙义峰

The Hedgehog (HH) signaling pathway, participating in process of survival, proliferation and differentiation in all kinds of cells in the body, is not only essential in normal embryonic development and organogenesis, but also closely related to the formation and progression of many sorts of neoplasms when activated aberrantly. This pathway is currently recognized as Hedgehog-Ptch-Smo-Gli in summary. Despite the efforts into lots of basic researches continuously improving its molecular regulation network in the past few years, the downstream transduction of it and the specific mechanism of the target genes at tumor onset are yet still unclear. Studies have shown that Indian Hedgehog (IHH) gene is one of the 3 mammal HH homologous genes. Along with its signaling pathway, IHH protein also interacts with other local factors in the microenvironment of the growth plate, especially the parathyroid hormone-related protein (PTHrP), constituting a negative feedback loop for the regulation of the proliferation and differentiation of chondrocytes, which plays a crucial role in normal bone growth and development. Deregulation of the feedback loop and continuous aberrant activation of the IHH pathway has been found to be involved in the formation and progression of cartilaginous tumors, ranging from benign lesions, such as enchondromas and osteochondromas, to malignant chondrosarcomas. Some of the benign lesions can be the precursors of malignant chondrosarcomas, which are notoriously difficult to treat as neither conventional chemotherapy nor radiotherapy is typically effective. Radical surgery, of which the result is still less than ideal because of the high rate of postoperative recurrence and lung metastasis, yet is the mainstay of treatment. As a result of large number of studies in fields of cytogenetics, molecular biology and transgenic mouse models in the past few years, there is a growing understanding of the role of this pathway in the pathogenesis of both the occurrence of primary chondrosarcoma and the malignant progression from benign cartilage lesions. It is the continuous aberrant activation of the IHH-PTHrP loop that has been recently demonstrated causing unrestricted proliferation of chondrocytes, the early event of tumor promotion. And additional genomic changes after that can further lead to the malignant transformation of chondrocytes. Thus IHH pathway targeted therapy may block this early event by inducing cartilage tumor cells toward a state of more differentiation and less invasiveness. Smo inhibitors were then widely studied and have currently entered clinical trials, however, facing challenges of no effect on the tumors caused by abnormal activation of the downstream molecules of its receptor and drug resistance caused by the absence of action sites resulting from gene mutation of Smo. In spite of this, scientists have also found that interventions targeting at Gli, the final part of this pathway, can block the transcription and activation of the downstream target genes, which may have a broader application prospect. With the recent encouraging preliminary data from experimental studies of specific inhibition of HH pathway in cancers of skin, pancreas, lung, prostate and other organs, we gradually see the hope that specific inhibitors targeting IHH pathway could be implemented into novel strategies for the treatment of chondrosarcomas.